Milbemycin intermediates and processes for their preparation

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a milonamide intermediate and a preparation method thereof. The preparation method comprises the following steps: reacting compound 7 with Nagata reagent in a solvent to obtain compound 8, wherein R 1 is benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3. The application realizes the conversion from compound 3 to compound 2 by constructing compound 7 and compound 8, can avoid directly using NaCN for addition in the existing route, the addition of compound 8 is better in stereoselectivity, and the purity and dr value of compound 2 can be improved through crystallization, and the application is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a milobalin intermediate and its preparation method. Background Technology

[0002] Peripheral neuropathic pain (PNP) is a type of pathological pain caused by peripheral nerve damage or dysfunction due to various reasons. Common clinical PNPs include diabetic peripheral neuropathy (PDPN), postherpetic neuralgia (PHN), and postoperative chronic pain. PDPN is the most common complication of diabetes, with an incidence rate exceeding 60% in diabetic patients, affecting approximately 22 million people. PHN is pain lasting for one month or more after the healing of shingles, with an annual incidence rate of 3.9–42.0 / 100,000, and 9%–34% of shingles patients develop PHN. The incidence of postoperative chronic pain varies considerably depending on the type of surgery, reportedly ranging from 10% to 50%. The highest incidence is observed after amputation, open-chest surgery, and coronary artery bypass surgery, reaching 30%–50%.

[0003] Mirogabalin besylate is a gamma-aminobutyric acid analog developed by Daiichi Sankyo Co., Ltd. of Japan for the treatment of peripheral neuropathic pain. Its mechanism of action is to act on the α2δ-1 subunit of the voltage-sensitive calcium channel complex. Its indications include postherpetic neuralgia, diabetic neuropathy, and peripheral nervous system disorders.

[0004]

[0005] In patent CN104755456B, the preparation route of milobalin benzylsulfonic acid (1) involves the following key intermediate 2, whose chemical name is (1R, 5S, 6S)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid.

[0006]

[0007] In patent CN104755456B, the synthesis of key intermediate 2 uses (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (3) as the starting material, and involves four steps: Knoevenagel condensation, addition with NaCN, decarboxylation and hydrolysis, and salt formation and dissociation. NaCN is used in the addition reaction, and the addition product has a low dr value. Therefore, after decarboxylation and hydrolysis, it needs to be salted with an amine for resolution. This is necessary to achieve an ee value of 98% for compound 6, with a total yield of only about 50%. The use of NaCN and the cumbersome operation of salt formation and subsequent dissociation to improve optical purity are highly detrimental to the large-scale industrial production of milobalin. Summary of the Invention

[0008] To address the problems of existing methods for preparing the key intermediate 2 of milobaline, such as the use of sodium cyanide, low stereoselectivity during addition, the need for subsequent salt formation and dissociation to improve optical purity, cumbersome procedures, and difficulty in industrial scale-up, this invention provides a milobaline intermediate and its preparation method. This method involves constructing new intermediate compounds 7 and 8, reacting compound 7 with Nagata reagent to prepare compound 8, and then further preparing compound 2 from compound 8, thus providing a new synthetic route for the key intermediate 2 of milobaline.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a method for preparing compound 8, comprising the following steps: reacting compound 7 and Nagata reagent in a solvent to obtain compound 8;

[0010] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0011] In some embodiments, compound 7 is prepared by a method comprising the steps of reacting compound 3 and compound 10 in a solvent in the presence of a catalyst and a base to obtain compound 7;

[0012] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3; The catalyst is TiCl4 or TiCl3(O) i One or more of Pr and AlCl3.

[0013] Secondly, the present invention provides a compound 8, the structure of which is shown below:

[0014] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0015] Thirdly, the present invention provides a compound 7 for preparing the above-mentioned compound 8, the structure of which is shown below:

[0016] Among them, R1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0017] Fourthly, the present invention provides a method for preparing compound 2, comprising the following steps: Compound 8 was prepared according to the preparation method described above; In a solvent, compound 8 was reacted in the presence of a base to give compound 2;

[0018] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0019] The beneficial effects achieved by this invention are as follows: This invention uses compounds 7 and 8 as intermediates to achieve the conversion from compound 3 to compound 2, resulting in a simpler overall process route. In the preparation of compound 8, the Nagata hydrocyanation reaction is used to synthesize compound 8, avoiding the use of NaCN, and the addition of compound 8 exhibits better stereoselectivity. In the preparation of compound 2, only one crystallization operation is required, which can significantly improve the purity and dr value of compound 2.

[0020] This invention is simple and easy to operate, has good reaction selectivity, easy-to-control impurities, and high yield. It helps to reduce production costs and the difficulty of process scale-up, making it suitable for large-scale industrial production of milobalin and possessing good industrial application value. Detailed Implementation

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this invention.

[0023] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0024] The first aspect of the present invention provides a method for preparing compound 8, comprising the following steps: reacting compound 7 and Nagata reagent in a solvent to obtain compound 8;

[0025] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0026] In the above reaction, when compound 7 reacts with the Nagata reagent, the Nagata reagent introduces a cyano group into the reaction site of compound 7, thereby obtaining compound 8 with a cyano-substituted structure. Compared with the prior art method of using NaCN to add to the corresponding unsaturated intermediate, the present invention uses the Nagata reagent for cyano introduction, which is beneficial to improving the stereoselectivity of the cyano addition reaction and reducing the safety and operational risks associated with directly using NaCN.

[0027] The Nagata reagent is a hydrocyanating reagent that catalyzes the Nagata cyanide hydrocyanation reaction, and can be a commercially available dialkyl aluminum cyanide reagent (e.g., (R...). 2 )2AlCN), or prepared by reacting cyanide with alkylaluminum reagents (e.g., R 3 (Prepared using CN and alkylaluminum reagents).

[0028] In some implementations, R 1 It is benzyl or -CH2CH2OCH3. The above R... 1 The ester group formed by the group can participate in the structural stability of compounds 7 and 8, and can be further transformed during the subsequent alkali treatment process to prepare compound 2. When R¹ is benzyl, the resulting intermediate has good hydrophobicity and ease of separation; R 1 When the intermediate is -CH2CH2OCH3, the resulting intermediate has good solubility, which is beneficial for subsequent reactions and scale-up operations.

