DPP1 inhibitor intermediate, preparation method thereof and application of DPP1 inhibitor intermediate in medicine

Abstract

The invention relates to a preparation method of a compound as shown in a formula (I) and an intermediate thereof. The method has the advantages of low starting material price, multi-step telescopic reaction, simple post-treatment operation, high yield, high chemical and chiral purity of a product and suitability for large-scale industrial production.

Description

A DPP1 inhibitor intermediate, its preparation method and use in medicine Technical Field

[0001] The present invention relates to a method for preparing a compound represented by formula (I) and an intermediate thereof. The method has low-cost starting materials, multi-step telescopic reactions, simple post-processing operations, high yield, high product chemical and chiral purity, and is suitable for large-scale industrial production. Background Art

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a cysteinyl protease of the lysosomal papain family that is involved in intracellular protein degradation. During neutrophil maturation, DPP1 cleaves the N-terminal dipeptide of target proteins, thereby activating neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (Pr3), and cathepsin G (CatG). DPP1 is associated with a variety of inflammatory diseases, including Wegener's granulomatosis, rheumatoid arthritis, lung inflammation, and viral infections. Studies have shown that DPP1 inhibition has a promising therapeutic effect on highly inflammatory lung diseases driven by neutrophils, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), and acute lung injury. Therefore, inhibiting the overactivation of NSPs by targeting DPP1 may have potential therapeutic applications in bronchiectasis.

[0003] WO2014140075A1 and WO2016016242A1 describe a class of compounds having DPP1 activity, wherein the compound represented by formula (C7) It can be used as a key intermediate for the synthesis of this type of product.

[0004] WO2014140075A1 discloses intermediate I-1.1, which is prepared using R8 and R9 as starting materials via Route 1. This preparation method suffers from the following problems: expensive starting materials, ultra-low temperature reaction requirements, low reaction conversion efficiency, the need for column chromatography purification, and difficulty in industrial scale-up production.

[0005] Route 1:

[0006] WO2016016242A1 discloses another intermediate, I-5.2.1, which is prepared using the following R14 as the starting material via the reaction in Route 2. This route has the following major drawbacks: the reaction requires asymmetric reduction, the catalyst is expensive and easily deactivated, the asymmetric reduction reaction produces a dehalogenation byproduct, and purification requires reverse-phase HPLC, resulting in high production costs and difficulty in scale-up.

[0007] Route 2:

[0008] Therefore, it is necessary to develop a route for preparing compound (I) with mild reaction conditions, simple operation, high reaction yield, high product chemical and chiral purity, convenient post-processing, low cost, and suitable for industrial production.

[0009] Summary of the Invention

[0010] The purpose of the present invention is to provide a method for preparing the compound represented by formula (I) and its intermediates.

[0011] The method of the invention has low-cost reaction starting materials, multi-step telescopic reaction, simple post-processing operation, high yield, high chemical and chiral purity of the product, and is suitable for large-scale industrial production.

[0012] The present invention provides a method for preparing a compound represented by formula (I), wherein the compound represented by formula (I) is prepared from a compound represented by formula (II).

[0013] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0014] The method for preparing the compound of formula (I) provided by the present invention can also prepare the compound of formula (II-1) from the compound of formula (III), prepare the compound of formula (II) from the compound of formula (II-1), and then prepare the compound of formula (I) from the compound of formula (II):

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

[0016] The method for preparing the compound of formula (I) provided by the present invention can also prepare the compound of formula (III) from the compound of formula (IV), prepare the compound of formula (II-1) from the compound of formula (III), prepare the compound of formula (II) from the compound of formula (II-1), and then prepare the compound of formula (I) from the compound of formula (II):

[0017] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0018] The preparation method of the compound represented by formula (I) provided by the present invention can also prepare the compound represented by formula (VI) from the compound represented by formula (VII-1) and the compound represented by formula (VII-2); prepare the compound represented by formula (V-1) from the compound represented by formula (VI); prepare the compound represented by formula (IV) from the compound represented by formula (V-1) and the compound represented by formula (V-2); prepare the compound represented by formula (III) from the compound represented by formula (IV); prepare the compound represented by formula (II-1) from the compound represented by formula (III); prepare the compound represented by formula (II) from the compound represented by formula (II-1); and then prepare the compound represented by formula (I) from the compound represented by formula (II):

[0019] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0020] The present invention provides a method for preparing a compound represented by formula (II), wherein a compound represented by formula (III) is used to prepare a compound represented by formula (II-1); a compound represented by formula (II) is prepared from a compound represented by formula (II-1).

