A method for preparing an intermediate of a soft sponge analogue

Abstract

This invention discloses a method for preparing an intermediate of a spongin analogue. The method includes the following steps: 1) reacting a compound of formula VI containing a carboxylic acid structure with R(+)-α-methylbenzylamine in an organic solvent, purifying the mixture to obtain a compound of formula VII in salt form; 2) reacting compound VII with tert-butyldimethylchlorosilane, followed by acidification to obtain compound VIII; 3) reacting compound VIII with N,O-dimethylhydroxyamine hydrochloride to obtain the intermediate of the spongin analogue. The preparation method of this invention can obtain the target product with high chiral purity in high yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing an intermediate of a spongin analogue. Background Technology

[0002] Halichondrin is a class of polyether macrocyclic lactone compounds, first isolated from the Japanese sponge (Halichondria okadai). Halichondrin compounds are potent inhibitors of microtubule protein, especially halichondrin B, which exhibits good anticancer activity both in vitro and in vivo. Its structural formula is shown below.

[0003] However, these compounds cannot be cultured in large quantities in sponges, and their complex structures make them difficult to synthesize artificially, resulting in a lack of such drugs for clinical trials.

[0004] Halaven (Eribulin mesylate) is a macrocyclic ketone analog obtained by simplifying the structure of erythromycin B. The structural formula of Eribulin is shown below. This compound retains the activity of leptin B and exhibits better water solubility and chemical stability compared to leptin B. It was approved by the FDA in November 2010 for the treatment of recurrent and metastatic breast cancer in patients who have received at least two prior chemotherapy regimens.

[0005] Compound X (structural formula is) This compound, forming the C20-C26 fragment of the leptin analogue, contains two chiral centers. The preparation method of compound X is disclosed in SYNLETT 2013, 24, 0327-0332, via the following synthetic route:

[0006]

[0007] This method uses a catalyst (R,R)-Jacobsen's salen (Co) to perform hydrolytic kinetic resolution of racemic epoxides, yielding a chiral starting material of formula II'. However, this chiral resolution step generates a large number of enantiomers as byproducts. Chiral starting material II' then reacts with diethyl malonate to generate a lactone of formula III'. The ethyl ester side chain of this lactone undergoes hydrolysis and decarboxylation, followed by methylation at C25 to form a C25 chiral center, resulting in a mixture of approximately 6 / 1 of the diastereomers of formula V. This mixture has very low chiral purity. This method does not separate these diastereomer impurities but directly introduces them into the next reaction step, where column chromatography is used for separation after multiple reaction steps. However, introducing diastereomer impurities into subsequent reaction steps generates a series of derived impurities, placing significant pressure on subsequent impurity removal and hindering the improvement and control of the final product's chiral purity, as well as hindering scale-up production. Furthermore, this method uses lactone and N,O-dimethylhydroxylamine hydrochloride to generate Weinreb amide. This reaction step uses excess AlMe3 as a catalyst, which is complex and not conducive to scale-up production. In addition, the yield of lactone in this step is low. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing an intermediate of a soft sponge analogue, which addresses the shortcomings and deficiencies of the prior art. This method produces a target product with high optical purity and high yield, and can be scaled up to a large scale.

[0009] To solve the above technical problems, the present invention adopts the following technical solution:

[0010] A compound of formula X The preparation method of the compound of formula VI, wherein TBSO is dimethyl tert-butylsiloxy, includes the following steps: 1) preparing the compound of formula VI. and R(+)-α-methylbenzylamine The reaction was carried out in an organic solvent, and the compound of formula VII was obtained after purification. 2) The compound of formula VII is reacted with tert-butyldimethylchlorosilane, and then acidified to obtain the compound of formula VIII. 3) The compound of formula VIII is reacted with N,O-dimethylhydroxyamine hydrochloride to obtain the compound of formula X.

[0011] The above-mentioned compound X is a fragment that constitutes the C20-C26 of the spongein analogue, which is an intermediate of the spongein analogue.

[0012] The reaction formula for step 1) is as follows:

[0013]

[0014] In some embodiments, in step 1), the organic solvent is selected from one or both of isopropyl acetate and methyl tert-butyl ether.