[0029] In some embodiments, the two Rs in compound 7 1 Similarly, the two Rs in compound 8 1 Same. Using the same R 1The group helps reduce the complexity of the substrate composition, making the preparation, separation and quality control of compounds 7 and 8 simpler.

[0030] In some embodiments, the solvent is an organic solvent. The organic solvent can be an alkane solvent and / or an aromatic solvent. Preferably, the alkane solvent is one or more of n-hexane and n-heptane. Alkane solvents have good compatibility with organoaluminum Nagata reagents and are less prone to undesirable side reactions with organoaluminum reagents, which is beneficial for maintaining the stability of the reaction system. Preferably, the aromatic solvent is one or more of benzene, toluene, and xylene. Aromatic solvents can dissolve compound 7 and the intermediates generated in the reaction, which is beneficial for the uniformity of the reaction. Considering safety and industrial applicability, toluene or xylene can be selected as the aromatic solvent in actual production.

[0031] In some embodiments, the Nagata reagent is (R 2 )2AlCN, or by R 3 CN and alkylaluminum reagents were used to prepare the solution; Among them, R 2 For Me, Et, i- Pr or i -Bu; R 3 It can be Na, K, H or TMS; The alkylaluminum reagent is EtAlCl2, Me3Al, Et3Al, or Et2AlCl.

[0032] In some implementations, R 2 For Me or Et. R 2 When the form is Me or Et, the resulting dialkylaluminum cyanide reagent exhibits good reactivity and can participate well in the cyano addition reaction of compound 7.

[0033] In some implementations, R 3 For TMS, R 3 CN stands for trimethylcyanosilane. When trimethylcyanosilane is combined with alkylaluminum reagents to generate Nagata reagents, it avoids the direct use of NaCN as an addition reagent and facilitates the reaction in non-aqueous organic systems.

[0034] In some embodiments, the alkylaluminum reagent is Et3Al. Et3Al is capable of reacting with a cyanide source (R... 3 CN) forms a Nagata reagent with cyano transfer capability, causing compound 7 to undergo a cyano addition reaction to generate compound 8. Simultaneously, Et3Al can be used in solution form, and the Et3Al solution can be a hexane solution of Et3Al. Preferably, the concentration of the hexane solution of Et3Al is 2 mol / L.

[0035] In some embodiments, the Nagata reagent is composed of R 3 CN and alkylaluminum reagent are prepared at 65~120℃, such as 65℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, etc., preferably at 65~75℃, for a preparation time of 0.1~5 hours, such as 0.1 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, etc., alkylaluminum reagent and R 3 The molar ratio of CN is 1:(1~5), for example, 1:1, 1:2, 1:3, 1:4, 1:5, etc. Within this temperature and time range, R³CN can form Nagata reagents relatively fully with alkylaluminum reagents.

[0036] Among them, R 3 CN can be added together with the alkylaluminum reagent in one step, or added in batches. When R 3 When CN and the alkylaluminum reagent are added together, R 3 The molar ratio of CN and the alkylaluminum reagent can be equivalent (e.g., approximately 1:1). When R 3 When CN and the alkylaluminum reagent are added in batches, the first batch of R 3 The molar amount of CN added can be the same as that of the alkylaluminum reagent, with the remaining R... 3 CN can be added simultaneously with compound 7.

[0037] In some embodiments, when the Nagata reagent is derived from R 3 When CN and the alkylaluminum reagent are prepared, the alkylaluminum reagent can be in solution form, preferably a solution dissolved in an alkane solvent (e.g., n-hexane); preferably, the concentration of the alkylaluminum reagent solution is 2 mol / L.

[0038] In some embodiments, the molar ratio of compound 7 to Nagata reagent is 1:(1~5), for example, 1:1, 1:2, 1:3, 1:4, 1:5, etc. Within this molar ratio range, compound 7 can fully contact Nagata reagent and undergo a cyano addition reaction. By adjusting the molar ratio of Nagata reagent to compound 7, a balance can be achieved between reaction conversion, reagent utilization, and post-processing burden. Preferably, the molar ratio of compound 7 to Nagata reagent is 1:(2~4).

[0039] In some embodiments, the reaction temperature between compound 7 and the Nagata reagent is 40–120°C, for example, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, etc. Within this temperature range, compound 7 can undergo a cyano addition reaction with the Nagata reagent to generate compound 8. Preferably, the reaction temperature is 55–75°C. Within this temperature range, the reaction rate, selectivity, and operational stability are relatively well-balanced, making it suitable for the preparation of compound 8.

[0040] In some embodiments, the reaction time between compound 7 and the Nagata reagent is 0.5 to 10 hours, for example, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, etc. The reaction time can be adjusted according to the reaction conversion, usually until compound 7 has basically reacted completely or compound 8 no longer increases significantly. If the reaction time is too short, compound 7 may not be completely converted; if the reaction time is too long, it may increase the formation of by-products or increase the process time cost. Preferably, the reaction time is 0.5 to 3 hours, for example, 2 hours.

[0041] In some embodiments, the reaction of compound 7 and Nagata reagent further includes the following post-treatment steps: adding sodium bicarbonate solution (preferably saturated sodium bicarbonate solution) to the reaction solution, then adding potassium sodium tartrate solution (preferably saturated potassium sodium tartrate solution), stirring, extracting the aqueous layer with an organic solvent (preferably n-heptane and / or ethyl acetate), extracting the organic layer with sodium bicarbonate solution (e.g., 5% sodium bicarbonate solution), removing the solvent from the organic layer, and obtaining compound 8.

[0042] In some embodiments, compound 7 is prepared by a method comprising the steps of reacting compound 3 and compound 10 in a solvent in the presence of a catalyst and a base to obtain compound 7;

[0043] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3; The catalyst is TiCl4 or TiCl3(O) i One or more of Pr and AlCl3.

[0044] Compound 3 and Compound 10 undergo a condensation reaction under the action of a catalyst and a base, introducing a malonic acid ester structure onto the bicyclic [3.2.0]heptene skeleton to obtain Compound 7. Compound 7 serves as a precursor for the subsequent Nagata cyanation reaction, containing reaction sites capable of further cyano group introduction. Therefore, the successful preparation of Compound 7 is a crucial basis for distinguishing this invention's route from existing technical routes.