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

[0022] The preparation method of the compound represented by formula (II) provided by the present invention can also prepare the compound of formula (III) from the compound of formula (IV), prepare the compound of formula (II-1) from the compound of formula (III), and then prepare the compound of formula (II) from the compound of formula (II-1):

[0023] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0024] The preparation method of the compound represented by formula (II) provided by the present invention can also prepare the compound of formula (VI) from the compound of formula (VII-1) and the compound of formula (VII-2); prepare the compound of formula (V-1) from the compound of formula (VI); prepare the compound of formula (IV) from the compound of formula (V-1) and the compound of formula (V-2); prepare the compound of formula (III) from the compound of formula (IV); prepare the compound of formula (II-1) from the compound of formula (III); and then prepare the compound of formula (II) from the compound of formula (II-1):

[0025] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0026] The present invention provides a method for preparing a compound represented by formula (III), wherein the compound represented by formula (III) is prepared from the compound represented by formula (IV).

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

[0028] The present invention provides a method for preparing a compound represented by formula (III), and can also prepare a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); prepare a compound of formula (V-1) from a compound of formula (VI); prepare a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2); and prepare a compound of formula (III) from a compound of formula (IV).

[0029] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0030] The present invention provides a method for preparing a compound represented by formula (IV), wherein a compound of formula (VI) is prepared from a compound of formula (VII-1) and a compound of formula (VII-2); a compound of formula (V-1) is prepared from a compound of formula (VI); and a compound of formula (IV) is prepared from a compound of formula (V-1) and a compound of formula (V-2).

[0031] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0032] In some embodiments of the method for preparing the compound of formula (I) according to the present invention, the method comprises the following steps:

[0033] wherein X is selected from a leaving group such as F, Cl, Br, I or OTf;

[0034] a: Prepare the compound represented by formula (I) from the compound represented by formula (II).

[0035] In some embodiments of the method for preparing the compound of formula (I) described above, the present invention may further comprise the following steps:

[0036] wherein X is selected from a leaving group such as F, Cl, Br, I or OTf;

[0037] b: preparing a compound of formula (II-1) from a compound of formula (III);

[0038] c: Prepare the compound of formula (II) from the compound of formula (II-1).

[0039] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the present invention further comprises the following steps:

[0040] wherein X is selected from a leaving group such as F, Cl, Br, I or OTf;

[0041] d: Prepare the compound of formula (III) from the compound of formula (IV).

[0042] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III) described above, the present invention may further include the following steps:

[0043] wherein X is selected from a leaving group, such as F, Cl, Br, I or OTf.

[0044] g: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2);

[0045] f: preparing a compound of formula (V-1) from a compound of formula (VI);

[0046] e: preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2).

[0047] In some embodiments of the method for preparing the compound of formula (I) described above, the present invention relates to:

[0048] a: The 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), wherein the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc)2O, and n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, and n-heptane; 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, and DBU, further preferably sodium bicarbonate, sodium carbonate, and sodium hydroxide, and more preferably sodium carbonate;

[0049] In some embodiments of the method for preparing the compound of formula (I) described above, the ratio of the compound of formula (II) to the organic solvent is 1:3-20, preferably 1:4-8.

[0050] In some embodiments of the method for preparing the compound of formula (I) described above, the reaction temperature is -10-60°C, preferably 0-30°C.

[0051] In some embodiments of the method for preparing the compound of formula (I) described above, the reaction time is 10-48 h, preferably 15-20 h.

[0052] In some embodiments of the method for preparing the compound of formula (I) described above, the drying time is 8-48 hours, preferably 12-24 hours.

[0053] In some embodiments of the method for preparing the compound of formula (I) described above, the base is added in a ratio of 1:0.5-3.0, preferably 1:1.0-1.5.

[0054] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the present invention relates to:

[0055] b: The 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, and isopropanol, more preferably ethanol and MTBE; the acid is preferably one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid, more preferably HCl;

[0056] c: reacting the compound of formula (II-1) in the presence of a chiral acid to obtain a compound of formula (II), wherein the chiral acid is preferably one or more of tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, lactic acid, diacetone-L-gulonic acid, mandelic acid, and phenoxypropionic acid, more preferably L(-)-tartaric acid;

[0057] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the L(-)-tartaric acid equivalent can be selected from 0.5-2.0 eq, preferably 0.6-1.0 eq;

[0058] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the ratio of the compound represented by formula (III) to the organic solvent is 1:2.0-10.0, preferably 1:3-5;

[0059] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the reaction temperature is -10-60°C, preferably 0-30°C;

[0060] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the reaction time is 3-12 h, preferably 4-6 h;

[0061] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) described above, the ratio of acid added is 1:1.0-6.0, preferably 1:2.0-4.0.

[0062] In some embodiments of the method for preparing the compounds of formula (I), formula (II) and formula (III) described above,

[0063] d: The compound of formula (IV) is prepared in the presence of a solvent, a cyaniding 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, and DMSO, more preferably DCM or Toluene; the cyaniding agent is preferably one or more of TMSCN, sodium cyanide, potassium cyanide, and lithium cyanide, more preferably TMSCN; the base is preferably one or more of CsF, KF, TBAF, Na2CO3, K3PO4, and Ti(OEt)4, more preferably CsF or KF, and even more preferably CsF;

[0064] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III) described above, the ratio of the compound represented by formula (IV) to the cyaniding agent is 1:1.0-3.0, preferably 1:1.3-1.7;

[0065] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III) described above, the reaction temperature is -10-30°C, preferably 0-10°C;

[0066] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III) described above, the reaction time is 10-24 h, preferably 12-16 h;

[0067] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III) described above, the base is used in a ratio of 1:0.05-2.0, preferably 1:0.1-0.3.

