Preparation method for KRAS inhibitor, intermediate thereof and preparation method for intermediate thereof

Abstract

Provided are a preparation method for a KRAS inhibitor, an intermediate thereof, and a preparation method for the intermediate thereof. The KRAS inhibitor can be prepared from the following low-cost raw materials by means of the following reaction. The preparation method has advantages such as low-cost and easy-to-obtain raw materials, shortened reaction steps, and high yield, and has good application prospects.

Description

Preparation method of KRAS inhibitor, intermediate thereof and preparation method of intermediate thereof

[0001] The present invention claims the following priority:

[0002] Application number CN202310895364X, filing date: July 19, 2023;

[0003] Application number CN202410941376.6, application date: July 12, 2024. Technical Field

[0004] The present invention provides a preparation method of a KRAS inhibitor, an intermediate thereof, and a preparation method of the intermediate thereof. Background Art

[0005] Cancer, a multi-stage process in which normal cells transform into tumor cells, is one of the top ten causes of death worldwide. Lung cancer is one of the most common cancers, with non-small cell lung cancer accounting for over 80%. Lung cancer also has a high incidence and diverse mutation types.

[0006] About 30% of cancer patients have RAS gene mutations. In cancer gene research, scientists discovered more than 20 years ago that RAS is a key gene in cancers including lung cancer, colorectal cancer, and pancreatic cancer.

[0007] In the United States, the three cancers with the highest mortality rates (pancreatic, colorectal, and lung cancer) also happen to be the three most common cancers with RAS mutations, accounting for 95%, 52%, and 31% of patients with these three cancers, respectively. KRAS mutations are the overwhelming majority in pancreatic, colorectal, and lung cancers, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder and head and neck cancers.

[0008] The KRAS gene mutation rate is 10–15% in Asian populations. KRAS is mutated in many cancers and is a major oncogene. KRAS-mutant tumors represent the most potentially targetable molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%-25% in NSCLC. In NSCLC, KRAS mutations primarily occur in codons 12 and 13. The most common codon variant, KRAS-G12C, accounts for approximately 39% of KRAS-mutant NSCLCs.

[0009] In lung adenocarcinoma, the probability of KRAS gene positivity accounts for 1 / 5-1 / 4, second only to the probability of EGFR positive mutations. The lack of targeted inhibitors makes both treatment and prognosis very difficult for patients with KRAS-positive non-small cell lung cancer. The "2013 NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer" clearly state that lung cancer patients must undergo KRAS gene testing before receiving EGFR-TKI treatment, and the decision on whether to use EGFR-TKI targeted drugs as clinical treatment measures will be based on the test results. If the KRAS gene is mutated, EGFR-TKI molecular targeted therapy is not recommended for patients.

[0010] WO2021052499A discloses compounds 29A and 29B having excellent ability to inhibit RAS-mediated signal transduction, and the synthesis route thereof is as follows:

[0011] The above route is a compound, but the synthesis route requires the introduction of methoxy protection and demethoxy protection, the linear synthesis steps are many, and the yield is low; Z1a is introduced by palladium catalyzed coupling, which is costly; compound 14 uses MOM as a protecting group, which easily introduces genotoxic impurities, and because of the introduction of the MOM protecting group, compound 15 has two axial chirality, which is not conducive to quality control, the reaction is more complicated, and the yield is not high; acryloyl chloride is used as an acrylation reagent, which is not conducive to quality control, the reaction is more complicated, and the yield is not high; chiral separation is performed after the last step, which is not conducive to the quality control of the raw material drug, and compound 19 is a pair of diastereomers, which are chirally separated by supercritical fluid chromatography (SFC) to obtain the final compound free base.

[0012] Therefore, a synthetic route with fewer synthetic steps and higher yield was designed, and the expensive coupling conditions were changed to avoid the introduction of genotoxic impurities easily caused by MOM as a protecting group, and the fact that acryloyl chloride was not conducive to quality control when used as an acrylation reagent. 3-Chloropropionyl chloride was selected as the acrylation reagent, and the chiral compounds were separated in advance to better control the raw materials, thereby better completing the synthesis of KRAS inhibitors and their intermediates.

[0013] Summary of the Invention

[0014] The technical problem to be solved by the present invention is to overcome the technical deficiencies of existing methods for preparing KRAS inhibitors and their intermediates, such as lengthy synthetic routes, poor quality control, expensive raw materials, low yields, or delayed resolution of chiral compounds. By providing a method for preparing a KRAS inhibitor, its intermediates, and methods for preparing the intermediates, the present invention provides at least any of the following advantages over existing methods: inexpensive and readily available starting materials, a shortened number of reaction steps, high yields, and avoids the potential for genotoxic impurities introduced by MOM as a protecting group and the inconvenient quality control of acryloyl chloride as an acrylation reagent. The method effectively resolves chiral compounds at an earlier stage, thus offering promising application prospects.

[0015] The present invention solves the above technical problems through the following technical solutions.

[0016] The first aspect of the present invention provides a method for preparing a compound of formula A5, comprising the following steps:

[0017] Step 1: Compound A1 and compound Z1a undergo aromatic nucleophilic substitution reaction to obtain a compound of formula A2;

[0018] Step 2: Esterification reaction of the compound of formula A2 and compound C to obtain a compound of formula A3;

[0019] Step 3: subjecting the compound of formula A3 to a halogenation reaction with a chlorination agent to obtain a compound of formula A4;

[0020] Step 4: Compound A4 is subjected to a ring-closure reaction to obtain compound A5;

[0021] Among them, R 1 is F or Cl; R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl, Br or I;

[0022] When R 3 When is H, the reaction does not go through the step of preparing the compound of formula A4 from the compound of formula A3.

[0023] In the present invention, the conditions and operations in the aromatic nucleophilic substitution reaction in step 1, the esterification reaction in step 2, the halogenation reaction in step 3, and the ring-closure reaction in step 4 are all conventional conditions and operations in the art. The following conditions and operations are particularly preferred in the present invention:

[0024] In step 1, the method for preparing the compound of formula A2 preferably comprises the following steps: in the presence of a base, in a solvent, subjecting the compound of formula A1 and the compound of formula Z1a to an aromatic nucleophilic substitution reaction to obtain the compound of formula A2;

[0025] The base is one or more of lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), NaH, t-BuOK, an alkali metal base (such as K2CO3) and an organic amine base (such as triethylamine);

[0026] Wherein, the base is preferably lithium hexamethyldisilazide.

[0027] Wherein, the molar ratio of the base to the compound of formula A1 is preferably (3-5):1, for example 4:1.

[0028] Wherein, the molar ratio of the compound of formula Z1a to the compound of formula A1 is preferably (1-3):1, for example 1.1:1.

[0029] The solvent is preferably one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, and a cycloalkane solvent. The aromatic hydrocarbon solvent may be one or more of toluene, xylene, and mesitylene. The ether solvent may be one or more of tetrahydrofuran, diethyl ether, and dioxane. The halogenated hydrocarbon solvent may be dichloromethane and / or chloroform. The cycloalkane solvent may be cyclohexane. In a preferred embodiment of the present invention, the solvent is an ether solvent, such as tetrahydrofuran.

[0030] The amount of the solvent is not particularly limited, as long as it does not affect the reaction. For example, the weight content of the compound of formula Z1a is preferably 10-40%, such as 22.5%, where the weight content is the percentage of the weight of the compound of formula Z1a to the total weight of the solvent and the compound of formula Z1a.

[0031] Among them, the compound of formula A1 is preferably

[0032] The aromatic nucleophilic substitution reaction temperature may be a conventional reaction temperature for this type of reaction, such as -15°C to 110°C, such as -15°C to 15°C, and such as -5°C to 5°C.

[0033] The progress of the aromatic nucleophilic substitution reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, NMR, or GC). The reaction endpoint is generally determined as the disappearance or non-reaction of the compound of Formula A1. The reaction time can be 1 to 10 hours, for example, 4 hours.

[0034] The preparation method may further include post-treatment, which may be conventional post-treatment in the art. For example, the post-treatment may include the following steps: after the aromatic nucleophilic substitution reaction is completed, heating to room temperature, quenching (e.g., adding acid (concentrated hydrochloric acid) and / or water), separating the liquids, washing (e.g., with an ether solvent (methyl tert-butyl ether)), precipitating the solid, filtering, and drying.

[0035] In step 2, the preparation method of the compound of formula A3 preferably comprises the following steps:

[0036] Step a: acylation reaction of the compound of formula A2 with an acylating agent in a solvent to obtain an acyl halide compound;

[0037] Step b: subjecting the acyl halide compound obtained in step 1 to an esterification reaction with the compound of formula C to obtain the compound of formula A3;

[0038] In step a, the solvent is preferably a chlorinated hydrocarbon solvent, such as dichloromethane.

[0039] In step a, the acylating agent is preferably oxalyl chloride.

[0040] In step a, the molar ratio of the acylating agent to the compound of formula A2 is preferably (1-3):1, for example 2:1.

[0041] In step a, the acylation reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably N,N-dimethylformamide. The mass ratio of the catalyst to the compound of formula A2 is preferably (0.001-0.1):1, for example 0.05:1.

[0042] In step a, the temperature of the acylation reaction is preferably 5°C-40°C, such as 15°C-25°C.

[0043] In step a, the progress of the acylation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, NMR, or GC), and the disappearance of the compound of formula A2 is generally used as the reaction endpoint. In the present invention, the acylation reaction time is preferably 20 minutes to 2 hours, for example, 0.5 hours.

[0044] The acyl halide compound obtained in step a is preferably directly subjected to the reaction in step b without post-treatment.

[0045] In step b, the compound of formula C is preferably methanol or ethanol.

[0046] In step b, the volume-to-mass ratio of the compound of formula C to the compound of formula A2 is preferably 1 L / kg-10 L / kg, for example 5 L / kg.

[0047] In step b, the reaction temperature is preferably 10°C-50°C, such as 30°C-40°C.

[0048] In step b, the progress of the reaction is monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, NMR or GC), and the disappearance of the acyl halide compound is taken as the reaction endpoint. In the present invention, the reaction time is preferably 0.5 hour to 3 hours, for example, 1 hour.

[0049] After the reaction is completed, a post-processing step may be further included. The post-processing step may be a conventional post-processing step in the art, such as concentration, extraction, brine washing, filtration, bleaching and concentration.

[0050] In step 3, the method for preparing the compound of formula A4 preferably comprises the following steps: subjecting the compound of formula A3 and a halogenating agent to a halogenation reaction in a solvent to obtain the compound of formula A4;

[0051] Wherein, the halogenating agent is preferably N-chlorosuccinimide (NCS), N-bromosuccinimide or N-iodosuccinimide, such as N-chlorosuccinimide.

[0052] Wherein, the molar ratio of the halogenating agent to the compound of formula A3 is preferably (1-2):1, for example 1.1:1.

[0053] Wherein, the compound of formula A3 is preferably

[0054] In the halogenation reaction, the solvent is preferably an amide solvent, such as N,N-dimethylformamide. The amount of the solvent used is not specifically limited, as long as it does not affect the reaction. In the present invention, the volume mass ratio of the solvent to the compound of formula A3 is preferably 1 L / kg to 5 L / kg, for example 3 L / kg.

[0055] The temperature of the halogenation reaction is preferably 30°C-80°C, such as 55°C-60°C.

[0056] The progress of the halogenation reaction is monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, NMR or GC), and the disappearance of the compound of formula A3 is generally used as the reaction endpoint. In the present invention, the halogenation reaction time is preferably 1 hour to 6 hours, for example, 3 hours.

[0057] In step 4, the method for preparing the compound of formula A5 is preferably as follows: in the presence of a base, a compound of formula A4 and acetic anhydride are subjected to a cyclization reaction in a solvent to obtain the compound of formula A5;

[0058] Wherein, the base is preferably an alkali metal base of tert-butoxide, such as lithium tert-butoxide.

[0059] Wherein, the molar ratio of the base to the compound of formula A4 is preferably (1-6):1, for example 4.5:1.

[0060] Wherein, the molar ratio of the acetic anhydride to the compound of formula A4 is preferably (1-6):1, for example 3.0:1.

[0061] Wherein, the compound of formula A4 is preferably

[0062] Wherein, the temperature of the cyclization reaction is preferably 5°C-50°C, such as room temperature.

[0063] The progress of the cyclization reaction is monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, NMR, or GC), and the disappearance of the compound of formula A4 is generally regarded as the reaction endpoint. The cyclization reaction time is preferably 1 to 5 hours, for example, 2 hours.

[0064] A second aspect of the present invention provides a method for preparing a compound of formula A2, comprising the following steps: subjecting compound A1 and compound Z1a to an aromatic nucleophilic substitution reaction to obtain a compound of formula A2;

[0065] Among them, R 1 is F or Cl.

[0066] Preferably, the preparation method of the compound of formula A2 comprises the following steps: in the presence of a base, in a solvent, subjecting the compound of formula A1 and the compound of formula Z1a to an aromatic nucleophilic substitution reaction to obtain the compound of formula A2; the base is lithium hexamethyldisilazide (LiHMDS).

[0067] The other conditions and operations of the aromatic nucleophilic substitution reaction are the same as those described above.

[0068] A third aspect of the present invention provides a method for preparing a compound of formula A3, comprising the following steps: subjecting a compound of formula A2 and a compound C to an esterification reaction to obtain a compound of formula A3;

[0069] Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0070] The conditions and operation of the esterification reaction are the same as those described above.

[0071] A fourth aspect of the present invention provides a method for preparing a compound of formula A4, comprising the following steps: subjecting a compound of formula A3 to a halogenation reaction with a halogenating agent to obtain a compound of formula A4;

[0072] Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0073] The conditions and operation of the halogenation reaction are the same as those described above.

[0074] In a fifth aspect, the present invention provides a compound of formula A2, a compound of formula A3 or a compound of formula A4:

[0075] Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl, Br or I;

[0076] The compound of formula A3 is preferably

[0077] The compound of formula A4 is preferably

[0078] A sixth aspect of the present invention provides a use of a substance L as a resolving agent in resolving a compound of formula AA5;

[0079] The substance L is one or more of D-3-bromocamphor-10-sulfonic acid, S-binaphthol phosphate, D-(+)-camphorsulfonic acid, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, S-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate, and S-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate.

[0080] or one or more of L-3-bromocamphor-10-sulfonic acid, R-binaphthol phosphate, L-(+)-camphorsulfonic acid, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol phosphate, and R-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate;

[0081] Among them, R 7 and R 8 are independently unsubstituted or substituted C 1-6 Alkyl or unsubstituted or substituted C1-6 R "and R' are independently H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, unsubstituted or substituted C 1-6 Alkyl or unsubstituted or substituted C 1-6 the substituted substituent is selected from F, Cl, Br, I, hydroxy, amino, nitro or cyano; p is 1 or 2, q is 1, 2 or 3; X is C or N.

[0082] The compound of formula AA5 is a compound with axial chirality, which can be A mixture, preferably a racemate of the compound of formula AA5.

[0083] In the application, the general formula of the compound of formula AA5 is preferably More preferred R 3 The definitions are the same as above.

[0084] In the application, the substance L is preferably S-binaphthol phosphate.

[0085] The application may also preferably include a method for resolving the compound of formula AA5, which comprises the following steps:

[0086] In a solvent, the compound of formula AA5 and the substance L are subjected to a salt-forming reaction to obtain a compound of formula AA5-L and a compound of formula AA5'-L;

[0087] The conditions and operations in the salt-forming reaction may be conventional conditions and operations in the art. The present invention particularly prefers the following conditions and operations:

[0088] The solvent may be one or more of a nitrile solvent, a ketone solvent, water, an ether solvent, an alkane solvent, a mixed solvent of an amine solvent, a mixed solvent of an ester solvent, or an alcohol solvent. The ketone solvent may be acetone. The ether solvent may be tetrahydrofuran and / or 2-methyltetrahydrofuran. The alkane solvent may be heptane. The nitrile solvent may be acetonitrile. The amine solvent may be isopropylamine. The alcohol solvent may be ethanol. The ester solvent may be ethyl acetate.

[0089] In a preferred embodiment of the present invention, the solvent is a mixed solvent of a ketone solvent and water (the volume ratio of the two is (10-30): 1, for example, a volume ratio of 19:1), a mixed solvent of an ether solvent and an alkane solvent (the volume ratio of the two is (0.25-4): 1, for example, a volume ratio of 1:1), a mixed solvent of a nitrile solvent and an amine solvent (the volume ratio of the two is (0.25-4): 1, for example, a volume ratio of 1:1), a mixed solvent of an ether solvent and an ester solvent (the volume ratio of the two is (0.25-4): 1, for example, a volume ratio of 1:1), a nitrile solvent or an alcohol solvent, for example, a mixed solvent of acetone and water with a volume ratio of 19:1, a mixed solvent of 2-methyltetrahydrofuran and heptane with a volume ratio of 1:1, a mixed solvent of acetonitrile and isopropylamine with a volume ratio of 1:1, a mixed solvent of tetrahydrofuran and ethyl acetate with a volume ratio of (1-9): 1, acetonitrile or ethanol (EtOH). The volume mass ratio of the solvent to the compound of formula AA5 can be 5 mL / g-40 mL / g, for example 20 mL / g.