[0045] In some implementations, R 1 It is benzyl or -CH2CH2OCH3; R 1 When the group is benzyl, the resulting compound 7 exhibits good separation convenience and can be used as an intermediate in the preparation of the corresponding benzyl ester compound 8. 1 When the form is -CH2CH2OCH3, the resulting compound 7 exhibits good solubility and adaptability to subsequent transformations.

[0046] In some embodiments, the two Rs in compound 10 1 Same. Using two Rs 1 Using the same malonate compounds helps reduce the complexity of the substrate composition and the possibility of different ester substituents coexisting in the reaction products, thus facilitating subsequent separation, detection and quality control.

[0047] In some embodiments, the catalyst is TiCl4. TiCl4 has strong Lewis acidity, and the reaction can be carried out at lower temperatures, which is beneficial for reducing side reactions and maintaining the stability of the substrate's bicyclic structure.

[0048] In some embodiments, the solvent is an ether solvent or an aromatic solvent. Ether solvents have good dissolving and dispersing properties, which is beneficial for homogenization of the reaction system and allows the reaction to proceed more smoothly. Aromatic solvents have good organic substrate dissolving ability and are relatively stable. The ether solvent is preferably a cyclic ether solvent, more preferably tetrahydrofuran; the aromatic solvent is preferably benzene, toluene, or xylene.

[0049] In some embodiments, the base is an organic base. The organic base is preferably a nitrogen-containing organic base, such as pyridine.

[0050] In some embodiments, the molar ratio of compound 3 to the catalyst is 1:(0.1~3), for example, 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:3, etc. Within this range, the catalyst can effectively promote the reaction between compound 3 and compound 10. Preferably, the molar ratio of compound 3 to the catalyst is 1:(0.5~2.5), more preferably 1:(1~2).

[0051] In some embodiments, the molar ratio of compound 3 to compound 10 is 1:(1~1.5), for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc. Within this range, compound 10 can participate in the condensation reaction sufficiently, while avoiding an excess of compound 10 that would increase the burden of post-processing. Preferably, the molar ratio of compound 3 to compound 10 is 1:(1~1.2), for example, 1:1.05.

[0052] In some embodiments, the molar ratio of compound 3 to the base is 1:(2~10), for example, 1:2, 1:3, 1:5, 1:7, 1:9, 1:10, etc. Within this range, it is beneficial to promote the reaction. Preferably, the molar ratio of compound 3 to the base is 1:(4~6), for example, 1:5.

[0053] In some embodiments, the reaction temperature between compound 3 and compound 10 is -20 to 25°C, such as -20°C, -10°C, 0°C, 10°C, 20°C, 25°C, etc. Using this temperature range can ensure the reaction proceeds while reducing the occurrence of side reactions. Preferably, the reaction temperature between compound 3 and compound 10 is -5 to 5°C. This temperature range is beneficial for controlling the reaction rate, making the reaction system more stable, and suitable for scale-up operations.

[0054] In some embodiments, the reaction time between compound 3 and compound 10 is 2 to 24 hours, such as 2 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours, etc. The reaction time can be adjusted according to the conversion of compound 3, usually based on the point that compound 3 has basically reacted completely or compound 7 no longer increases significantly. If the reaction time is too short, compound 3 may not be completely converted; if the reaction time is too long, it may increase the formation of by-products and process time costs.

[0055] Preferably, the reaction time of compound 3 and compound 10 is 2 to 12 hours, such as 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, etc.

[0056] In some embodiments, the preparation method of compound 7 further includes the following post-processing steps: water quenching reaction, extraction with a mixed solution of n-heptane and ethyl acetate (preferably n-heptane and ethyl acetate 4:1), washing with sodium chloride solution (preferably saturated sodium chloride solution), and removal of solvent (preferably removing solvent under reduced pressure) to obtain compound 7.

[0057] A second aspect of the present invention provides a compound 8, the structure of which is shown below:

[0058] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0059] A third aspect of the present invention provides a compound 7 for preparing compound 8 of claim 7, characterized in that its structure is as follows:

[0060] Among them, R 1It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0061] A fourth aspect of this invention provides a method for preparing compound 2, comprising the following steps: Compound 8 was prepared according to the preparation method described in claim 1; In a solvent, compound 8 was reacted in the presence of a base to give compound 2;

[0062] Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0063] In the above reaction, in the presence of a base, the ester group structure in compound 8 can be transformed, and after decarboxylation and hydrolysis, compound 2 is obtained. Compound 2 is a key intermediate in the preparation route of milobalin, and its structure retains the cyano group and bicyclic [3.2.0]heptene skeleton introduced in compound 8.

[0064] In some implementations, R 1 It is benzyl or -CH2CH2OCH3. R 1 The group is benzyl, and the corresponding compound 8 is a benzyl ester intermediate; R 1 The intermediate is -CH2CH2OCH3, and the corresponding compound 8 is a 2-methoxyethyl ester type intermediate. Both are more favorable for further conversion under alkaline conditions, thus preparing compound 2.

[0065] In some embodiments, the solvent used to prepare compound 2 is an alcohol solvent, a nitrile solvent, or a mixture of a nitrile solvent and water.

[0066] The alcohol solvent is one or more of methanol, ethanol, and isopropanol. Alcohol solvents can effectively dissolve compound 8 and the base, and facilitate the uniformity of the base treatment reaction. Preferably, the alcohol solvent is ethanol. Ethanol has good substrate solubility and industrial applicability, and is easy to remove and recover, making it suitable as a reaction solvent for the conversion of compound 8 to compound 2. The nitrile solvent is acetonitrile. Acetonitrile can be used as an organic solvent in the reaction or post-treatment, and can also be used in the subsequent crystallization process to improve the purity and diastereomeric ratio of compound 2. In the mixed solvent of nitrile solvent and water, the volume ratio of nitrile solvent to water is (1~10):1. When using a mixed system of nitrile solvent and water, the solubility of compound 8, the base, and the reaction intermediate can be balanced by adjusting the ratio of the organic phase and the water phase, making the reaction and post-treatment processes easier to control.