[0068] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above,

[0069] g: Compound (VII-1) and compound (VII-2) are reacted in the presence of a base to obtain a compound of formula (VI), wherein the base is preferably one or more of LiHMDS, NaHMDS, KHMDS, LDA, BuLi, and potassium tert-butoxide, more preferably LiHMDS, NaHMDS, KHMDS, and even more preferably LiHMDS;

[0070] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the LiHMDS equivalent is 1.3 eq;

[0071] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the compound represented by formula (VII-1) to the base is 1:1.0-3.0, preferably 1:1.2-1.5;

[0072] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction temperature is -10-30°C, preferably 0-10°C;

[0073] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction time is 1-10 h, preferably 2-5 h;

[0074] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above,

[0075] f: preparing a compound of formula (VI) in the presence of an acid and an organic solvent to obtain a compound of formula (V-1), wherein 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, and trimethylsilyl chloride, more preferably TsOH;

[0076] 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, and isopropanol, more preferably toluene;

[0077] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the TsOH equivalent can be selected from 1.0 eq, 2.0 eq, and 4.0 eq, preferably 2.0 eq;

[0078] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the compound represented by formula (VI) to the acid is 1:1.0-5.0, preferably 1:1.5-3.0;

[0079] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction temperature is 40-100° C., preferably 60-80° C.;

[0080] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction time is 0.5-10 h, preferably 1-5 h;

[0081] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the organic solvent used is 1:5-15, preferably 1:7-12.

[0082] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above,

[0083] e: the compound of formula (V-1) and the compound of formula (V-2) are prepared in the presence of an organic solvent and a dehydrating agent to obtain a compound of formula (IV), wherein the organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, and acetonitrile, preferably toluene;

[0084] The dehydrating agent 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, and HOAc / molecular sieve, preferably anhydrous CuSO4 and HOAc / molecular sieve;

[0085] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the anhydrous copper sulfate equivalent is 3.0 eq;

[0086] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the acetic acid / molecular sieve system is that the volume of acetic acid is 2 times that of the intermediate V-1;

[0087] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the compound represented by formula (V-1) to the dehydrating agent is 1:1.0-6.0, preferably 1:2.0-4.0;

[0088] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction temperature is 10-80° C., preferably 30-50° C.;

[0089] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the reaction time is 6-24 h, preferably 8-16 h;

[0090] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV) described above, the ratio of the organic solvent used is 1:5-20, preferably 1:8-16.

[0091] The present invention also provides a method for preparing the compound represented by formula (C7):

[0092] in:

[0093] g: C1 reacts in the presence of an organic solvent and a base to produce C2;

[0094] f: C2 reacts in the presence of an organic solvent and an acid to produce C3;

[0095] e: C3 reacts in the presence of an organic solvent and a dehydrating agent to produce C4;

[0096] d: C4 reacts in the presence of a solvent, a base, and a cyaniding agent to produce C5-1;

[0097] b: C5-1 reacts in the presence of an acid to produce C6.

[0098] c: C6 reacts in the presence of an organic solvent, a base, and a chiral acid to produce C6-b;

[0099] a: C6-b reacts in the presence of an organic solvent and a base to obtain C7.

[0100] In some embodiments of the method for preparing the compound of formula (C7) described above, the present invention relates to:

[0101] g: the organic solvent is selected from one or more of tetrahydrofuran, dichloromethane, MTBE, and n-heptane;

[0102] The base is selected from one or more of LiHMDS, NaHMDS, and KHMDS, preferably LiHMDS;

[0103] 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, and trimethylsilyl chloride, preferably TsOH;

[0104] The organic solvent is one or more selected from the group consisting of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol, and isopropanol, preferably toluene;

[0105] e: the organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, and acetonitrile, preferably toluene; the dehydrating agent 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, and HOAc / molecular sieve, preferably anhydrous CuSO4 and HOAc / molecular sieve;

[0106] d: The solvent is selected from one or more of DCM, DMF, THF, n-heptane, ACN, Toluene, and DMSO, preferably DCM or Toluene; the cyaniding agent is selected from one or more of TMSCN, sodium cyanide, potassium cyanide, and lithium cyanide, preferably TMSCN; the base is selected from one or more of CsF, KF, TBAF, Na2CO3, K3PO4, and Ti(OEt)4, preferably CsF or KF, more preferably CsF;

[0107] b: the organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol, and isopropanol, preferably ethanol and MTBE; the acid is selected from one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid, preferably HCl;

[0108] c: the chiral acid solvent is selected from one or more of tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, lactic acid, diacetone-L-gulonic acid, mandelic acid, and phenoxypropionic acid, preferably L(-)-tartaric acid;

[0109] a: The organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc)2O, and n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, and n-heptane; 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, and DBU, preferably sodium carbonate.

