DPP1 inhibitor intermediates, methods for preparing them, and their use in pharmaceuticals

Abstract

The present invention relates to a method for preparing a compound represented by formula (I) and its intermediates. This method uses inexpensive starting materials and a multi-step telescopic reaction, is simple in terms of post-processing, achieves high yields, and produces products with high chemical and chiral purity, making it suitable for large-scale industrial production. TIFF2026522510000036.tif22170

Description

[Technical Field]

[0001] This disclosure relates to a method for preparing a compound represented by formula (I) and its intermediates. The method is characterized by low-cost reaction starting materials, a multi-step telescopic reaction, a simple work-up process, high yield, and high chemical and chiral purity of the product, making it suitable for large-scale industrial production. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a cysteine ​​protease belonging to the lysosomal papain family, involved in the degradation of intracellular proteins. During neutrophil maturation, DPP1 activates neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (Pr3), and cathepsin G (CatG), by cleaving the N-terminal dipeptide of target proteins. DPP1 has been shown to be involved in various inflammatory diseases, including Wegener's granulomatosis, rheumatoid arthritis, pulmonary inflammation, and viral infections. Studies have shown that inhibiting DPP1 has favorable therapeutic effects against neutrophil-induced, highly inflammatory lung diseases, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), and acute lung injury. Therefore, inhibiting the hyperactivation of NSPs by targeting DPP1 may have potential therapeutic effects against bronchiectasis.

[0003] WO2014 / 140075A1 and WO2016 / 016242A1 describe a group of compounds possessing DPP1 activity, and the compound represented by formula (C7) can be used as an important intermediate for synthesizing this group of products.

[0004] [ka]

[0005] WO2014 / 140075A1 discloses intermediate I-1.1, which is prepared by Route 1 using R8 and R9 as starting materials. This preparation method has several problems, mainly including the high cost of the starting materials, the need for very low reaction temperatures, low reaction conversion efficiency, the need for purification by column chromatography, and the difficulty of industrial scale-up production.

[0006] [ka]

[0007] WO2016 / 016242A1 discloses another intermediate I-5.2.1 prepared by Route 2 using R14 as the starting material, as described below. This route has several problems, mainly including the need for asymmetric reduction in the reaction, high catalyst cost and catalyst deactivation, generation of dehalogenation byproducts during the asymmetric reduction reaction, the need for purification by reverse-phase HPLC, high manufacturing costs, and difficulty in scale-up production.

[0008] [ka] [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2014 / 140075 [Patent Document 2] International Publication No. 2016 / 016242 [Overview of the project] [Problems that the invention aims to solve]

[0010] Therefore, there is a need to develop a route for preparing compound (I) characterized by mild reaction conditions, simple operation, high reaction yield, high chemical purity and chiral purity of the product, simple work-up, low cost, and suitability for industrial production.

[0011] Summary of the Invention An object of the present disclosure is to provide a method for preparing a compound represented by formula (I) and its intermediate.

Advantages of the Invention

[0012] The method of the present disclosure features low-cost reaction starting materials, multi-step telescoping reactions, simple work-up procedures, high yields, and high chemical purity and chiral purity of the products, and is suitable for large-scale industrial production.

Modes for Carrying Out the Invention

[0013] The present disclosure provides a method for preparing a compound represented by formula (I), wherein the compound represented by formula (I) is prepared from a compound of formula (II):

[0014]

Chemical formula

[0015] Here, X is a leaving group such as F, Cl, Br, I or OTf.

[0016] The method for preparing the compound represented by formula (I) provided by the present disclosure may further include: preparing a compound of formula (II-1) from a compound of formula (III); preparing a compound of formula (II) from a compound of formula (II-1); and preparing a compound represented by formula (I) from a compound of formula (II):

[0017]

Chemical formula

[0018] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0019] A method for preparing a compound represented by formula (I) provided in this disclosure may further include: preparing a compound of formula (III) from a compound of formula (IV); preparing a compound of formula (II-1) from a compound of formula (III); preparing a compound of formula (II) from a compound of formula (II-1); and preparing a compound represented by formula (I) from a compound of formula (II):

[0020] [ka]

[0021] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0022] A method for preparing a compound represented by formula (I) provided in this disclosure may further include: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); preparing a compound of formula (V-1) from a compound of formula (VI); preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2); preparing a compound of formula (III) from a compound of formula (IV); preparing a compound of formula (II-1) from a compound of formula (III); preparing a compound of formula (II) from a compound of formula (II-1); and preparing a compound represented by formula (I) from a compound of formula (II):

[0023] [ka]

[0024] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0025] This disclosure provides a method for preparing a compound represented by formula (II), wherein the compound of formula (II-1) is prepared from the compound of formula (III); and the compound of formula (II) is prepared from the compound of formula (II-1):

[0026] [ka]

[0027] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0028] A method for preparing a compound represented by formula (II) provided in this disclosure may further include: preparing a compound of formula (III) from a compound of formula (IV); preparing a compound of formula (II-1) from a compound of formula (III); and preparing a compound of formula (II) from a compound of formula (II-1):

[0029] [ka]

[0030] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0031] A method for preparing a compound represented by formula (II) provided in this disclosure may further include: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); preparing a compound of formula (V-1) from a compound of formula (VI); preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2); preparing a compound of formula (III) from a compound of formula (IV); preparing a compound of formula (II-1) from a compound of formula (III); and preparing a compound of formula (II) from a compound of formula (II-1):

[0032] [ka]

[0033] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0034] This disclosure provides a method for preparing a compound represented by formula (III), wherein the compound of formula (III) is prepared from the compound of formula (IV):

[0035] [ka]

[0036] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0037] A method for preparing a compound represented by formula (III) provided in this disclosure may further include: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); preparing a compound of formula (V-1) from a compound of formula (VI); preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2); and preparing a compound of formula (III) from a compound of formula (IV):

[0038] [ka]

[0039] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0040] This disclosure provides a method for preparing a compound represented by formula (IV), wherein the compound of formula (VI) is prepared from the compound of formula (VII-1) and the compound of formula (VII-2); the compound of formula (V-1) is prepared from the compound of formula (VI); and the compound of formula (IV) is prepared from the compound of formula (V-1) and the compound of formula (V-2):

[0041] [ka]

[0042] Here, X is a leaving group such as F, Cl, Br, I, or OTf.