[0067] In some embodiments, the base is an inorganic strong base. Preferably, the inorganic strong base is an alkali metal hydroxide. The alkali metal hydroxide can be one or more of lithium hydroxide, sodium hydroxide, or potassium hydroxide. More preferably, the inorganic strong base is potassium hydroxide. Potassium hydroxide has good solubility in alcohol solvents and water, and can effectively promote the ester group conversion, hydrolysis, and decarboxylation process in compound 8, making it suitable for the preparation of compound 2.

[0068] In some embodiments, the molar ratio of compound 8 to the base is 1:(2~10), for example, 1:2, 1:3, 1:4, 1:6, 1:8, 1:9, 1:10, etc. Within this range, the base can sufficiently promote the conversion of compound 8 to compound 2. If the amount of base is too low, the conversion of compound 8 may be incomplete; if the amount of base is too high, it may increase the salt load, the difficulty of post-processing, and the risk of side reactions. Preferably, the molar ratio of compound 8 to the base is 1:(2~4). This range is beneficial for achieving a better balance between reaction conversion rate and post-processing convenience.

[0069] In some embodiments, the reaction for preparing compound 2 includes reacting compound 8 first with an alcoholic solution of a base, and then with an aqueous solution of a base to obtain compound 2.

[0070] When using the segmented alkali treatment method described above, the first stage is carried out in an alcohol solution, which facilitates sufficient contact between compound 8 and the alkali and promotes ester group conversion and decarboxylation-related reactions. The second stage involves adding an aqueous alkali solution, which further facilitates the hydrolysis process, converting the reaction system to the target compound 2. Compared to a single strong aqueous alkali treatment, the segmented treatment method makes it easier to control the reaction process, reduces the risk of side reactions caused by excessively high local alkali concentrations, and is also beneficial for temperature and system state control during scale-up production.

[0071] In some embodiments, the alcohol in the alcoholic solution of the alkali is one or more selected from methanol, ethanol, and isopropanol. Preferably, the alcoholic solution of the alkali is a potassium hydroxide ethanol solution.

[0072] In some embodiments, the concentration of the alcoholic solution of the base is 0.1~10 mol / L, for example, 0.1 mol / L, 0.5 mol / L, 0.7 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 4 mol / L, 6 mol / L, 8 mol / L, 10 mol / L, etc. This concentration range ensures that the base has sufficient reactivity in the alcohol phase, while avoiding excessively high base concentrations that could lead to overly vigorous reactions or excessive salt loads in the post-treatment process.

[0073] In some embodiments, the reaction temperature of compound 8 with the alcoholic solution of the base is 80-140°C, for example, 80°C, 85°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, etc. Within this temperature range, compound 8 can undergo the base treatment reaction well. At too low a temperature, the reaction rate may be slow; at too high a temperature, side reactions and solvent pressure control may increase. Preferably, the reaction temperature of compound 8 with the alcoholic solution of the base is 100-110°C. Within this temperature range, the reaction rate and reaction selectivity are well-balanced, making it suitable for the preparation of compound 2.

[0074] In some embodiments, the reaction time of compound 8 with the alcoholic solution of the base is 4 to 12 hours, for example, 4 hours, 4.5 hours, 5 hours, 6 hours, 8 hours, 9 hours, 10 hours, etc. The reaction time can be adjusted according to the reaction situation, generally until the product no longer increases significantly. The reaction time can also be adjusted according to the conversion of compound 8, generally until compound 8 has essentially reacted completely or the target product no longer increases significantly. Preferably, the reaction time of compound 8 with the alcoholic solution of the base is 6 to 8 hours, for example, about 7 hours.

[0075] In some embodiments, the concentration of the aqueous solution of alkali is 0.1~10 mol / L, for example, 0.1 mol / L, 0.4 mol / L, 0.8 mol / L, 1 mol / L, 1.6 mol / L, 2 mol / L, 4 mol / L, 6 mol / L, 8 mol / L, 10 mol / L, etc. By controlling the concentration of the aqueous solution of alkali, the hydrolysis reaction can be further promoted, and the increase in side reactions or post-processing burden caused by excessively high alkali concentration can be avoided.

[0076] In some embodiments, the aqueous solution of the alkali is an aqueous solution of potassium hydroxide.

[0077] In some embodiments, the reaction temperature with the aqueous solution of the alkali is 0–50°C, for example, 0°C, 5°C, 10°C, 20°C, 26°C, 30°C, 34°C, 40°C, 50°C, etc. Within this temperature range, the hydrolysis reaction can proceed more smoothly and is beneficial in reducing the risk of degradation of the target product in a strongly alkaline aqueous phase. Preferably, the reaction temperature with the aqueous solution of the alkali is 15–30°C.

[0078] In some embodiments, the reaction time with the aqueous solution of the alkali is 1 to 6 hours, for example, 1 hour, 1.2 hours, 2 hours, 2.6 hours, 3 hours, 5 hours, 5.5 hours, 6 hours, etc. The reaction time can be adjusted according to the reaction situation, generally until the product no longer increases significantly. If the reaction time is too short, hydrolysis may be incomplete; if the reaction time is too long, it may increase process time costs and may cause the target product to remain in the alkaline system for too long. Preferably, the reaction time with the aqueous solution of the alkali is 1 to 3 hours, for example, 2 hours.

[0079] In some embodiments, the system obtained from the first-stage reaction may be filtered and / or washed before the addition of the aqueous alkali solution. Filtration can remove insoluble salts or solid impurities, reducing their impact on subsequent hydrolysis reactions and product quality.

[0080] In some embodiments, the preparation method of compound 2 further includes a post-treatment step. The post-treatment step includes: after the reaction is complete, removing the alcohol solvent from the reaction system, adding water, performing a first extraction with a haloalkane solvent, separating and retaining the aqueous layer; then adjusting the obtained aqueous layer to acidity, performing a second extraction with a haloalkane solvent, combining the organic layers obtained from the second extraction and removing the solvent to obtain crude compound 2. The alcohol solvent can be ethanol; the haloalkane solvent can be dichloromethane; the acidity condition can be adjusting the pH of the aqueous layer to 1-3, and further to approximately 2; the acid used to adjust the pH can be hydrochloric acid, for example, 1 mol / L hydrochloric acid.