[0110] In some embodiments of the method for preparing the compound of formula (C7) described above, the present invention relates to:

[0111] g: the organic solvent is tetrahydrofuran, and the base is LiHMDS;

[0112] f: the acid is TsOH, and the organic solvent is toluene;

[0113] e: the dehydrating agent is selected from anhydrous CuSO4, HOAc / molecular sieve;

[0114] d: The cyaniding agent is TMSCN and the base is CsF;

[0115] b: the organic solvent is selected from ethanol and MTBE, and the acid is HCl;

[0116] c: the chiral acid solvent is L(-)-tartaric acid;

[0117] a: The organic solvent is selected from one or more of dichloromethane, MTBE, (Boc)2O, and n-heptane; and the base is sodium carbonate.

[0118] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the post-treatment in step g comprises refining the crude compound of formula (VI).

[0119] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the purification of the crude product after post-treatment in step g comprises the following steps:

[0120] 1) adding n-heptane to the concentrated crude product of the compound of formula (VI), stirring, and filtering;

[0121] 2) adding magnesium chloride to the filtrate, stirring, and filtering;

[0122] 3) The filtrate was washed with EDTA-Na, the liquids were separated, and the organic phase was concentrated; toluene was added to the concentrate and distilled.

[0123] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the post-treatment in step f comprises refining the crude compound of formula (V-1).

[0124] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the purification of the crude product after post-treatment in step f comprises the following steps:

[0125] Add NaHCO3 solution to the mixture containing the compound of formula (V-1), wash, separate the liquids, and collect the organic phase to obtain the compound of formula (V-1).

[0126] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the post-treatment in step e comprises refining the crude compound of formula (IV).

[0127] In some embodiments of the method for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), the purification of the crude product after post-treatment in step f comprises the following steps:

[0128] Add NaHCO3 solution to the mixture containing the compound of formula (IV), wash, and separate the liquid to obtain the compound of formula (IV).

[0129] In some embodiments of the method for preparing the compounds of formula (I), formula (II) and formula (III) according to the present invention, the post-treatment in step d comprises purifying the crude compound of formula (III).

[0130] In some embodiments of the method for preparing the compounds of formula (I), formula (II), and formula (III), the purification of the crude product after post-treatment in step d comprises the following steps:

[0131] 1) adding sodium carbonate solution to the compound of formula (III), separating the liquids to obtain an organic phase;

[0132] 2) adding a mixed solution of sodium carbonate and sodium chloride and a sodium chloride solution to the organic phase in sequence, separating the liquids, and collecting the organic phase to obtain a compound of formula (III).

[0133] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) according to the present invention, step b includes reaction and post-treatment.

[0134] In some embodiments of the method for preparing the compounds of formula (I) and formula (II), the reaction in step b comprises the following steps:

[0135] Add hydrochloric acid / ethanol to the compound of formula (III), control the temperature, and stir to react.

[0136] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) according to the present invention, the purification of the crude product after post-treatment in step b comprises the following steps:

[0137] Stir, filter, wash the filter cake, and collect the filter cake to obtain the compound of formula (II-1).

[0138] In some embodiments of the method for preparing the compounds of formula (I) and formula (II) according to the present invention, step c includes reaction and post-treatment.

[0139] In some embodiments of the method for preparing the compounds of formula (I) and formula (II), the reaction in step c comprises the following steps:

[0140] 1) reacting the compound of formula (II-1) in the presence of dichloromethane and sodium carbonate;

[0141] 2) Separate the liquids, extract the aqueous phase with dichloromethane, combine the organic phases and concentrate;

[0142] 3) Add MeOH and a methanol solution of L(-)-tartaric acid to the concentrate and stir to react.

[0143] In some embodiments of the method for preparing the compounds of formula (I) and formula (II), the post-treatment in step c comprises the following steps:

[0144] Filter, wash the filter cake with MTBE, and collect the filter cake to obtain the compound of formula (II-1).

[0145] In some embodiments of the method for preparing the compound of formula (I) according to the present invention, the post-treatment in step a comprises purifying the crude compound of formula (I).

[0146] In some embodiments of the method for preparing the compound of formula (I) according to the present invention, the purification of the crude product after post-treatment in step a comprises the following steps:

[0147] 1) adding n-heptane to the compound of formula (I), stirring, heating, and concentrating;

[0148] 2) adding n-heptane, stirring, filtering, and washing the filter cake with a mixture of MTBE and n-heptane to obtain a wet product of the compound of formula (I);

[0149] 3) controlling the temperature and drying to obtain the compound of formula (I).

[0150] The present invention provides a method for preparing a compound represented by formula (I), which has the advantages of low-cost reaction starting materials, multi-step telescopic reaction, simple post-processing operation, high yield, high chemical and chiral purity of the product, and suitability for large-scale industrial production.