[0090] When the solvent is a mixed solvent of a ketone solvent and water, a mixed solvent of an ether solvent and an alkane solvent, a mixed solvent of a nitrile solvent and an amine solvent, a mixed solvent of an ether solvent and an ester solvent, a nitrile solvent or an alcohol solvent, the compound of formula AA5-L or the compound of formula AA5'-L can be obtained directly by filtration without going through the crystallization step, and the filtrate can be recovered (to recover the resolving agent and the compound of formula AA5).

[0091] In a preferred embodiment of the present invention, when the substance L is D-3-bromocamphor-10-sulfonic acid, the solvent is a mixed solvent of a ketone solvent-water, a mixed solvent of a nitrile solvent-amine solvent, or a mixed solvent of an ether solvent-ester solvent.

[0092] When the substance L is S-binaphthol phosphate, the solvent is preferably a ketone solvent-water mixed solvent, an ether solvent-alkane solvent mixed solvent, a nitrile solvent-amine solvent mixed solvent, an ether solvent-ester solvent mixed solvent or an alcohol solvent.

[0093] When the substance L is D-(+)-camphorsulfonic acid, the solvent is preferably a mixed solvent of ketone solvent-water, a mixed solvent of ether solvent-alkane solvent, or a mixed solvent of nitrile solvent-amine solvent.

[0094] The molar ratio of the compound of formula AA5 to the substance L is based on the conventional amount used in chiral resolution in the art, such as 1:(0.5-3), for example 1:1.

[0095] The temperature of the salt-forming reaction is conventional in the art, for example, heating to reflux of the solvent. The reaction temperature can be 10-70°C, for example, 40-50°C.

[0096] After the salt-forming reaction is completed, the following post-treatment operation may be further included: crystallization; in the crystallization, the solvent is preferably a mixed solvent of a ketone solvent-water, a mixed solvent of an ether solvent-alkane solvent, a mixed solvent of a nitrile solvent-amine solvent, a mixed solvent of an ether solvent-ester solvent, a nitrile solvent or an alcohol solvent, such as a mixed solvent of acetone-water with a volume ratio of 19:1, a mixed solvent of 2-methyltetrahydrofuran-heptane with a volume ratio of 1:1, a mixed solvent of acetonitrile-isopropylamine with a volume ratio of 1:1, a mixed solvent of ethyl acetate-tetrahydrofuran with a volume ratio of 1:1, acetonitrile or ethanol (EtOH).

[0097] After the crystallization is completed, the method preferably further includes filtering and washing.

[0098] The mother liquor after the crystallization can also be used to recover the above-mentioned resolving agent and (The above-mentioned resolving agent recovered can be recycled for the resolution of the compound of formula AA5; It can also be converted into the above-mentioned compound of formula A5 by methods in the art for recycling).

[0099] The application may also include a free reaction of the compound of formula AA5-L or the compound of formula AA5'-L with a free reagent to obtain a compound of formula DD5 or DD5';

[0100] Among them, R 7 、R 8 , R", R', X, substance L, p and q are as defined above.

[0101] The conditions and operations in the free reaction are conventional conditions and operations in the art. The present invention particularly prefers the following conditions and operations:

[0102] The free reagent can be a conventional base or acid for this type of hydrolysis reaction in the art, preferably an alkali metal bicarbonate or hydrochloric acid, such as sodium bicarbonate.

[0103] The molar ratio of the compound of formula AA5-L or the compound of formula AA5'-L to the free reagent is the conventional molar ratio of this type of free reaction in the art, preferably 1:(1-4), for example, more preferably 1:2.

[0104] The free reaction temperature is a conventional temperature for this type of free reaction in the art, and is preferably 10°C-30°C in the present invention.

[0105] The post-treatment after the free reaction preferably includes filtration, washing and recovery of the filtrate.

[0106] In the application, the compound of formula AA5-L can be a compound of formula A5-L or a compound of formula B5-L, and correspondingly, the compound of formula DD5 can be D5 or E5;

[0107] The compound of formula AA5'-L can be a compound of formula A5'-L or a compound of formula B5'-L; correspondingly, the compound of formula DD5 can be D5' or E5';

[0108] R 3 The definitions of and substance L are the same as described above.

[0109] Wherein, the compound of formula A5-L or the compound of formula B5-L can be

[0110] Wherein, the compound of formula A5'-L or the compound of formula B5'-L can be

[0111] A sixth aspect of the present invention provides a method for purifying a substance M, comprising the following steps: crystallizing the substance M in a solvent to obtain the compound of formula AA5-L or the compound of formula AA5'-L;

[0112] The substance M includes the above-mentioned compound of formula AA5-L and the above-mentioned compound of formula AA5'-L;

[0113] Among them, R 7 、R 8 , R", R', X and substance L are as defined above.

[0114] The operation and conditions of the salt-forming reaction are also the same as described above.

[0115] In a preferred embodiment of the present invention, the substance M is any one of the following mixtures:

[0116] mixture of mixture of mixture of mixture of mixture, or mixture.

[0117] Preferably, the molar ratio of the two compounds in the above mixture is 1:1.

[0118] In a seventh aspect, the present invention provides a method for preparing a compound of formula AA5-L or a compound of formula AA5'-L: in a solvent, the compound of formula AA5 and a substance L are subjected to a salt-forming reaction to obtain the compound of formula AA5-L or the compound of formula AA5'-L;

[0119] Among them, R 7 、R 8 , R", R', X, substance L, p and q are as defined above;

[0120] The general formula of the compound of formula AA5 is Preferably

[0121] R 3 is H, F, Cl, Br or I.

[0122] The conditions and operation of the salt-forming reaction are the same as those described above.

[0123] In an eighth aspect, the present invention provides a method for preparing the compound of formula DD5 or DD5', comprising the steps of: subjecting the compound of formula AA5-L or AA5'-L to a freeing reaction with a free reagent to obtain the compound of formula DD5 or DD5';

[0124] Among them, R 7 、R 8 , R", R', X and substance L are as defined above.

[0125] The compound of formula AA5-L may be a compound of formula A5-L or a compound of formula B5-L; correspondingly, the compound of formula DD5 may be D5 or E5;

[0126] The compound of formula AA5'-L can be a compound of formula A5'-L or a compound of formula B5'-L; correspondingly, the compound of formula DD5 can be D5' or E5';

[0127] R 3 is H, F, Cl, Br or I.

[0128] The conditions and operation of the free reaction are as described above.

[0129] In an eighth aspect, the present invention provides a compound of formula AA5-L, a compound of formula AA5-L' or a substance M; the substance M comprises the compound of formula AA5-L and the compound of formula AA5'-L:

[0130] The R 7 、R 8 , R", R', X, substance L, p and q are as defined above.

[0131] The general formula of the compound of formula AA5-L is preferably R 3 The definitions of , X and substance L are the same as described above.

[0132] The general formula of the compound of formula AA5'-L is preferably R 3 The definitions of , X and substance L are the same as described above.

[0133] The compound of formula AA5-L is preferably any one of the following compounds:

[0134] The compound of formula AA5'-L is preferably any one of the following compounds:

[0135] The substance M is preferably mixture;

[0136] More preferably, a mixture of any of the following groups:

[0137] mixture of mixture of mixture of mixture of mixture, or mixture.

[0138] Preferably, the molar ratio of the compound of formula AA5-L to the compound of formula AA5'-L in the above mixture is 1:1.

[0139] A ninth aspect of the present invention provides a method for preparing a compound of formula D6, comprising the following steps:

[0140] In a continuous flow reactor, in the presence of a solvent and in the presence or absence of a catalyst, the compound of formula D5 is subjected to a nitration reaction as shown below with nitric acid to obtain the compound of formula D6; when the catalyst is present, it is a nitrite;

[0141] R 3 is H, F, Cl, Br or I.

[0142] A ninth aspect of the present invention provides a method for preparing a compound of formula D6, comprising the following steps:

[0143] In a continuous flow reactor, the compound of formula D5 is subjected to a nitration reaction with nitric acid as shown below in the presence of a solvent and a catalyst to obtain the compound of formula D6; the catalyst is a nitrite;

[0144] R 3 is H, F, Cl, Br or I.

[0145] The continuous flow reactor can be a conventional reactor in continuous flow reactions, such as a shell-and-tube reactor or a microreactor.

[0146] In the nitration reaction, the nitrite is a conventional nitrite in the art, preferably an alkali metal nitrite, such as sodium nitrite, or another example, a 30% sodium nitrite aqueous solution.

[0147] In the nitration reaction, the molar ratio of the nitrite to the compound of formula D5 is a conventional molar ratio in the art, preferably (0.01-3):1, for example 0.7:1.

[0148] In the nitration reaction, the molar ratio of the nitric acid to the compound of formula D5 is a conventional molar ratio in the art, preferably (1-10):1, for example 2.7:1.

[0149] In the nitration reaction, the molar ratio of the nitric acid to the compound of formula D5 is a conventional molar ratio in the art, preferably (1-10):1, such as 2.7:1 or 4:1.

[0150] In the nitration reaction, the solvent is a conventional solvent in the art, preferably a carboxylic acid organic solvent and / or water. The carboxylic acid organic solvent may be acetic acid and / or propionic acid. When the organic solvent is acetic acid and propionic acid, the mass ratio of the propionic acid to the acetic acid is preferably (0.5-10):1, for example, 2:1. When the organic solvent is acetic acid, the volume mass ratio of the acetic acid to the D5 compound is preferably (1-30) mL / g, for example, 4 mL / g.

[0151] The compound of formula D5 is preferably

[0152] In the nitration reaction, the reaction is carried out at a temperature conventional for such reactions, for example, at -40°C to 100°C, for example, 5°C.

[0153] In the nitration reaction, the reaction is carried out at a temperature conventional for such reactions, for example, at -40°C to 100°C, for example, 5°C or 70°C.

[0154] In the preparation method of the present invention, the solvent, the compound of formula D5 and nitric acid can be mixed in a variety of ways to carry out a continuous flow reaction. For example, each component of the material can be sampled simultaneously for a continuous flow reaction, or any components can be mixed together to form a group of materials or several groups of materials that are sampled simultaneously or sequentially for reaction.

[0155] In the preparation method of the present invention, the catalyst, the solvent, the compound of formula D5, and nitric acid can be mixed in a variety of ways to conduct a continuous flow reaction. For example, each component of the material can be simultaneously sampled for a continuous flow reaction, or any components of the material can be mixed together to form a single material group or multiple material groups, which can be sampled simultaneously or sequentially for reaction. In a preferred embodiment of the present invention, when the optional components are mixed together to form a single material group or multiple material groups, which can be sampled sequentially for reaction, the solvent and the compound of formula D5 constitute material a; nitric acid constitutes material b; and the catalyst constitutes material c. Material a and material b are simultaneously fed and mixed uniformly to form a mixed solution, and then material c is further mixed uniformly with the mixed solution.

[0156] In a preferred embodiment of the present invention, when the arbitrary components are mixed together to form a material group or several material groups, which are sequentially sampled for reaction, the solvent and the compound of formula D5 constitute material a; nitric acid is material b; the catalyst is not present; the material a and the material b are fed simultaneously and mixed uniformly to obtain a mixed solution.

[0157] The injection speed of the material a can be 1 mL / min-20000 mL / min, for example, 19.4 mL / min. The injection speed of the material a can be 1 mL / min-20000 mL / min, for example, 19.4 mL / min or 1 mL / min.

[0158] The injection speed of the material b can be 0.1 mL / min-2000 mL / min, for example, 1.2 mL / min. The injection speed of the material b can be 0.1 mL / min-2000 mL / min, for example, 1.2 mL / min or 0.17 mL / min.

[0159] The injection speed of the material c can be 0.1 mL / min-2000 mL / min, for example, 1.1 mL / min.

[0160] In the present invention, the progress of the reaction is monitored by conventional monitoring methods in the art, such as online infrared or high performance liquid chromatography for full-process online monitoring of the reaction; generally, the disappearance or no-reaction of the compound of formula D5 is regarded as the endpoint of the reaction.

[0161] The residence time of the catalyst, the solvent, the compound of formula D5 and the nitric acid in the continuous flow reactor can be 0.5 min to 20 min, for example, 1.5 min.

[0162] The residence time of the catalyst, the solvent, the compound of formula D5 and the nitric acid in the continuous flow reactor can be 0.5 min to 40 min, for example, 1.5 min or 25 min.

[0163] In a preferred embodiment of the present invention, the reaction liquid obtained after the nitration reaction is completed in a continuous flow reactor is preferably subjected to post-treatment after continuing the reaction under conventional batch reaction conditions (for example, at 5° C. for 30 minutes).

[0164] In the present invention, the post-treatment steps are conventional post-treatment steps in the art, such as adjusting the pH value to be weakly acidic (such as adjusting the pH to 6 with NaOH), filtering and drying.

[0165] In the present invention, the preparation method of the compound of formula D6 may also include the preparation method of the compound of formula D5; the conditions and operations of the preparation method of the compound of formula D5 are the same as described above.

[0166] In a tenth aspect, the present invention provides a method for preparing a compound of formula C3, comprising the following steps: subjecting a compound of formula C1 and a compound N to a substitution reaction in a solvent in the presence of an alkaline reagent, a palladium catalyst, and a phosphine ligand to obtain the compound of formula C3;

[0167] The compound N is a compound of formula C2, a compound of formula C2', a compound of formula C2" or

[0168] Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group; R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; each R 6 are independently H, a hydroxy protecting group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

[0169] L is a connecting bond (i.e., N in -NH- is connected to ring A) or -C(=O)-;

[0170] Ring A is phenyl, substituted phenyl, naphthyl or substituted naphthyl; the substituents in the substituted phenyl and the substituents in the substituted naphthyl are independently nitro, F, Cl, Br, C 1-4Alkyl, C 1-4 an alkoxy group or a phenyl group.

[0171] R 4 In the above, the amino protecting group is a group used to protect amino groups in the field of organic chemistry, such as -(-Boc).

[0172] Each R 6 In the embodiment, the hydroxyl protecting group is a group used to protect amino groups in the field of organic chemistry, for example (THP) or (MOM).

[0173] The conditions and operations of the substitution reaction are conventional conditions and operations for such reactions in the art. The present invention particularly prefers the following conditions and operations:

[0174] The alkaline agent may be an alkali metal fluoride and / or an alkali metal phosphate. The alkali metal fluoride may be potassium fluoride or cesium fluoride. The alkali metal phosphate may be dipotassium hydrogen phosphate.

[0175] The molar ratio of the alkaline reagent to the compound of formula C1 can be (2-8):1, for example 5:1.

[0176] The palladium catalyst is preferably one or more of Pd2(dba)3, Pd(OAc)2, [Pd(C3H5)Cl]2, Pd(PPh3)4, Pd(CF3COO)2, Pd(TFA)2, Pd(MeCN)2Cl2 and [(cinnamyl)PdCl]2.

[0177] The molar ratio of the palladium catalyst to the compound of formula C1 can be (0.01%-5%):1, or can be (0.1%-3%):1, for example, 0.15%:1, 0.25%:1, 0.35%:1, 0.4%:1, 1.1%:1, 1.5%:1, 1.6%:1, 1.8%:1, 2.0%:1, 2.5%:1 or 3%:1.

[0178] The phosphine ligand is preferably one or more of PPh3, BI-DIME, Ph2DavePHOS, DTP-DPEPhos, Tris(p-anisyl)phosphine, AntPhos, DBFphos, cataCXium PCy, Ph2Cy, AmgenPHOS, HiersoPHOS-6, DBFphos, (p-anisyl)3P, Ph2P(tBu), Cy2P(o-Tol), Ph2DavePHOS, p-NMe2-Cy-JohnPHOS, (t-Bu)2P(n-hexyl)HBF4 and (Rac)-AntPhos.

[0179] When the compound N is a compound of formula C2, the palladium catalyst is preferably Pd2(dba)3, and the phosphine ligand is preferably PPh3 and / or SylPhos.

[0180] When the compound N is a compound of formula C2", the alkaline agent is preferably an alkali metal phosphate; the palladium catalyst is preferably [Pd(C3H5)Cl]2 and / or Pd(CF3COO)2; and the phosphine ligand is preferably Ph2P(t-Bu) and / or PPh3.

[0181] When the compound N is When the alkaline agent is preferably an alkali metal phosphate; the palladium catalyst is preferably Pd(CF3COO)2; and the phosphine ligand is preferably a mixture of PPh3 and PPh3O.

[0182] The molar ratio of the phosphine ligand to the compound of formula C1 can be (0.02%-16%):1, or (0.6%-12%):1, for example, 0.6%:1, 1.0%:1, 1.4%:1, 1.5%:1, 1.6%:1, 2.2%:1, 3%:1, 4%:1 or 12%:1.

[0183] The molar ratio of the compound N to the compound of formula C1 can be (1-3):1, for example, 1.05:1, 1.1:1 or 1.3:1.