[0081] The first and second extractions serve different purposes. The first extraction is conducted under unacidified aqueous conditions, where compound 2 is primarily retained in the aqueous layer as a salt. Neutral or weakly polar organic impurities are more easily removed by halogenated alkane solvents; therefore, this step is mainly for pre-removal of impurities. The second extraction is conducted after the aqueous layer has been acidified. After acidification, compound 2 transforms from its salt form to a free acid form, increasing its partitioning ability in halogenated alkane solvents. Therefore, this step is mainly used to transfer the target compound 2 from the aqueous layer to the organic layer. Through these two extraction stages, impurity removal and target product recovery can be carried out separately, which helps reduce the residual organic impurities in the crude product.

[0082] In some embodiments, the crude compound 2 can be further purified by crystallization. The crystallization purification includes: dissolving the crude compound 2 in acetonitrile, stirring to induce crystallization at low temperature, filtering, and obtaining compound 2. The acetonitrile can be anhydrous acetonitrile; the crystallization temperature can be -10 to -30°C, preferably about -20°C; the crystallization time can be 1 to 20 hours, for example, stirring overnight; the mass-to-volume ratio of the crude compound 2 to acetonitrile can be 1:(0.2 to 10), preferably 1:(0.5 to 2), where the unit of mass-to-volume ratio is g / mL.

[0083] Acetonitrile-based low-temperature crystallization is used to further improve the purity and diastereomeric proportion of compound 2. Typically, the content of diastereomeric compound 2' (as shown below) in the crude product of compound 2 obtained is 1-10%. Under low-temperature conditions, the solubility of target compound 2 in acetonitrile decreases and it precipitates, while some impurities and diastereomeric compounds remain more in the mother liquor, thus achieving purification. Compared with the existing method of improving product quality through salt formation and subsequent dissociation, the above acetonitrile crystallization operation is more direct, and the post-processing steps are relatively simplified, which is beneficial for the scale-up preparation of compound 2.

[0084] In some embodiments, the post-treatment and purification steps of compound 2 include, in sequence: after the reaction, ethanol is evaporated, water is added, and the mixture is extracted with dichloromethane and the aqueous layer is retained; the pH of the aqueous layer is adjusted to approximately 2 using hydrochloric acid, and then extracted with dichloromethane; the organic layers are combined and concentrated under reduced pressure to obtain crude compound 2; the crude compound 2 is dissolved in anhydrous acetonitrile, stirred at approximately -20°C to induce crystallization, and filtered to obtain compound 2. In this process, the first dichloromethane extraction is used to remove non-target organic impurities, the second dichloromethane extraction after acidification is used to recover the target compound 2, and the low-temperature crystallization with acetonitrile is used to further improve the quality of compound 2.

[0085] The present invention will be described below through specific embodiments. It should be noted that these embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0086] Example 1:

[0087] Anhydrous THF (1.5 L) was added to a 3 L jacketed flask, and the mixture was cooled to 5–-5 °C. Titanium tetrachloride (TiCl4, 80.5 mL, 734.3 mmol, 2 eq.) was then injected, and the mixture was stirred at this temperature for 15 min. Next, compound 3 (50 g, 367 mmol, 1 eq.) and dibenzyl malonate (96.3 mL, 385.5 mmol, 1.05 eq.) were added to the jacketed flask, and the mixture was stirred at this temperature for 2 h. Pyridine (147.7 mL, 1.84 mol, 5 eq.) was added to the above reaction mixture, and the mixture was stirred at this temperature for 2 h, then allowed to react overnight. The reaction was quenched with 500 mL of water. After separation, the aqueous layer was extracted with n-heptane and ethyl acetate (4:1) (500 mL × 4). The organic layer was washed with saturated brine (200 mL), and the mixture was concentrated under reduced pressure to give compound 7a, a yellow oil, 145.6 g, yield 98.5%, HPLC purity 94.8%.

[0088] LCMS [M+H] + 403 [MH] - 401.

[0089] 1 H NMR (400 MHz, Chloroform- d ) δ 7.40 – 7.27 (m, 10H), 5.26 – 5.15 (m, 5H), 4.29 – 4.15 (m, 1H), 3.29 (ddd, J = 19.0, 8.5, 3.6 Hz, 1H), 2.87 (q, J = 6.8 Hz, 1H), 2.75 – 2.56 (m, 2H), 2.26 – 2.13 (m, 1H), 2.05 (q, J = 7.3 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). Example 2:

[0090] At room temperature, triethylaluminum (Et3Al, 2M n-hexane solution, 500 mL, 1.0 mol, 3 eq.) and trimethylcyanosilane (TMSCN, 374.3 mL, 3.0 mol, 9 eq.) were added to a 5 L jacketed flask and stirred at 65–75 °C for 1 h. Then, at room temperature, compound 7a (133.8 g, 333.0 mmol, 1 eq.) obtained in Example 1 was added to the above solution and stirred at 55–65 °C for 1 h. The temperature was lowered to 5–-5 °C, and saturated sodium bicarbonate solution (500 mL) was slowly added dropwise, followed by saturated sodium potassium tartrate solution (2600 mL). The mixture was stirred overnight at room temperature. After separation, the aqueous layer was extracted with n-heptane (600 ml × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (800 ml × 4). The organic layer was concentrated under reduced pressure to obtain compound 8a, a yellow oily substance, 135.0 g, yield 94.5%, HPLC purity 95.0%, diastereomer at the cyano position 4.2%, dr = 23:1.

[0091] LCMS [M+H] + 430, [MH] - 428.

