A method for preparing a pyran-substituted morpholine compound

Abstract

The application discloses a preparation method of a pyran-substituted morpholine compound. The application provides a preparation method of a compound as shown in formula I. The preparation method has low cost, high yield, and can obtain a target product with high optical purity without chiral separation, is simple and easy to implement, and has a good application prospect.

Description

Technical Field

[0001] This invention relates to a method for preparing pyran-substituted morpholine compounds. Background Technology

[0002] Hematopoietic progenitor cell kinase 1 (HPK1, also known as MAP4K1) is a member of the MAP4K family and is a serine / threonine kinase. It is mainly expressed in immune cells and plays a role in regulating immune cell function. Pyran-substituted morpholine compounds are important pharmaceutical intermediates with good in vivo metabolic data; therefore, developing a method for preparing pyran-substituted morpholine compounds is particularly important.

[0003] Among the known literature, patent WO2022237830A1 reports a class of nitrogen-containing heterocyclic compounds, of which compounds A-9, A-34, A-35, and A-38 containing the (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine fragment have good HPK1 kinase inhibitory activity. However, the chirality of this fragment in the patent is obtained by chiral resolution.

[0004] Therefore, it is particularly important to develop a simple, easy-to-implement, and inexpensive synthetic route for (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for preparing (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine, which are limited in number, costly, and have low yields. This invention provides a method for preparing (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine. This method has a high yield, can obtain the target product with high optical purity without chiral resolution, is low in cost, simple and easy to implement, and has good application prospects.

[0006] This invention provides a method for preparing (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine, which includes the following steps:

[0007] Step 1: In the presence of a basic reagent, compound IX reacts with methanol to give compound VIII;

[0008] ;

[0009] Step 2: In an organic solvent, in the presence of lanthanum chloride-lithium dichloride tetrahydrofuran and isopropyl magnesium chloride tetrahydrofuran, compound VIII reacts with compound tetrahydropyranone to give compound VII;

[0010] ;

[0011] Step 3: In trifluoroacetic acid, in the presence of triethylsilane, compound VII reacts to give compound VI;

[0012] ;

[0013] Step 4: In an organic solvent, in the presence of butyllithium, compound VI reacts with compound N-Boc morpholinone to give compound V;

[0014] ;

[0015] Step 5: In an organic solvent, in the presence of sodium borohydride and D-tartaric acid, compound V reacts to give compound IV;

[0016] ;

[0017] Step 6: In an organic solvent, in the presence of N,N-isopropylethylamine and methanesulfonic anhydride, compound IV reacts to give compound III;

[0018] ;

[0019] Step 7 includes the following two options:

[0020] Option 1 includes the following steps a and b:

[0021] Step a: In an organic solvent and in the presence of a basic reagent, compound III reacts to give compound II;

[0022] ;

[0023] Step b: In dichloromethane, in the presence of trifluoroacetic acid, compound II reacts to give compound I;

[0024] ;

[0025] Option 2: In an organic solvent, in the presence of dioxane hydrochloride and aqueous sodium hydroxide solution, compound III reacts to yield compound I;

[0026] .

[0027] In step 1, the organic solvent is methanol.

[0028] In step 1, the mass ratio of compound IX to the organic solvent is the conventional mass-volume ratio for such reactions in the art, preferably 1 g / (1-10) mL, more preferably 1 g / 5 mL.

[0029] In step 1, the alkaline reagent is a conventional alkaline reagent for this type of reaction in the art, preferably an inorganic base, and more preferably sodium hydroxide.

[0030] In step 1, the molar ratio of the alkaline reagent to compound IX is a conventional molar ratio for such reactions in the art, preferably (1-5):1, and more preferably 3:1.

[0031] In step 1, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably 65-70℃.

[0032] In step 1, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). Generally, the reaction endpoint is defined as the disappearance or cessation of the reaction raw materials or the cessation of the reaction, or the cessation of the increase of the product. The reaction time can be 1-24 hours, for example, 3-12 hours.

[0033] In step 1, the reaction includes the following steps: compound IX is dissolved in methanol, stirred until dissolved, sodium hydroxide is added, the temperature is raised, and the internal temperature is maintained at 65-70℃ while stirring; after the reaction is completed, the temperature is lowered to 0-5℃, stirred to precipitate crystals, filtered, the filter cake is washed once with cold methanol, ethyl acetate and saturated brine are added to the filter cake, and the mixture is stirred and separated; the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, and evaporated to dryness with ethyl acetate to obtain compound VIII.

[0034] In step 2, the organic solvent is conventional for this type of reaction in the art, preferably an ether solvent, and more preferably tetrahydrofuran.

[0035] In step 2, the mass ratio of compound VIII to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably 20 g / (50-150) mL, more preferably 20 g / 100 mL.

[0036] In step 2, the molar ratio of the tetrahydropyranone to compound VI is a conventional molar ratio for such reactions in the art, preferably 1.6:1.

[0037] In step 2, the molar ratio of lanthanum chloride, lithium dichloride tetrahydrofuran, and compound VIII is a conventional molar ratio for such reactions in the art, preferably 1:(5-15), and more preferably 1:10.

[0038] In step 2, the molar ratio of the isopropyl magnesium chloride tetrahydrofuran to compound VIII is a conventional molar ratio for such reactions in the art, preferably (0.5-1.5):1, more preferably 1.1:1.

[0039] In step 2, the reaction feed order is compound VIII, isopropyl magnesium chloride tetrahydrofuran, and a tetrahydrofuran solution of lanthanum chloride, lithium dichloride tetrahydrofuran / tetrahydropyranone.