[0151] Unless otherwise stated, the terms used in this specification and claims have the following meanings.

[0152] The reaction process of the present invention is tracked by HPLC, HNMR or thin layer chromatography to determine whether the reaction is completed.

[0153] In the present invention, the internal temperature refers to the temperature of the reaction system. DETAILED DESCRIPTION

[0154] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0155] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0156] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0157] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).

[0158] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0159] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0160] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0161] The ratios shown in the silica gel column chromatography of the present invention are volume ratios.

[0162] The "equivalent" in the present invention refers to a molar ratio.

[0163] The “dosage ratio” is the ratio of the weight of the material (kg) to the volume of the solvent (L).

[0164] LDA: lithium diisopropylamide

[0165] BuLi: n-butyllithium

[0166] LiHMDS: lithium bis(trimethylsilyl)amide

[0167] DMF:N,N-dimethylformamide

[0168] THF:Tetrahydrofuran

[0169] DCM: dichloromethane

[0170] TsOH: p-toluenesulfonic acid

[0171] CuSO4: copper sulfate

[0172] Zn(OAc)2: Zinc acetate

[0173] Co(OAc)2·4H2O: Cobalt acetate hydrate

[0174] Na2SO4: sodium sulfate

[0175] MgSO4: magnesium sulfate

[0176] Ti(Oi-Pr)4:Tetraisopropyl titanium

[0177] DCC / DMAP: N,N'-dicyclohexylcarbodiimide / 4-dimethylaminopyridine

[0178] EDCI / DMAP: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 4-dimethylaminopyridine

[0179] HOAc / molecular sieve: acetic acid / molecular sieve system

[0180] CsF: Cesium Fluoride

[0181] KF: Potassium fluoride

[0182] NH4F (ammonium fluoride)

[0183] TBAF: Tetrabutylammonium fluoride

[0184] Na2CO3: sodium carbonate solution

[0185] NaHCO3: sodium bicarbonate solution

[0186] NaOH: sodium hydroxide

[0187] K3PO4: Potassium phosphate

[0188] Ti(OEt)4:Isopropyl titanate

[0189] n-heptane: n-heptane

[0190] ACN: Acetonitrile

[0191] Toluene:Toluene

[0192] DMSO: dimethyl sulfoxide

[0193] TMSCN: Trimethylsilyl cyanide

[0194] tartaric acid: tartaric acid

[0195] MTBE: Methyl tert-butyl ether

[0196] DIPEA: N,N-diisopropylethylamine

[0197] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0198] (Boc)2O: Di-tert-butyl carbonate

[0199] OTF: Trifluoromethanesulfonate

[0200] Example

[0201] (S)-tert-Butyl-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate (C7)

[0202] tert-butyl(S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate(C7)

[0203] Step 1: 4-Bromo-2-fluoro-1-(2-methoxyvinyl)benzene (C2)

[0204] 4-bromo-2-fluoro-1-(2-methoxyvinyl)benzene(C2)

[0205] Reaction: THF (8V) and LiHMDS (1.34eq) were added to the reactor. After the addition was completed, the mixture was stirred and cooled to 0±5°C under nitrogen protection; (methoxymethyl)triphenylphosphine chloride (1.3eq) was added in batches, kept warm at 0±5°C, and stirred for about 2h; then the temperature was controlled at 0±5°C, and a THF (2V) solution of C1 (53.0kg, 1.0eq) was added dropwise. After keeping the temperature at 0±5°C for about 2 hours, sampling and monitoring were performed. The control limit C1 / C1+C2≤2.0% was stopped.

[0206] Post-treatment: water (5V) was added to the reaction system to quench the reaction, the aqueous phase was extracted with MTBE (5V), stirred and separated, and the organic phase was concentrated and dried; n-heptane (10V) was added to the concentrate, stirred for about 1h, and filtered; magnesium chloride (1.5eq) was added to the filtrate, stirred at 60±5°C for about 16h, filtered, and the filtrate was washed with 5% EDTA-Na (5V), separated, the organic phase was concentrated and dried, and toluene (5V) was added and evaporated to give compound C2 (48.3kg, yield: 80.0%).

[0207] 1 H NMR (300 MHz, CDCl3) δ7.84(t,1H),7.17-7.04(m,1H),6.18(d,1H),5.33(d,1H),3.74(d,2H).

[0208] GCMS m / z=230.00

[0209] Step 2: 2-(4-bromo-2-fluorophenyl)acetaldehyde (C3)

[0210] 2-(4-bromo-2-fluorophenyl)acetaldehyde(C3)

[0211] Reaction: Add C2 (53.0 kg, 1.0 eq), toluene (10 V), and water (1 V) to a reactor with stirring. After addition, replace the atmosphere with nitrogen three times, raise the temperature to 70±5°C, add p-toluenesulfonic acid monohydrate (3.0 eq), and react at 70±5°C for approximately 1 hour. Samples were taken for monitoring. The reaction was stopped when the control limit (C2 / C2+C3) was ≤ 5.0%.