[0184] The compound N is preferably

[0185] The solvent can be an ether solvent-water mixed solvent or a nitrile solvent-water mixed solvent, such as a dioxane-water mixed solvent (for example, the volume ratio of the two is 2:1) or an acetonitrile-water mixed solvent (for example, the volume ratio of the two is 2:1).

[0186] The temperature of the substitution reaction can be 40°C-150°C, or 60°C-90°C.

[0187] The progress of the substitution reaction is monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, NMR, or LCMS), and the reaction endpoint is generally determined as the disappearance or cessation of reaction of the compound of Formula C1. In the present invention, the reaction time can be 1 to 24 hours, e.g., 3 hours or 2.5 hours.

[0188] The post-treatment steps after the substitution reaction can be conventional post-treatment steps for such reactions in the art, such as solid precipitation, filtration and drying.

[0189] The preparation method of the compound of formula C3 may further include the preparation method of the compound of formula C1; the preparation method of the compound C1 preferably includes the following steps:

[0190] In a solvent, the compound of formula D9 undergoes a Mitsunobu reaction with the compound of formula X9a to obtain the compound of formula C1;

[0191] The conditions and operations of the Mitsunobu reaction are conventional conditions and operations in the art.

[0192] The preparation method of the compound of formula C3 may also include the preparation method of the compound of formula D9; the preparation method of the compound of formula D9 is method I and method II:

[0193] Method I:

[0194] The method comprises the following steps: in a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, subjecting a compound of formula D8 to the following reaction to obtain the compound of formula D9;

[0195] The metal catalyst is a platinum catalyst or a palladium catalyst;

[0196] Method II:

[0197] The method comprises the following steps: subjecting a compound of formula D8 to a reduction reaction in a solvent (isopropyl acetate) in the presence of a reducing agent (such as iron powder) and acetic acid to obtain the compound of formula D9;

[0198] Among them, R 3 is H, F, Cl or Br; R 4 It is an amino protecting group.

[0199] In method I, the continuous flow reactor can be a conventional reactor in continuous flow reactions, such as a shell and tube reactor or a microreactor.

[0200] In method I, the metal catalyst is supported on a conventional carrier in the art, preferably carbon. The content of the metal in the metal catalyst is the conventional content in the art.

[0201] In Method I, the reaction is preferably carried out in the presence of an acid catalyst. The acid catalyst is preferably acetic acid. When the reaction is carried out in the presence of an acid catalyst, the reaction can be carried out in a one-step process or a two-step process. The one-step process preferably involves directly introducing the acid catalyst into the reaction system, and then carrying out hydrogenation and ring closure in a continuous flow reactor. The two-step process preferably involves hydrogenating the compound of Formula D8, and then adding an acid catalyst to the reaction solution after the hydrogenation to carry out ring closure.

[0202] In method I, the solvent is a conventional solvent in the art, preferably one or more of an ester solvent, an ether solvent, and a carboxylic acid organic solvent, preferably an ester solvent. In a preferred embodiment of the present invention, the solvent is one or more of ethyl acetate, tetrahydrofuran, and isopropyl acetate, and another example is ethyl acetate (which can reduce production costs and simplify post-processing operations).

[0203] In method I, the amount of the solvent is not specifically limited, and preferably the minimum amount of solvent is used to achieve the best effect. The mass ratio of the solvent to the compound of formula D8 is preferably (10-40):1, for example 10:1, 20:1, 30:1, 35:1 or 40:1.

[0204] In methods I and II, the compound of formula D8 is preferably

[0205] In method I, the reaction is carried out at a temperature conventional for such reactions, for example, at 55°C to 100°C, such as 70°C, 80°C or 85°C.

[0206] In method I, the reaction is carried out at a temperature conventional for such reactions, for example, at 50°C to 100°C, such as 50°C, 60°C, 70°C, 80°C or 85°C.

[0207] In method I, the reaction can be carried out under pressure, for example, at a pressure of 0.3 MPa-5 MPa, for example, 1 MPa.

[0208] In method I, in the preparation method of the present invention, the base, the solvent, the compound of formula D8, and H2 can be mixed in a variety of ways to carry out a continuous flow reaction. For example, each component of the material is separately and simultaneously introduced into the continuous flow reaction, or any components of the material are mixed together to form a group of material groups or several groups of material groups that are simultaneously introduced into the reaction. In a preferred embodiment of the present invention, when the solvent and the compound of formula D8 constitute material a, and hydrogen is material b, material a and material b are separately and simultaneously introduced into the reaction. When the reaction is carried out in the presence of an acid catalyst, the material a can also be the solvent, the compound of formula D8, and the acid catalyst that constitute the raw material liquid.

[0209] The injection speed of the material a can be 0.1 mL / min-5 mL / min, for example, 1 mL / min.

[0210] The injection speed of the material b can be 5 mL / min-100 mL / min, for example, 60 mL / min.

[0211] Wherein, the material a and the material b can be preheated to 55°C-100°C (eg, 70°C, 80°C or 85°C) before being fed for reaction.

[0212] Wherein, the material a and the material b can be preheated to 50°C-100°C (eg, 50°C, 60°C, 70°C, 80°C or 85°C) before being fed for reaction.

[0213] In method I, the progress of the reaction is monitored by conventional monitoring methods in the art, such as online infrared or high-performance liquid chromatography for full-process online monitoring of the reaction; the disappearance or no-reaction of the compound of formula D8 is generally regarded as the endpoint of the reaction.

[0214] In method I, the residence time of the material a and the material b in the continuous flow reactor can be 1 min-10 min, for example, 5 min.

[0215] In method I, in a preferred embodiment of the present invention, the metal catalyst is a platinum catalyst; the reaction is carried out in the presence of an acid catalyst; the reaction is completed in a one-step process; and the solvent is ethyl acetate.

[0216] In the present invention, after the reaction is completed, a post-processing step may be further included. The post-processing step may be a conventional post-processing step in the art, such as extraction, alkali washing (7% sodium bicarbonate solution), saturated brine washing and concentration.

[0217] The preparation method of the compound of formula C3 may also include the preparation method of the compound of formula D8; the preparation method of the compound of formula D8 comprises the following steps:

[0218] In the presence of a base (such as N,N-diisopropylethylamine), the compound of formula D7 and the compound of formula Y7a are subjected to the following reaction in a solvent (such as acetonitrile) to obtain the compound of formula D8;

[0219] The preparation method of the compound of formula C3 may also include the preparation method of the compound of formula D7; the preparation method of the compound of formula D7 comprises the following steps:

[0220] In the presence of a base (such as N,N-diisopropylethylamine), the compound of formula D6 and phosphorus oxychloride are reacted in a solvent (such as acetonitrile) to obtain the compound of formula D7;

[0221] The preparation method of the compound of formula C3 may also include the preparation method of the compound of formula D6; the preparation method of the compound of formula D6 is the same as described above.

[0222] The eleventh aspect of the present invention provides a method for preparing a compound of formula D9, comprising the following steps:

[0223] In a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, the compound of formula D8 is subjected to the following reaction to obtain the compound of formula D9;

[0224] The metal catalyst is a platinum catalyst or a palladium catalyst;

[0225] Among them, R 3 is H, F, Cl or Br; R 4 It is an amino protecting group.

[0226] The conditions and operations in the preparation method of the compound of formula D9 are the same as those described above.

[0227] The twelfth aspect of the present invention provides a compound of formula C1, C2 or C2':

[0228] Among them, R 3 、R 4 、R 5 , L, Ring A and The definitions are the same as above.

[0229] Formula C1 is preferably

[0230] Formula C2 is preferably

[0231] Formula C2' is preferably

[0232] In a thirteenth aspect, the present invention provides a method for preparing a compound of formula C2 or a compound of formula C2', comprising the following steps: reacting a compound of formula C2a with a "compound of formula C2-1-SM or a compound of formula C2-3-SM" in a solvent to obtain the compound of formula C2 or the compound of formula C2';

[0233] R 5 , A and L are defined as above.

[0234] In the present invention, the solvent can be a conventional solvent for this type of reaction, preferably one or more of an ether solvent, a nitrile solvent, an aromatic hydrocarbon solvent and an amide solvent, and more preferably a mixed solvent of toluene and N,N-dimethylformamide (volume ratio of 6.5:1), a mixed solvent of toluene and acetonitrile, tetrahydrofuran or toluene.

[0235] In the present invention, the molar ratio of the "compound of formula C2-1-SM or the compound of formula C2-3-SM" to the compound of formula C2a can be the conventional amount used in the art, preferably (0.9-1.2):1, for example 0.9:1 or 1.0:1.

[0236] In the present invention, the reaction temperature may be a conventional temperature for such reactions in the art, preferably 20°C-120°C, such as 30°C, 80°C or 115°C.

[0237] In the present invention, the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, NMR, or LCMS). The reaction endpoint is generally determined as the disappearance or cessation of reaction of the compound of formula C2a or the compound of formula C2-1-SM or the compound of formula C2-3-SM. In the present invention, the reaction time can be 1 to 5 hours, for example, 3 hours or 2.5 hours.

[0238] In the present invention, the post-processing steps after the reaction can be conventional post-processing steps for such reactions in the art, such as cooling, washing, distillation, filtration and drying.

[0239] A fourteenth aspect of the present invention provides a method for preparing a compound of formula C6, comprising the following steps: reacting a compound of formula C4 and a compound of formula C5 in a solvent (e.g., a mixed solvent of dichloromethane and N-methylpyrrolidone in a weight ratio of 28:1) to obtain the compound of formula C6 by carrying out the following reaction (e.g., the reaction temperature is 0-15°C);

[0240] R 3 is H, F, Cl, Br or I.

[0241] The method for preparing the compound of formula C6 may further comprise the following steps: subjecting the compound of formula C3 to a deprotection reaction in a solvent in the presence of a deprotection agent (e.g., hydrochloric acid) to obtain the compound of formula C4;

[0242] R 4 is an amino protecting group, for example -Boc.

[0243] A fifteenth aspect of the present invention provides a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt (e.g., sulfate) thereof, which is any of the following schemes:

[0244] Option 1:

[0245] The method comprises the following steps: a preparation method of a compound of formula A5;

[0246] and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula A5;

[0247] The preparation method of the compound of formula A5 comprises the following steps:

[0248] Step 1: Compound A1 and compound Z1a undergo aromatic nucleophilic substitution reaction to obtain compound A2;

[0249] Step 2: Esterification reaction of compound A2 and compound C to obtain compound A3;

[0250] Step 3: Compound A3 is subjected to a halogenation reaction with a halogenating agent to obtain Compound A4;

[0251] Step 4: Compound A4 undergoes ring-closure reaction to obtain compound A5;

[0252] Among them, R 1 is F or Cl; R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

[0253] Option 2:

[0254] The method comprises the following steps: a preparation method of a compound of formula A2;

[0255] and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula A2;

[0256] The preparation method of the compound of formula A2 comprises the following steps: in the presence of a base, in a solvent, subjecting the compound of formula A1 and the compound of formula Z1a to an aromatic nucleophilic substitution reaction to obtain the compound of formula A2;

[0257] The base is lithium hexamethyldisilazide (LiHMDS);

[0258] Option 3:

[0259] The method comprises the following steps: a preparation method of a compound of formula D6;

[0260] and, the compound of formula D6 is further prepared to obtain a compound of formula C7 or a pharmaceutically acceptable salt thereof;

[0261] The preparation method of the compound of formula D6 comprises the following steps: in a continuous flow reactor, in the presence of a nitrite catalyst, nitric acid and a solvent, subjecting the compound of formula D5 to a nitration reaction as shown below to obtain the compound of formula D6;

[0262] R 3 is H, F, Cl or Br;

[0263] Scheme 4: It comprises the following steps: a method for preparing a compound of formula D9;

[0264] and, a method for preparing a compound of formula C7 or a salt thereof by further preparing the compound of formula D9;

[0265] The preparation method of the compound of formula D9 comprises the following steps: in a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, subjecting the compound of formula D8 to the following reaction to obtain the compound of formula D9;

[0266] The metal catalyst is a platinum catalyst or a palladium catalyst;

[0267] Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group;

[0268] Option 5:

[0269] The method comprises the following steps: a preparation method of a compound of formula C3;

[0270] and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula C3;

[0271] The preparation method of the compound of formula C3 comprises the following steps: in the presence of an alkaline reagent, a palladium catalyst and a phosphine ligand, subjecting the compound of formula C1 and compound N to a substitution reaction in a solvent to obtain the compound of formula C3;

[0272] The compound N is a compound of formula C2, a compound of formula C2', a compound of formula C2" or

[0273] Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group; R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; each R 6 are independently H, a hydroxy protecting group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

[0274] L is a connecting bond (i.e., N in -NH- is connected to ring A) or -C(=O)-;

[0275] Ring A is phenyl, substituted phenyl, naphthyl or substituted naphthyl; the substituents in the substituted phenyl and the substituents in the substituted naphthyl are independently nitro, F, Cl, Br, C 1-4 Alkyl, C 1-4 an alkoxy or phenyl group;

[0276] Option 6:

[0277] It includes the following steps:

[0278] Step a): Compound C4 and compound C5 are subjected to the following reaction in a solvent (e.g., a mixed solvent of dichloromethane and N-methylpyrrolidone in a weight ratio of 28:1) (e.g., the reaction temperature is 0-15° C.) to obtain the compound C6;

[0279] Step b): Dechlorination of the compound of formula C6 to prepare the compound of formula C7 (e.g., in the presence of K3PO4 at 45-52°C);

[0280] R 3 is H, F, Cl or Br.

[0281] In the method for preparing the compound of formula C7 or a pharmaceutically acceptable salt thereof, Scheme 1 and Scheme 2 preferably prepare the compound of formula C7 or a pharmaceutically acceptable salt thereof through the following reaction route:

[0282] Preferably, the conditions and operations in the preparation method of the compound of formula A2, the preparation method of the compound of formula A5, the preparation method of the compound of formula D6, the preparation method of the compound of formula D9 and the preparation method of the compound of formula C3 are the same as described above.

[0283] In the method for preparing the compound of formula C7 or a pharmaceutically acceptable salt thereof, Scheme 3 preferably uses the following reaction route to prepare the compound of formula C7 or a pharmaceutically acceptable salt thereof:

[0284] Preferably, the conditions and operations in the preparation method of the compound of formula D6, the preparation method of the compound of formula D9 and the preparation method of the compound of formula C3 are the same as described above.

[0285] In the method for preparing the compound of formula C7 or a pharmaceutically acceptable salt thereof, Scheme 4 preferably uses the following reaction route to prepare the compound of formula C7 or a pharmaceutically acceptable salt thereof:

[0286] Preferably, the conditions and operations in the preparation method of the compound of formula D9 and the preparation method of the compound of formula C3 are the same as described above.

[0287] In the method for preparing the compound of formula C7 or a pharmaceutically acceptable salt thereof, Scheme 5 preferably uses the following reaction route to prepare the compound of formula C7 or a pharmaceutically acceptable salt thereof:

[0288] Preferably, the conditions and operations in the preparation method of the compound of formula C3 are the same as described above.

[0289] A sixteenth aspect of the present invention provides a use of a substance X in preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof:

[0290] The substance X is the compound of formula A2, the compound of formula A3, the compound of formula A4, the compound of formula A5-L or the compound of formula C1;

[0291] Among them, R 2 、R 3 、R 4 and R 6 The definitions are the same as above.

[0292] The compound of formula A3 is preferably

[0293] The compound of formula A4 is preferably

[0294] The compound of formula A5-L is preferably

[0295] The compound of formula C1 is preferably

[0296] The compound of formula A2, the compound of formula A3, the compound of formula A4, the compound of formula A5-L or the compound of formula C1 can be prepared as follows to prepare a compound of formula C7 or a pharmaceutically acceptable salt thereof:

[0297] For example, the compound of formula A2 can be prepared from the compound of formula C7 or a pharmaceutically acceptable salt thereof by the following route: the compound of formula A2 → the compound of formula A3 → the compound of formula A4 → the compound of formula A5 → the compound of formula D5 → the compound of formula D6 → the compound of formula D7 → the compound of formula D8 → the compound of formula D9 → the compound of formula C1 → the compound of formula C2 → the compound of formula C3 → the compound of formula C4 → the compound of formula C6 → the compound of formula C7;

[0298] For example, the above-mentioned compound of formula A3 can be prepared from the above-mentioned compound of formula C7 or a pharmaceutically acceptable salt thereof by the following route: the above-mentioned compound of formula A3 → the above-mentioned compound of formula A4 → the above-mentioned compound of formula A5 → the above-mentioned compound of formula D5 → the above-mentioned compound of formula D6 → the above-mentioned compound of formula D7 → the above-mentioned compound of formula D8 → the above-mentioned compound of formula D9 → the above-mentioned compound of formula C1 → the above-mentioned compound of formula C2 → the above-mentioned compound of formula C3 → the above-mentioned compound of formula C4 → the above-mentioned compound of formula C6 → the above-mentioned compound of formula C7;

[0299] For example, the compound of formula A4 can be prepared from the compound of formula C7 or a pharmaceutically acceptable salt thereof by the following route: the compound of formula A4 → the compound of formula A5 → the compound of formula D5 → the compound of formula D6 → the compound of formula D7 → the compound of formula D8 → the compound of formula D9 → the compound of formula C1 → the compound of formula C2 → the compound of formula C3 → the compound of formula C4 → the compound of formula C6 → the compound of formula C7;

[0300] For example, the compound of formula A5-L can be prepared from the compound of formula C7 or a pharmaceutically acceptable salt thereof by the following route: the compound of formula A5-L → the compound of formula D5 → the compound of formula D6 → the compound of formula D7 → the compound of formula D8 → the compound of formula D9 → the compound of formula C1 → the compound of formula C2 → the compound of formula C3 → the compound of formula C4 → the compound of formula C6 → the compound of formula C7;

[0301] For example, the above-mentioned compound of formula C1 can be prepared into the above-mentioned compound of formula C7 or a pharmaceutically acceptable salt thereof by the following route: the above-mentioned compound of formula C1 → the above-mentioned compound of formula C2 → the above-mentioned compound of formula C3 → the above-mentioned compound of formula C4 → the above-mentioned compound of formula C6 → the above-mentioned compound of formula C7.