[0043] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the method includes the following steps:

[0044] [ka]

[0045] Here, X is a leaving group such as F, Cl, Br, I, or OTf; a: Prepare the compound represented by formula (I) from the compound of formula (II).

[0046] In some embodiments of the method for preparing the compound of formula (I) described herein, the method may further include the following steps:

[0047] [ka]

[0048] Here, X is a leaving group such as F, Cl, Br, I, or OTf; b: Prepare the compound of formula (II-1) from the compound of formula (III); c: Prepare the compound of formula (II) from the compound of formula (II-1).

[0049] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) described herein, the methods further include the following steps:

[0050] [ka]

[0051] Here, X is a leaving group such as F, Cl, Br, I, or OTf; d: Prepare the compound of formula (III) from the compound of formula (IV).

[0052] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) described herein, the methods may further include the following steps:

[0053] [ka]

[0054] Here, X is a leaving group such as F, Cl, Br, I, or OTf. g: Prepare the compound of formula (VI) from the compound of formula (VII-1) and the compound of formula (VII-2); f: Prepare the compound of formula (V-1) from the compound of formula (VI); e: Prepare the compound of formula (IV) from the compound of formula (V-1) and the compound of formula (V-2).

[0055] In some embodiments of the method for preparing the compound of formula (I) described herein, a: A compound represented by formula (II) is reacted in the presence of an organic solvent and a base to obtain a compound represented by formula (I), where the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc)2O, or n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, or n-heptane; and the base is preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA, or DBU, even more preferably sodium bicarbonate, sodium carbonate, or sodium hydroxide, and more preferably sodium carbonate.

[0056] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the ratio of the amount of the compound represented by formula (II) to the amount of the organic solvent is 1:3 to 20, preferably 1:4 to 8.

[0057] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the reaction temperature is -10°C to 60°C, preferably 0°C to 30°C.

[0058] In some embodiments of the method for preparing the compound of formula (I) described herein, the reaction time is 10 to 48 hours, preferably 15 to 20 hours.

[0059] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the drying time is 8 to 48 hours, preferably 12 to 24 hours.

[0060] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the base addition ratio is 1:0.5 to 3.0, preferably 1:1.0 to 1.5.

[0061] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) described herein, b: A compound of formula (III) is reacted in the presence of an organic solvent and an acid to obtain a compound of formula (II-1), wherein the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol, or isopropanol, and more preferably ethanol or MTBE; the acid is preferably one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, and more preferably HCl; c: The compound of formula (II-1) is reacted in the presence of a chiral acid to obtain the compound of formula (II), where the chiral acid is preferably one or more of tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, lactic acid, diacetone-L-guronic acid, mandelic acid, or phenoxypropionic acid, and more preferably L(-)-tartaric acid.

[0062] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the equivalent amount of L(-)-tartaric acid may be selected from 0.5 to 2.0 eq, preferably 0.6 to 1.0 eq.

[0063] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the ratio of the amount of the compound represented by formula (III) to the amount of the organic solvent is 1:2.0 to 10.0, preferably 1:3 to 5.

[0064] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the reaction temperature is -10°C to 60°C, preferably 0°C to 30°C.

[0065] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) described herein, the reaction time is 3 to 12 hours, preferably 4 to 6 hours.

[0066] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the acid addition ratio is 1:1.0 to 6.0, preferably 1:2.0 to 4.0.

[0067] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) described herein, d: A compound of formula (IV) is reacted in the presence of a solvent, a cyanidating agent, and a base to obtain a compound of formula (III), wherein the solvent is preferably one or more of DCM, DMF, THF, n-heptane, ACN, toluene, or DMSO, and more preferably DCM or toluene; the cyanidating agent is preferably one or more of TMSCN, sodium cyanide, potassium cyanide, or lithium cyanide, and more preferably TMSCN; and the base is preferably one or more of CsF, KF, TBAF, Na2CO3, K3PO4, or Ti(OEt)4, more preferably CsF or KF, and even more preferably CsF.

[0068] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) according to this disclosure, the ratio of the amount of the compound represented by formula (IV) to the amount of the cyanidating reagent is 1:1.0 to 3.0, preferably 1:1.3 to 1.7.

[0069] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) described herein, the reaction temperature is -10°C to 30°C, preferably 0°C to 10°C.

[0070] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) according to this disclosure, the reaction time is 10 to 24 hours, preferably 12 to 16 hours.

[0071] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) according to this disclosure, the base is used in a ratio of 1:0.05 to 2.0, preferably 1:0.1 to 0.3.

[0072] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, g: Compound (VI) is obtained by reacting the compound of formula (VII-1) and the compound of formula (VII-2) in the presence of a base, where the base is preferably one or more of LiHMDS, NaHMDS, KHMDS, LDA, BuLi, or potassium tert-butoxide, more preferably LiHMDS, NaHMDS, or KHMDS, and even more preferably LiHMDS.