[0212] Post-treatment: After the reaction is complete, the liquid is separated, and the aqueous phase is extracted twice with toluene (2V); the organic phases are combined and washed once with 5% NaHCO3 solution (4V), the liquid is separated, and the organic phase is collected to obtain a toluene solution of C3 (total weight: 755.9 kg, content: 4.90%, yield: 74.1%), which is directly used in the next reaction.

[0213] GCMS: 215.90.

[0214] Step 3: (R,E)-N-(2-(4-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfenamide (C4)

[0215] (R,E)-N-(2-(4-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(C4)

[0216] Reaction: Add a toluene solution of C3 (37.0 kg, 1.0 eq), S-tert-butylsulfenamide (1.3 eq), and anhydrous copper sulfate (3.0 eq) to a reactor with stirring. After addition, heat the reaction mixture to 40±5°C and stir under nitrogen for 10 hours. Samples were taken for monitoring. The reaction was stopped when the control limit of C3 / C3+C4 was ≤ 20.0%.

[0217] Post-treatment: After the reaction is complete, pad with diatomaceous earth, filter the reaction solution, rinse the filter cake with toluene (1V), collect the filtrate, wash the filtrate twice with 5% sodium bicarbonate solution, let it stand and separate the liquid to obtain a toluene solution of C4 (total weight: 859.5 kg, content: 4.6%, yield: 72.4%), which is directly used in the next reaction.

[0218] 1 H NMR (300 MHz, CDCl3) δ8.10-7.96(m,1H),7.18(m,2H),7.09-6.92(m,1H),3.85-3.66(m,1H),1.08(s,9H).

[0219] LCMS m / z=320.0[M+1] +

[0220] The C4 in this step can also be prepared using the following method:

[0221] Reaction: To a reactor, add a solution of C3 (27.0 kg, 1.0 eq) in toluene (370 kg), S-tert-butylsulfenamide (1.3 eq.), acetic acid (2.5 V), and molecular sieves (108 kg) with stirring. After addition, replace the atmosphere with nitrogen three times, raise the temperature to 40 ± 5°C, and stir for 12 hours. Sampling and monitoring are performed. The reaction is stopped when the control limit (C3 / C3 + C4) is ≤ 20.0%.

[0222] Post-treatment: After the reaction is complete, the temperature is lowered to 20±5°C, a diatomaceous earth pad is used, the reaction solution is filtered, the filter cake is rinsed with toluene (2V), the filtrate is collected, and the filtrate is washed twice with 5% sodium bicarbonate solution. The solution is allowed to stand and separate to obtain a toluene solution of C4 (total weight: 366.6 kg, content: 5.0%, yield: 67.2%), which is directly used in the next reaction.

[0223] Step 4: (R)-N-((S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)-2-methylpropane-2-sulfenamide (C5-1)

[0224] (R)-N-((S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)-2-methylpropane-2-sulfinamide(C5-1)

[0225] Reaction: Add a toluene solution of C4 (39.5 kg, 1.0 eq) to a reactor, start stirring, and then add cesium fluoride (0.2 eq). Nitrogen is replaced three times, and the temperature is lowered to 0±5°C under nitrogen protection. Trimethylsilyl cyanide (1.5 eq) is slowly added dropwise, and the temperature is controlled at 0±5°C during the addition process. After the addition is completed, the temperature is maintained at 0±5°C and stirred for 12 hours. Sampling is monitored. The reaction is stopped when the control limit C4 / C4+C5 ≤ 2.0%.

[0226] Post-treatment: After the reaction is complete, 1% sodium carbonate solution is added to the system to quench the reaction, the pH is adjusted to 8, and the mixture is allowed to stand and separate to obtain an organic phase. The organic phase is washed with a mixed solution of 0.5% sodium carbonate and 3.0% sodium chloride (5v×3) and a 5.0% sodium chloride solution (5v×2) in sequence. The mixture is allowed to stand and separate, and the organic phase is collected to obtain a toluene solution of C5-1 (total weight: 862.5kg, content: 4.3%, yield: 88.2%), which is directly used in the next reaction.

[0227] LCMS m / z=347.2[M+1] +

[0228] C5-1 in this step can also be prepared using the following method:

[0229] Reaction: To the reactor, add a solution of C4 (0.2 kg, 1.0 eq) in toluene (2 kg, 1.0 eq), start stirring, and then add potassium fluoride (0.2 eq); cool to 0±5°C under nitrogen protection, slowly add trimethylsilyl cyanide (1.5 eq) dropwise, after the dropwise addition, control the temperature at 0±5°C and stir for 16 hours, take samples for monitoring, and stop the reaction when the control limit C4 / C4+C5≤2.0%.

[0230] Post-treatment: After the reaction is complete, 5% sodium carbonate solution is added to the system to quench the reaction, the pH is adjusted to 8, and the liquid is allowed to stand to obtain an organic phase. The organic phase is washed with a mixed solution of 5.0% sodium carbonate and 5.0% sodium chloride in turn, and the liquid is allowed to stand to collect the organic phase. The organic phase is concentrated to dryness to obtain a toluene solution of C5-1 (crude product: 0.23 kg, yield: 100%), which is directly used in the next reaction.