[0015] In some embodiments, in step 1), the temperature of the reaction is -5 to 5°C.

[0016] In some implementations, step 1) includes recrystallization.

[0017] In some embodiments, step 1) includes filtration, drying, and recrystallization.

[0018] Preferably, the solvent for recrystallization is a mixture of ether solvents and alcohol solvents.

[0019] More preferably, the ether solvent is selected from one or both of methyl tert-butyl ether and isopropyl ether, and the alcohol solvent is selected from one or a combination of n-butanol, isopropanol and isobutanol.

[0020] More preferably, the volume ratio of the ether solvent to the alcohol solvent is 5 to 15:1.

[0021] In some embodiments, in step 1), the molar ratio of the compound of formula VI and R(+)-α-methylbenzylamine is 1:1.1 to 1.5.

[0022] In some embodiments, in step 1), the compound of formula VI is first dissolved in the organic solvent to obtain an organic solution, the organic solution is cooled to -5 to 5°C, and the R(+)-α-methylbenzylamine is added dropwise to the organic solution under stirring to carry out the reaction.

[0023] In some embodiments, in step 1), the isopropyl acetate solution of compound VI is cooled to -5 to 5°C, and R(+)-α-methylbenzylamine is slowly added dropwise with stirring, reacting at -5 to 5°C for 1 hour. The mixture is filtered, and the filter cake is collected. The filtrate is concentrated under reduced pressure, methyl tert-butyl ether is added, the mixture is stirred, filtered, and the filter cake is collected again. The filter cakes are combined, dried, and the crude product of compound VII is obtained. The crude product is then recrystallized and purified, filtered, washed, and dried to obtain the pure product of compound VII, with an optical purity ee value >99%.

[0024] The reaction formula for step 2) is as follows:

[0025]

[0026] In some embodiments, the temperature of the reaction in step 2) is 20–30°C.

[0027] In some embodiments, in step 2), the reaction is carried out in the presence of imidazole, wherein the molar ratio of imidazole to compound VII is 8–10:1. Imidazole is an acid-binding agent, which favors the forward reaction.

[0028] In some embodiments, in step 2), the molar ratio of the tert-butyldimethylchlorosilane to the compound of formula VII is 2 to 4:1.

[0029] In some embodiments, citric acid is used to perform the acidification in step 2).

[0030] In some embodiments, in step 2), compound VII is dissolved in N,N-dimethylformamide to obtain a solution of compound VII, which is cooled to 0°C, and imidazole is added to the solution. Then, tert-butyldimethylchlorosilane (TBSCl) is added dropwise to the solution at 10–15°C. The mixture is first stirred for a period of time under ice bath cooling, and then the temperature is raised to 20–30°C to carry out the reaction. After the reaction is complete, methanol is added to quench the reaction. The reaction solution is diluted with water, and its pH is adjusted to 4–5 with citric acid solution. Finally, the mixture is extracted with toluene, washed, dried, and concentrated to obtain crude compound VIII, which is purified by column chromatography to obtain compound VIII.

[0031] The reaction formula for step 3) is as follows:

[0032]

[0033] In some embodiments, the temperature of the reaction in step 3) is 15–20°C.

[0034] In some embodiments, in step 3), the molar ratio of the N,O-dimethylhydroxyamine hydrochloride and the compound of formula VIII is 1.2 to 1.8:1.

[0035] In some embodiments, in step 3), the reaction is carried out in the presence of a base and a condensing agent, wherein the base is selected from triethylamine or N,N-diisopropylethylamine, and the condensing agent is selected from one or more combinations of urea-ion peptide condensing agent TBTU, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI, and amide condensing agent HOBT.

[0036] Preferably, the molar ratio of the base to the compound of formula VIII is 2 to 3:1.

[0037] Preferably, the molar ratio of the condensing agent to the compound of formula VIII is 1.1 to 1.5:1.