[0040] In step 2, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -40 to 0°C, for example -30 ± 5°C.

[0041] In step 2, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR). Generally, the reaction endpoint is defined as when the reactants disappear or cease to react, or when the products no longer increase, for example, 0.5 hours.

[0042] In step 3, the mass ratio of compound VII to the trifluoroacetic acid is a conventional mass-volume ratio for such reactions in the art, preferably (5-15):1, and more preferably 10:1.

[0043] In step 3, the molar ratio of triethylsilane to compound VII is a conventional molar ratio for such reactions in the art, preferably (1-5):1, and more preferably 2:1.

[0044] In step 3, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably (0-25)℃, more preferably 10℃-15℃.

[0045] In step 3, the reaction is as follows: trifluoroacetic acid is added, the temperature is lowered to 10°C, triethylsilane is added with stirring, compound VII is added in batches, stirring is continued, after the reaction is completed, trifluoroacetic acid and triethylsilane are concentrated, dichloromethane is added, the pH is adjusted to 8-9 with saturated sodium carbonate solution, the liquid is separated, the aqueous phase is extracted with dichloromethane again, the organic phases are combined, the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, evaporated to dryness, n-heptane and methyl tert-butyl ether are added, the temperature is raised to 50°C, stirred, cooled to room temperature, stirring is continued, filtered, the filter cake is washed with n-heptane / MTBE, the filter cake is dried to obtain compound VI.

[0046] In step 3, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR). The reaction endpoint is generally defined as the disappearance or cessation of the reaction raw materials or the cessation of the reaction, or the cessation of the increase of the product, for example, 0.5 hours.

[0047] In step 4, the organic solvent is conventional for this type of reaction in the art, preferably an ether solvent, and more preferably tetrahydrofuran.

[0048] In step 4, the mass ratio of compound VI to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (20-50) g / L, and more preferably 40 g / L.

[0049] In step 4, the molar ratio of N-Boc morpholinone to compound VI is a conventional molar ratio for such reactions in the art, preferably (0.5-1.5):1, more preferably 1.1:1.

[0050] In step 4, the molar ratio of butyllithium to compound VI is a conventional molar ratio for such reactions in the art, preferably (0.5-1.5):1, and more preferably 1.05:1.

[0051] In step 4, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -90 to -80°C.

[0052] In step 4, the reaction is carried out as follows:

[0053] (i) Butyllithium is added to a solution of compound VI and the organic solvent to react and obtain reaction system A;

[0054] (ii) Add the solution of the compound N-Boc morpholinone and the organic solvent to the above reaction system A to carry out the reaction; preferably, dropwise addition.

[0055] In step 4, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR). Generally, the reaction endpoint is defined as when the reactants disappear or cease to react, or when the products no longer increase, for example, 0.5 hours.

[0056] In step 5, the organic solvent is conventional for this type of reaction in the art, preferably an ether solvent, and more preferably tetrahydrofuran.

[0057] In step 5, the mass ratio of compound V to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (10-40) g / L, and more preferably 20 g / L.

[0058] In step 5, the molar ratio of sodium borohydride to compound V is a conventional molar ratio for such reactions in the art, preferably (2-6):1, and more preferably 4:1.

[0059] In step 5, the molar ratio of D-tartaric acid to compound V is a conventional molar ratio for such reactions in the art, preferably (1-5):1, and more preferably 3:1.

[0060] In step 5, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -20 to 15°C, and more preferably 0°C.

[0061] In step 5, the reaction is carried out as follows:

[0062] (i) D-tartaric acid is added to the solution of sodium borohydride and the organic solvent to react and obtain reaction system A;

[0063] (ii) The compound V and the solution of the organic solvent are added to the reaction system A for reaction.

[0064] In step 5, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally defined as when the reactants disappear or cease to react, or when the products no longer increase, for example, 16 hours.

[0065] In step 6, the organic solvent is conventional for this type of reaction in the art, and preferably dichloromethane.

[0066] In step 6, the mass ratio of compound IV to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (20-60) g / L, and more preferably 40 g / L.

[0067] In step 6, the molar ratio of N,N-isopropylethylamine to compound IV is a conventional molar ratio for such reactions in the art, preferably (2-6):1, and more preferably 4:1.

[0068] In step 6, the molar ratio of methanesulfonic anhydride to compound IV is a conventional molar ratio for such reactions in the art, preferably (1-4):1, and more preferably 2:1.

[0069] In step 6, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -15 to 10°C, and more preferably 0°C.

[0070] In step 6, the reaction is carried out as follows: an organic solvent solution of methanesulfonic anhydride is added to a solution of compound IV, N,N-isopropylethylamine and the organic solvent for reaction.

[0071] In step 6, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally defined as when the reactants disappear or cease to react, or when the products no longer increase, for example, 2 hours.

[0072] In step a, the organic solvent is conventional for this type of reaction in the art, preferably an ether solvent, and more preferably tetrahydrofuran.

[0073] In step a, the mass ratio of compound III to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (25-45) g / L, more preferably 35 g / L.

[0074] In step a, the alkaline reagent is a base commonly used in such reactions in the art, preferably an inorganic base, and more preferably sodium hydroxide.

[0075] In step a, the molar ratio of the basic reagent to compound III is a conventional ratio for such reactions in the art, preferably (5-15):1, more preferably 10:1.

[0076] In step a, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -15 to 10°C, and more preferably 0°C.