[0302] Preferably, the preparation method of the compound of formula C7 or its pharmaceutically acceptable salt is the same as described above.

[0303] The following are the abbreviations used in this invention and their corresponding Chinese full names:

[0304] LiHMDS: lithium hexamethyldisilazide; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DCM: dichloromethane; NCS: N-chlorosuccinimide; R-BNPA: R-binaphthol phosphate; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; Pd(TFA)2: palladium trifluoroacetate; [(cinnamyl)PdCl]2: (polyimide-cinnamyl)palladium(II) chloride dimer; 2-MeTHF: 2-methyltetrahydrofuran; ACN: acetonitrile; IPA: isopropanol; IP AC: isopropyl acetate; DIEA: N,N-diisopropylethylamine; EA: ethyl acrylate; BI-DIME: 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]phosphine oxide pentane conjugated; Ph3P: triphenylphosphine; DTP-DPEPhos: 2,2"-(di-o-tolylphosphino)diphenyl ether; AntPhos: 4-(9-anthryl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]phosphine oxide pentane conjugated; DBFphos: 4,6-bis(diphenylphosphino)dibenzofuran; cataCXium PCy: 2-(dicyclohexylphosphino)-1-phenyl-1H-pyrrole; cataCXium PInCy: 2-(dicyclohexylphosphino)-1-phenylindole; cataCXium POMeCy: 2-(dicyclohexylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole; Ph2Cy: diphenylcyclopropane; (p-anisyl)3P: tri(p-methoxyphenyl)phosphine; Ph2P(tBu): diphenyl tert-butylphosphine; Cy2P(o-Tol): dicyclohexyl(o-tolyl)phosphine; (t-Bu)2P(n-hexyl)HBF4: di(tert-butyl)(n-hexyl)phosphine tetrafluoroborate; Cy-cBRIDP: dicyclohexyl-bridged bisphosphine ligand.

[0305] In the present invention, "room temperature" refers to 10-30°C.

[0306] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0307] The reagents and raw materials used in the present invention are commercially available.

[0308] The positive progress of the present invention is that: compared with the prior art, the present invention (1) overcomes the problem of methoxy protection and deprotection, reducing the two-step synthesis; avoids palladium-catalyzed coupling, and greatly reduces the cost; in particular, it can also use low-priced dichloronicotinic acid (about 2,000 yuan / kg) as a starting material for the reaction, which significantly reduces the cost and shortens the reaction steps compared to the expensive trichloronicotinic acid (about 40,000 yuan / kg);

[0309] (2) The side chain is introduced by Mitsunobu, avoiding the MOM protecting group, which is beneficial to quality control;

[0310] (3) Compound AA5 is salified with a resolving agent to obtain a single-configuration compound DD5. This advances chiral separation, facilitates quality control, significantly reduces costs, and facilitates scale-up production.

[0311] (4) C5 as an acrylation agent is beneficial for quality control.

[0312] In summary, the preparation method of the present invention has at least one or more advantages: high yield, greatly reduced cost, and better quality control. DETAILED DESCRIPTION

[0313] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0314] The preparation routes of the compounds of formula C7 and formula C8 of the present invention are as follows:

[0315] Preparation of raw materials

[0316] Preparation of compound of formula C2-1

[0317] C2a (18.4 g, 135.14 mmol), C2-1-SM (20.07 g, 128.71 mmol), and THF (300 mL) were added to a 500 mL reaction flask under nitrogen. The system was heated with the external bath set at 38°C and the internal temperature at 32°C. After incubation for 3 hours, a sample was taken and sent for LCMS. The reaction was complete. The system was filtered while hot, and the filter cake was rinsed with 50 mL of acetonitrile and dried under vacuum at 30°C to obtain 23.4 g of product C2-1, a yield of 71%.

[0318] 1 H-NMR (400MHz, DMSO-d6): 6.63(dd,1H),6.71(d,1H),7.11(m,1H),7.35(dd,1H),7.55(m,1H),8.01(s,1H),10.05(s,1H).

[0319] MS (m / z, ESI+): 257.10.

[0320] Preparation of compound of formula C2-2

[0321] C2a (10.7 g, 67.64 mmol) and toluene (78 g) were added to a 250 ml reaction flask under nitrogen protection. The system was heated to 80°C. A suspension of C2-2-SM (10.04 g, 64.42 mmol) and acetonitrile (95 g) was added dropwise to the reaction system. After 3 hours of incubation, a sample was taken and sent for LCMS. The reaction was complete. The reaction solution was transferred to a single-necked flask and concentrated to obtain a black oil. 40 ml of methyl tert-butyl ether and 320 ml of petroleum ether were added, stirred and filtered, and the filtrate was concentrated to obtain a solid. The solid was slurried with petroleum ether:ethyl acetate = 10:1, 5 Vol, at 25°C for 18 hours, filtered, and the filter cake was dissolved in petroleum ether:ethyl acetate = 5:1 and passed through a silica gel pad. The filtrate was concentrated to obtain a yellow solid, which was dried to obtain 10.1 g, a yield of 56.4%.

[0322] 1 H-NMR (400MHz, DMSO-d6): 6.25(d,2H),6.45(dd,1H),6.65(d,1H),6.89(d,2H),7.02(t,2H),7.20(dd,1H),8.01(s,2H),9.90(s,1H).

[0323] MS (m / z, ESI+): 279.10.

[0324] Preparation of compound of formula C2'-1

[0325] C2a (544.0 mg, 1.0 eq.) and N-methyliminodiacetic acid C2-3-SM (660.0 mg, 1.2 eq.) were added to a 25 mL three-necked flask, and toluene (15.0 mL) and N,N-dimethylformamide (2.3 mL) were added. The reaction temperature was raised to 115° C. and the reaction was stirred at 115° C. for 2.5 hours. The reaction solution was cooled to 55° C. and distilled under reduced pressure until no liquid was dripped. Water (20.0 mL) was added to precipitate an off-white solid. The mixture was stirred at room temperature for 1.5 hours, filtered, and the filter cake was dried in vacuo at 45° C. for 15 hours to obtain 600.0 mg of off-white solid C2'-1.

[0326] 1 H-NMR (400MHz, DMSO-d6): δ9.94(1H,d), 7.20-7.15(1H,m), 6.60-6.49(2H,m), 4.28(4H,dd), 2.69(1H,s).

[0327] Example 1 Preparation of the compound of formula A2-1

[0328] Method 1:

[0329] LiHMDS (1180 kg) was added to a 3000 L reactor (1) and cooled to -5-5°C. In a 500 L reactor (2), A1-1 (63.7 kg, 1.0 eq.) was added to a tetrahydrofuran solution of Z1a (267 kg, 22.5% by weight, 1.1 eq.) and stirred. The solution in reactor (2) was then slowly added to reactor (1), maintaining an internal temperature of -5-5°C. After stirring for 4 hours, a sample was taken for control. The temperature was raised to 5-25°C, and 31% concentrated hydrochloric acid (450 kg) was added dropwise to a pH of 0.5-1.0. Water (956 kg) was added and stirred for one hour, and the mixture was separated. The aqueous phase was washed once with MTBE (235 kg). 10% sodium carbonate solution (470 kg) was slowly added to the aqueous phase until the pH reached 6.0-6.5. The wet product was filtered and dried to obtain 82.3 kg of product with a weight content of 89.3% and a yield of 76%. No double substitution by-products were detected by central control testing. and positional isomerization by-products

[0330] 1H NMR (400MHz, DMSO-d6) δ13.68(s,1H),9.74(s,1H),8.35(d,J=4.8Hz,1H),8.19(d,J=8.1Hz, 1H), 7.18 (dd, J = 4.9, 0.8Hz, 1H), 6.79 (d, J = 8.1Hz, 1H), 3.13 (hept, J = 6.7Hz, 1H), 2.13 (s, 3H), 1.13 (d, J = 6.7Hz, 6H).

[0331] Method 2:

[0332] LiHMDS in method 1 was replaced with NaHMDS, and other operations and conditions were the same. After in-process control, HPLC in-process control detected about 16.2% Z1a, 6.6% A1-1, 58.1% A2-1 and 19.0% position isomerization by-products. No double substitution by-products

[0333] Example 2 Preparation of the compound of formula A3-1

[0334] Prepare a 500L reactor, protect with nitrogen, add dichloromethane (100L, 5vol.), add A2-1 (20kg, 1.0eq.), and add DMF (1kg) to the reaction. Turn on the chilled water and reduce the internal temperature to 15°C. Add oxalyl chloride (15.6kg, 2.0eq.) and slowly add it dropwise to the reaction system, controlling the dripping rate to keep the system temperature above 25°C. After the dripping is complete, stir and react at 15-25°C for 30 minutes. Take a sample and monitor the reaction by TLC, and the reaction is complete. Prepare another 500L reactor, draw in methanol (100L, 5vol.), add the reaction solution dropwise to the methanol, controlling the dripping rate to keep the system temperature above 40°C. After the dripping is complete, stir at 30-40°C for 1 hour. Take a sample and monitor by TLC, and the conversion is complete. Concentrate at 50°C until no droplets flow out. Dissolve the concentrate in 200L of ethyl acetate at 20-30°C. Adjust the pH of the aqueous phase to 8 with saturated sodium bicarbonate at 20-30°C. Separate the phases, and extract the aqueous phase twice with ethyl acetate until clear. Combine the organic phases and wash with semi-saturated brine. Filter, rinse, and concentrate the filtrate. Add 40 L of methanol to the concentrate and heat to dissolve. Once completely dissolved, cool to 0°C and stir at this temperature for 2 hours. Centrifuge the solid, rinse with a small amount of cold methanol, and dry to obtain 19.8 kg of an off-white solid (95% yield).

[0335] 1H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.35(d,J=4.9Hz,1H),8.21(d,J=8.1Hz,1H),7.18(dd,J=4.9,0 .8Hz,1H),6.82(d,J=8.1Hz,1H),3.91(s,3H),3.11(h,J=6.7Hz,1H),2.12(s,3H),1.17–1.07(m,6H).

[0336] Example 3 Preparation of the compound of formula A3-2

[0337] The compound of formula A3-2 was prepared by referring to the preparation method of the compound of formula A3-1 in Example 2. The yield of the compound of formula A3-2 was 82%.

[0338] 1 H NMR (400M, CDCl3) 9.53ppm (s, 1H), 8.41ppm (d, J = 4.8Hz, 1H), 8.15ppm (d, J = 8.0Hz, 1H), 7.06ppm (d, J = 5.2Hz, 1H), 6.04ppm (d, J=8.4Hz, 1H), 4.41ppm (q, J=7.2Hz, 2H), 3.21ppm (m, 1H), 2.20ppm (s, 3H), 1.43ppm (t, J=7.2Hz, 3H), 1.24ppm (d, J=6.8Hz, 6H).

[0339] [M+H] + =334.2,336.2.

[0340] Example 4 Preparation of Compound A3-3

[0341] The compound of formula A3-3 was prepared by referring to the preparation method of the compound of formula A3-1 in Example 2. The yield of the compound of formula A3-3 was 88%.

[0342] 1 H NMR(400M, CDCl3)9.57ppm(s,1H),8.40ppm(d,J=4.8Hz,1H),8.13ppm(d,J=8.0Hz,1H),7.05ppm(d,J=5.2Hz,1H),6.63pp m(d,J=8.4Hz,1H),5.28ppm(m,1H),3.22ppm(m,1H),2.20ppm(s,3H),1.41ppm(d,J=6.4Hz,6H),1.24ppm(d,J=6.4Hz,6H).

[0343] [M+H]+ =348.2,350.2.

[0344] Example 5 Preparation of the compound of formula A4-1

[0345] Prepare a 200L reactor under nitrogen atmosphere. Add DMF (60L, 3Vol.) and A3-1 (20kg, 1.0eq.). Slowly add NCS (9.4kg, 1.1eq.) to the reactor. Heat to 55-60°C and react for 3 hours. Monitor the reaction by TLC. Cool to 20-25°C. Add water (120L, 6Vol.) dropwise to the reaction mixture. Stir at 20-25°C for 1 hour. Centrifuge, wash with water, and dry to obtain A4-1 (19.9kg, 90% yield).

[0346] 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.36(d,J=4.8Hz,1H),8.31(s,1H),7.19(dd,J=4 .8,0.8Hz,1H),3.92(s,3H),3.11(p,J=6.7Hz,1H),2.13(s,3H),1.12(d,J=6.6Hz,6H).

[0347] Example 6 Preparation of the compound of formula A4-2

[0348] The compound of formula A4-2 was prepared by referring to the preparation method of the compound of formula A4-1 in Example 5. The yield of the compound of formula A4-2 was 86%.

[0349] 1 H NMR(400M, CDCl3)9.44ppm(s,1H),8.42ppm(d,J=4.8Hz,1H),8.24ppm(s,1H),7.06ppm(d,J=5.2Hz,1H),4.4 3ppm (q, J = 6.8Hz, 2H), 3.18ppm (m, 1H), 2.19ppm (s, 3H), 1.45ppm (t, J = 7.2Hz, 3H), 1.23ppm (d, J = 6.8Hz, 6H).

[0350] [M+H] + =368.2,370.0.

[0351] Example 7 Preparation of Compound A4-3

[0352] The compound of formula A4-3 was prepared by referring to the preparation method of the compound of formula A4-1 in Example 5. The yield of the compound of formula A4-3 was 91%.

[0353] 1 H NMR(400M, CDCl3)9.48ppm(s,1H),8.42ppm(d,J=4.8Hz,1H),8.22ppm(s,1H),7.07ppm(d, J=4.8Hz,1H),5.30ppm(m,1H),3.19ppm(m,1H),2.19ppm(s,3H),1.42ppm(d,J=6.4Hz,6H), 1.24ppm(d,J=6.8Hz,6H).

[0354] [M+H] + =382.0,384.0.

[0355] Example 8 Preparation of Compound A5-1

[0356] Prepare a 1000L reactor and protect with nitrogen. Add DMF (200L, 10Vol.), add A4-1 (19.5kg, 1.0eq.), replace the atmosphere with nitrogen, turn on the chilled water, and lower the internal temperature to -5°C. Add lithium tert-butoxide (20.2kg, 4.5eq.) in batches. After addition, insulate and stir at -5°C for 30 minutes. Add acetic anhydride (16.7kg, 3.0eq.) dropwise, maintaining the internal temperature at 0-5°C. After addition, insulate and stir for 2 hours. Add 20% aqueous potassium carbonate solution (40kg). Stir and react at 5-10°C for 5 hours. Monitor the reaction by TLC plate sampling to confirm the reaction is complete. Add methyl tert-butyl ether (120L, 6Vol.) and then water (250L, 13Vol.) and stir for 1 hour. Separate the liquids and filter the aqueous phase through a pad of diatomaceous earth. The mixture was washed with water and extracted once with 120 L of methyl tert-butyl ether. The organic phase was separated and the pH of the aqueous phase was adjusted to 6 with 6N hydrochloric acid to precipitate a solid. The mixture was stirred for 5 hours, centrifuged, washed with water, and dried to obtain A5-1 (16.3 kg, 81% yield).

[0357] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.53(d,J=4.9Hz,1H),8.46(s,1H),7.33(d,J=5. 0Hz, 1H), 6.05 (s, 1H), 2.57 (q, J = 6.7Hz, 1H), 1.92 (s, 3H), 1.02 (dd, J = 23.6, 6.7Hz, 6H).

[0358] Example 9 Preparation of Compound D5

[0359] Screening of resolving agents

[0360] 1. Place 20 mg of the compound of formula A5 and an equimolar amount of the ligand (see Table 1) in an HPLC vial, add 0.3-0.5 mL of the corresponding solvent (see Table 1 for details), and suspend and stir at room temperature for 3 days (750 rpm).