[0038] In some embodiments, in step 3), compound VIII is dissolved in N,N-dimethylformamide to obtain a solution of compound VIII. The solution is cooled to 5-10°C, and N,O-dimethylhydroxyamine hydrochloride is added in batches, followed by the addition of a base. The reaction system is cooled to -5 to 5°C, a condensing agent is added, and the temperature of the reaction system is controlled at 10-20°C. The reaction is then carried out at 15-20°C. After the reaction is complete, water is added to quench the reaction, citric acid solution is added to adjust the pH of the reaction system to 4-5, and finally, the mixture is extracted with toluene, washed, and concentrated to obtain crude compound X, which is then purified by column chromatography to obtain compound X.

[0039] Through research, the inventors discovered that using the optical chiral resolving agent R(+)-α-methylbenzylamine... Reaction with a compound of formula VI yields a mixture of two non-corresponding isomers, which can be purified, for example by recrystallization, to isolate the compound of formula VII with specific chirality. The compound has high chiral purity, reaching over 99%. Compound VII is then subjected to a hydroxyl protection reaction with tert-butyldimethylchlorosilane to obtain compound VIII. This compound VIII reacts with N,O-dimethylhydroxyamine hydrochloride to obtain the target product compound X, which has high chiral purity. Furthermore, compound VIII is in acid form, and compared to the lactone form, the reaction of compound VIII with N,O-dimethylhydroxyamine hydrochloride yields a higher yield, thus achieving a high yield of the target product.

[0040] In some embodiments, the preparation method further includes using compound V. The steps involve hydrolysis under alkaline conditions followed by acidification to obtain compound VI.

[0041] The reaction formula for this step is as follows:

[0042]

[0043] In some embodiments, the alkaline conditions are formed by adding one or more bases selected from sodium hydroxide, lithium hydroxide, and potassium hydroxide. Preferably, the molar ratio of the base to the compound of formula V is 1.1 to 2:1.

[0044] In some embodiments, the hydrolysis is performed at room temperature.

[0045] In some embodiments, compound V is added to tetrahydrofuran and stirred until homogeneous to obtain a solution of compound V. An aqueous solution of the base (approximately 3-4 mol / L) is added dropwise to the solution of compound V. The reaction is carried out at 10–25°C for 2–5 hours. The reaction solution is concentrated under reduced pressure, extracted with ethyl acetate, and the aqueous layer is adjusted to pH < 6 with a 3-4 mol / L aqueous hydrochloric acid solution, extracted with isopropyl acetate, and used directly in the next step.

[0046] In some embodiments, the preparation method further includes using a compound of formula IV. The step involves reacting the compound with iodomethane under alkaline conditions to obtain compound V.

[0047] The reaction formula for this step is as follows:

[0048]

[0049] In some embodiments, the reaction temperature is -70°C to -60°C.

[0050] In some embodiments, the alkaline conditions are formed by adding a base selected from lithium bis(trimethylsilylamino)hydroxide (LiHMDS) or lithium diisopropylaminohydroxide (Diisopropylamino)hydroxide. Preferably, the molar ratio of the base to the compound of formula IV is 1 to 1.1:1.

[0051] In some embodiments, the molar ratio of iodomethane and compound of formula IV is 1 to 1.2:1.

[0052] In some embodiments, the reaction is carried out in the presence of a polar solvent selected from 1,3-dimethyl-2-imidazolinone or hexamethylphosphoric triamine.

[0053] Preferably, the molar ratio of the polar solvent to the compound of formula IV is 1 to 2:1.

[0054] In some embodiments, the compound of formula IV is dissolved in tetrahydrofuran to obtain a solution of compound IV, and the solution is cooled to -70°C to -60°C. A tetrahydrofuran solution of the base is added dropwise to the solution, and the reaction is carried out with stirring. A polar solvent dissolved in tetrahydrofuran is also added dropwise to the solution, and the reaction continues with stirring. Iodomethane is then added dropwise to the above reaction solution. After the reaction is complete, the reaction is quenched with a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried, filtered, and concentrated under reduced pressure to obtain the crude compound of formula V.

[0055] The compound V obtained in this step is a mixture of diastereomers. The inventors discovered that if the reaction route described in the background art literature is used, and the diastereomer impurities of compound V are not separated, but the mixture is directly reacted with N,O-dimethylhydroxylamine hydrochloride to generate compound IV', then compound IV' will also be a mixture. This results in the final target compound X being a mixture of diastereomers, with low chiral purity and difficulty in separating the diastereomers.