[0077] In step a, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally defined as the disappearance or cessation of the reaction raw materials or the cessation of the reaction, or the cessation of the increase of the product, for example, 16 hours.

[0078] In step a, the reaction is as follows: Compound III and tetrahydrofuran are added, the temperature is lowered to 0°C, sodium hydrogen is added in batches, the temperature is raised to room temperature and stirred for 16 hours, after the reaction is completed, the temperature is lowered to 0°C, saturated ammonium chloride solution is slowly added dropwise to quench the reaction, and the mixture is extracted twice with methyl tert-butyl ether until no product is found in the aqueous phase. The organic phases are combined, washed with saturated brine, concentrated, and eluted by column chromatography using a petroleum ether / ethyl acetate system to obtain compound II.

[0079] In step b, the mass ratio of compound II to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (18-30) g / L, more preferably 24 g / L.

[0080] In step b, the mass-to-volume ratio of compound II to trifluoroacetic acid is a conventional ratio for such reactions in the art, preferably (80-150) g / L, more preferably 120 g / L.

[0081] In step b, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -15 to 10°C, and more preferably 0°C.

[0082] In step b, the progress of the reaction can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally defined as the disappearance or cessation of the reaction raw materials or the cessation of the reaction, or the cessation of the increase of the product, for example, 2 hours.

[0083] In step b, the reaction is as follows: Compound II and dichloromethane are added, the temperature is lowered to 0°C, trifluoroacetic acid is slowly added dropwise, and stirring is continued for 2 hours. After the reaction is completed, most of the solvent is removed by concentration, and the dichloromethane is distilled twice. The residue is dissolved in dichloromethane, and the pH is adjusted to alkaline with 5% sodium bicarbonate solution under water bath conditions. The liquid phase is separated, and the aqueous phase is extracted with dichloromethane again. The organic phases are combined, washed with saturated brine, dried, filtered, and concentrated to obtain compound I.

[0084] In the second embodiment, the organic solvent is conventional for this type of reaction in the art, preferably an ether solvent or an alcohol solvent, and more preferably dioxane or methanol.

[0085] In the second embodiment, the mass ratio of compound III to the organic solvent is a conventional mass-volume ratio for such reactions in the art, preferably (50-150) g / L, and more preferably 100 g / L.

[0086] In the second embodiment, the mass-to-volume ratio of the sodium hydroxide aqueous solution is a conventional ratio for such reactions in the art, preferably (150-250) g / L, and more preferably 200 g / L.

[0087] In the second embodiment, the mass-to-volume ratio of compound III to the sodium hydroxide aqueous solution is a conventional ratio for such reactions in the art, preferably (150-250) g / L, and more preferably 200 g / L.

[0088] In the second embodiment, the reaction temperature is the conventional temperature for this type of reaction in the art, preferably -15-25℃, and more preferably 0-10℃.

[0089] In the second scheme, the progress of the reaction can be detected using conventional monitoring methods in the art (such as TLC, HPLC or NMR). Generally, the reaction endpoint is taken as when the reactants disappear or stop reacting, or when the products no longer increase, for example, 16 hours.

[0090] In Scheme 2, the reaction is carried out as follows: Compound III and 4M dioxane hydrochloride solution are added, the temperature is lowered to 0-10℃, and the mixture is stirred for 2 hours. After the reaction is completed, the dioxane hydrochloride is removed by concentration, methanol is added, the temperature is lowered to 0-10℃, and an aqueous solution of sodium hydroxide is slowly added dropwise. After the addition is completed, the mixture is raised to room temperature and stirred for 16 hours. The mixture is filtered, the wet product is washed with water, and dried to obtain Compound I.

[0091] The reaction also includes a post-processing step, which is a conventional post-processing method for this type of compound in the art, such as quenching with water, quenching with acid or alkali, adjusting the pH of the reaction solution, extraction with organic solvent or concentration under reduced pressure.

[0092] The reaction process includes a purification step, which is a conventional purification method for this type of compound in the art, such as column chromatography or preparative plate separation.

[0093] The present invention also provides a compound as shown in Formula VIII or a salt thereof;

[0094] .

[0095] The present invention also provides a method for preparing a compound as shown in Formula VIII, comprising the following steps: reacting compound IX in an organic solvent in the presence of a basic reagent to obtain compound VIII;

[0096] ;

[0097] The preparation conditions of the compound as shown in Formula VIII are as described in any embodiment of the present invention.

[0098] The present invention also provides a compound as shown in Formula VII or a salt thereof;

[0099] .

[0100] The present invention also provides a method for preparing a compound as shown in formula VII, comprising the following steps: in an organic solvent, in the presence of lanthanum chloride-lithium dichloride tetrahydrofuran and isopropyl magnesium chloride tetrahydrofuran, reacting compound VIII with compound tetrahydropyranone to obtain compound VII;

[0101] ;

[0102] The preparation conditions of the method for preparing the compound as shown in Formula VII are as described in any embodiment of the present invention.

[0103] Preferably, the method for preparing the compound as shown in Formula VII further includes the preparation of compound VIII; the preparation conditions of compound VIII are as described in any embodiment of the present invention.

[0104] The present invention also provides a compound as shown in Formula VI or a salt thereof;

[0105] .

[0106] The present invention also provides a method for preparing a compound as shown in Formula VI, comprising the following steps: reacting compound VII in trifluoroacetic acid in the presence of triethylsilane to obtain compound VI;

[0107] ;

[0108] The preparation conditions of the method for preparing the compound as shown in Formula VI are as described in any embodiment of the present invention.