[0073] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, the equivalent amount of LiHMDS is 1.3 eq.

[0074] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the ratio of the amount of the compound represented by formula (VII-1) to the amount of the base is 1:1.0 to 3.0, preferably 1:1.2 to 1.5.

[0075] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction temperature is -10°C to 30°C, preferably 0°C to 10°C.

[0076] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction time is 1 to 10 hours, preferably 2 to 5 hours.

[0077] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, f: A compound of formula (VI) is reacted in the presence of an acid and an organic solvent to obtain a compound of formula (V-1), where the acid is preferably one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride, or trimethylchlorosilane, and more preferably TsOH; The organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol, or isopropanol, and is more preferably toluene.

[0078] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the equivalent amount of TsOH can be selected from 1.0 eq, 2.0 eq, or 4.0 eq, and is preferably 2.0 eq.

[0079] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the ratio of the amount of the compound represented by formula (VI) to the amount of the acid is 1:1.0 to 5.0, preferably 1:1.5 to 3.0.

[0080] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction temperature is 40°C to 100°C, preferably 60°C to 80°C.

[0081] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction time is 0.5 to 10 hours, preferably 1 to 5 hours.

[0082] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, the organic solvent is used in a ratio of 1:5 to 15, preferably 1:7 to 12.

[0083] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, e: Compound (IV) is obtained by reacting the compound of formula (V-1) and the compound of formula (V-2) in the presence of an organic solvent and a dehydrating agent, wherein the organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, or acetonitrile, and is preferably toluene; The dehydrating reagent is preferably one or more of anhydrous CuSO4, Zn(OAc)2, Co(OAc)2·4H2O, Na2SO4, MgSO4, Ti(Oi-Pr)4, DCC / DMAP, EDCI / DMAP, or HOAc / molecular sieve, and is preferably anhydrous CuSO4 or HOAc / molecular sieve.

[0084] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, the equivalent amount of anhydrous copper sulfate is 3.0 eq.

[0085] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described herein, the amount of acetic acid in the acetic acid / molecular sieve system is twice the volume of intermediate V-1.

[0086] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the ratio of the amount of the compound represented by formula (V-1) to the amount of the dehydrating reagent is 1:1.0 to 6.0, preferably 1:2.0 to 4.0.

[0087] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction temperature is 10°C to 80°C, preferably 30°C to 50°C.

[0088] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the reaction time is 6 to 24 hours, preferably 8 to 16 hours.

[0089] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the organic solvent is used in a ratio of 1:5 to 20, preferably 1:8 to 16.

[0090] This disclosure further provides a method for preparing a compound represented by formula (C7):

[0091] [ka]

[0092] Here, G: C2 is obtained by reacting C1 in the presence of an organic solvent and a base; f: C3 is obtained by reacting C2 in the presence of an organic solvent and an acid; e: C4 is obtained by reacting C3 in the presence of an organic solvent and a dehydrating agent; d: C5-1 is obtained by reacting C4 in the presence of a solvent, a base, and a cyanide reagent; b: C6 is obtained by reacting C5-1 in the presence of an acid; c: C6 is reacted with a base and a chiral acid to obtain C6-b; C7 is obtained by reacting a:C6-b in the presence of an organic solvent and a base.

[0093] In some embodiments of the method for preparing the compound of formula (C7) described herein, g: The organic solvent is selected from one or more of tetrahydrofuran, dichloromethane, MTBE, or n-heptane; The base is selected from one or more of LiHMDS, NaHMDS, or KHMDS, preferably LiHMDS; f: The acid is selected from one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride, or trimethylchlorosilane, preferably TsOH; The organic solvent is selected from one or more of the following: dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol, or isopropanol, preferably toluene; e: The organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, or acetonitrile, preferably toluene; and the dehydrating reagent is selected from one or more of anhydrous CuSO4, Zn(OAc)2, Co(OAc)2·4H2O, Na2SO4, MgSO4, Ti(Oi-Pr)4, DCC / DMAP, EDCI / DMAP, or HOAc / molecular sieve, preferably anhydrous CuSO4 or HOAc / molecular sieve; d: The solvent is selected from one or more of DCM, DMF, THF, n-heptane, ACN, toluene, or DMSO, preferably DCM or toluene; the cyanidating agent is selected from one or more of TMSCN, sodium cyanide, potassium cyanide, or lithium cyanide, preferably TMSCN; and the base is selected from one or more of CsF, KF, TBAF, Na2CO3, K3PO4, or Ti(OEt)4, preferably CsF or KF, and more preferably CsF; b: The organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol, or isopropanol, preferably ethanol or MTBE; and the acid is selected from one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably HCl; c: The chiral acid solvent is selected from one or more of tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, lactic acid, diacetone-L-guronic acid, mandelic acid, or phenoxypropionic acid, preferably L(-)-tartaric acid; a: The organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc)2O, or n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, or n-heptane; and the base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA, or DBU, preferably sodium carbonate.

[0094] In some embodiments of the method for preparing the compound of formula (C7) described herein, g: The organic solvent is tetrahydrofuran, and the base is LiHMDS; f: The acid is TsOH, and the organic solvent is toluene; e: The dehydrating agent is selected from anhydrous CuSO4 or HOAc / molecular sieve; d: The cyanide reagent is TMSCN, and the base is CsF; b: The organic solvent is selected from ethanol or MTBE, and the acid is HCl; c: The chiral acid solvent is L(-)-tartaric acid; a: The organic solvent is selected from one or more of dichloromethane, MTBE, (Boc)2O, or n-heptane; the base is sodium carbonate.