[0231] Step 5: (S)-2-amino-3-(4-bromo-2-fluorophenyl)propionitrile hydrochloride (C6)

[0232] (S)-2-amino-3-(4-bromo-2-fluorophenyl)propanenitrile hydrogen chloride(C6)

[0233] Reaction: Add C5-1 (37.0 kg, 1.0 eq) in toluene to the reactor, start stirring, replace with nitrogen three times, cool to 0±5°C under nitrogen protection, slowly add hydrochloric acid / ethanol (2.5 eq), control the temperature at 0±5°C during the addition process, raise the temperature to 20±5°C after the addition is completed, keep warm and stir for 4 hours, take samples for monitoring, and stop the reaction when the control limit C5-1 / C6+C5-1≤2.0%.

[0234] Post-treatment: After the reaction is completed, cool to 10±5°C and stir for 1 hour; filter and wash the filter cake with MTBE (2V); collect the filter cake to obtain the wet product C6 (total weight: 63.8 kg, content: 63.8%, yield: 100%), which is directly used in the next reaction.

[0235] 1 H NMR (400MHz, DMSO) δ9.00(s,2H),7.64(dd,1H),7.45-7.37(m,2H),4.84(t,1H),3.26-3.16(m,2H).

[0236] LCMS m / z=243.0[M-HCl+H] +

[0237] Step 6: (S)-2-amino-3-(4-bromo-2-fluorophenyl)propionitrile L-tartrate (C6-b)

[0238] (S)-2-amino-3-(4-bromo-2-fluorophenyl)propanenitrile(2R,3R)-2,3-dihydroxysuccinic acid(C6-b)

[0239] Reaction: C6 (58.4 kg, 1.0 eq) and dichloromethane (6 V) were added to the reactor, stirring was started, nitrogen was replaced three times, the temperature was cooled to 5±5 ° C, the temperature was controlled at 5±5 ° C, 5% sodium carbonate solution (10 V) was added dropwise, and after the dropwise addition, the temperature was raised to 20±5 ° C, stirred for 1 hour, allowed to stand and the liquid was separated, the aqueous phase was extracted once with DCM (3 V), the organic phases were combined, concentrated to about 2 times the system, cooled to 20±5 ° C, MeOH (3.5 V) was added, and a methanol (3.5 V) solution of L (-) -tartaric acid (0.8 eq) was added dropwise. After the dropwise addition, the mixture was kept warm at 15±5 ° C and stirred for 4 hours.

[0240] Post-treatment: After the reaction is completed, the mixture is filtered and the filter cake is washed with MTBE (3V); the filter cake is collected to obtain the wet product C6-b (total weight: 92.2 kg, content (free base): 36.9%, yield: 67.0%), which is directly used in the next reaction.

[0241] Purity: 98.2%

[0242] Chiral purity: 99.6%

[0243] Step 7: (S)-tert-Butyl-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate (C7)

[0244] tert-butyl(S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamate(C7)

[0245] Reaction: C6-b (54.8 kg, 1.0 eq) and dichloromethane MTBE (6 V) were added to the reactor, stirring was started, the temperature was lowered to 0±5°C, 5% sodium carbonate solution (1.1 eq) was added dropwise, and after the dropwise addition, the mixture was stirred for 20 min at a temperature of 0±5°C. (Boc)2O (1.6 eq) in MTBE (1 V) was added dropwise to the system. After the dropwise addition, the mixture was heated to 20±5°C, stirred for 15 hours at a temperature of 0±5°C, and sampling was performed for monitoring. The reaction was stopped when the control limit C6-b / C6-b+7≤1.0%.

[0246] Post-treatment: After the reaction is completed, the liquid is allowed to stand and separate, the aqueous phase is extracted once with MTBE (1V), and the organic phases are combined; n-heptane (10V) is added, stirred and heated to 35±5°C, and concentrated to about 10 times the volume; the temperature is cooled to 10±5°C, n-heptane (10V) is added, stirred for 3h and then filtered, and the filter cake is washed with MTBE:n-heptane = 1:7 (2V) to obtain C7 wet product, which is dried at 35±5°C for about 16 hours to obtain compound C7 (weight: 34.4kg, yield: 71.0%).

[0247] Purity: 99.6%

[0248] Chiral purity: 100.0%

[0249] 1 H NMR (400MHz, DMSO) δ7.84(s,1H),7.54(dd,1H),7.47-7.28(m,2H),4.69(d,1H),3.08(qd,2H),1.38(s,9H).

[0250] LCMS m / z=287.0[M-56+H]+ .

[0251] In summary, the method for preparing the compound represented by formula (I) provided by the present invention has the advantages of low-cost reaction starting materials, multi-step telescopic reaction, simple post-processing operation, 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), characterized in that: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; a: Prepare the compound represented by formula (I) from the compound represented by formula (II).