[0109] Preferably, the method for preparing the compound as shown in Formula VI further includes the preparation of compound VII; the preparation conditions of compound VII are as described in any embodiment of the present invention.

[0110] The present invention also provides a compound as shown in Formula V or a salt thereof;

[0111] .

[0112] The present invention also provides a method for preparing a compound as shown in formula V, comprising the following steps: reacting compound VI and compound N-Boc morpholinone in an organic solvent in the presence of butyllithium to obtain compound V;

[0113] ;

[0114] The preparation conditions of the compound as shown in Formula V are as described in any embodiment of the present invention.

[0115] Preferably, the method for preparing the compound as shown in Formula V further includes the preparation of compound VI; the preparation conditions of compound VI are as described in any embodiment of the present invention.

[0116] The present invention also provides a compound as shown in Formula IV or a salt thereof;

[0117] .

[0118] The present invention also provides a method for preparing a compound as shown in Formula IV, comprising the following steps: in an organic solvent, in the presence of sodium borohydride and D-tartaric acid, compound V reacts to obtain compound IV;

[0119] ;

[0120] The preparation conditions of the compound as shown in Formula IV are as described in any embodiment of the present invention.

[0121] Preferably, the method for preparing the compound as shown in Formula IV further includes the preparation of compound V; the preparation conditions of compound V are as described in any embodiment of the present invention.

[0122] The present invention also provides a compound as shown in Formula III or a salt thereof;

[0123] .

[0124] The present invention also provides a method for preparing a compound as shown in Formula III, comprising the following steps: reacting compound IV in an organic solvent in the presence of N,N-isopropylethylamine and methanesulfonic anhydride to obtain compound III;

[0125] ;

[0126] The preparation conditions of the method for preparing the compound as shown in Formula III are as described in any embodiment of the present invention.

[0127] Preferably, the method for preparing the compound as shown in Formula III further includes the preparation of compound IV; the preparation conditions of compound IV are as described in any embodiment of the present invention.

[0128] The present invention also provides a compound as shown in Formula II or a salt thereof;

[0129] .

[0130] The present invention also provides a method for preparing a compound as shown in Formula II, comprising the following steps: in an organic solvent, in the presence of a basic reagent, compound III undergoes a cyclization reaction to obtain compound II;

[0131] ;

[0132] The preparation conditions of the compound as shown in Formula II are as described in any embodiment of the present invention.

[0133] Preferably, the method for preparing the compound as shown in Formula II further includes the preparation of compound III; the preparation conditions of compound III are as described in any embodiment of the present invention.

[0134] The present invention also provides a compound as shown in Formula I or a salt thereof;

[0135] .

[0136] The present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: reacting compound II in dichloromethane in the presence of trifluoroacetic acid to obtain compound I;

[0137] ;

[0138] The preparation conditions of the method for preparing the compound as shown in Formula I are as described in any embodiment of the present invention.

[0139] Preferably, the method for preparing the compound as shown in Formula I further includes the preparation of compound II; the preparation conditions of compound II are as described in any embodiment of the present invention.

[0140] The present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: in an organic solvent, in the presence of dioxane hydrochloride and an aqueous sodium hydroxide solution, compound III reacts to obtain compound I;

[0141] ;

[0142] The preparation conditions of the method for preparing the compound as shown in Formula I are as described in any embodiment of the present invention.

[0143] Preferably, the method for preparing the compound as shown in Formula I further includes the preparation of compound III; the preparation conditions of compound III are as described in any embodiment of the present invention.

[0144] The reagents and raw materials used in this invention are all commercially available.

[0145] The positive and progressive effects of this invention are as follows: the method for synthesizing compound (R)-3-(5-chloro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine provided by this invention is low in cost, high in yield, simple and easy to implement, and has good application prospects. Detailed Implementation

[0146] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0147]

[0148] Example 1

[0149]

[0150] Add 10g of compound IX and 50mL of methanol to the reaction flask, stir until dissolved, add 3.58g of sodium hydroxide, heat to 65-70℃ and stir overnight. Take a sample to test until the reaction is complete.

[0151] After the reaction was complete, the temperature was lowered to 0-5℃, and the mixture was stirred to induce crystallization for 1 hour. The mixture was then filtered, and the filter cake was washed once with 10 mL of cold methanol. 50 mL of ethyl acetate and 50 mL of saturated brine were added to the filter cake, and the mixture was stirred and separated. The organic phase was washed once with 50 mL of saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated to dryness to give 9.2 g of compound VIII as a white solid with a purity of 99% and a yield of 89%. 1 H NMR, CDCl3, 7.34-7.33(m, 1H), 6.75(d, 1H), 3.92(s, 3H)).

[0152] Example 2

[0153]

[0154] Add 18.68 g of tetrahydropyranone to the reaction flask, cool to 0 °C, and slowly add 20.73 mL of 0.6 M lanthanum chloride-lithium dichloride tetrahydrofuran solution for later use.

[0155] Add 40g of compound VIII and 200mL of tetrahydrofuran to the reaction flask, stir until dissolved, cool to -30℃, and slowly add 68.41mL of 2M isopropyl magnesium chloride tetrahydrofuran solution. Take a sample to detect the reaction until it is complete. Raise the temperature to -5~0℃, and slowly add the prepared lanthanum chloride-lithium dichloride / tetrahydropyranone tetrahydrofuran solution. Continue stirring for 10min, and take a sample to detect the reaction until it is complete.