[0092] 1 H NMR (400 MHz, Chloroform- d ) δ 7.39 – 7.28 (m, 10H), 5.29 – 5.16 (m, 4H), 5.13 – 5.07 (m, 1H), 3.78 – 3.63 (m, 2H), 3.14 (p, J = 7.8 Hz, 1H), 2.67 (ddd, J = 12.7, 8.7, 2.7 Hz, 1H), 2.50 (dd, J = 16.8, 7.6 Hz, 1H), 2.19 –1.94 (m, 3H), 1.78 (dd, J = 12.7, 7.8 Hz, 1H), 1.02 (t, J = 7.4 Hz, 3H). Example 3:

[0093] At room temperature, Et3Al (2M n-hexane solution, 5 mL, 9.97 mmol, 3 eq.) and TMSCN (1.25 mL, 9.97 mmol, 3 eq.) were added to 10 mL of toluene and refluxed at 110 °C for 1 h. Then, at room temperature, compound 7a (1.338 g, 3.32 mmol, 1 eq.) obtained in Example 1 and TMSCN (2.5 mL, 19.9 mmol, 6 eq.) were added sequentially to the above solution and stirred at 55–65 °C for 1 h. The temperature was lowered to 5–-5 °C, and saturated sodium bicarbonate solution (5 mL) was slowly added dropwise, followed by saturated sodium potassium tartrate solution (30 mL). The mixture was stirred overnight at room temperature. After separation, the aqueous layer was extracted with n-heptane and ethyl acetate (4:1) (10 ml × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (10 ml × 4). The organic layer was concentrated under reduced pressure to give compound 8a, a yellow oily substance, 1.22 g, yield 85.4%, HPLC purity 94.0%, diastereomer 4.4%, dr = 21:1.

[0094] Example 4:

[0095] Compound 8a (12.4 g, 28.9 mmol, 1 eq.) obtained in Example 2 was dissolved in anhydrous ethanol (37 ml). A potassium hydroxide ethanol solution (0.5 M, 57.8 ml, 28.9 mmol, 1 eq.) was added to the solution in an oil bath at 100–110 °C, and the reaction was carried out for 7 h at this temperature. The insoluble residue was filtered off, and the filter residue was washed with anhydrous ethanol (40 ml). An aqueous potassium hydroxide solution (1 M, 28.9 ml, 28.9 mmol, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0096] After evaporating the ethanol, the mixture was extracted with DCM (50 ml × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (80 ml × 3). The organic layers were combined and concentrated under reduced pressure to obtain 6.1 g of an oily substance with an HPLC purity of 91.8%, diastereomers of 3.8%, and dr = 24:1. The oily substance (6.1 g) was dissolved in 5 ml of anhydrous acetonitrile, stirred overnight at -20 °C, and filtered to obtain 4.64 g of white crystals, with a yield of 78.3%, an HPLC purity of 99.1%, diastereomers of 0.33%, and dr = 300:1.

[0097] LCMS [MH] - 204.

[0098] 1 H NMR (400 MHz, Chloroform- d) δ 8.63 (brs, 1H) 5.27 (s, 1H), 3.80 –3.63 (m, 1H), 3.14 (p, J = 7.7 Hz, 1H), 2.80 – 2.69 (m, 1H), 2.67 (d, J = 2.1Hz, 2H), 2.52 (dd, J = 16.8, 7.7 Hz, 1H), 2.14 (d, J = 7.5 Hz, 2H), 2.05 (d, J =16.9 Hz, 1H), 1.73 (dd, J = 12.6, 7.7 Hz, 1H), 1.08 (t, J = 7.5 Hz, 3H). Note: The proton NMR data of the obtained key intermediate 2 is consistent with the original patent CN104755456B.

[0099] Example 5:

[0100] Solid potassium hydroxide (KOH, 1.62 g, 28.87 mmol, 1 eq.) was added to 95 mL of ethanol. After the KOH was completely dissolved, compound 8a (12.4 g, 28.9 mmol, 1 eq.) prepared by scale-up method according to Example 3 was added, and the mixture was refluxed at 85–95 °C for 7 h. A KOH aqueous solution (1 M, 28.9 mL, 28.9 mmol, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0101] After evaporating the ethanol, the mixture was extracted with DCM (50 ml × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (80 ml × 3). The organic layers were combined and concentrated under reduced pressure to obtain 6.4 g of an oily substance with an HPLC purity of 92.1%, diastereomers of 3.5%, and dr = 26:1. The oily substance (6.4 g) was dissolved in 5 ml of anhydrous acetonitrile, stirred overnight at -20 °C, and filtered to obtain 4.8 g of white crystals with a yield of 81.0%, an HPLC purity of 99.3%, diastereomers of 0.31%, and dr = 290:1.

[0102] Example 6:

[0103] Solid potassium hydroxide (KOH, 3.24 g, 57.8 mmol, 1 eq.) was added to a mixture of 1,4-dioxane and water (4:1, 190 ml). After the KOH was completely dissolved, compound 8a (24.8 g, 57.8 mmol, 1 eq.) was added, and the mixture was refluxed at 85–95 °C for 7 h. A KOH aqueous solution (1 M, 57.8 ml, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0104] After evaporation to remove 1,4-dioxane, the mixture was extracted with DCM (100 ml × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (160 ml × 3). The organic layers were combined and concentrated under reduced pressure to obtain 9.8 g of an oily substance with an HPLC purity of 83.9%, diastereomers 7.6%, and dr = 11:1. This oily substance (1 g) was dissolved in 1 ml of anhydrous acetonitrile, stirred overnight at -20 °C, and filtered to obtain 0.76 g of white crystals with a purification yield of 76.0%, an HPLC purity of 98.8%, diastereomers 0.35%, and dr = 282:1.

[0105] Example 7: The above-mentioned oily substance was prepared according to Example 6. The oily substance (4.0 g) was left at room temperature for 15 days to obtain oily substance B (4.0 g), with a purity reduced to 52.0%, diastereomers 7.4%, and dr=7:1. Oily substance B (1 g) was dissolved in 1 ml of anhydrous acetonitrile, then stirred overnight at -20°C, and filtered to obtain 0.42 g of white crystals, with a purification yield of 42.0%, HPLC purity of 88.9%, diastereomers 1.1%, and dr=81:1.

[0106] Example 8:

[0107] Anhydrous THF (2 L) was added to a 5 L jacketed flask, and the mixture was cooled to 5–-5 °C. TiCl4 (160 mL, 1.468 mol, 2 eq.) was then injected, and the mixture was stirred at this temperature for 15 min. Compound 3 (100 g, 0.734 mol, 1 eq.) and compound 11 (177.8 g, 0.807 mol, 1.1 eq.) were then added to the jacketed flask, and the mixture was stirred at this temperature for 2 h. Pyridine (236 mL, 2.937 mol, 4 eq.) was added to the above reaction mixture, and the mixture was stirred at this temperature for 2 h, then allowed to react overnight. The reaction was quenched with 1 L of water. After separation, the aqueous layer was extracted with n-heptane and ethyl acetate (4:1) (1 L × 4). The organic layer was washed with saturated brine (400 mL), and concentrated under reduced pressure to obtain compound 7b, a yellow oil, 248.4 g, 100% yield, HPLC purity 93.4%.