[0056] In some embodiments, the preparation method further includes using a compound of formula III. The step involves carrying out a hydrolytic decarboxylation reaction in a mixed solvent of water and an organic solvent to obtain the compound of formula IV.

[0057] The reaction formula for this step is as follows:

[0058]

[0059] In some embodiments, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylaniline.

[0060] In some embodiments, the volume ratio of water to organic solvent in the mixed solvent is 10 to 15:1.

[0061] In some embodiments, the hydrolysis decarboxylation reaction takes 12-16 hours.

[0062] In some embodiments, the compound of formula III and the inorganic salt are added to a mixed solvent, which is then heated under reflux to carry out the hydrolytic decarboxylation reaction. After the reaction is complete, water is added until the inorganic salt is completely dissolved, and the mixture is extracted with methyl tert-butyl ether. The organic layer is washed with water and a saturated sodium chloride solution, dried, filtered, and concentrated to obtain the crude compound of formula IV. The crude compound is then distilled under reduced pressure to obtain the compound of formula IV.

[0063] In some embodiments, the inorganic salt is selected from sodium chloride and magnesium chloride.

[0064] In some embodiments, the preparation method further includes using a compound of formula II. The step involves a condensation reaction with dimethyl malonate under alkaline conditions to obtain the compound of formula III.

[0065] The reaction formula for this step is as follows:

[0066]

[0067] In some embodiments, the molar ratio of the dimethyl malonate to the compound of formula II is 1 to 2:1.

[0068] In some embodiments, the alkaline conditions are formed by adding a base selected from sodium ethoxide or sodium methoxide. Preferably, the molar ratio of the base to the compound of formula II is 1 to 2:1.

[0069] In some embodiments, the reaction is carried out in a solvent selected from ethanol or methanol.

[0070] In some embodiments, the solvent is cooled to -5°C, and the base is added. Then, compound II and dimethyl malonate are added at room temperature, and the mixture is stirred overnight at room temperature to carry out a condensation reaction. The reaction solution is concentrated under reduced pressure, and an aqueous citric acid solution is added while maintaining the temperature below 30°C to achieve a pH of 5-6. The solution is extracted with ethyl acetate, dried, and concentrated to obtain crude product III, which is used directly in the next reaction step.

[0071] In some embodiments, the preparation method further includes using a compound of formula I. The step involves reacting (R)-epoxychloropropane with an allyl Grignard reagent in the presence of cuprous iodide under an inert gas atmosphere to obtain the compound of formula II.

[0072] The reaction formula for this step is as follows:

[0073]

[0074] In some embodiments, the Grignard reagent is selected from allyl magnesium chloride or allyl magnesium bromide.

[0075] In some embodiments, the molar ratio of the Grignard reagent to the compound of formula I is 1.1 to 1.5:1.

[0076] In some embodiments, the reaction temperature is -65 to -55°C.

[0077] In some embodiments, the reaction is carried out in tetrahydrofuran.

[0078] Preferably, the volume-to-mass ratio of the tetrahydrofuran to the compound of formula I is 5–10 L: 1 kg.

[0079] In some embodiments, the molar ratio of cuprous iodide to compound of formula I is 0.01 to 0.1:1.

[0080] In some embodiments, under nitrogen protection, compound I is added to tetrahydrofuran and cooled to -45°C to -50°C, followed by the addition of cuprous iodide. Then, a Grignard reagent is slowly added dropwise, with the temperature controlled to not exceed -55°C during the addition. After the reaction is complete, the temperature is controlled below -45°C, and the reaction is quenched by adding an aqueous solution of ammonium chloride. The mixture is stirred, the layers are separated, and the aqueous layer is extracted with ethyl acetate. The organic phases are combined, washed, dried, and concentrated to obtain compound II.

[0081] In some embodiments, the preparation method employs the following reaction route:

[0082]

[0083] This invention also provides a method suitable for preparing compound X. The intermediate, wherein TBSO is dimethyl tert-butylsiloxy, has the structure shown in formula VI, VII or VIII:

[0084]

[0085] TBSO stands for dimethyl tert-butylsiloxy.