[0156] After the reaction was complete, the reaction solution was quenched dropwise in 100 mL of 0℃ water, then the pH was adjusted to 6-7 with 20% acetic acid aqueous solution. Ethyl acetate was added for extraction twice (100 mL × 2). The combined organic phases were washed twice with brine (100 mL × 2), dried over anhydrous sodium sulfate, and then evaporated to dryness. 120 mL of n-heptane and 12 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 12 h. The mixture was filtered, and the filter cake was washed once with 40 mL of n-heptane / ethyl acetate = 10 / 1. The filter cake was dried to give 25.8 g of compound VII, a white solid with a purity of 90.3% and a yield of 70%. 1H NMR, CDCl3, 7.344-7.339(d, 1H), 6.943- 6.938(d, 1H), 4.239(s, 1H), 4.070-4.007(m, 2H), 3.928(s, 3H), 3.884-3.856(dd, 2H), 2.882-2.804(td, 2H),1.903-1.971(d, 2H)).

[0157] Example 3

[0158]

[0159] Add 213.0 g of trifluoroacetic acid to the reaction flask, cool to 10 °C, and add 14.46 g of triethylsilane while stirring. Divide the mixture into 20 g portions of compound VII. Continue stirring for 30 min, and take a sample to test until the reaction is complete.

[0160] After the reaction was complete, most of the trifluoroacetic acid and triethylsilane were concentrated. 100 mL of dichloromethane was added, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The mixture was separated, and the aqueous phase was extracted once more with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. 50 mL of n-heptane and 10 mL of methyl tert-butyl ether were added, and the mixture was heated to 50 °C and stirred for 4 h. The mixture was then cooled to room temperature and stirred for another 2 h. The mixture was filtered, and the filter cake was washed once with n-heptane / MTBE = 5 / 1. The filter cake was dried to give 23.7 g of compound VI, a white solid with a purity of 92.04% and a yield of 83%. 1 H NMR, CDCl3, 7.244-7.216(d, 1H),6.855-6.837(d, 1H), 4.111-4.071(dd, 2H), 3.861(s, 3H), 3.571-3.507(m, 3H),2.548-2.465(m, 2H), 1.498-1.462(dd, 2H)).

[0161] Example 4

[0162]

[0163] Add 20.0 g of compound VI and 250 ml of tetrahydrofuran to the reaction flask, cool to -90 to -85°C, slowly add 27.5 ml of 2.5 M butyllithium, continue stirring for 20 min, and take a sample to detect the reaction until complete. Then slowly add 14.5 g of a tetrahydrofuran solution of N-Boc morpholinone (15 ml), and continue stirring for 20 min. Take a sample to detect the reaction until complete.

[0164] After the reaction was complete, a saturated ammonium chloride solution was added dropwise to quench the reaction mixture. The temperature was raised to room temperature, and the mixture was extracted with ethyl acetate and water until no product was found in the aqueous phase. The organic phases were combined, washed twice with saturated brine, concentrated, and 20 mL of dichloromethane was added. Crystallization occurred at room temperature with stirring. A solid precipitated, and 100 mL of n-heptane was added dropwise. The temperature was lowered to 0 °C, and stirring was continued for 30 min. The mixture was filtered, and the filter cake was washed with a 1 / 5 mixture of dichloromethane and n-heptane to give 18.0 g of compound V as a white solid, with a yield of 64.3%. 1 H NMRCDCl3, 6.950-6.945 (d, 1H), 6.832-6.827 (d, 1H), 4.457 (s, 2H), 4.041-4.001(m, 2H), 3.863 (s, 3H), 3.663-3.637 (m, 2H), 3.452-3.373 (m, 4H), 2.874-2.844(m, 1H), 2.473-2.430 (m, 2H), 1.46 (s, 11H)).

[0165] Example 5

[0166]

[0167] 707 mg of sodium borohydride and 40 ml of tetrahydrofuran were added to the reaction flask. 2.1 g of D-tartaric acid was added in portions at room temperature, resulting in the generation of numerous bubbles. After the addition was complete, the mixture was heated to reflux and reacted for 4 hours. The temperature was then lowered to 0°C, and 2.0 g of a tetrahydrofuran solution (5 ml) of compound V was slowly added dropwise. Stirring was continued for 16 hours, and samples were taken to analyze the reaction until it was complete.

[0168] After the reaction was complete, 20 mL of methyl tert-butyl ether was added, and the reaction was quenched by slow dropwise addition of saturated ammonium chloride solution at 0 °C. The mixture was separated, and the aqueous phase was extracted again with methyl tert-butyl ether until no product was obtained. The organic phases were combined. The organic phases were washed with saturated sodium bicarbonate solution and brine, respectively, concentrated, and then 10 mL of methyl tert-butyl ether and 5 mL of n-heptane were added. The mixture was heated to 65 °C to dissolve the product, stirred for 30 min, slowly cooled to room temperature, filtered, and the filter cake was washed with a 1 / 2 mixture of MTBE and n-heptane to give 1.66 g of compound IV as a white solid, yield 83%, ee value 100%, MS: m / z = 430.20, [M+H] + .

[0169] Example 6

[0170]

[0171] Add 800 mg of compound IV, 20 ml of dichloromethane and 962 mg of N,N-isopropylethylamine to the reaction flask, cool to 0 °C, slowly add 648 mg of dichloromethane solution of methanesulfonic anhydride, continue stirring for 2 h, and take a sample to detect the reaction until it is complete.