[0108] 1 H NMR (400 MHz, Chloroform- d ) δ 5.43 – 5.32 (m, 1H), 4.39 – 4.18 (m,5H), 3.68 – 3.53 (m, 4H), 3.40 – 3.27 (m, 7H), 2.89 (q, J = 6.7 Hz, 1H), 2.78– 2.60 (m, 2H), 2.21 (ddd, J = 16.6, 3.9Hz, 1H), 2.09 (q, J = 7.5 Hz, 2H), 1.06(t, J = 7.4 Hz, 3H). Example 9:

[0109] At room temperature, Et3Al (2M n-hexane solution, 1L, 2mol, 3eq.) and TMSCN (748.6ml, 6mol, 9eq.) were added to a 5L jacketed flask and stirred at 65–75°C for 1 h. Then, at room temperature, compound 7b (225g, 666mmol, 1eq.) obtained in Example 8 was added to the above solution and stirred at 55–65°C for 1 h. The temperature was lowered to 5–-5°C, and saturated sodium bicarbonate solution (1L) was slowly added dropwise. Then, the reaction mixture was added to saturated potassium sodium tartrate solution (5.2L) and stirred overnight at room temperature. After separation, the aqueous layer was extracted with n-heptane (1.2 L × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (1.6 L × 4). The organic layer was concentrated under reduced pressure to give compound 8b, a yellow oily substance, 237.5 g, yield 97.7%, HPLC purity 95.2%, diastereomers 3.9%, dr = 24:1.

[0110] 1 H NMR (400 MHz, Chloroform- d ) δ 5.26 (d, J = 2.0 Hz, 1H), 4.42 – 4.23(m, 4H), 3.79 – 3.68 (m, 2H), 3.65 – 3.52 (m, 4H), 3.36 (d, J = 0.7 Hz, 6H), 3.15 (p, J = 7.7 Hz, 1H), 2.72 (ddd, J= 12.7, 8.7, 2.8 Hz, 1H), 2.58 – 2.46(m, 1H), 2.20 – 1.99 (m, 3H), 1.81 (dd, J = 12.8, 7.9 Hz, 1H), 1.07 (t, J = 7.4Hz, 3H). Example 10:

[0111] Solid potassium hydroxide (KOH, 30 g, 534.9 mmol, 1.1 eq.) was added to 1.6 L of ethanol. After the KOH was completely dissolved, compound 8b (177.7 g, 486.3 mmol, 1 eq.) obtained in Example 9 was added, and the mixture was refluxed at 85–95 °C for 7.5 h. An aqueous solution of KOH (1 M, 486.3 ml, 486.3 mmol, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0112] After evaporating the ethanol, 500 ml of water was added, and the mixture was extracted with DCM (1 L × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (1 L × 3). The organic layers were combined and concentrated under reduced pressure to obtain 93.2 g of an oily substance with an HPLC purity of 91.5%, diastereomers of 3.2%, and dr = 28:1. The oily substance (93.2 g) was dissolved in 200 ml of anhydrous acetonitrile, stirred overnight at -20 °C, and filtered to obtain 74.5 g of white crystals (compound 2) with a crystallization yield of 80.0%, an HPLC purity of 99.0%, diastereomers of 0.48%, and dr = 206:1.

[0113] Compound 2 prepared in this embodiment: LCMS[MH]-204.

[0114] The compound 2 prepared in this embodiment has the same retention time on HPLC as the compound 2 prepared in Example 4.

[0115] Comparative Example 1: The oily substance (1g) obtained in Example 6 was dissolved in 18ml of anhydrous acetonitrile, and then R-(+)-1-phenylethylamine (0.31ml) was added. The mixture was stirred overnight at room temperature and filtered to obtain 0.47g of white crystals. The salt yield was 29.5%, the HPLC purity was 85.9%, the diastereomer was 0.95%, and the dr=90:1.

[0116] Comparative Example 2: The oily substance (1g) obtained in Example 6 was dissolved in 10ml of toluene, and then benzylamine (0.53ml) was added. The mixture was stirred overnight at room temperature, and no solid precipitated.

[0117] Comparative Example 3: The oily substance B (1g) obtained in Example 7 was dissolved in 5ml of anhydrous acetonitrile, and then R-(+)-1-phenylethylamine (0.62ml) was added. The mixture was stirred overnight at room temperature and filtered to obtain 0.45g of white solid. The salt yield was 28.4%, the HPLC purity was 70.1%, the diastereomer was 2.5%, and the dr=28:1.

[0118] Comparative Example 4: The oily substance B (1g) obtained in Example 7 was dissolved in 5ml of toluene, and then benzylamine (0.52ml) was added. The mixture was stirred overnight at room temperature, and no solid precipitated.

[0119] Comparative Example 5: The oily substance (1g) obtained in Example 6 was dissolved in a mixed solution of anhydrous acetonitrile and water (4:1, 1ml), and then stirred overnight at -20°C. No solid precipitated.

[0120] Comparative Example 6: The oily substance (1g) obtained in Example 6 was dissolved in 1ml of isopropanol and then stirred overnight at -20°C. No solid precipitated.

[0121] Comparative Example 7:

[0122] At room temperature, triethylaluminum (Et3Al, 2M n-hexane solution, 5 mL, 10 mmol, 3 eq.) and trimethylcyanosilane (TMSCN, 3.75 mL, 30 mmol, 9 eq.) were added to a Schlenk tube and stirred at 65–75 °C for 1 h. Then, at room temperature, compound 4 (0.925 g, 3.33 mmol, 1 eq.) was added to the above solution and stirred at 55–65 °C for 1 h. The mixture was cooled to 5–-5 °C, and saturated sodium bicarbonate solution (5 mL) was slowly added dropwise, followed by saturated sodium potassium tartrate solution (26 mL). The mixture was stirred overnight at room temperature. After separation, the aqueous layer was extracted with n-heptane (6 ml × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (10 ml × 4). The organic layer was concentrated under reduced pressure to obtain compound 5, a yellow oily substance, 0.86 g, yield 84.7%, HPLC purity 85.5%, diastereomer 11.3%, dr = 7.6:1.