[0086] Compared with the prior art, the present invention has the following technical advantages:

[0087] 1. This invention first uses the optical chiral resolving agent R(+)-α-methylbenzylamine. The compound of formula VI was reacted with the salt, and diastereomeric impurities were removed by recrystallization and other purification methods to prepare a compound of formula VII (salt) with a chiral purity of over 99%. This compound was then protected with a hydroxyl group, and its carboxyl moiety was reacted with N,O-dimethylhydroxyamine hydrochloride via a Weinreb amide reaction to obtain the target product, formula X, with high chiral purity in high yield. Compared to the routes in the background art literature, this reaction route significantly improves both the chiral purity and yield of the target product.

[0088] 2. By selecting a specific type of mixed solvent as the recrystallization solvent, the present invention can effectively separate the diastereomers of compound VII, thereby further improving its chiral purity, and also further improving the chiral purity of the target compound X.

[0089] 3. The present invention can use inexpensive and readily available chiral raw material (R)-epoxychloropropane as a starting material. It first reacts with Grignard reagent to prepare compound II, and then reacts compound II with dimethyl malonate to prepare compound III. Its hydrolysis, decarboxylation and methylation can prepare compound V, thus avoiding the large number of enantiomer byproducts generated by the chiral resolution step in the background art literature.

[0090] 4. Compared to the lactone form of compound V, the carboxylic acid form of this invention exhibits a significantly higher yield of Weinreb amide in reaction with N,O-dimethylhydroxylamine hydrochloride. The reaction and purification processes of this invention are simple to operate, with mild and controllable reaction conditions, facilitating industrial production. Attached Figure Description

[0091] Figure 1The NMR spectrum of the compound of formula II prepared in Example 1;

[0092] Figure 2 The NMR spectrum of the compound of formula IV prepared in Example 1;

[0093] Figure 3 The NMR spectrum of the compound of formula VII prepared in Example 1;

[0094] Figure 4 The NMR spectrum of compound X prepared in Example 1; Detailed Implementation

[0095] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of protection of the present invention.

[0096] The technical features of the embodiments described below can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the embodiments below are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0097] The following embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this invention should be determined by the appended claims.

[0098] Example 1

[0099] This embodiment provides a method for preparing a compound of formula X:

[0100] Step 1: Preparation of Compound II

[0101] Under nitrogen protection, (R)-epimycyl propane (10.0 kg, 10⁸ mol) and tetrahydrofuran (50.0 L) were added to a 200 L reactor. Stirring and cold circulation were initiated, and the temperature was maintained between -45 and -50 °C. Cuprous iodide (2.06 kg, 10.8 mol) was added. The temperature was controlled to not exceed -55 °C, and a tetrahydrofuran solution of allyl magnesium chloride (140 L, 1 M) was slowly added dropwise. After the reaction was complete, the reaction was quenched by adding an aqueous solution of ammonium chloride, maintaining the temperature below -45 °C. Water was added and stirred, and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried, filtered, and concentrated to obtain compound II in 95% yield.

[0102] The proton NMR spectrum of compound II in CDCl3 is as follows: Figure 1The specific values ​​are as follows: 1 H NMR (400MHz, CDCl3): 5.77-5.87(m,1H),4.99-5.09(m,2H),3.82-3.84(m,1H),3.63(dd, J=3.6,11.2Hz,1H),3.49(dd,J=7.2,11.2Hz,1H),2.14-2.27(m,3H),1.61-1.67(m,2H).

[0103] Step 2: Preparation of Compound III

[0104] Methanol (20.0 L) was added to a 30 L reactor and cooled to -5 °C. Sodium methoxide (2.40 kg, 44.4 mol) was then added. At room temperature, compound II (3.98 kg, 29.6 mol) and dimethyl malonate (4.69 kg, 35.52 mol) were added sequentially, and the mixture was stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure. The concentration temperature was controlled below 30 °C, and an aqueous citric acid solution was added to maintain the pH at 5.5. Ethyl acetate was added for extraction, the organic layer was dried, and the mixture was concentrated to obtain 4.95 kg of crude compound III, which was used directly in the next reaction step.