[0095] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the workup in step g includes purifying the crude compound of formula (VI).

[0096] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the purification of the crude product in the workup of step g includes the following steps: 1) Add n-heptane to the crude concentrate of the compound of formula (VI), stir the mixture, and filter it; 2) Add magnesium chloride to the filtrate, stir the mixture, and filter it; 3) Wash the filtrate with EDTA-Na, perform phase separation, concentrate the organic phase, add toluene to the concentrate and distill.

[0097] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the workup in step f includes purifying the crude compound of formula (V-1).

[0098] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the purification of the crude product in the workup of step f includes the following steps: The compound of formula (V-1) is obtained by washing a mixture containing the compound of formula (V-1) with NaHCO3 solution, performing phase separation, and recovering the organic phase.

[0099] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the workup in step e includes purifying the crude compound of formula (IV).

[0100] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) according to this disclosure, the purification of the crude product in the workup of step f includes the following steps: The compound of formula (IV) is obtained by washing a mixture containing the compound of formula (IV) with NaHCO3 solution and performing phase separation.

[0101] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) according to this disclosure, the workup in step d includes purifying the crude compound of formula (III).

[0102] In some embodiments of the methods for preparing the compounds of formula (I), formula (II), and formula (III) according to this disclosure, the purification of the crude product in the workup of step d includes the following steps: 1) Add a sodium carbonate solution to the compound of formula (III) and perform phase separation to obtain the organic phase; 2) A mixed solution of sodium carbonate and sodium chloride and a sodium chloride solution are sequentially added to the organic phase, phase separation is performed, and the organic phase is recovered to obtain the compound of formula (III).

[0103] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, step b includes a reaction and workup.

[0104] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the reaction in step b includes the following steps: Hydrochloric acid / ethanol is added to the compound of formula (III), and the mixture is stirred while controlling the temperature to allow it to react.

[0105] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the purification of the crude product in the workup of step b includes the following steps: The mixture is stirred and filtered, the filtered cake is washed, and the filtered cake is recovered to obtain the compound of formula (II-1).

[0106] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, step c includes a reaction and workup.

[0107] In some embodiments of the methods for preparing the compounds of formula (I) and formula (II) according to this disclosure, the reaction in step c includes the following steps: 1) React the compound of formula (II-1) in the presence of dichloromethane and sodium carbonate; 2) Perform phase separation, extract the aqueous phase with dichloromethane, and concentrate it together with the organic phase; 3) Add MeOH and L(-)-tartaric acid in methanol to the concentrate, and stir the mixture to allow it to react.

[0108] In some embodiments of the methods for preparing compounds of formula (I) and formula (II) according to this disclosure, the workup in step c includes the following steps: The compound of formula (II-1) is obtained by filtering, washing the filter cake with MTBE, and recovering the filter cake.

[0109] In some embodiments of the method for preparing the compound of formula (I) according to the present disclosure, the workup in step a includes purifying the crude compound of formula (I).

[0110] In some embodiments of the method for preparing the compound of formula (I) according to this disclosure, the purification of the crude product in the workup of step a includes the following steps: 1) Add n-heptane to the compound of formula (I), stir and heat the mixture, and concentrate it; 2) Add n-heptane, stir the mixture and filter it, and wash the filtered cake with a mixed solution of MTBE and n-heptane to obtain the wet product of the compound of formula (I); 3) By controlling the temperature and drying the wet product, the compound of formula (I) is obtained.

[0111] The method for preparing the compound represented by formula (I) provided herein offers advantages such as low-cost reaction starting materials, a multi-step telescopic reaction, a simple work-up process, high yield, high chemical and chiral purity of the product, and suitability for large-scale industrial production.

[0112] Unless otherwise stated, terms used in the specification and claims of this application have the following meanings:

[0113] In the reactions of this disclosure, the reaction process is tracked by HPLC, HNMR, or thin-layer chromatography to determine whether the reaction is complete.

[0114] In this disclosure, internal temperature refers to the temperature of the reaction system.

[0115] Detailed description of the embodiment The technical solutions of this disclosure will be described in detail by the following embodiments, but the scope of protection of this disclosure includes, but is not limited to, these embodiments.

[0116] The structure of a compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The value is given in units of ppm. NMR is measured using an NMR spectrometer (Bruker Avance III 400 and Bruker Avance 300), with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0117] MS is measured using Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0118] HPLC measurements are performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18, 100 × 4.6 mm).

[0119] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF is used. 254 Or Qingdao GF 254 Silica gel plates are used, with silica gel plates for thin-layer chromatography (TLC) having a specification of 0.15 mm to 0.20 mm, and those for separating and purifying products by thin-layer chromatography having a specification of 0.4 mm to 0.5 mm.

[0120] For column chromatography, Yantai Huanghai silica gel with a mesh size of 200-300 is commonly used as the support material.

[0121] The known starting materials of this disclosure can be synthesized by or in accordance with methods known in the art, or can be purchased from Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., J&K Scientific Co., Ltd., and other companies.

[0122] The ratios shown in the silica gel column chromatography of this disclosure are volume ratios.

[0123] In this disclosure, the term "equivalent" refers to a molar ratio.