[0172] After the reaction was complete, water was slowly added dropwise to quench the reaction mixture. The mixture was separated, and the aqueous phase was extracted with dichloromethane until no product was obtained. The organic phases were combined. The organic phase was washed with saturated brine, concentrated, and subjected to column chromatography: gradient elution with petroleum ether / ethyl acetate gave 700 mg of compound III as a white frothy substance, with a yield of 74%. 1 H NMR, CDCl3, 7.045-7.040 (d, 1H), 6.862-6.857 (d, 1H), 6.041-6.027 (d, 1H), 4.91 (br. s., 1H), 4.093 - 4.049(m, 2H), 3.834 (s, 3H), 3.603-3.577 (m, 1H), 3.556-3.494 (m, 6H), 3.339-3.326(d, 2H), 2.968 (s, 3H), 1.463-1.452 (m, 11H), 1.334-1.240 (m, 2H)).

[0173] Example 7

[0174]

[0175] Add 700 mg of compound III and 20 ml of tetrahydrofuran to the reaction flask, cool to 0 °C, add 331 mg of sodium hydrogen in portions, heat to room temperature and stir for 16 h, and take a sample to detect the reaction until it is complete.

[0176] After the reaction was complete, the temperature was lowered to 0°C, and the reaction solution was quenched by slow dropwise addition of saturated ammonium chloride solution. The mixture was extracted twice with methyl tert-butyl ether until no product was observed in the aqueous phase. The organic phases were combined. The organic phase was washed with saturated brine, concentrated, and subjected to column chromatography: elution with petroleum ether / ethyl acetate gave 160 mg of compound II as a white solid, yield 27.7%, MS: m / z = 412.18, [M+H]. + .

[0177] Example 8

[0178]

[0179] Add 60 mg of compound II and 2.5 ml of dichloromethane to the reaction flask, cool to 0°C, slowly add 0.5 ml of trifluoroacetic acid, continue stirring for 2 hours, and take a sample to detect the reaction until it is complete.

[0180] After the reaction was complete, most of the solvent was removed by concentration. The dichloromethane was distilled twice, and the residue was dissolved in 10 ml of dichloromethane. The pH was adjusted to alkaline with 5% sodium bicarbonate solution under water bath conditions. The mixture was separated, and the aqueous phase was extracted again with dichloromethane. The combined organic phases were washed with saturated brine. The organic phase was dried, filtered, and concentrated to give 25 mg of compound I as a pale yellow solid, with a yield of 55%. 1 H NMR,CDCl3, 7.382 (d, 1H), 6.834-6.830 (d, 1H), 4.261 (d, 1H), 4.116-4.078 (dd,2H), 3.911-3.07 (m, 1H), 3.851 (s, 3H), 3.755-3.748 (m, 2H), 3.692-3.686 (m,2H), 3.542 (t, 1H), 3.221-3.213 (td, 2H), 3.092-3.063 (m, 1H), 2.576-2.549(d, 2H), 1.456-1.298 (m, 2H)).

[0181] Example 9

[0182]

[0183] Add 200 mg of compound III and 2 ml of 4M dioxane hydrochloride solution to the reaction flask, cool to 0-10℃, stir for 2 h, and take a sample to detect the reaction until it is complete.

[0184] After the reaction was complete, the dioxane hydrochloride was removed by concentration. 2 ml of methanol was added, and the temperature was lowered to 0-10°C. A 1 ml solution of 200 mg sodium hydroxide was slowly added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 16 hours. A sample was taken to check for complete reaction. The mixture was filtered, the wet product was washed with water, and dried to give 36 mg of compound I as a white solid, with a yield of 29%. 1 H NMR, CDCl3, 7.382 (d, 1H),6.834-6.830 (d, 1H), 4.261 (d, 1H), 4.116-4.078 (dd, 2H), 3.911-3.07 (m, 1H),3.851 (s, 3H), 3.755-3.748 (m, 2H), 3.692-3.686 (m, 2H), 3.542 (t, 1H), 3.221-3.213 (td, 2H), 3.092-3.063 (m, 1H), 2.576-2.549 (d, 2H), 1.456-1.298(m, 2H)).

Claims

1. A method for preparing a compound as shown in Formula I, characterized in that, It includes the following steps: Step 1: In the presence of a basic reagent, compound IX reacts with methanol to give compound VIII; ； Step 2: In an organic solvent, in the presence of lanthanum chloride-lithium dichloride tetrahydrofuran and isopropyl magnesium chloride tetrahydrofuran, compound VIII reacts with compound tetrahydropyranone to give compound VII; ； Step 3: In trifluoroacetic acid, in the presence of triethylsilane, compound VII reacts to give compound VI; ； Step 4: In an organic solvent, in the presence of butyllithium, compound VI reacts with compound N-Boc morpholinone to give compound V; ； Step 5: In an organic solvent, in the presence of sodium borohydride and D-tartaric acid, compound V reacts to give compound IV; ； Step 6: In an organic solvent, in the presence of N,N-isopropylethylamine and methanesulfonic anhydride, compound IV reacts to give compound III; ； Step 7 includes the following two options: Option 1 includes the following steps a and b: Step a: In an organic solvent and in the presence of a basic reagent, compound III reacts to give compound II; ； Step b: In dichloromethane, in the presence of trifluoroacetic acid, compound II reacts to give compound I; ； Option 2: In an organic solvent, in the presence of dioxane hydrochloride and aqueous sodium hydroxide solution, compound III reacts to yield compound I; 。 2. The preparation method according to claim 1, characterized in that, In step 1, one or more of the following conditions are satisfied: (1) The mass-to-volume ratio of compound IX to the methanol is 1 g / (1-10) mL; (2) The alkaline reagent is an inorganic base; (3) The molar ratio of the alkaline reagent to compound IX is (1-5):1; (4) The reaction temperature is 65-70℃; (5) The reaction time is 1-24 hours; (6) The reaction is carried out in the following steps: Compound IX is dissolved in methanol, stirred until dissolved, sodium hydroxide is added, the temperature is raised and kept at 65-70℃ while stirring; after the reaction is completed, the temperature is lowered to 0-5℃, stirred to precipitate crystals, filtered, the filter cake is washed once with cold methanol, ethyl acetate and saturated brine are added to the filter cake, and the mixture is stirred and separated; the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, and evaporated to dryness with ethyl acetate to obtain compound VIII.