[0105] Step 3: Preparation of Formula IV Compound

[0106] Compound III (4.95 kg, crude product), sodium chloride (7.25 kg, 125 mol), water (140 L), and dimethyl sulfoxide (14.0 L) were added to a 30 L reactor and heated under reflux overnight. Water was added until the sodium chloride was completely dissolved, and the mixture was extracted with methyl tert-butyl ether. The organic layers were combined, washed successively with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound IV. Compound IV was then obtained by vacuum distillation, which was a colorless liquid. The combined yield of steps 2 and 3 was 75%.

[0107] The proton NMR spectrum of compound IV in CDCl3 is as follows: Figure 2 The specific values ​​are as follows: 1 H NMR (400MHz, CDCl3): 1 H NMR(400MHz, CDCl3): 5.76-5.86(m,1H),5.00-5.09(m,2H),4.47-4.54(m,1H) ,2.51-2.55(m,2H),2.17-2.37(m,3H),1.80-1.91(m,2H),1.58-1.74(m,1H).

[0108] Step 4: Preparation of compound V

[0109] Compound IV (600 g, 4.28 mol) and tetrahydrofuran (3 L) were added to a 20 L reaction flask and cooled to -60 °C to 70 °C. A tetrahydrofuran solution of bis(trimethylsilylaminolithium) LiHMDS (4.71 L, 4.71 mol, 1 M) was added dropwise, and the mixture was stirred for 60 minutes. 1,3-Dimethyl-2-imidazolinone (586 g, 5.14 mol) was dissolved in tetrahydrofuran (300 mL) and added dropwise to the above reaction solution, and the mixture was stirred for 45 minutes. Iodomethane (668 g, 4.71 mol) was added dropwise to the above reaction solution. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 640 g of crude compound V, which was used directly in the next reaction step.

[0110] Step 5: Preparation of Compound VI

[0111] Add 600 g (3.89 mol) of crude compound V and 450 ml of tetrahydrofuran to a 5 L reaction flask. Add dropwise a prepared sodium hydroxide aqueous solution (17 L, 1.1 L) to the reaction solution. After the addition is complete, stir at room temperature for 2 hours to complete the reaction. Concentrate the reaction solution under reduced pressure, extract with ethyl acetate, adjust the pH of the aqueous layer to <6 with 3 mol / L hydrochloric acid aqueous solution, and extract with isopropyl acetate to obtain an isopropyl acetate solution of compound VI, which can be used directly in the next step.

[0112] Step 6: Preparation of Compound VII

[0113] A solution of isopropyl acetate of compound VI (formula VI) was added to a 5 L reaction flask and cooled to 0 °C. R(+)-α-methylbenzylamine (519 g, 4.28 mol) was slowly added dropwise, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filter cake was collected. The filtrate was concentrated under reduced pressure, and the concentrate was mixed with methyl tert-butyl ether and slurried. The mixture was then filtered, the filter cakes were combined, and dried to obtain the crude product of compound VII.

[0114] Recrystallization: The crude compound of formula VII and methyl tert-butyl ether (3.00 L) were added to a 5 L reaction flask, and the mixture was heated to reflux. Isopropanol was slowly added until the solution became clear; the total volume of isopropanol added was 0.3 L. The mixture was cooled to crystallize, filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain compound VII, which was a white solid. The combined yield of steps 4-6 was 55%.

[0115] The proton NMR spectrum of compound VII in CDCl3 is as follows: Figure 3 The specific values ​​are as follows: 1 H NMR (400MHz, CDCl3): 1H NMR (400MHz, CDCl3): 7.28-7.39(m,5H),5.77-5.84(m,1H),4.99(dd,J=1.6,17.2Hz,1H),4.93(d,J=10.4,1H),4.18-4.23(q,J =6.8,1H),3.61-3.67(m,1H),2.41-2.49(m,1H),1.97-2.18(m,2H),1.56-1.62(m,1H),1.36-1.52(m,6H),1.01(d,J=6.8,3H).