[0124] "Ratio of quantities" refers to the ratio of the weight (kg) of a substance to the volume (L) of a solvent. LDA: Lithium diisopropylamide BuLi:n-butyllithium lithium LiHMDS: Lithium bis(trimethylsilyl)amide DMF: N,N-dimethylformamide THF: Tetrahydrofuran DCM: Dichloromethane TsOH: p-toluenesulfonic acid CuSO4: Copper sulfate Zn(OAc)2: Zinc acetate Co(OAc)2·4H2O: Cobalt acetate hydrate Na2SO4: Sodium sulfate MgSO4: Magnesium sulfate Ti(Oi-Pr)4: Titanium tetraisopropoxide DCC / DMAP: N,N'-Dicyclohexylcarbodiimide / 4-Dimethylaminopyridine EDCI / DMAP: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 4-dimethylaminopyridine HOAc / Molecular Sieve: Acetic Acid / Molecular Sieve System CsF: Cesium fluoride KF: Potassium Fluoride NH4F: Ammonium fluoride TBAF: Tetrabutylammonium fluoride Na2CO3: Sodium carbonate solution NaHCO3: Sodium bicarbonate solution NaOH: Sodium hydroxide K3PO4: Potassium phosphate Ti(OEt)4: Isopropyl titanate n-Heptane ACN: Acetonitrile Toluene DMSO: Dimethyl sulfoxide TMSCN: Trimethylsilylcyanide Tartaric acid MTBE: Methyl tert-butyl ether DIPEA: N,N-diisopropylethylamine DBU:1,8-Diazabicyclo[5.4.0]Undeca-7-En (Boc)2O: Ditert-butyl dicarbonate OTF: Trifluoromethanesulfonate [Examples]

[0125] tert-butyl(S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate(C7)

[0126] [ka]

[0127] Step 1: 4-Bromo-2-fluoro-1-(2-methoxyvinyl)benzene(C2)

[0128] [ka]

[0129] [reaction] THF (8V) and LiHMDS (1.34eq) were added to the reaction vessel. After the addition was complete, the mixture was stirred under a nitrogen atmosphere and cooled to 0°C ± 5°C. (Methoxymethyl)triphenylphosphonium chloride (1.3eq) was added in installments, and the mixture was stirred for approximately 2 hours while maintaining a temperature of 0°C ± 5°C. Then, a solution of C1 (53.0 kg, 1.0eq) in THF (2V) was added dropwise while controlling the temperature to 0°C ± 5°C, and the mixture was reacted for approximately 2 hours while maintaining the temperature at 0°C ± 5°C. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C1 / C1 + C2 ≤ 2.0% was met.

[0130] [Workup] The reaction was quenched by adding water (5V) to the reaction system. The aqueous phase was extracted with MTBE (5V), the mixture was stirred, and phase separation was performed. The organic phase was concentrated and subjected to a rotary evaporator. n-heptane (10V) was added to the concentrate, the mixture was stirred for about 1 hour, and filtered. Magnesium chloride (1.5eq) was added to the filtrate, the mixture was stirred at 60°C ± 5°C for about 16 hours, and filtered. The filtrate was washed with 5% EDTA-Na (5V), and phase separation was performed. The organic phase was concentrated and subjected to a rotary evaporator, and the residue was subjected to azeotropic distillation with toluene (5V) to obtain compound C2 (48.3 kg, yield: 80.0%). 1 H NMR (300MHz, CDCl3) δ:7.84(t,1H),7.17-7.04(m,1H),6.18(d,1H),5.33(d,1H),3.74(d,2H). GCMS: m / z = 230.00

[0131] Step 2: 2-(4-bromo-2-fluorophenyl)acetaldehyde (C3)

[0132] [ka]

[0133] [reaction] C2 (53.0 kg, 1.0 eq), toluene (10V), and water (1V) were added to the reaction vessel under stirring. After the addition was complete, the mixture was purged three times with nitrogen and heated to 70°C ± 5°C. p-toluenesulfonic acid monohydrate (3.0 eq) was added, and the mixture was reacted for approximately 1 hour while maintaining a temperature of 70°C ± 5°C. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C2 / C2 + C3 ≤ 5.0% was met.

[0134] [Workup] After the reaction was complete, the phases were separated, and the aqueous phase was extracted twice with toluene (2V). The organic phase was combined with the aqueous phase and washed once with a 5% NaHCO3 solution (4V). After phase separation, the organic phase was recovered to obtain a C3 solution in toluene (total weight: 755.9 kg, content: 4.90%, yield: 74.1%), which was used directly in the next reaction. GCMS:215.90

[0135] Step 3: (R,E)-N-(2-(4-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (C4)

[0136] [ka]

[0137] [reaction] A solution of C3 (37.0 kg, 1.0 eq) in toluene, (S)-tert-butylsulfinamide (1.3 eq), and anhydrous copper sulfate (3.0 eq) were added to the reaction vessel under stirring. After the addition was complete, the reaction mixture was heated to 40°C ± 5°C under a nitrogen atmosphere and stirred for 10 hours while maintaining a constant temperature. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C3 / C3 + C4 ≤ 20.0% was met.

[0138] [Workup] After the reaction was complete, the reaction mixture was filtered on diatomaceous earth. The filter cake was washed with toluene (1V) and the filtrate was collected. The filtrate was washed twice with a 5% sodium bicarbonate solution and allowed to stand to separate the phases, yielding a C4 solution in toluene (total weight: 859.5 kg, content: 4.6%, yield: 72.4%), which was used directly in the next reaction. 1 H NMR (300MHz, CDCl3): δ 8.10-7.96 (m, 1H), 7.18 (m, 2H), 7.09-6.92 (m, 1H), 3.85-3.66 (m, 1H), 1.08 (s, 9H). LCMS: m / z = 320.0 [M+1] +

[0139] C4 in this step can also be prepared using the following method: [reaction] In a reaction vessel, a solution of C3 (27.0 kg, 1.0 eq) in toluene (370 kg), (S)-tert-butylsulfinamide (1.3 eq), acetic acid (2.5 V), and molecular sieves (108 kg) were added under stirring. After the addition was complete, the mixture was purged three times with nitrogen, heated to 40°C ± 5°C, and stirred for 12 hours while maintaining a constant temperature. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C3 / C3 + C4 ≤ 20.0% was met.