3. The preparation method according to claim 2, characterized in that, In step 1, one or more of the following conditions are satisfied: (1) The mass-to-volume ratio of compound IX to the methanol is 1 g / 5 mL; (2) The alkaline reagent is sodium hydroxide; (3) The molar ratio of the alkaline reagent to compound IX is 3:1; (4) The reaction time is 3-12 hours.

4. The preparation method according to claim 1, characterized in that, In step 2, one or more of the following conditions must be met: (1) The organic solvent is an ether solvent; (2) The mass-to-volume ratio of compound VIII to the organic solvent is 20 g / (50-150) mL; (3) The molar ratio of the tetrahydropyranone to compound VIII is 1.6:1; (4) The molar ratio of lanthanum chloride, lithium dichloride tetrahydrofuran and compound VIII is 1:(5-15); (5) The molar ratio of the isopropyl magnesium chloride tetrahydrofuran to compound VIII is (0.5-1.5):1; (6) The reaction temperature is -40 to 0℃; (7) The reaction time is 0.5 hours; (8) The reaction is carried out by the following steps: adding the tetrahydropyranone and the lanthanum chloride-lithium dichloride tetrahydrofuran solution to the solution of compound VIII and the organic solvent to carry out the reaction.

5. The preparation method according to claim 4, characterized in that, In step 2, one or more of the following conditions must be met: (1) The organic solvent is tetrahydrofuran; (2) The mass-to-volume ratio of compound VIII to the organic solvent is 20 g / 100 mL; (3) The molar ratio of lanthanum chloride, lithium dichloride tetrahydrofuran and compound VIII is 1:10; (4) The molar ratio of the isopropyl magnesium chloride tetrahydrofuran to compound VIII is 1.1:1; (5) The reaction temperature is -30±5℃; (6) The addition is done dropwise.

6. The preparation method according to claim 1, characterized in that, In step 3, one or more of the following conditions must be met: (1) The molar ratio of the triethylsilane to compound VII is (1-5):1; (2) The reaction temperature is (0-25)℃; (3) The reaction time is 0.5 hours; (4) The reaction is as follows: trifluoroacetic acid is added, the temperature is lowered to 10°C, triethylsilane is added under stirring, compound VII is added in batches, stirring is continued, after the reaction is completed, trifluoroacetic acid and triethylsilane are concentrated, dichloromethane is added, the pH is adjusted to 8-9 with saturated sodium carbonate solution, the liquid is separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, the organic phases are washed with saturated brine, dried with anhydrous sodium sulfate, evaporated, n-heptane and methyl tert-butyl ether are added, the temperature is raised to 50°C, stirred, cooled to room temperature, stirring is continued, filtered, the filter cake is washed with n-heptane / MTBE, the filter cake is dried to obtain compound VI.

7. The preparation method according to claim 6, characterized in that, In step 3, one or two of the following conditions must be met: (1) The molar ratio of the triethylsilane to compound VII is 2:1; (2) The reaction temperature is 10℃-15℃.

8. The preparation method according to claim 1, characterized in that, In step 4, one or more of the following conditions must be met: (1) The organic solvent is an ether solvent; (2) The mass-to-volume ratio of compound VI to the organic solvent is (20-50) g / L; (3) The molar ratio of N-Boc morpholinone to compound VI is (0.5-1.5):1; (4) The molar ratio of butyllithium to compound VI is (0.5-1.5):1; (5) The reaction temperature is -90 to -80°C; (6) The reaction time is 0.5 hours; (7) The reaction is carried out in the following steps: (i) Butyllithium is added to a solution of compound VI and the organic solvent to react and obtain reaction system A; (ii) The compound N-Boc morpholinone and the organic solvent are added to the above reaction system A to carry out the reaction.

9. The preparation method according to claim 8, characterized in that, In step 4, one or more of the following conditions must be met: (1) The organic solvent is tetrahydrofuran; (2) The mass-to-volume ratio of compound VI to the organic solvent is 40 g / L; (3) The molar ratio of N-Boc morpholinone to compound VI is 1.1:1; (4) The molar ratio of butyllithium to compound VI is 1.05:1; (5) The addition is done dropwise.

10. The preparation method according to claim 1, characterized in that, In step 5, one or more of the following conditions must be met: (1) The organic solvent is an ether solvent; (2) The mass-to-volume ratio of compound V to the organic solvent is (10-40) g / L; (3) The molar ratio of sodium borohydride to compound V is (2-6):1; (4) The molar ratio of D-tartaric acid to compound V is (1-5):1; (5) The reaction temperature is -20 to 15℃; (6) The reaction time is 16 hours; (7) The reaction is carried out in the following steps: (i) D-tartaric acid is added to the solution of sodium borohydride and the organic solvent to react and obtain reaction system A; (ii) The compound V and the solution of the organic solvent are added to the reaction system A for reaction.