[0361] 2. Centrifuge and separate the mother liquor and solid. The mother liquor is used for HPLC concentration test, and the solid is vacuum dried at 50°C and then characterized by XRPD.

[0362] 3. For systems that remain clear after stirring at room temperature, transfer to 5°C and continue magnetic stirring for ~2 days. If the solution remains clear after stirring at 5°C, induce solid precipitation by adding room temperature antisolvent (the antisolvent is EtOAc). If the solution remains clear after adding 6 mL of antisolvent, stop adding and evaporate in the open air at room temperature to induce solid precipitation. The resulting suspension is centrifuged, and the mother liquor is separated for HPLC analysis. The solid is dried under vacuum at 50°C and characterized by XRPD.

[0363] The results are shown in Table 1-2.

[0364] Table 1. Summary of HPLC results of chiral separation screening test mother liquor (I / II)

[0365] Table 2. Summary of HPLC results of chiral separation screening test mother liquor (II / II) Note: In Tables 1 and 2, the data for A5-L and A5'-L are the concentrations of the corresponding isomers in the mother liquor, in mg / mL. Absolute value of ee = |C A5-L -C A5’-L ∣ / (C A5-L +C A5’-L )*100%.

[0366] As shown in Table 1, the absolute values ​​of the ee of the mother liquors obtained under different experimental conditions were calculated based on the concentrations of the two isomers. Among them, the absolute values ​​of the ee of the mother liquors in the D-3-bromocamphor-10-sulfonic acid, S-binaphthol phosphate, and D-(+)-camphorsulfonic acid systems were relatively high (up to 66-84%), indicating potential resolution effects. The concentrations of the two isomers in the mother liquors of the other resolution systems were similar, indicating no obvious resolution effects.

[0367] For the S-binaphthol phosphate system with a higher absolute value of mother liquor ee, further confirmation was performed by testing the absolute value of the corresponding solid phase ee. The results are shown in Table 3.

[0368] Table 3. Mother liquor and solid phase HPLC results of S-binaphthol phosphate system Note: The data corresponding to A5-L and A5'-L in the table are the concentrations of the corresponding isomers in the mother liquor, in mg / mL. Absolute value of ee = |CA5’-L -C A5’-L ∣ / (C A5-P1 +C A5-P2 )*100%.

[0369] As shown in Table 3, there is a significant difference in the contents of the two isomers in some solid phases, which further confirms that the system has a resolution effect. 1 H-NMR showed that the salt formation ratio of binaphthol phosphate A5-L was 1:1.

[0370] 1 H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.58(d,J=5.1Hz,1H),8.47(s,1H),8 .15(d,J=8.8Hz,2H),8.08(d,J=8.2Hz,2H),7.57–7.48(m,4H),7.51–7.42(m ,1H),7.36(ddd,J=8.3,6.9,1.3Hz,2H),7.23(d,J=8.5Hz,2H),6.06(s,1H) ,2.63(p,J=6.8Hz,1H),1.98(d,J=9.3Hz,3H),1.05(dd,J=23.6,6.7Hz,6H).

[0371] Preparation of compound of formula D5-1

[0372] Method 1:

[0373] Prepare a 500L reactor under nitrogen. Pump in tetrahydrofuran (260kg, 18V) and ethyl acetate (29kg, 2V) and stir thoroughly. Add A5-1 (16kg, 1.0eq.) and R-binaphthol phosphate (15.3kg, 1.0eq.) and raise the temperature to 50°C. Maintain at 50°C and stir for 3 hours. After the temperature is maintained, cool naturally to 25°C. Filter the solids and wash the filter cake with a small amount of solvent (tetrahydrofuran:ethyl acetate = 9:1). Drain the solid phosphate A5-L-1.

[0374] Prepare a 500 L reactor. Pump in saturated sodium bicarbonate solution (140 L, 10 V). Slowly add the resolved phosphate A5-L-1, releasing bubbles. Stir at room temperature for 5 hours. Filter and adjust the pH of the aqueous phase to 6-7 with 1 N hydrochloric acid to precipitate solids. Filter the solids and dry them to obtain D5-1 (6.0 kg, 37% yield, 98.5% ee).

[0375] Method 2:

[0376] A5-1 (500.0 mg, 1.0 eq) and R-binaphthol phosphate (478.0 mg, 1.0 eq) were dissolved in methanol (5.0 mL). The mixture was stirred at 25°C for 3 h, filtered, and methyl tert-butyl ether (10.0 mL) was added dropwise to the filtrate. The mixture was stirred at 25°C for another 6 h, filtered, and the filter cake was washed with methyl tert-butyl ether (2.0 mL). The filter cake was dried under reduced pressure for 3 h to obtain 470.0 mg of an off-white solid. EE value: 89.64%.

[0377] Preparation of compound of formula D5-2

[0378] Method 1:

[0379] Compound D5-2 was prepared according to Method 1 in the preparation method of compound D5-1. 1 H NMR and ee values ​​are as follows:

[0380] 1 H NMR (400MHz, D6-DMSO) δ12.25(s,1H),8.48(d,J=4Hz,1H),8.30(d,J=8Hz,1H),7.37(d,J=8Hz,1H),7.2 6(d,J=4Hz,1H),6.00(s,1H),2.44-2.54(m,1H),1.87(s,3H),1.02(d,J=8Hz,3H),0.95(d,J=8Hz,3H).

[0381] MS(ESI):[M+H] + m / z Calcd for C 17 H 16 ClN3O2 330.09; Found 330.09.

[0382] ee value of D5-2: 100%.

[0383] Method 2:

[0384] A5-2 (500.0 mg, 1.0 eq) and R-binaphthol phosphate (528.1 mg, 1.0 eq) were dissolved in methanol (5.0 mL), stirred at 25° C. for 3 h, filtered, and the filter cake was washed with methyl tert-butyl ether (2.0 mL). The filter cake was dried under reduced pressure for 3 h to obtain 470.0 mg of an off-white solid. The off-white solid (140.0 mg) was added to an aqueous NaHCO solution for dissociation, filtered, and dried to obtain an off-white solid (measured ee value: 100%). Its NMR data was basically the same as that of method 1.

[0385] Preparation of compound of formula D5-3

[0386] Method 1:

[0387] Compounds of formula A2-3, A4-4 and A5-3 were prepared according to the procedures of Examples 1, 3 and 8, respectively. Compound D5-3 was prepared according to Method 1 in the preparation of compound D5-1.

[0388] 1 H NMR and ee values ​​are as follows:

[0389] 1 H NMR (400MHz, D6-DMSO) δ9.59 (s, 1H), 8.33 (d, J = 4Hz, 1H), 8.17 (d, J = 8Hz, 1H), 7.17 (d, J = 4Hz, 1H), 3.06-3.32 (m, 1H), 2.11 (s, 3H), 1.11 (d, J = 4Hz, 6H).

[0390] MS(ESI):[M+H] + m / z Calcd for C 17 H 15 ClFN3O2 324.08; Found 324.10.

[0391] 1 H NMR (400MHz, D6-DMSO) δ9.30 (s, 1H), 8.34 (d, J = 4Hz, 1H), 8.22 (d, J = 12Hz, 1H), 7.1 6(d,J=4Hz,1H),3.91(s,3H),3.07-3.13(m,1H),2.10(s,3H),1.10(d,J=4Hz,6H).

[0392] MS(ESI):[M+H] + m / z Calcd for C 16 H 17 ClFN3O2 338.10; Found 338.10.

[0393] 1 H NMR (400MHz, D6-DMSO) δ12.38(s,1H),8.48(d,J=4Hz,1H),8.31(d,J=8Hz,1H),7.26(d,J=4H z, 1H), 6.04 (s, 1H), 2.44-2.54 (m, 1H), 1.87 (s, 3H), 1.02 (d, J = 8Hz, 3H), 0.95 (d, J = 8Hz, 3H).

[0394] MS(ESI):[M+H] + m / z Calcd for C 17 H 15 ClFN3O2 348.08; Found 348.10.

[0395] The ee value of compound D5-3 is 91.3%.

[0396] Method 2:

[0397] A5-3 (500.0 mg, 1.0 eq) and R-binaphthol phosphate (500.7 mg, 1.0 eq) were dissolved in methanol (5.0 mL), stirred at 25° C. for 3 h, filtered, and methyl tert-butyl ether (10.0 mL) was added dropwise to the filtrate. Stirring and reaction were continued at 25° C. for 6 h, filtered, and the filter cake was washed with methyl tert-butyl ether (2.0 mL). The filter cake was dried under reduced pressure for 3 h to obtain 470.0 mg of an off-white solid. The above-mentioned off-white solid (140.0 mg) was added to a NaHCO3 aqueous solution for dissociation, filtered, and dried to obtain an off-white solid (measured ee value: 91.28%). Its NMR data was basically the same as that of method 1.

[0398] Recovery of splitting reagent L and A5-1

[0399] Split:

[0400] A5-1 (30 g, 1.0 eq, analytical yield: 85%), alcohol (10 V), and R-binaphthol phosphate (1.0 eq) were added to a reaction vessel at 20-25°C and stirred for 3 h. The mixture was filtered, and methyl tert-butyl ether (20 V) was added dropwise to the filtrate, stirring for 5 h. The mixture was filtered, and the filter cake was dried under reduced pressure at 45±5°C to yield A5-L-1 (25.5 g). The filtrate was recovered.

[0401] free:

[0402] Dissolve NaHCO₃ (2.0 eq) in H₂O (14 V) and add the above-mentioned A5-L-1. Stir for 5 h. Add NaCl (1.7 wt %) in two portions and stir at 20±5°C for 3 h. Filter, wash the filter cake with 10% NaCl (2 V), and recover the resolution reagent L. Adjust the pH to 5-6 by adding 1N hydrochloric acid dropwise to precipitate a solid, which is then filtered to obtain crude D5-1.

[0403] purification:

[0404] The crude product of D5-1 was slurried in MeOH (7V) at 20-25°C, H2O (3.5V) was added dropwise, stirred for 3h, filtered, and the filter cake was washed with H2O (2.0V). The filter cake was dried under reduced pressure at 60±5°C to obtain D5.

[0405] The filtrate recovered from the resolution step is processed to recover the resolving agent and A5-1:

[0406] The separated filtrate was concentrated to dryness, and a NaHCO₃ aqueous solution (2.0 eq. of NaHCO₃ dissolved in 14 V of H₂O) was added, stirring for 5 h. NaCl (1.7 wt %) was added in two portions, stirring at 20±5°C for 3 h. The mixture was filtered, and the filter cake was washed with 10% NaCl (2 V) to recover L. The filtrate was dropwise added with 1N hydrochloric acid to adjust the pH to 5-6, resulting in the precipitation of a solid, which was filtered to obtain crude D5'-1 (isomer) in a 45% yield.

[0407] D5'-1 (12.0 g, 1.0 eq) and acetone (60.0 mL, 5.0 v) were added to the reaction flask and stirred to dissolve. H2O (60.0 mL, 5.0 V) was added and KMnO4 (11.45 g, 2.2 eq) was added at 20±5°C. The mixture was stirred and reacted at 20±5°C for 3 h (the residual raw material was ≤2.0%). The mixture was filtered through celite and the filter cake was washed with acetone (3.0 v). The filtrate was concentrated under reduced pressure at 40°C to remove the acetone. KOH (7.4 g, 4.0 eq) was added and the mixture was stirred and reacted at 40°C for 17 h (the residual raw material was ≤2.0%). The reaction mixture was cooled to 25°C and filtered to obtain 8 g of a white solid (potassium salt). The wet product was added with water (2 V) and stirred. The pH was adjusted to 6 with 2M hydrochloric acid. The white solid A5-1 was obtained by suction filtration and dried under vacuum at 40°C to obtain 6.7 g of a white solid (60% yield).

[0408] Preparation of compound of formula E5-1

[0409] operate:

[0410] 1. Add 2.0 g of B5-1 to a 100 mL three-necked flask;

[0411] 2. Add 40 mL of acetonitrile, replace with nitrogen protection, and heat to 40°C. If the solution does not dissolve clearly,

[0412] 3. Add 2.0 g of R-binaphthol phosphate and stir at 40°C for about ten minutes until dissolved;

[0413] 4. Continue stirring until solid begins to precipitate after 20 minutes, and continue stirring for 2 hours;

[0414] 5. A large amount of solid precipitated, cooled to 25°C and filtered;

[0415] 6. The filter cake was washed with 10 mL of acetonitrile and dried to obtain 2.0 g of B5-L-1 salt;

[0416] 7. The ee value of the sample tested is 95.2%;

[0417] 8. Free, add 2g of B5-L-1 salt to 50mL of 2N hydrochloric acid and stir at 25℃ for 16h;

[0418] 9. Filter and wash the filter cake with 5 mL of water;

[0419] 10. Collect the filtrate, adjust the pH to 7-8 with sodium bicarbonate, and extract twice with 20 mL of ethyl acetate;

[0420] 11. Combine the ethyl acetate phases, wash once with 20 mL of saturated sodium chloride aqueous solution, and dry over anhydrous sodium sulfate;

[0421] 12. Filter and concentrate to dryness to obtain 1.0 g of E5-1 with an ee value of 93% and a yield of 50%.

[0422] 13. 1.0 g of the obtained solid was added to 20 mL of acetonitrile and heated to 40°C. The solution did not dissolve.

[0423] 14. Add 1.0 g of R-binaphthol phosphate and stir at 40°C for 10 minutes to dissolve. Continue the reaction for 2 hours to precipitate a large amount of solid.

[0424] 15. Cool to 25°C and filter to obtain 1.4 g of solid salt B5-L-1, with a secondary salt yield of 70% and an ee value of 99.2%.

[0425] Example 10 Preparation of compound of formula D6-1

[0426] Path 1:

[0427] Microchannel system: micro mixer + PTFA tubing with an inner diameter of 1.58 mm and a volume of approximately 30 ml (approximately 15 m);

[0428] Raw materials: D5-1: 2.43 g; propionic acid: 12.61 g; acetic acid: 5.33 g;

[0429] Nitration reagent: 65-68% nitric acid: about 2.7eq; 30% sodium nitrite solution: about 0.7eq;

[0430] Mixing sequence: In a micro mixer, D5-1 is first mixed with nitric acid and then with sodium nitrite solution;

[0431] Reaction temperature: 5°C

[0432] Feed rate: raw material solution: 19.4 ml / min; nitric acid: 1.2 ml / min; sodium nitrite solution: 1.1 ml / min;

[0433] The microchannel reaction was carried out under the above conditions, with a theoretical reaction time of about 1.5 minutes and a total feeding time of about 1 minute. Samples of the reaction liquid were taken at about 20 seconds and about 45 seconds after feeding, and the samples were tested after pretreatment according to the post-processing process. The remaining reaction liquid was poured into a receiving bottle, and the reaction was continued with stirring at 5°C for about 30 minutes. After that, 20 volumes of ice water were added, and the pH was adjusted to about 6 with 30% NaOH solution. The product was filtered and dried to obtain 2.40 g in total.

[0434] Table 4

[0435] Path 2:

[0436] New implementation examples:

[0437] S1. Prepare D5-1 solution:

[0438] Weigh D5-1 (40.2 g, 96.02 mmol). The purity of the batch of D5-1 used is 87%. Take acetic acid (161 mL) and stir for 30 minutes to dissolve it to obtain an acetic acid solution of D5-1.

[0439] S2. Microchannel reactor balance:

[0440] 1) Set the fluid reactor to control the temperature to 70 degrees and the back pressure to 0 MPa;

[0441] 2) The fluid reactor was first washed with 60 mL of acetic acid at a flow rate of 5 mL / min;

[0442] 3) Set up two feed pumps, acetic acid 5 mL / min, and HNO3 0.85 mL / min, respectively, and feed for 10 minutes to replace the solvent in the reactor channel.

[0443] S3. Feed reaction:

[0444] 1) Switch the feed pump and set the feed rate to 1 mL / min of D5-1 solution and 0.17 mL / min of HNO3 (4.0 eq). Mix the mixture and feed it into the reactor. The reaction residence time is 25 min. The reaction solution is directly collected into 200 mL of ice water to quench the reaction.

[0445] 2) The reaction is complete in 3.5 hours;

[0446] 3) After the D5-1 solution was added, acetic acid 1 mL / min and HNO3 0.17 mL / min (4.0 eq) were added to continue the reaction for 60 min until the reaction was complete.

[0447] S4. Post-processing:

[0448] According to the batch reaction post-processing operation process, 39.8 g of D6-1 was obtained with a content yield of 91.00%.

[0449] Example 11 Preparation of the compound of formula D7-1

[0450] Under a nitrogen atmosphere, add acetonitrile (105 kg, 6 v) and D6-1 (26.5 kg, 87.0% analytical yield, 1.0 eq) to a 1000 L reactor (1). Replace the reaction mixture with nitrogen twice and cool to -15±5°C. Add DIEA (32.5 kg, 4.0 eq) dropwise, and stir the reaction mixture at -15±5°C for 30 min. Add POCl3 (34.1 kg, 4.0 eq) to the reactor, stir at 0±5°C for 30 min, and then heat to 45±5°C and stir for 4 h.