[0116] Step 7: Preparation of Compound VIII

[0117] Compound VII (400 g, 1.36 mol) and N,N-dimethylformamide (2.50 L) were added to a 5 L reaction flask and cooled to 0 °C. Imidazole (926 g, 13.6 mol) was then added. The reaction temperature was controlled at 10–15 °C, and tert-butyldimethylchlorosilane (410 g, 0.72 mol) was added dropwise. The reaction was carried out in an ice bath for 1 hour, then brought to room temperature (25 °C) and allowed to proceed until the starting material disappeared. The reaction was quenched with methanol, diluted with water, and the pH was adjusted to 4.5 with citric acid solution. The mixture was extracted with toluene, and the organic layer was washed with water and saturated brine, dried, and concentrated to obtain crude compound VIII. The crude compound VIII was purified by column chromatography as a colorless oil with a yield of 85%.

[0118] Step 8: Preparation of Compound X

[0119] In a 5L reaction flask, compound VIII (200g, 0.70mol) and N,N-dimethylformamide (1L) were added, stirred, and cooled to 10°C. N,O-dimethylhydroxylamine hydrochloride (102g, 0.05mol) was added in portions, followed by N,N-diisopropylethylamine (226g, 0.75mol). The mixture was cooled to 0°C, and HATU (293g, 0.77mol) was added. The reaction was continued at 15–20°C until the starting material disappeared. The reaction was quenched with water, and the pH was adjusted to 4.5 with citric acid solution. The mixture was extracted with toluene, and the combined organic layers were washed successively with sodium carbonate solution, water, and saturated brine. The crude product was concentrated and purified by column chromatography to obtain compound VIII in 92% yield with an optical chiral purity of 99.7%.

[0120] The proton NMR spectrum of compound X in CDCl3 is as follows: Figure 4 The specific values ​​are as follows: 1 H NMR (400MHz, CDCl3): 1H NMR (400MHz, CDCl3): 5.76-5.86(m,1H),4.92-5.03(m,2H),3.69(s,3H),3.65-3.68(m,1H),3.17(s,3H),3.00(s,1 H),2.04-2.15(m,2H),1.90-1.96(m,1H).1.41-1.58(m,3H).1.12(d,J=6.8,3H).0.876(s,9H),0.03(d,J=3.2,6H).

[0121] Example 2

[0122] This embodiment provides a method for preparing compound X: the steps are basically the same as in Example 1, except that the recrystallization step in step 6 is slightly different, as follows: The crude compound of formula VII and methyl tert-butyl ether (2.50 L) are added to a 5 L reaction flask, heated to reflux, and isopropanol is slowly added until clear, with a total volume of isopropanol added of 0.5 L. The mixture is cooled to crystallize, filtered, the filter cake is washed with methyl tert-butyl ether, and dried to obtain compound VII, which is a white solid. The total yield of steps 4-6 is 60%.

[0123] Example 3

[0124] This embodiment provides a method for preparing compound X: the steps are basically the same as in Example 1, except that the recrystallization step in step 6 is slightly different, as follows: The crude compound of formula VII and isopropyl ether (3L) are added to a 5L reaction flask, heated to reflux, and isopropanol is slowly added until clear, with a total volume of 0.3L of isopropanol added. The mixture is cooled to crystallize, filtered, the filter cake is washed with isopropyl ether, and dried to obtain compound VII, which is a white solid. The total yield of steps 4-6 is 54%.

[0125] Example 4

[0126] This embodiment provides a method for preparing compound X: the steps are basically the same as in Example 1, except that the recrystallization step in step 6 is slightly different, as follows: The crude compound of formula VII and isopropyl ether (2.5 L) are added to a 5 L reaction flask, heated to reflux, and n-butanol is slowly added until clear. The total volume of n-butanol added is 0.2 L. The mixture is cooled to crystallize, filtered, the filter cake is washed with isopropyl ether, and dried to obtain compound VII, which is a white solid. The total yield of steps 4-6 is 62%.