11. The preparation method according to claim 10, characterized in that, In step 5, one or more of the following conditions must be met: (1) The organic solvent is tetrahydrofuran; (2) The mass-to-volume ratio of compound V to the organic solvent is 20 g / L; (3) The molar ratio of sodium borohydride to compound V is 4:1; (4) The molar ratio of D-tartaric acid to compound V is 3:1; (5) The reaction temperature is 0℃.

12. The preparation method according to claim 1, characterized in that, In step 6, one or more of the following conditions must be met: (1) The organic solvent is dichloromethane; (2) The mass-to-volume ratio of compound IV to the organic solvent is (20-60) g / L; (3) The molar ratio of N,N-isopropylethylamine to compound IV is (2-6):1; (4) The molar ratio of the methanesulfonic anhydride to compound IV is (1-4):1; (5) The reaction temperature is -15 to 10℃; (6) The reaction time is 2 hours; (7) The reaction is carried out by the following steps: adding an organic solvent solution of methanesulfonic anhydride to a solution of compound IV, N,N-isopropylethylamine and the organic solvent for reaction.

13. The preparation method according to claim 12, characterized in that, In step 6, one or more of the following conditions must be met: (1) The mass-to-volume ratio of compound IV to the organic solvent is 40 g / L; (2) The molar ratio of N,N-isopropylethylamine to compound IV is 4:1; (3) The molar ratio of the methanesulfonic anhydride to compound IV is 2:1; (4) The reaction temperature is 0℃.

14. The preparation method according to claim 1, characterized in that, In step a, one or more of the following conditions are satisfied: (1) The organic solvent is an ether solvent; (2) The mass-to-volume ratio of compound III to the organic solvent is (25-45) g / L; (3) The alkaline reagent is an inorganic base; (4) The molar ratio of the alkaline reagent to compound III is (5-15):1; (5) The reaction temperature is -15 to 10℃; (6) The reaction time is 16 hours; (7) The reaction is carried out in the following steps: Compound III and tetrahydrofuran are added, the temperature is lowered to 0°C, sodium hydrogen is added in batches, the temperature is raised to room temperature and stirred for 16 hours. After the reaction is completed, the temperature is lowered to 0°C, saturated ammonium chloride solution is slowly added dropwise to quench the reaction solution, and the solution is extracted twice with methyl tert-butyl ether until no product is found in the aqueous phase. The organic phases are combined, washed with saturated brine, concentrated, and column chromatography is performed: the solution is eluted with petroleum ether / ethyl acetate system to obtain compound II.

15. The preparation method according to claim 14, characterized in that, In step a, one or more of the following conditions are satisfied: (1) The organic solvent is tetrahydrofuran; (2) The mass-to-volume ratio of compound III to the organic solvent is 35 g / L; (3) The alkaline reagent is sodium hydrogen; (4) The molar ratio of the alkaline reagent to compound III is 10:1; (5) The reaction temperature is 0℃.

16. The preparation method according to claim 1, characterized in that, In step b, one or more of the following conditions are satisfied: (1) The mass-to-volume ratio of compound II to the dichloromethane is (18-30) g / L; (2) The mass-to-volume ratio of compound II to trifluoroacetic acid is (80-150) g / L; (3) The reaction temperature is -15 to 10℃; (4) The reaction time is 2 hours; (5) The reaction is carried out in the following steps: Compound II and dichloromethane are added, the temperature is lowered to 0°C, trifluoroacetic acid is slowly added dropwise, and stirring is continued for 2 hours. After the reaction is completed, most of the solvent is removed by concentration, dichloromethane is distilled twice, the residue is dissolved in dichloromethane, the pH is adjusted to alkaline with 5% sodium bicarbonate solution under water bath, the liquid is separated, the aqueous phase is extracted with dichloromethane again, the organic phases are combined, washed with saturated brine, the organic phase is dried, filtered, and concentrated to obtain compound I.

17. The preparation method according to claim 16, characterized in that, In step b, one or more of the following conditions are satisfied: (1) The mass-to-volume ratio of compound II to the dichloromethane is 24 g / L; (2) The mass-to-volume ratio of compound II to trifluoroacetic acid is 120 g / L; (3) The reaction temperature is 0℃.

18. The preparation method according to claim 1, characterized in that, In Scheme 2, one or more of the following conditions are satisfied: (1) The organic solvent is an ether solvent or an alcohol solvent; (2) The mass-to-volume ratio of compound III to the organic solvent is (50-150) g / L; (3) The mass-to-volume ratio of the sodium hydroxide aqueous solution is (150-250) g / L; (4) The mass-to-volume ratio of compound III to the aqueous sodium hydroxide solution is (150-250) g / L; (5) The reaction temperature is -15 to 25℃; (6) The reaction time is 16 hours; (7) The reaction is carried out in the following steps: add compound III and 4M dioxane hydrochloride solution, cool to 0-10℃, stir for 2h, after the reaction is completed, concentrate to remove dioxane hydrochloride, add methanol, cool to 0-10℃, slowly add sodium hydroxide aqueous solution, after the addition is completed, raise to room temperature and stir for 16 hours, filter, rinse the wet product with water, dry, and obtain compound I.

19. The preparation method according to claim 18, characterized in that, In Scheme 2, one or more of the following conditions are satisfied: (1) The organic solvent is dioxane or methanol; (2) The mass-to-volume ratio of compound III to the organic solvent is 100 g / L; (3) The mass-to-volume ratio of the sodium hydroxide aqueous solution is 200 g / L; (4) The mass-to-volume ratio of compound III to the sodium hydroxide aqueous solution is 200 g / L; (5) The reaction temperature is 0-10℃.

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