[0451] To a 3000L reactor 2, add water (448kg, 20v) and NaHCO₃ (28kg, 6.0eq) and cool to 0±5°C. The reaction mixture from reactor 1 was added dropwise to reactor 2, maintaining the temperature below 5°C. NaHCO₃ (28kg, 6.0eq) was added at 0±5°C. The reaction mixture was extracted once with DCM (178kg, 6v), and the organic phase was filtered through diatomaceous earth (20kg). The organic phase was washed once with water (127.5kg, 5v) and concentrated to 1-1.5v. n-heptane (104.7kg) was added to the concentrate. Further concentration was performed. After concentration, the mixture was filtered, the filter cake was washed with n-heptane, and vacuum dried to yield D7-1 (20kg, 94% purity, 72.8% yield (analytical yield)).

[0452] 1 H-NMR (400MHz, DMSO-d6) δ 8.82 (s, 1H), 8.50 (d, J = 4.9Hz, 1H), 7.26 (d, J = 4.9Hz, 1H), 2.63 (p, J = 6.7Hz, 1H), 1.90 (s, 3H), 0.94 (dd, J = 17.3, 6.6Hz, 6H).

[0453] Example 12 Preparation of Compound D8-1

[0454] To a 1500 L reactor (1), add acetonitrile (47 kg), Y7a (13.5 kg, 1.0 eq), and DIEA (10.6 kg, 2.0 eq). Under a nitrogen atmosphere, add D7-1 (20 kg, 1.0 eq) and acetonitrile (78 kg, 5 V). Cool to 5°C-20°C and react for 30 h. Add MTBE (112 kg) and 2% HCl (83 kg) and adjust the temperature to 20°C. Separate the liquid. Wash once with 10% NH4Cl (200 kg), filter, and then wash once with water and 10% NaCl (100 kg). Concentrate the organic phase, add ethyl acetate (110 kg), and filter through celite. Concentrate the filtrate and replace with IPA (approximately 9 V). Water (90 kg, 4.5 V) was slowly added dropwise at 40±5°C, stirred for 2 h, cooled to 20-25°C, filtered and vacuum dried to obtain D8-1 (18.5 kg, 97.3% purity).

[0455] Example 13 Preparation of compound of formula D9-1

[0456] Add acetic acid (48.3 kg), anhydrous MgSO₄ (4.8 kg, 0.5 wt%), and iron powder (4.2 kg) to a 100 L reactor and heat to 40-45°C. Slowly add a solution of D8-1 (9.2 kg, 1.0 eq) in isopropyl acetate (37 kg) dropwise to the reactor. Continue stirring and react for 3 hours.

[0457] The mixture was cooled to 25°C and worked up with another batch. Isopropyl acetate (80 kg) was added and filtered through celite, followed by the addition of isopropyl acetate (80 kg). The filtrate was washed three times with water, once with 5% NaHCO₃, and once with 5% NaCl. The organic phase was passed through a silica gel pad, concentrated, and the solvent replaced with DCM to yield a DCM solution of D9-1 (200 kg, 7.5% by weight, 94.9% yield).

[0458] Example 14 Preparation of compound of formula D9-1

[0459] Mixed solvent configuration

[0460] Weigh 60.00 g of ethyl acetate and 40.00 g of acetic acid, and stir for about 5 minutes to obtain a mixed solvent;

[0461] Raw material D8-1 reaction solution configuration

[0462] Weigh 0.5042 g of D8 sample, add 5.10 g of the prepared mixed solvent, and dissolve (ultrasound can be used to promote the dissolution of small particles. No undissolved particles should exist, otherwise there is a risk of clogging the reactor pipeline);

[0463] Hydrogenation reactor equilibrium

[0464] (1) Open the SO5 hydrogenation reactor, the catalyst column tube is a platinum-carbon catalyst filled column, and the reactor channel is replaced with nitrogen;

[0465] (2) Set the reactor back pressure to 1.0 MPa (hydrogen pressure in the reaction system), set the preheater and reactor temperature to 85°C, set the feed rate to 1.0 ml / min, and pass the prepared ethyl acetate / acetic acid blank mixed solvent;

[0466] (3) Equilibrate the system for about 30 minutes;

[0467] Feed and reaction

[0468] (1) Switch the feed pump and introduce the prepared D8-1 reaction solution. After about 5 minutes of feeding, the solution at the outlet is collected separately as the product solution;

[0469] (2) After the reaction solution was fed, the blank solvent was switched to feed, and the feed was continued and the reaction solution was received for about 30 min, and a total of 30.10 g of product solution was received;

[0470] Water washing and quenching

[0471] (1) Add 50.00 g of water to the received product solution, stir for about 20 min, let it stand, separate the liquids, and collect the upper organic phase;

[0472] (2) Add 50.00 g of water to the above organic phase solution, stir for about 20 min, let it stand, separate the liquids, and collect the upper organic phase;

[0473] (3) Add 50.00 g of 7% sodium bicarbonate solution to the organic phase, stir for about 20 min, let stand, separate the liquids, and collect the upper organic phase;

[0474] (4) Add 25.00 g of 5% sodium chloride solution to the above organic phase, stir for about 20 minutes, let it stand, separate the liquids, and collect the upper organic phase

[0475] concentrate

[0476] The mixture was concentrated at 45°C until no liquid was left, and then the concentration was continued for 30 min. The solid was scraped off the wall of the bottle and crushed, and the concentration was continued for 30 min. 0.4450 g of product was obtained with a yield of 97.5% and a purity of 98.6%, of which the D8-1 / (D8-1 + D9-1) ratio was 0.15%.

[0477] Example 15 Preparation of compound of formula D9-1

[0478] According to the operating method of Example 14, the catalyst column, solvent and temperature were replaced with the column and solvent in the following table.

[0479] Table 5

[0480] It can be seen that (1) the raw material D8 reacted almost completely under the catalysis of palladium carbon and platinum carbon, but the raw material D8 could not react completely in the ruthenium carbon catalytic system;

[0481] (2) Compared with palladium-carbon and platinum-carbon catalysts, more chlorine impurities are generated under the catalysis of palladium-carbon;

[0482] (3) In summary, platinum-carbon catalyst is preferred as the catalyst for D8 hydrogenation reaction.

[0483] Example 16 Preparation of compound of formula D9-1

[0484] The operation method of Example 14 was followed, except that the solvent and reaction temperature were replaced with those in the following table.

[0485] Table 6

[0486] As can be seen from the above table, the generated unring-closed intermediate cannot be completely ring-closed to form product D9-1, so a catalyst needs to be introduced to further complete the ring-closure reaction of the unring-closed intermediate.

[0487] Example 17 Preparation of Compound D9-1

[0488] The operation method of Example 14 was followed, except that the solvent and reaction temperature were replaced with those in the following table, and the catalyst was added.

[0489] Table 7

[0490] It can be seen that the acetic acid-catalyzed ring-closure can achieve a good ring-closure reaction through the following two processes: (1) two-step method: first, catalytic hydrogenation of the D8 raw material is carried out, and after the hydrogenation is completed, the reaction liquid is collected and then acetic acid is added to catalyze the ring-closure; (2) one-step method: acetic acid is directly introduced into the solvent system, hydrogenated and ring-closed in the microchannel system.

[0491] Example 18 Preparation of the compound of formula D9-1

[0492] The operation method of Example 14 was followed, except that the solvent and reaction temperature were replaced with those in the following table, and the catalyst was added.

[0493] Table 8

[0494] It can be seen that under the reaction system of the present invention, both ethyl acetate and isopropyl acetate can achieve good reaction effects, D8 / (D8+D9) is less than 1%, and the intermediate is basically completely ring-closed, and the purity of the product D9 exceeds 98%. In addition, the amount of solvent used can be reduced by 10 times, wherein the ratio of low-cost carboxylic acid to ethyl acetate can reach 2:3.

[0495] The method of the present invention can achieve excellent reaction effects while reducing production costs.

[0496] Example 19 Preparation of Compound of Formula C1-1

[0497] To a 1000L reactor, add a dichloromethane solution (200kg) of D9-1 (15kg, 1.0eq), 28 (2.6kg, 1.2eq), and PPh3 (14kg, 2.1eq). The reaction mixture was cooled to 5±5°C, and DEAD (9.3kg, 2.1eq) was added dropwise. Stirring was continued for 4h. After the reaction was complete, water (60kg) was slowly added, the mixture was separated, and the aqueous phase was washed once with dichloromethane (78kg). The organic phase was concentrated, replaced with MTBE (90kg), cooled to 5±5°C, and filtered. The filtrate was extracted with 5% citric acid solution (240kg). The aqueous phase was washed twice with MTBE (90kg). NaHCO3 was added to adjust the pH to 7-8. The mixture was extracted three times with MTBE (90kg). The organic phases were combined, concentrated, and replaced with MeCN (approximately 45 kg, 4 v). Water (105 kg) was then slowly added dropwise at 40°C. The mixture was cooled, filtered, and dried under vacuum to obtain the product (12.2 kg, 99.7% purity, 70.2% weight yield).

[0498] 1H-NMR (400MHz, DMSO-d6) δ8.56(d,J=4.9Hz,1H),8.21(d,J=1.3Hz,1H),7.32(dd,J=4.8,0.9Hz,1H),4.59(dd,J= 22.1,13.6Hz,1H),4.37(dd,J=19.5,11.9Hz,2H),4.26–4.08(m,1H),3.85(dd,J=29.7,4.2Hz,1H),3.44(dd,J=1 3.7,4.6Hz,1H),3.30–3.23(m,1H),3.12(dd,J=12.4,3.7Hz,1H),2.65(dq,J=10.0,6.5,4.8Hz,1H),2.41–2.16( m,1H),2.05(d,J=8.9Hz,6H),1.83(d,J=1.7Hz,3H),1.45(d,J=13.1Hz,12H),1.07(ddd,J=27.0,6.7,1.8Hz,6H).

[0499] Example 20 Preparation of Compound C3-1

[0500] Prepare 5 L of dioxane / water (volume ratio = 2:1) solvent and purge with nitrogen for 0.5 hours. Add 2.5 L of the prepared solvent to a 10 L reactor. Replace the nitrogen atmosphere three times. Add C1-1 (250 g, 380 mmol, 1.0 eq.), cesium fluoride (288.3 g, 1.90 mol, 5.0 eq.), and palladium tetrakistriphenylphosphine (13.2 g, 11.4 mmol, 0.03 eq.). Add C2-1 (117 g, 56 mmol, 1.2 eq.), replace the nitrogen atmosphere three times, and heat the reaction mixture to 80-85°C. React for 3 hours. Add water to precipitate, filter, and dry to obtain product C3-1 (270 g, 96.8% yield).

[0501] 1H-NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.42(d,J=4.9Hz,1H),8.23(s,1H),7.26–7.16(m,2H),6.70(d,J=8. 3Hz,1H),6.62(ddd,J=9.3,8.3,0.9Hz,1H),4.64(d,J=13.6Hz,1H),4.45–4.31(m,1H),4.25(ddd,J=13.7,6 .3,4.6Hz,1H),3.83(s,1H),3.51–3.24(m,2H),3.18(dd,J=12.3,3.8Hz,1H),2.72(p,J=6.7Hz,1H),2.42–2 .21(m,2H),2.07(s,6H),1.80(s,3H),1.48(d,J=12.1Hz,13H),1.12(d,J=6.7Hz,3H),0.95(d,J=6.7Hz,3H).

[0502] Example 21 Preparation of Compound C3-1

[0503] Except for the following conditions, other reaction conditions and operations are the same as Example 20.

[0504] A reaction flask was charged with 1.0 equivalent (13 mg) of C1-1, 1.05 equivalents of C2-1, 1.0 mol% of Pd(dba), 4.0 mol% of PPh, 5.0 equivalents of KHPO, 8.0 volumes of 1,4-dioxane, and 4 volumes of water. The mixture was heated to 90°C and reacted for 16 hours. The reaction conversion was 100% and the product had an HPLC purity of 93.80%. The NMR data were essentially the same as in Example 20.

[0505] Example 22 Preparation of Compound C3-1

[0506] According to the conditions and operations of the preparation method of the compound of formula C3-1 in Example 20, the palladium catalyst, ligand, base and temperature are replaced with the conditions in Table 9.

[0507] Table 9

[0508] Example 23 Preparation of Compound C3-1

[0509] A reaction flask was charged with 1.0 equivalent of C1-1 (13 mg, 20 μmol), 1.05 equivalents of C2-2, 1.1 mol% Pd2(dba)3, 2.2 mol% SylPhos, 5.0 equivalents of KF, 8.0 volumes of 1,4-dioxane, and 4 volumes of water. The mixture was heated to 90°C and allowed to react for 16 hours. The reaction conversion reached 100%, the product had an HPLC purity of 84.96%, and the weight yield was 89.02%. NMR data were essentially the same as in Example 20.

[0510] Example 24 Preparation of Compound C3-1

[0511] According to the conditions and operations of the preparation method of the compound of formula C3-1 in Example 23, the palladium catalyst, ligand, base and temperature were replaced with the conditions in Table 10.

[0512] Table 10

[0513] Example 25 Preparation of Compound C3-2

[0514] To a reaction flask were added 1.0 equivalent of C1-1 (batch size 13 mg, 20 umol), 1.05 equivalents of C2"-1, 1.1 mol% Pd2(dba), 32.2 mol% SylPhos, 5.0 equivalents of KF, 8.0 volumes of 1,4-dioxane, and 4 volumes of water. The mixture was heated to 90°C and reacted for 16 hours. The reaction conversion was 100%, the product had an HPLC purity of 84.96%, and the weight content yield was 89.02%. The NMR data were essentially the same as in Example 20.

[0515] Example 26 Preparation of Compound C3-2

[0516] According to the conditions and operations of the preparation method of the compound of formula C3-2 in Example 25, the palladium catalyst, ligand, base and temperature are replaced with the conditions in Table 11.

[0517] Table 11

[0518] Example 27 Preparation of Compound C3-1

[0519] Method 1:

[0520] Purified water (26.7 kg) and dioxane (54.9 kg) were added to the reactor and stirred to prepare solution 1. Solution 1 (20.2 kg) and Solution 2 (1.72 kg, 1.3 equiv.) was added to a reactor. Solution 1 (40.4 kg), C1-1 (4.0 kg, 1.0 equiv.), and CsF (4.63 kg, 5.0 equiv.) were added to the reactor and the atmosphere was purged with nitrogen three times. Pd(PPh3)4 (0.211 kg, 0.03 equiv.) was added, the mixture was heated to 80-90°C, and Solution 2 was added dropwise. Stirring was continued for 2.5-3.5 hours. If unreacted, additional CsF and Pd(PPh3)4 were added until the reaction was complete. Purified water (30.1 kg) was slowly added at 75-90°C and the temperature was slowly lowered to 10-25°C. The mixture was stirred for 7-15 hours, filtered, and dried under vacuum to yield product C3-1 (4.2 kg, 94% yield). 1H-NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.42(d,J=4.9Hz,1H),8.23(s,1H),7.26–7.16(m,2H),6.70(d,J=8 .3Hz,1H),6.62(ddd,J=9.3,8.3,0.9Hz,1H),4.64(d,J=13.6Hz,1H),4.45–4.31(m,1H),4.25(ddd,J=13.7,6 .3,4.6Hz,1H),3.83(s,1H),3.51–3.24(m,2H),3.18(dd,J=12.3,3.8Hz,1H),2.72(p,J=6.7Hz,1H),2.42–2 .21(m,2H),2.07(s,6H),1.80(s,3H),1.48(d,J=12.1Hz,13H),1.12(d,J=6.7Hz,3H),0.95(d,J=6.7Hz,3H).

[0521] Method 2:

[0522] Under nitrogen protection, 1.0 equivalent of C1-1 (feeding scale 13 mg, 20 umol) and 1.3 equivalent of 3 mol% Pd(CF3COO)2, 9 mol% PPh3, 3 mol% PPh3O, 5.0 equivalents of K2HPO4, 10.0 volumes of 1,4-dioxane, and 5 volumes of water. Heat to 90°C and react for 10 minutes, achieving 100% conversion and a weight yield of 99.5%.

[0523] Example 28 Preparation of Compound C3-1

[0524] According to the conditions and operations of the preparation method of the compound of formula C3-1 in Example 27, the palladium catalyst, ligand, base and temperature were replaced with the conditions in Table 12.

[0525] Table 12

[0526] Example 29 Preparation of Compound C3-1

[0527] Under nitrogen protection, the reaction flask was charged with 1.0 equivalent of C1-1, 1.3 equivalents of C2"-2, 3 mol% of Pd(CF3COO)2, 9 mol% of PPh3, 3 mol% of PPh3O, 5.0 equivalents of K2HPO4, 10.0 volumes of 1,4-dioxane and 5 volumes of water. The reaction was heated to 90°C and reacted for 10 minutes. The reaction conversion was 100% and the weight yield was 99.9%.