[0140] [Workup] After the reaction was complete, the reaction mixture was cooled to 20°C ± 5°C and filtered on diatomaceous earth. The filtered cake was washed with toluene (2V) and the filtrate was collected. The filtrate was washed twice with a 5% sodium bicarbonate solution and allowed to stand to separate the phases, yielding a C4 solution in toluene (total weight: 366.6 kg, content: 5.0%, yield: 67.2%), which was used directly in the next reaction.

[0141] Step 4: (R)-N-((S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)-2-methylpropane-2-sulfinamide(C5-1)

[0142] [ka]

[0143] [reaction] A solution of C4 (39.5 kg, 1.0 eq) in toluene was added to the reaction vessel, and stirring was started. Subsequently, cesium fluoride (0.2 eq) was added. The mixture was purged three times with nitrogen and cooled to 0°C ± 5°C under a nitrogen atmosphere. Trimethylsilyl cyanide (1.5 eq) was slowly added dropwise while maintaining a temperature of 0°C ± 5°C during the addition. After the addition was complete, the mixture was stirred for 12 hours while maintaining the temperature at 0°C ± 5°C. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C4 / C4+C5 ≤ 2.0% was met.

[0144] [Workup] After the reaction was complete, a 1% sodium carbonate solution was added to the system to stop the reaction and adjust the pH to approximately 8. The system was allowed to stand and phase separation was performed to obtain the organic phase. The organic phase was sequentially washed with a mixed solution of 0.5% sodium carbonate and 3.0% sodium chloride (5V x 3) and a 5.0% sodium chloride solution (5V x 2). Subsequently, the resulting system was allowed to stand and phase separation was performed, and the organic phase was recovered to obtain a C5-1 solution in toluene (total weight: 862.5 kg, content: 4.3%, yield: 88.2%), which was used directly in the next reaction. LCMS: m / z = 347.2[M+1] +

[0145] C5-1 in this step can also be prepared using the following method: [reaction] A solution of C4 (0.2 kg, 1.0 eq) in toluene (2 kg, 1.0 eq) was added to the reaction vessel, and stirring was started. Subsequently, potassium fluoride (0.2 eq) was added. The mixture was cooled to 0°C ± 5°C under a nitrogen atmosphere, and trimethylsilyl cyanide (1.5 eq) was slowly added dropwise. After the dropwise addition was complete, the mixture was stirred for 16 hours while maintaining a temperature of 0°C ± 5°C. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C4 / C4+C5 ≤ 2.0% was met.

[0146] [Workup] After the reaction was complete, a 5% sodium carbonate solution was added to the system to stop the reaction and adjust the pH to approximately 8. The system was allowed to stand to separate phases, yielding an organic phase. The organic phase was sequentially washed with a mixed solution of 5.0% sodium carbonate and 5.0% sodium chloride. The resulting system was then allowed to separate phases, the organic phase was recovered, and concentrated until dry to obtain a C5-1 solution in toluene (crude: 0.23 kg, yield: 100%), which was used directly in the next reaction.

[0147] Step 5: (S)-2-amino-3-(4-bromo-2-fluorophenyl)propannitrile hydrochloride (C6)

[0148] [ka]

[0149] [reaction] A solution of C5-1 (37.0 kg, 1.0 eq) in toluene was added to the reaction vessel, and stirring was started. The mixture was purged three times with nitrogen and cooled to 0°C ± 5°C under a nitrogen atmosphere. Hydrochloric acid / ethanol (2.5 eq) was slowly added dropwise, while controlling the temperature to 0°C ± 5°C during the addition. After the addition was complete, the mixture was heated to 20°C ± 5°C and stirred for 4 hours while maintaining a constant temperature. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C5-1 / C6 + C5-1 ≤ 2.0% was met.

[0150] [Work-up] After the reaction was completed, the reaction mixture was cooled to 10 °C ± 5 °C, stirred for 1 hour, and filtered. The filter cake was washed with MTBE (2V), and the filter cake was recovered to obtain a wet product of C6 (total weight: 63.8 kg, content: 63.8%, yield: 100%), which was used directly in the next reaction. 1 1H NMR (400 MHz, DMSO): δ 9.00 (s, 2H), 7.64 (dd, 1H), 7.45 - 7.37 (m, 2H), 4.84 (t, 1H), 3.26 - 3.16 (m, 2H). LCMS: m / z = 243.0 [M - HCl + H] +

[0151] Step 6: (S)-2-Amino-3-(4-bromo-2-fluorophenyl)propanenitrile L-tartrate (C6-b)

[0152] [Chemical formula]

[0153] [Reaction] C6 (58.4 kg, 1.0 eq) and dichloromethane (6V) were added to a reaction kettle, and stirring was started. The mixture was purged with nitrogen three times, cooled to 5 °C ± 5 °C, and a 5% sodium carbonate solution (10V) was added dropwise while controlling the temperature at 5 ± 5 °C. After the dropwise addition was completed, the mixture was warmed to 20 °C ± 5 °C and stirred for 1 hour while maintaining the temperature constant. The system was left to stand for phase separation, and the aqueous phase was extracted once with DCM (3V). The organic phases were combined and concentrated to about half of the initial volume. The resulting system was cooled to 20 °C ± 5 °C, MeOH (3.5V) was added, and subsequently, a solution of L(-)-tartaric acid (0.8 eq) in methanol (3.5V) was added dropwise. After the dropwise addition was completed, the mixture was stirred for 4 hours while maintaining the temperature at 15 °C ± 5 °C.