[0123] Results analysis: As shown in Examples 2, 9, and Comparative Example 7, under the same type of Et3Al / TMSCN cyanation system, when compound 4 in the existing route is converted to compound 5, the HPLC purity of the resulting product is 85.5%, the diastereomeric content is 11.3%, and the dr is only 7.6:1. However, when compound 8a or 8b is prepared using compound 7a or 7b as substrates in this invention, the HPLC purity of the resulting product is approximately 95%, and the dr ratios can reach 23:1 and 24:1, respectively. These results indicate that the technical effect of this invention does not solely stem from the Nagata cyanation system itself, but is closely related to the structure of the new intermediate compound 7; by constructing compound 7 and further preparing compound 8, the diastereoselectivity of the cyano addition reaction can be improved.

[0124] As shown in Examples 6 and 7 and Comparative Examples 1-4, when R-(+)-1-phenylethylamine was used to salt the fresh crude compound 2 or the oily substance B after storage, the salt yield was only 29.5% and 28.4%, respectively, and the HPLC purity and dr value of the obtained solid were lower than those of the corresponding crude product after crystallization with anhydrous acetonitrile; when benzylamine was used, no solid precipitation was observed. These results indicate that the crude compound 2 obtained by the route of this invention is not suitable for purification using the salt-forming separation method in existing routes.

[0125] As shown in Example 6 and Comparative Examples 5 and 6, after low-temperature crystallization with anhydrous acetonitrile, the HPLC purity of the crude compound 2 obtained in Example 6 increased from 83.9% to 98.8%, the diastereomer content decreased from 7.6% to 0.35%, and the dr ratio increased from 11:1 to 282:1. Furthermore, no solid precipitation was observed when using a mixed solvent of acetonitrile and water or isopropanol as the crystallization solvent. These results indicate that anhydrous acetonitrile has a good crystallization separation effect on compound 2 and its diastereomers, and can improve the purity and dr value of compound 2 without introducing resolving amines or adding a desalting step.

[0126] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0127] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the protection scope of the present invention.

Claims

1. A method for preparing compound 8, characterized in that, The process includes the following steps: reacting compound 7 with Nagata reagent in a solvent to obtain compound 8; Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

2. The method for preparing compound 8 according to claim 1, characterized in that, The Nagata reagent is (R) 2 )2AlCN, or by R 3 CN and alkylaluminum reagents were used to prepare the solution; Among them, R 2 For Me, Et, i- Pr or i -Bu; R 3 It can be Na, K, H or TMS; The alkylaluminum reagent is EtAlCl2, Me3Al, Et3Al, or Et2AlCl.

3. The method for preparing compound 8 according to claim 1, characterized in that, R 1 It is benzyl or -CH2CH2OCH3; And / or, the solvent is an alkane solvent and / or an aromatic solvent; And / or, the molar ratio of compound 7 to Nagata reagent is 1:(1~5); And / or, the temperature of the reaction is 40~120°C; And / or, the reaction time is 0.5 to 10 hours.

4. The method for preparing compound 8 according to claim 2, characterized in that, The Nagata reagent was prepared by reacting R3CN with an alkylaluminum reagent at 65–120 °C for 0.1–5 hours. 3 The molar ratio of CN is 1:(1~5).

5. The method for preparing compound 8 according to claim 1, characterized in that, Compound 7 is prepared by a method comprising the following steps: reacting compound 3 and compound 10 in a solvent in the presence of a catalyst and a base to obtain compound 7; Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3; The catalyst is TiCl4 or TiCl3(O) i One or more of Pr and AlCl3.

6. The method for preparing compound 8 according to claim 5, characterized in that, R 1 It is benzyl or -CH2CH2OCH3; And / or, the solvent is an ether solvent or an aromatic solvent; And / or, the base is an organic base; And / or, the molar ratio of compound 3 to the catalyst is 1:(0.1~3); And / or, the molar ratio of compound 3 to compound 10 is 1:(1~1.5); And / or, the molar ratio of compound 3 to the base is 1:(2~10); And / or, the reaction temperature of compound 3 and compound 10 is -20 to 25°C; And / or, the reaction time of compound 3 and compound 10 is 2 to 24 hours.

7. A compound 8, characterized in that, Its structure is as follows: Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

8. A compound 7 for preparing compound 8 of claim 7, characterized in that, Its structure is as follows: Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

9. A method for preparing compound 2, characterized in that, Includes the following steps: Compound 8 was prepared according to the preparation method described in claim 1; In a solvent, compound 8 was reacted in the presence of a base to give compound 2; Among them, R 1 It can be benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

10. The method for preparing compound 2 according to claim 9, characterized in that, The reaction includes reacting compound 8 first with an alcoholic solution of a base, and then with an aqueous solution of a base to obtain compound 2; Wherein, the alcohol in the alcoholic solution of the alkali is one or more of methanol, ethanol and isopropanol; And / or, the concentration of the alcoholic solution of the base is 0.1~10 mol / L; And / or, the reaction temperature of compound 8 with the alcoholic solution of the base is 80~140°C; And / or, the reaction time of compound 8 with the alcoholic solution of the base is 4 to 12 hours; And / or, the concentration of the aqueous solution of the base is 0.1~10 mol / L; And / or, the reaction temperature with the aqueous solution of the base is 0~50°C; And / or, the reaction time with the aqueous solution of the base is 1 to 6 hours.

11. The method for preparing compound 2 according to claim 9, characterized in that, R 1 It is benzyl or -CH2CH2OCH3; And / or, the solvent is an alcohol solvent, a nitrile solvent, or a mixture of a nitrile solvent and water; And / or, the base is an inorganic strong base; And / or, the molar ratio of compound 8 to the base is 1:(2~10).

12. The method for preparing compound 2 according to claim 11, characterized in that, The alcohol solvent is one or more of methanol, ethanol, and isopropanol; And / or, the nitrile solvent is acetonitrile; And / or, in the mixed solvent of nitrile solvent and water, the volume ratio of nitrile solvent to water is (1~10):1; And / or, the inorganic strong base is an alkali metal hydroxide.

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