[0528] Example 30 Preparation of Compound C4-1

[0529] DCM (21.8 kg) and C3-1 (4.14 kg) were added to a reactor. 4N HCl (7.7 kg of concentrated hydrochloric acid in 10.2 kg of water) was slowly added to the reactor and the reaction continued for 1.5-2.5 hours. The reaction mixture was filtered through celite, and the filter cake was washed with purified water. The aqueous phase was separated by adding 15% Na2CO3 solution (6.8 kg of Na2CO3 dissolved in 38.1 kg of water). The aqueous phase was extracted once with ethyl acetate (22.3 kg). The organic phases were combined and washed once with 20% NaCl (14.9 kg). Mercaptosilica gel (0.8 kg) was added to the organic phase and stirred for 6-12 hours. The mixture was filtered. The filtrate was concentrated to 3.3-4.3 volumes, and n-heptane (18.3 kg) was slowly added. Stirring was continued for 2-16 hours, filtered, and dried under vacuum to obtain product C4-1 (3.32 kg, 93% yield). 1H-NMR (400MHz, DMSO-d6) δ8.45(d,J=4.9Hz,1H),8.25(s,1H),7.23(td,J=8.5,6.3Hz,2H),6.75(d,J=8.3Hz, 1H),6.65(ddd,J=9.1,8.3,0.9Hz,1H),4.49–4.26(m,2H),3.77–3.64(m,1H),3.52(d,J=13.7Hz,1H),3.39(dd, J=13.9,4.5Hz,1H),3.30(q,J=6.3,4.9Hz,2H),3.20–3.08(m,1H),2.84–2.67(m,1H),2.40(dp,J=18.4,6.0Hz ,2H),2.13(s,6H),1.81(d,J=12.4Hz,3H),1.56(d,J=6.8Hz,3H),1.15(d,J=7.6Hz,4H),0.99(t,J=5.9Hz,3H).

[0530] Example 31 Preparation of Compound C6-1

[0531] DCM (85.14 kg), C4-1 (3.22 kg, 1.0 equiv.), and NMP (3.34 kg) were added to a reactor and stirred to dissolve. The temperature was then cooled to 0-5°C, followed by the slow addition of a DCM solution (21.6 kg) of C5 (0.75 kg, 1.10 equiv.). After stirring at 0-15°C for 1-2 hours, n-heptane (32.98 kg) was slowly added and stirred for 1-3 hours. The reaction mixture was filtered and dried under vacuum to yield product C6-1 (3.19 kg, 83%).

[0532] Example 30 Preparation of the compound of formula C7-1 and its sulfate

[0533] Add THF (22.48 kg) and C6-1 (3.10 kg) to a reactor at 10-25°C, then slowly add K3PO4 solution (made up of 4.64 kg purified water and 1.74 kg K3PO4). Stir and separate. Add K3PO4 solution (made up of 6.32 kg purified water and 3.50 kg K3PO4) to the organic phase. Stir the reaction mixture at 45-52°C for 10-24 hours. After completion of the reaction, cool to 15-25°C and separate the layers. Wash the organic phase three times with 25% NaCl (31 kg, 10X), add anhydrous MgSO4 (1.54 kg), stir for 6-12 hours, and filter. Add molecular sieves (3.13 kg) to the filtrate, stir at 0-5°C for 6-12 hours, and filter. Add THF to 20 volumes, add 0.1X water, and slowly add 1.5N H2SO4 solution (2.97 kg). Stir at 10-20°C for 8-21 hours, heat to 45-50°C, and continue stirring for 1-3 hours. Cool to 10-20°C, stir for 2-3 hours, filter the reaction mixture, wash with acetone, and vacuum dry to obtain the product. Slurry the mixture with acetone and water, filter, and vacuum dry to obtain the product (2.49 kg, 97% yield).

[0534] The H NMR data are shown in Table 13 (deuterated dimethyl sulfoxide solvent):

[0535] Table 13

[0536] The above describes exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the scope of protection of this application.

Claims

1. A method for preparing a compound of formula A5, characterized in that: It includes the following steps: Step 1: subjecting compound A1 and compound Z1a to an aromatic nucleophilic substitution reaction to obtain a compound of formula A2; Step 2: subjecting the compound of formula A2 and compound C to an esterification reaction to obtain a compound of formula A3; Step 3: subjecting the compound of formula A3 to a chlorination reaction with a chlorinating agent to obtain a compound of formula A4; Step 4: Compound A4 is subjected to ring-closing reaction to obtain compound A5; Among them, R 1 is F or Cl; R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl, Br or I; When R 3 When is H, the reaction can be performed without the step of preparing the compound of formula A4 from the compound of formula A3.

2. The method for preparing the compound of formula A5 according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In step 1, the preparation method of the compound of formula A2 comprises the following steps: in the presence of a base, in a solvent, subjecting the compound of formula A1 and the compound of formula Z1a to an aromatic nucleophilic substitution reaction to obtain the compound of formula A2; The base is one or more of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, NaH, t-BuOK, an alkali metal base and an organic amine base; (2) In step 2, the preparation method of the compound of formula A3 comprises the following steps: Step a: In a solvent, subjecting the compound of formula A2 to an acylating agent for acylation reaction to obtain an acyl halide compound; Step b: subjecting the acyl halide compound obtained in step 1 to an esterification reaction with the compound of formula C to obtain the compound of formula A3; (3) In step 3, the method for preparing the compound of formula A4 comprises the following steps: subjecting the compound of formula A3 and a halogenating agent to a halogenation reaction in a solvent to obtain the compound of formula A4; (4) In step 4, the preparation method of the compound of formula A5 is as follows: in the presence of a base, a compound of formula A4 and acetic anhydride are subjected to a cyclization reaction in a solvent to obtain the compound of formula A5; 3. The method for preparing the compound of formula A5 according to claim 2, characterized in that: It meets one or more of the following conditions: (1) In step 1, the base is lithium hexamethyldisilazide; (2) In step 1, the molar ratio of the base to the compound of formula A1 is (3-5):1, for example 4:1; (3) In step 1, the molar ratio of the compound of formula Z1a to the compound of formula A1 is (1-3):1, for example 1.1:1; (4) In step 1, the solvent is one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent and a cycloalkane solvent, preferably an ether solvent; The aromatic hydrocarbon solvent may be one or more of toluene, xylene and mesitylene; The ether solvent may be one or more of tetrahydrofuran, diethyl ether and dioxane; The halogenated hydrocarbon solvent may be dichloromethane and / or chloroform; The cycloalkane solvent may be cyclohexane; (5) In step 1, the weight content of the compound of formula Z1a is 10-40%, for example 22.5%; (6) In step 1, the compound of formula A1 is (7) In step 1, the aromatic nucleophilic substitution reaction temperature is -15°C to 110°C, can be -15°C to 15°C, and can also be -5°C to 5°C; (8) In step a of step 2, the solvent is a chlorinated hydrocarbon solvent, such as dichloromethane; (9) In step a of step 2, the acylating agent is oxalyl chloride; (10) In step a of step 2, the molar ratio of the acylating agent to the compound of formula A2 is (1-3):1, for example 2:1; (11) In step a of step 2, the acylation reaction is carried out in the presence of a catalyst; The catalyst is preferably N,N-dimethylformamide; The mass ratio of the catalyst to the compound of formula A2 is preferably (0.001-0.1):1, for example 0.05:1; (12) In step a of step 2, the temperature of the acylation reaction is 5°C-40°C, for example, 15°C-25°C; (13) In step b of step 2, the compound of formula C is methanol or ethanol; (14) In step b of step 2, the volume mass ratio of the compound of formula C to the compound of formula A2 is 1 L / kg-10 L / kg, for example 5 L / kg; (15) In step b of step 2, the reaction temperature is 10°C-50°C, for example 30°C-40°C; (16) In step 3, the halogenating agent is N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, For example, N-chlorosuccinimide; (17) In step 3, the molar ratio of the halogenating agent to the compound of formula A3 is (1-2):1, for example 1.1:1; (18) In step 3, the compound of formula A3 is (19) In step 3, the solvent is an amide solvent, such as N,N-dimethylformamide; (20) In step 3, the volume mass ratio of the solvent to the compound of formula A3 is 1 L / kg-5 L / kg, for example 3 L / kg; (21) In step 3, the temperature of the halogenation reaction is 30°C-80°C, for example, 55°C-60°C; (22) In step 4, the base is an alkali metal base of tert-butoxide, such as lithium tert-butoxide; (23) In step 4, the molar ratio of the base to the compound of formula A4 is (1-6):1, for example 4.5:1; (24) In step 4, the molar ratio of the acetic anhydride to the compound of formula A4 is (1-6):1, for example 3.0:1; (25) In step 4, the compound of formula A4 is (26) In step 4, the temperature of the cyclization reaction is 5°C-50°C, such as room temperature.

4. A method for preparing a compound, characterized in that: The preparation method is a preparation method of a compound of formula A2, a preparation method of a compound of formula A3 or a preparation method of a compound of formula A4; The preparation method of the compound of formula A2 comprises the following steps: subjecting compound A1 and compound Z1a to an aromatic nucleophilic substitution reaction to obtain a compound of formula A2; Among them, R 1 is F or Cl; the other conditions and operations of the aromatic nucleophilic substitution reaction may be as described in claim 2 or 3; The preparation method of the compound of formula A3 comprises the following steps: subjecting the compound of formula A2 and compound C to an esterification reaction to obtain the compound of formula A3; Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; The conditions and operation of the esterification reaction may be as described in claim 2 or 3; The preparation method of the compound of formula A4 comprises the following steps: subjecting the compound of formula A3 to a halogenation reaction with a halogenating agent to obtain the compound of formula A4; Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, the conditions and operation of the halogenation reaction can be as described in claim 2 or 3.

5. A compound of formula A2, A3 or A4: in, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl, Br or I; The compound of formula A3 is preferably The compound of formula A4 is preferably 6. Use of a substance L as a resolving agent in resolving a compound of formula AA5, characterized in that: The substance L is one or more of D-3-bromocamphor-10-sulfonic acid, S-binaphthol phosphate, D-(+)-camphorsulfonic acid, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, S-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate, and S-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate. or one or more of L-3-bromocamphor-10-sulfonic acid, R-binaphthol phosphate, L-(+)-camphorsulfonic acid, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate; Among them, R 7 and R 8 are independently unsubstituted or substituted C 1-6 Alkyl or unsubstituted or substituted C 1-6 R" and R' are independently H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, unsubstituted or substituted C 1-6 Alkyl or unsubstituted or substituted C 1-6 The substituted substituent is selected from F, Cl, Br, I, hydroxyl, amino, nitro or cyano; p is 1 or 2, q is 1, 2 or 3; X is C or N.

7. Use of the substance L as claimed in claim 6 as a resolving agent in resolving a compound of formula AA5, characterized in that: It meets one or more of the following conditions: (1) The general formula of the compound of formula AA5 is Preferably R 3 is H, F, Cl, Br or I; (2) The substance L is S-binaphthol phosphate; (3) The application also includes a method for splitting a compound of formula AA5, which comprises the following steps: in a solvent, subjecting the compound of formula AA5 and the substance L to a salt-forming reaction to obtain a compound of formula AA5-L and a compound of formula AA5'-L; 8. Use of the substance L as claimed in claim 7 as a resolving agent in resolving a compound of formula AA5, characterized in that: It meets one or more of the following conditions: (1) The solvent is one or more of a nitrile solvent, a ketone solvent, water, an ether solvent, an alkane solvent, a mixed solvent of an amine solvent, a mixed solvent of an ester solvent, or an alcohol solvent; preferably a mixed solvent of a ketone solvent-water, a mixed solvent of an ether solvent-alkane solvent, a mixed solvent of a nitrile solvent-amine solvent, a mixed solvent of an ether solvent-ester solvent, a nitrile solvent, or an alcohol solvent, such as a mixed solvent of acetone-water with a volume ratio of 19:1, a mixed solvent of 2-methyltetrahydrofuran-heptane with a volume ratio of 1:1, a mixed solvent of acetonitrile-isopropylamine with a volume ratio of 1:1, a mixed solvent of tetrahydrofuran-ethyl acetate with a volume ratio of (1-9):1, acetonitrile, or ethanol; When the substance L is D-3-bromocamphor-10-sulfonic acid, the solvent is preferably a mixed solvent of ketone solvent-water, a mixed solvent of nitrile solvent-amine solvent, or a mixed solvent of ether solvent-ester solvent; When the substance L is S-binaphthol phosphate, the solvent is a mixed solvent of ketone solvent-water, a mixed solvent of ether solvent-alkane solvent, a mixed solvent of nitrile solvent-amine solvent, a mixed solvent of ether solvent-ester solvent or an alcohol solvent; When the substance L is D-(+)-camphorsulfonic acid, the solvent is preferably a mixed solvent of ketone solvent-water, a mixed solvent of ether solvent-alkane solvent, or a mixed solvent of nitrile solvent-amine solvent; (2) the volume mass ratio of the solvent to the compound of formula AA5 is 5 mL / g-40 mL / g, for example 20 mL / g; (3) The molar ratio of the compound of formula AA5 to the substance L is 1:(0.5-3), for example 1:1; (4) The temperature of the salt-forming reaction is 10-70°C, for example 40°C-50°C; (5) After the salt-forming reaction is completed, the following post-treatment operations are further included: crystallization; In the crystallization, the solvent is preferably a mixed solvent of ketone solvent-water, a mixed solvent of ether solvent-alkane solvent, a mixed solvent of nitrile solvent-amine solvent, a mixed solvent of ether solvent-ester solvent, a nitrile solvent or an alcohol solvent, such as a mixed solvent of acetone-water with a volume ratio of 19:1, a mixed solvent of 2-methyltetrahydrofuran-heptane with a volume ratio of 1:1, a mixed solvent of acetonitrile-isopropylamine with a volume ratio of 1:1, a mixed solvent of ethyl acetate-tetrahydrofuran with a volume ratio of 1:1, acetonitrile or ethanol; The mother liquor after the crystallization is preferably used to recover the above-mentioned resolving agent and (6) The use also includes a free reaction of the compound of formula AA5-L or the compound of formula AA5'-L with a free reagent to obtain a compound of formula DD5 or DD5'; Among them, R 7 , R 8 , R", R', X, substance L, p and q are all as defined in claim 6 or 7.

9. Use of the substance L as claimed in claim 8 as a resolving agent in resolving a compound of formula AA5, characterized in that: It meets one or more of the following conditions: (1) The free reagent is an alkali metal bicarbonate or hydrochloric acid, such as sodium bicarbonate; (2) The free reaction temperature is 10°C-30°C; (3) The compound of formula AA5-L is (4) The compound of formula AA5-L is 10. A method for preparing a compound of formula AA5-L, a compound of formula AA5'-L, a compound of formula DD5 or DD5', characterized in that: The preparation method of the compound of formula AA5-L or the compound of formula AA5'-L comprises the following steps: in a solvent, subjecting the compound of formula AA5 and substance L to a salt-forming reaction to obtain the compound of formula AA5-L or the compound of formula AA5'-L; Among them, R 7 , R 8 , R", R', X, substance L, p and q are as defined in claim 6 or 7; The general formula of the compound of formula AA5 is Preferably R 3 is H, F, Cl, Br or I; The operation and conditions of the salt-forming reaction are also the same as those described in claim 8; The preparation method of the compound of formula DD5 or DD5' comprises the following steps: subjecting the compound of formula AA5-L or AA5'-L to a free reaction with a free reagent to obtain the compound of formula DD5 or DD5'; Among them, R 7 , R 8 , R", R', X, substance L, p and q are as defined in claim 6 or 7; The compound of formula AA5-L is preferably a compound of formula A5-L or a compound of formula B5-L; correspondingly, the compound of formula DD5 is preferably D5 or E5; The compound of formula AA5'-L is preferably a compound of formula A5'-L or a compound of formula B5'-L; accordingly, the compound of formula DD5 is preferably D5' or E5'; R 3 is H, F, Cl, Br or I.

11. A compound of formula AA5-L, a compound of formula AA5'-L or a substance M; the substance M comprises the compound of formula AA5-L and the compound of formula AA5'-L: in, R 7 , R 8 , R", R', X, substance L, p and q are defined as in any one of claims 6 to 9: The compound of formula AA5-L is preferably Compound, R 3 is H, F, Cl, Br or I; More preferably, any of the following compounds: The compound of formula AA5'-L is preferably Compound, R 3 is H, F, Cl, Br or I; More preferably, any of the following compounds: The substance M is preferably A mixture of R 3 is H, F, Cl, Br or I; More preferably, it is a mixture of any of the following groups: mixture of mixture of mixture of mixture of mixture, or mixture of Preferably, the molar ratio of the compound of formula AA5-L to the compound of formula AA5'-L in the mixture is 1:

1.

12. A method for preparing a compound of formula D6, characterized in that: The method comprises the following steps: in a continuous flow reactor, in the presence of a solvent and in the presence or absence of a catalyst, subjecting a compound of formula D5 to a nitration reaction as shown below with nitric acid to obtain the compound of formula D6; the catalyst is nitrite when present; R 3 is H, F, Cl, Br or I.