[0154] [Work-up] After the reaction was complete, the mixture was filtered, and the filtered cake was washed with MTBE (3V). By recovering the filtered cake, the wet product of C6-b (total weight: 92.2 kg, content (free base): 36.9%, yield: 67.0%) was obtained and used directly in the next reaction. Purity: 98.2% Chiral purity: 99.6%

[0155] Step 7: tert-butyl(S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate(C7)

[0156] [ka]

[0157] [reaction] C6-b (54.8 kg, 1.0 eq) and dichloromethane MTBE (6V) were added to the reaction vessel, and stirring was started. The mixture was cooled to 0°C ± 5°C, and 5% sodium carbonate solution (1.1 eq) was added dropwise. After the dropwise addition was complete, the mixture was stirred for 20 minutes while maintaining a temperature of 0°C ± 5°C, and (Boc)2O (1.6 eq) solution in MTBE (1V) was added dropwise to the system. After the dropwise addition was complete, the mixture was heated to 20°C ± 5°C and stirred for 15 hours while maintaining a constant temperature. The reaction mixture was sampled and monitored. The reaction was stopped when the in-process control limit of C6-b / C6-b+7 ≤ 1.0% was met.

[0158] [Workup] After the reaction was complete, the system was allowed to stand and phase separation was performed. The aqueous phase was extracted once with MTBE (1V), and the organic phase was combined. After adding n-heptane (10V), the mixture was stirred and heated to 35°C ± 5°C to concentrate to about one-tenth of the initial volume. The concentrate was cooled to 10°C ± 5°C, and n-heptane (10V) was added. The mixture was stirred for 3 hours and then filtered. The filtered cake was washed with a mixture of MTBE:n-heptane = 1:7 (2V) to obtain the wet product of C7. This wet product was dried at 35°C ± 5°C for about 16 hours to obtain compound C7 (weight: 34.4 kg, yield: 71.0%). Purity: 99.6% Chiral purity: 100.0% 1 H NMR (400MHz, DMSO): δ 7.84 (s, 1H), 7.54 (dd, 1H), 7.47-7.28 (m, 2H), 4.69 (d, 1H), 3.08 (qd, 2H), 1.38 (s, 9H). LCMS: m / z = 287.0 [M-56+H] +

[0159] In summary, the method for preparing the compound represented by formula (I) provided herein has advantages such as low-cost reaction starting materials, a multi-step telescopic reaction, a simple work-up process, high yield, high chemical and chiral purity of the product, and suitability for large-scale industrial production.

Claims

1. A method for preparing a compound represented by formula (I), comprising the following: 【Chemistry 1】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. a: Prepare the compound represented by formula (I) from the compound of formula (II).

2. The preparation method according to claim 1, wherein the above method further includes the following steps: 【Chemistry 2】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. b: Prepare the compound of formula (II-1) from the compound of formula (III); c: Prepare the compound of formula (II) from the compound of formula (II-1).

3. A method for preparing a compound represented by formula (II), comprising the following: 【Transformation 3】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. b: Prepare the compound of formula (II-1) from the compound of formula (III); c: Prepare the compound of formula (II) from the compound of formula (II-1).

4. The preparation method according to claim 2 or 3, wherein the above method further includes the following steps: 【Chemistry 4】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. d: Prepare the compound of formula (III) from the compound of formula (IV).

5. A method for preparing a compound represented by formula (III), comprising the following: 【Transformation 5】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. d: Prepare the compound of formula (III) from the compound of formula (IV).

6. The preparation method according to claim 4 or 5, wherein the method further includes the following steps: 【Transformation 6】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. g: Prepare the compound of formula (VI) from the compound of formula (VII-1) and the compound of formula (VII-2); f: Prepare the compound of formula (V-1) from the compound of formula (VI); e: Prepare the compound of formula (IV) from the compound of formula (V-1) and the compound of formula (V-2).

7. A method for preparing a compound represented by formula (IV), comprising the following: 【Transformation 7】 Here, X is a leaving group such as F, Cl, Br, I, or OTf. g: Prepare the compound of formula (VI) from the compound of formula (VII-1) and the compound of formula (VII-2); f: Prepare the compound of formula (V-1) from the compound of formula (VI); e: Prepare the compound of formula (IV) from the compound of formula (V-1) and the compound of formula (V-2).

8. A preparation method according to any one of claims 1, 2, 4, and 6, wherein, a: A compound represented by formula (II) is reacted in the presence of an organic solvent and a base to obtain a compound represented by formula (I). Here, the organic solvent is preferably dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc) ２ One or more of O or n-heptanes, more preferably dichloromethane, MTBE, (Boc) ２ It is one or more of O or n-heptanes; The base is preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA, or DBU, and is more preferably sodium carbonate.