[0127] Example 5

[0128] This embodiment provides a method for preparing compound X: the steps are basically the same as in Example 1, except that the recrystallization step in step 6 is slightly different, as follows: The crude compound of formula VII and methyl tert-butyl ether (3 L) are added to a 5 L reaction flask, heated to reflux, and isobutanol is slowly added until clear, with a total volume of 0.25 L of isobutanol added. The mixture is cooled to crystallize, filtered, the filter cake is washed with methyl tert-butyl ether, and dried to obtain compound VII, which is a white solid. The total yield of steps 4-6 is 57%.

[0129] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound of formula X The preparation method, wherein TBSO is dimethyl tert-butylsiloxy, is characterized by: The preparation method includes the following steps: 1) preparing compound VI and R(+)-α-methylbenzylamine The reaction was carried out in an organic solvent, and the compound of formula VII was obtained after purification. ;2) Reaction of compound VII with tert-butyldimethylchlorosilane, followed by acidification, yields compound VIII. ;3) Reacting compound VIII with N,O-dimethylhydroxyamine hydrochloride to obtain compound X; In step 1), the purification includes recrystallization, wherein the solvent for recrystallization is a mixture of ether solvents and alcohol solvents, wherein the ether solvent is selected from one or both of methyl tert-butyl ether and isopropyl ether; and the alcohol solvent is selected from one or a combination of n-butanol, isopropanol and isobutanol. In step 1), the organic solvent is selected from isopropyl acetate; In step 2), the reaction is carried out in the presence of imidazole; In step 3), the reaction is carried out in the presence of a base and a condensing agent; The preparation method further includes processing compound V. The steps involve hydrolysis under alkaline conditions followed by acidification to obtain compound VI.

2. The preparation method according to claim 1, characterized in that: In step 1), the reaction temperature is -5 to 5°C.

3. The preparation method according to claim 1, characterized in that: In step 1), the molar ratio of the compound of formula VI and R(+)-α-methylbenzylamine is 1:1.1 to 1.

5.

4. The preparation method according to claim 1, characterized in that: In step 1), the organic solvent containing the compound of formula VI is cooled to -5 to 5°C, and R(+)-α-methylbenzylamine is added dropwise to the organic solvent under stirring to carry out the reaction.

5. The preparation method according to claim 1, characterized in that: In step 2), the reaction temperature is 20–30°C.

6. The preparation method according to claim 1, characterized in that: In step 2), the molar ratio of the imidazole and the compound of formula VII is 8 to 10:

1.

7. The preparation method according to claim 1, characterized in that: In step 2), the molar ratio of tert-butyldimethylchlorosilane to compound VII is 2 to 4:

1.

8. The preparation method according to claim 1, characterized in that: In step 2), citric acid is used for the acidification.

9. The preparation method according to claim 1, characterized in that: In step 3), the reaction temperature is 15–20°C.

10. The preparation method according to claim 1, characterized in that: In step 3), the base is selected from triethylamine or N,N-diisopropylethylamine, and the condensing agent is selected from one or more combinations of urea-ion peptide condensing agent TBTU, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ester HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI, and amide condensing agent HOBT.

11. The preparation method according to claim 1, characterized in that: In step 3), the molar ratio of N,O-dimethylhydroxyamine hydrochloride and compound VIII is 1.2 to 1.8:

1.

12. The preparation method according to claim 1, characterized in that: The preparation method further includes using compound of formula IV. The step involves reacting the compound with iodomethane under alkaline conditions to obtain compound V.

13. The preparation method according to claim 12, characterized in that: The preparation method further includes using compound of formula III. The step involves carrying out a hydrolytic decarboxylation reaction in a mixed solvent of water and an organic solvent to obtain the compound of formula IV.

14. The preparation method according to claim 13, characterized in that: The preparation method further includes using compound of formula II. The step involves a condensation reaction with dimethyl malonate under alkaline conditions to obtain the compound of formula III.

15. The preparation method according to claim 14, characterized in that: The preparation method further includes using compound I. The step involves reacting (R)-epoxychloropropane with an allyl Grignard reagent in the presence of cuprous iodide under an inert gas atmosphere to obtain the compound of formula II.

16. A method suitable for preparing compound X An intermediate, wherein TBSO is a dimethyl tert-butylsiloxy group, characterized in that: The intermediate has the structure shown in formula VI, formula VII or formula VIII:

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