2. The preparation method according to claim 1, characterized in that: Further comprising the steps of: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; b: preparing a compound of formula (II-1) from a 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), characterized in that: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; b: preparing a compound of formula (II-1) from a 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, characterized in that: Further comprising the steps of: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; d: Preparing the compound of formula (III) from the compound of formula (IV).

5. A method for preparing a compound represented by formula (III), characterized in that: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; d: Preparing the compound of formula (III) from the compound of formula (IV).

6. The preparation method according to claim 4 or 5, characterized in that: Further comprising the steps of: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; g: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); f: preparing a compound of formula (V-1) from a compound of formula (VI); e: preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2).

7. A method for preparing a compound represented by formula (IV), characterized in that: wherein X is selected from a leaving group such as F, Cl, Br, I or OTf; g: preparing a compound of formula (VI) from a compound of formula (VII-1) and a compound of formula (VII-2); f: preparing a compound of formula (V-1) from a compound of formula (VI); e: preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2).

8. The preparation method according to any one of claims 1, 2, 4 and 6, characterized in that: a: The compound represented by formula (II) is reacted in the presence of an organic solvent and a base to obtain the compound represented by formula (I), The organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc)2O, and n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, and n-heptane; 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, and DBU, more preferably sodium carbonate.

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

10. The preparation method according to any one of claims 4 to 6, characterized in that: d: The compound of formula (IV) is prepared in the presence of a solvent, a cyaniding agent and a base to obtain a compound of formula (III), The solvent is preferably one or more of DCM, DMF, THF, n-heptane, ACN, Toluene, and DMSO, more preferably DCM or Toluene; The cyaniding agent is preferably one or more of TMSCN, sodium cyanide, potassium cyanide, and lithium cyanide, more preferably TMSCN; The base is preferably one or more of CsF, KF, TBAF, Na2CO3, K3PO4, Ti(OEt)4, more preferably CsF or KF, and even more preferably CsF.

11. The preparation method according to any one of claims 6 or 7, characterized in that: g: The compound of formula (VII-1) and the compound of formula (VII-2) are prepared in the presence of a base to obtain a compound of formula (VI), The base is preferably one or more of LiHMDS, NaHMDS, KHMDS, LDA, BuLi, and potassium tert-butoxide, more preferably LiHMDS, NaHMDS, and KHMDS, and more preferably LiHMDS; f: The compound of formula (VI) is prepared in the presence of an acid and an organic solvent to obtain a compound of formula (V-1), 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, and trimethylsilyl chloride, 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, and isopropanol, more preferably toluene; e: The compound of formula (V-1) and the compound of formula (V-2) are prepared in the presence of an organic solvent and a dehydrating agent to obtain a compound of formula (IV), The organic solvent is preferably one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid, and acetonitrile, more preferably toluene; The dehydration 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, HOAc / molecular sieve, and more preferably anhydrous CuSO4 and HOAc / molecular sieve.

12. A method for preparing a compound represented by formula (C7), characterized in that: in: g: C1 reacts in the presence of an organic solvent and a base to produce C2; f: C2 reacts in the presence of an organic solvent and an acid to produce C3; e: C3 reacts in the presence of an organic solvent and a dehydrating agent to produce C4; d: C4 reacts in the presence of a solvent, a base and a cyaniding agent to obtain C5-1; b: C5-1 reacts in the presence of an acid to produce C6; c: C6 is reacted in the presence of an organic solvent, a base and a chiral acid to obtain C6-b; a: C6-b is reacted in the presence of an organic solvent and a base to obtain C7.

13. The preparation method according to claim 12, characterized in that: g: the organic solvent is selected from one or more of tetrahydrofuran, dichloromethane, MTBE and n-heptane; The base is selected from one or more of LiHMDS, NaHMDS, and 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, trimethylsilyl chloride, 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, and 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, and acetonitrile, preferably toluene; the dehydrating agent 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, and HOAc / molecular sieve, preferably anhydrous CuSO4 and HOAc / molecular sieve; d: The solvent is selected from one or more of DCM, DMF, THF, n-heptane, ACN, Toluene, and DMSO, preferably DCM or Toluene; the cyaniding agent is selected from one or more of TMSCN, sodium cyanide, potassium cyanide, and lithium cyanide, preferably TMSCN; the base is selected from one or more of CsF, KF, TBAF, Na2CO3, K3PO4, and 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, isopropanol, preferably ethanol and MTBE; the acid is selected from one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, preferably HCl; c: the chiral acid solvent is selected from one or more of tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, lactic acid, diacetone-L-gulonic acid, mandelic acid, 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, and n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc)2O, and n-heptane; 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, and DBU, preferably sodium carbonate.

14. The preparation method according to claim 12 or 13, characterized in that: 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, HOAc / molecular sieve; d: the cyaniding agent is TMSCN, and the base is CsF; b: the organic solvent is selected from ethanol and 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, and n-heptane; the base is sodium carbonate.

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