9. A preparation method according to any one of claims 2, 3, 4, and 6, wherein, b: The compound of formula (III) is reacted in the presence of an organic solvent and an acid to obtain the compound of formula (II-1). Here, the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol, or isopropanol, and more preferably ethanol or MTBE; The acid is preferably one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, and more preferably HCl; c: The compound of formula (II-1) is reacted in the presence of a chiral acid solvent to obtain the compound of formula (II). Here, the chiral acid solvent is preferably one or more of tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, lactic acid, diacetone-L-guronic acid, mandelic acid, or phenoxypropionic acid, and more preferably L(-)-tartaric acid.

10. A preparation method according to any one of claims 4 to 6, wherein, d: The compound of formula (IV) is reacted in the presence of a solvent, a cyanide reagent, and a base to obtain the compound of formula (III). Here, the solvent is preferably one or more of DCM, DMF, THF, n-heptane, ACN, toluene, or DMSO, and more preferably DCM or toluene; The cyanidating reagent is preferably one or more of TMSCN, sodium cyanide, potassium cyanide, or lithium cyanide, and more preferably TMSCN; The base is preferably CsF, KF, TBAF, Na ２ CO ３ _K ３ PO ４ Or Ti(OEt) ４ It is one or more of the following, more preferably CsF or KF, and even more preferably CsF.

11. A preparation method according to claim 6 or 7, wherein, g: Compound (VI) is obtained by reacting the compound of formula (VII-1) and the compound of formula (VII-2) in the presence of a base. Here, the base is preferably one or more of LiHMDS, NaHMDS, KHMDS, LDA, BuLi, or potassium tert-butoxide, more preferably LiHMDS, NaHMDS, or KHMDS, and even more preferably LiHMDS; f: The compound of formula (VI) is reacted in the presence of an acid and an organic solvent to obtain the compound of formula (V-1). Here, the acid is preferably one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride, or trimethylchlorosilane, and more preferably TsOH; The organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol, or isopropanol, and more preferably toluene; e: Compound (IV) is obtained by reacting the compound of formula (V-1) and the compound of formula (V-2) in the presence of an organic solvent and a dehydrating agent. Here, the organic solvent is preferably one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, or acetonitrile, and more preferably toluene; The dehydration reagent is preferably anhydrous CuSO ４ , Zn(OAc) ２ , Co(OAc) ２ ·4H ２ O, Na ２ SO ４ , MgSO ４ , Ti(O-i-Pr) ４ , DCC / DMAP, EDCI / DMAP or one or more of HOAc / molecular sieve, more preferably anhydrous CuSO ４ or HOAc / molecular sieve.

12. A method for preparing a compound represented by formula (C7), comprising the following: 【Transformation 8】 Here, g: C2 is obtained by reacting C1 in the presence of an organic solvent and a base; f: C3 is obtained by reacting C2 in the presence of an organic solvent and an acid; e: C4 is obtained by reacting C3 in the presence of an organic solvent and a dehydrating agent; d: C5-1 is obtained by reacting C4 in the presence of a solvent, a base, and a cyanide reagent; b: C6 is obtained by reacting C5-1 in the presence of an acid; c: C6-b is obtained by reacting C6 in the presence of an organic solvent, a base, and a chiral acid; a: C7 is obtained by reacting C6-b in the presence of an organic solvent and a base.

13. A preparation method according to claim 12, wherein, g: The organic solvent is selected from one or more of tetrahydrofuran, dichloromethane, MTBE, or n-heptane; The base is selected from one or more of LiHMDS, NaHMDS, or KHMDS, and is preferably LiHMDS; f: The acid is selected from one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride, or trimethylchlorosilane, preferably TsOH; The organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol, or isopropanol, and is preferably toluene; e: The organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, or acetonitrile, preferably toluene; and the dehydrating agent is anhydrous CuSO4 ４ , Zn (OAc) ２ Co(OAc) ２ 4H ２ O, Na ２ SO ４ MgSO ４ , Ti(Oi-Pr) ４ , selected from one or more of DCC / DMAP, EDCI / DMAP, or HOAc / Molecular Sieve, preferably anhydrous CuSO4 ４ or HOAc / molecular sieve; d: The solvent is selected from one or more of DCM, DMF, THF, n-heptane, ACN, toluene, or DMSO, preferably DCM or toluene; the cyanidating reagent is selected from one or more of TMSCN, sodium cyanide, potassium cyanide, or lithium cyanide, preferably TMSCN; and the base is CsF, KF, TBAF, Na ２ CO ３ _K ３ PO ４ Or Ti(OEt) ４ One or more of the following are selected, preferably CsF or KF, and more preferably CsF; b: The organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol, or isopropanol, preferably ethanol or MTBE; and the acid is selected from one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably HCl; c: The chiral acid solvent is selected from one or more of tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, lactic acid, diacetone-L-guronic acid, mandelic acid, or phenoxypropionic acid, preferably L(-)-tartaric acid; a: The organic solvents are dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc) ２ Selected from one or more O or n-heptanes, more preferably dichloromethane, MTBE, (Boc) ２ The base is one or more of O or n-heptane; and the base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA or DBU, preferably sodium carbonate.

14. A preparation method according to claim 12 or 13, wherein, g: The organic solvent is tetrahydrofuran, and the base is LiHMDS; f: The acid is TsOH, and the organic solvent is toluene; e: The dehydrating reagent is anhydrous CuSO4 ４ Or selected from HOAc / molecular sieves; d: The cyanidating reagent is TMSCN, and the base is CsF; b: The organic solvent is selected from ethanol or MTBE, and the acid is HCl; c: The chiral acid solvent is L(-)-tartaric acid; a: The organic solvent is dichloromethane, MTBE, (Boc) ２ Selected from one or more of O or n-heptane; the base is sodium carbonate.

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