13. The method for preparing the compound of formula D6 according to claim 12, characterized in that: It meets one or more of the following conditions: (1) In the nitration reaction, the nitrite is an alkali metal nitrite, such as sodium nitrite, or a 30% sodium nitrite aqueous solution; (2) In the nitration reaction, the molar ratio of the nitrite to the compound of formula D5 is (0.01-3):1, for example 0.7:1; (3) In the nitration reaction, the molar ratio of the nitric acid to the compound of formula D5 is (1-10):1, for example 2.7:1 or 4:1; (4) In the nitration reaction, the solvent is a carboxylic acid organic solvent and / or water; The carboxylic acid organic solvent may be acetic acid and / or propionic acid; When the organic solvent may be acetic acid and propionic acid, the mass ratio of the propionic acid to the acetic acid is preferably (0.5-10):1, for example 2:1; When the organic solvent may be acetic acid, the volume mass ratio of the acetic acid to the D5 compound is preferably (1-30) mL / g, for example 4 mL / g; (6) The compound of formula D5 is (7) The feed temperature of the nitration reaction is -40°C to 100°C, for example, 5°C or 70°C; (8) The solvent, the compound of formula D5 and each component of nitric acid are sampled simultaneously for continuous flow reaction, or any components are mixed together to form a material group or several material groups and sampled simultaneously or sequentially for reaction; or the catalyst, the solvent, the compound of formula D5 and each component of nitric acid are sampled simultaneously for continuous flow reaction, or any components are mixed together to form a material group or several material groups and sampled simultaneously or sequentially for reaction; when the any components are mixed together to form a material group or several material groups and sampled sequentially for reaction, the solvent and the compound of formula D5 constitute material a; nitric acid is material b; the catalyst is material c; when the catalyst is not present, the material a and the material b are simultaneously fed and mixed evenly. To obtain a mixed liquid; or the material a and the material b are fed simultaneously and mixed evenly to obtain a mixed liquid, and then the material c is mixed evenly with the mixed liquid; The injection speed of the material a can be 1 mL / min-20000 mL / min, for example 19.4 mL / min or 1 mL / min; The injection speed of the material b can be 0.1 mL / min-2000 mL / min, for example 1.2 mL / min or 0.17 mL / min; The injection speed of the material c can be 0.1 mL / min-2000 mL / min, for example 1.1 mL / min; (9) The residence time of the catalyst, the solvent, the compound of formula D5 and the nitric acid in the continuous flow reactor is 0.5 min to 40 min, for example, 1.5 min or 25 min; (10) The reaction liquid obtained after the nitration reaction is completed in the continuous flow reactor, the reaction liquid is continued to react under conventional batch reaction conditions and then post-treated; (11) The method for preparing the compound of formula D6 also includes the method for preparing the compound of formula D5; the method for preparing the compound of formula D5 is as described in claim 8 or 9.

14. A method for preparing a compound of formula C3, characterized in that: The method comprises the following steps: in the presence of an alkaline reagent, a palladium catalyst and a phosphine ligand, subjecting a compound of formula C1 and a compound N to a substitution reaction in a solvent to obtain the compound of formula C3; The compound N is a compound of formula C2, a compound of formula C2', a compound of formula C2" or Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group; R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 6 are independently H, a hydroxy protecting group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; L is a connecting bond or -C(=O)-; Ring A is phenyl, substituted phenyl, naphthyl or substituted naphthyl; the substituents in the substituted phenyl and the substituents in the substituted naphthyl are independently nitro, F, Cl, Br, C 1-4 Alkyl, C 1-4 of an alkoxy group or a phenyl group.

15. The method for preparing the compound of formula C3 according to claim 14, characterized in that: It meets one or more of the following conditions: (1)R 4 In the above, the amino protecting group is -Boc; (2) Each R 6 In the embodiment, the hydroxy protecting group is (3) The alkaline agent is an alkali metal fluoride and / or an alkali metal phosphate; The alkali metal fluoride salt may be potassium fluoride or cesium fluoride; The alkali metal phosphate may be dipotassium hydrogen phosphate; (4) The molar ratio of the alkaline reagent to the compound of formula C1 is (2-8):1, for example 5:1; (5) The palladium catalyst is one or more of Pd2(dba)3, Pd(OAc)2, [Pd(C3H5)Cl]2, Pd(PPh3)4, Pd(CF3COO)2, Pd(TFA)2, Pd(MeCN)2Cl2 and [(cinnamyl)PdCl]2; (6) The molar ratio of the palladium catalyst to the compound of formula C1 is (0.01%-5%):1, and can be (0.1%-3%):1, for example, 0.15%:1, 0.25%:1, 0.35%:1, 0.4%:1, 1.1%:1, 1.5%:1, 1.6%:1, 1.8%:1, 2.0%:1, 2.5%:1 or 3%:1; (7) The phosphine ligand is one or more of PPh3, BI-DIME, Ph2DavePHOS, DTP-DPEPhos, Tris(p-anisyl)phosphine, AntPhos, DBFphos, cataCXium PCy, Ph2Cy, AmgenPHOS, HiersoPHOS-6, DBFphos, (p-anisyl)3P, Ph2P(tBu), Cy2P(o-Tol), Ph2DavePHOS, p-NMe2-Cy-JohnPHOS, (t-Bu)2P(n-hexyl)HBF4 and (Rac)-AntPhos; (8) The molar ratio of the phosphine ligand to the compound of formula C1 is (0.02%-16%):1, which can be (0.6%-12%):1, for example, 0.6%:1, 1.0%:1, 1.4%:1, 1.5%:1, 1.6%:1, 2.2%:1, 3%:1, 4%:1 or 12%:1; (9) The molar ratio of the compound N to the compound of formula C1 is (1-3):1, for example, 1.05:1, 1.1:1 or 1.3:1; (10) The compound N is (11) The solvent is a mixed solvent of an ether solvent-water or a mixed solvent of a nitrile solvent-water, and may be a mixed solvent of dioxane-water or a mixed solvent of acetonitrile-water; (12) The temperature of the substitution reaction is 40°C-150°C, and can be 60°C-90°C.

16. The method for preparing the compound of formula C3 according to claim 15, characterized in that: (1) When the compound N is a compound of formula C2, the palladium catalyst is Pd2(dba)3, and the phosphine ligand is PPh3 and / or SylPhos; (2) When the compound N is a compound of formula C2", the alkaline agent is an alkali metal phosphate; the palladium catalyst is [Pd(C3H5)Cl]2 and / or Pd(CF3COO)2; the phosphine ligand is Ph2P(t-Bu) and / or PPh3; (3) When the compound N is When the alkaline agent is an alkali metal phosphate; the palladium catalyst is Pd(CF3COO)2; the phosphine ligand is a mixture of PPh3 and PPh3O; (4) The method for preparing the compound of formula C3 also includes a method for preparing the compound of formula C1; the method for preparing the compound of formula C1 includes the following steps: In a solvent, the compound of formula D9 is subjected to a Mitsunobu reaction with the compound of formula X9a to obtain the compound of formula C1; 17. The method for preparing the compound of formula C3 according to claim 16, characterized in that: It also includes a method for preparing a compound of formula D9; the method for preparing the compound of formula D9 is method I and method II: Method I: It comprises the following steps: in a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, subjecting the compound of formula D8 to the following reaction to obtain the compound of formula D9; The metal catalyst is a platinum catalyst or a palladium catalyst; Method II: It comprises the following steps: in the presence of a reducing agent and acetic acid, subjecting the compound of formula D8 to a reduction reaction in a solvent to obtain the compound of formula D9; Among them, R 3 is H, F, Cl or Br; R 4 It is an amino protecting group.

18. The method for preparing the compound of formula C3 according to claim 17, characterized in that: It meets one or more of the following conditions: (1) In method I, the continuous flow reactor is a tubular reactor or a microreactor; (2) In method I, the metal catalyst is supported on carbon; (3) In method I, the reaction is carried out in the presence of an acid catalyst; The acid catalyst is preferably acetic acid; When the reaction is carried out in the presence of an acid catalyst, the reaction can be carried out in a one-step process or a two-step process; The one-step method is preferably to directly introduce the acid catalyst into the reaction system, and to carry out hydrogenation and ring closure in a continuous flow reactor; The two-step method is preferably to hydrogenate the compound of formula D8, and then add an acid catalyst to the reaction solution after the hydrogenation to perform ring closure; (4) In method I, the solvent is one or more of an ester solvent, an ether solvent and a carboxylic acid organic solvent, preferably an ester solvent; The ester solvent is preferably ethyl acetate and / or isopropyl acetate, more preferably ethyl acetate; The ester solvent is preferably tetrahydrofuran; (5) In method I, the mass ratio of the solvent to the compound of formula D8 is (10-40):1, for example, 10:1, 20:1, 30:1, 35:1 or 40:1; (6) In methods I and II, the compound of formula D8 is (7) In method I, the reaction is carried out at 50°C-100°C, for example, 70°C, 80°C or 85°C; (8) In method I, the reaction is carried out under pressure, for example, at a pressure of 0.3 MPa-5 MPa, for example, 1 MPa; (9) In method I, the base, the solvent, the compound of formula D8 and H2 are separately introduced simultaneously to carry out a continuous flow reaction, or any components in the materials are mixed together to form a group of materials or several groups of materials are introduced simultaneously to carry out the reaction; When the solvent and the compound of formula D8 constitute material a, and hydrogen is material b, material a and material b are fed simultaneously to react; When the reaction is carried out in the presence of an acid catalyst, the material a may also be a raw material liquid composed of the solvent, the compound of formula D8 and the acid catalyst; The injection speed of the material a can be 0.1 mL / min-5 mL / min, for example 1 mL / min; The injection speed of the material b can be 5 mL / min-100 mL / min, for example 60 mL / min; The material a and the material b can be preheated to 50°C-100°C before feeding for reaction; The residence time of the material a and the material b in the continuous flow reactor can be 1 min-10 min, for example 5 min; (10) The method for preparing the compound of formula C3 also includes a method for preparing the compound of formula D8; the method for preparing the compound of formula D8 comprises the following steps: In the presence of a base, the compound of formula D7 and the compound of formula Y7a are subjected to the following reaction in a solvent to obtain the compound of formula D8; 19. The method for preparing the compound of formula C3 according to claim 18, characterized in that: It meets one or both of the following conditions: (1) In the method for preparing the compound of formula D9, the metal catalyst is a platinum catalyst; the reaction is carried out in the presence of an acid catalyst; the reaction is completed in a one-step process; and the solvent is ethyl acetate; (2) The method for preparing the compound of formula C3 also includes a method for preparing the compound of formula D7; the method for preparing the compound of formula D7 comprises the following steps: In the presence of a base, the compound of formula D6 and phosphorus oxychloride are reacted in a solvent in the following manner to obtain the compound of formula D7; Preferably, the preparation method of the compound of formula C3 may also include the preparation method of the compound of formula D6; the preparation method of the compound of formula D6 is as described in claim 12 or 13.

20. A method for preparing a compound of formula D9, a compound of formula C2 or a compound of formula C2', characterized in that: The preparation method of the compound of formula D9 comprises the following steps: In a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, the compound of formula D8 is subjected to the following reaction to obtain the compound of formula D9; The metal catalyst is a platinum catalyst or a palladium catalyst; Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group; The conditions and operations in the preparation method of the compound of formula D9 may be as described in claim 17 or 18; The preparation method of the compound of formula C2 or the compound of formula C2' comprises the following steps: reacting the compound of formula C2a with "the compound of formula C2-1-SM or the compound of formula C2-3-SM" in a solvent to obtain the compound of formula C2 or the compound of formula C2'; R 5 , A and L are defined as in claim 14.

21. A compound of formula C1, C2 or C2': in, R 3 , R 4 , R 5 , L, Ring A and The definition of as in claim 14; Formula C1 is preferably Formula C2 is preferably Formula C2' is preferably 22. A method for preparing a compound of formula C6, characterized in that: The method comprises the following steps: subjecting a compound of formula C4 and a compound of formula C5 to the following reaction in a solvent to obtain the compound of formula C6; R 3 is H, F, Cl, Br or I; Preferably, the preparation method of the compound of formula C6 further comprises the following steps: subjecting the compound of formula C3 to a deprotection reaction in a solvent in the presence of a deprotection agent according to the following formula to obtain the compound of formula C4; R 4 is an amino protecting group, such as -Boc.

23. A method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof, characterized in that: It is any of the following options: Scenario 1: It comprises the following steps: a method for preparing a compound of formula A5; and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof by further preparing the compound of formula A5; Wherein, the preparation method of the compound of formula A5 comprises the following steps: Step 1: Compound A1 and compound Z1a undergo aromatic nucleophilic substitution reaction to obtain compound A2; Step 2: subjecting compound A2 and compound C to an esterification reaction to obtain compound A3; Step 3: subjecting compound A3 to a halogenating reaction with a halogenating agent to obtain compound A4; Step 4: Compound A4 is subjected to a ring-closing reaction to obtain compound A5; Scenario 2: It comprises the following steps: a method for preparing a compound of formula A2; and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula A2; The preparation method of the compound of formula A2 comprises the following steps: in the presence of a base, in a solvent, subjecting the compound of formula A1 and the compound of formula Z1a to an aromatic nucleophilic substitution reaction to obtain the compound of formula A2; The base is lithium hexamethyldisilazide; Scenario 3: It comprises the following steps: a method for preparing a compound of formula D6; and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula D6; The method for preparing the compound of formula D6 comprises the following steps: in a continuous flow reactor, in the presence of a nitrite catalyst or in the absence of nitric acid, in the presence of nitric acid and a solvent, subjecting the compound of formula D5 to a nitration reaction as shown below to obtain the compound of formula D6; Scheme 4: It comprises the following steps: a method for preparing a compound of formula D9; and, a method for preparing a compound of formula C7 or a salt thereof by further preparing the compound of formula D9; The preparation method of the compound of formula D9 comprises the following steps: in a continuous flow reactor, in the presence of hydrogen, a metal catalyst and a solvent, subjecting the compound of formula D8 to the following reaction to obtain the compound of formula D9; The metal catalyst is a platinum catalyst or a palladium catalyst; Solution 5: It comprises the following steps: a method for preparing a compound of formula C3; and, a method for preparing a compound of formula C7 or a pharmaceutically acceptable salt thereof from the compound of formula C3; The preparation method of the compound of formula C3 comprises the following steps: in the presence of an alkaline reagent, a palladium catalyst and a phosphine ligand, subjecting the compound of formula C1 and compound N to a substitution reaction in a solvent to obtain the compound of formula C3; The compound N is a compound of formula C2, a compound of formula C2', a compound of formula C2" or Among them, R 3 is H, F, Cl or Br; R 4 is an amino protecting group; R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; each R 6 are independently H, a hydroxy protecting group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; L is a connecting bond or -C(=O)-; Ring A is phenyl, substituted phenyl, naphthyl or substituted naphthyl; the substituents in the substituted phenyl and the substituents in the substituted naphthyl are independently nitro, F, Cl, Br, C 1-4 Alkyl, C 1-4 an alkoxy or phenyl group; Solution 6: It includes the following steps: Step a): Compound C4 and compound C5 are subjected to the following reaction in a solvent to obtain compound C6; Step b): preparing a compound of formula C7 by dechlorination of a compound of formula C6 (e.g., reacting at 45-52° C. in the presence of K3PO4); In schemes 1-6, R 1 is F or Cl; R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl or Br; R 4 is an amino protecting group; Preferably, Scheme 1 and Scheme 2 prepare the compound of formula C7 or a pharmaceutically acceptable salt thereof through the following reaction route: Scheme 3 The compound of formula C7 or a pharmaceutically acceptable salt thereof is prepared by the following reaction route: Scheme 4 The compound of formula C7 or a pharmaceutically acceptable salt thereof is prepared by the following reaction route: Scheme 5 The compound of formula C7 or a pharmaceutically acceptable salt thereof is prepared by the following reaction route: More preferably, the conditions and operations of the preparation method of the compounds of formula A2 to formula A5 are as described in any one of claims 1-3, the conditions and operations of the preparation method of the compound of formula D6 are as described in claim 12 or 13, the conditions and operations of the preparation method of the compound of formula D9 are as described in any one of claims 16-18, and the conditions and operations in the preparation method of the compound of formula C3 are as described in any one of claims 14-19.

24. Use of a substance X in the preparation of a compound of formula C7 or a pharmaceutically acceptable salt thereof, characterized in that: The substance X is a compound of formula A2, a compound of formula A3, a compound of formula A4, a compound of formula A5-L or a compound of formula C1; Among them, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R 3 is H, F, Cl, Br or I; R 4 is an amino protecting group; L is one or more of D-3-bromocamphor-10-sulfonic acid, S-binaphthol phosphate, D-(+)-camphorsulfonic acid, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, S-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol phosphonate, and S-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bishydrogen phosphate, or L-3-bromocamphor-10-sulfonic acid, R-binaphthol phosphate, L-(+)-camphorsulfonic acid, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-binaphthol phosphonate, and R-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'- One or more of bis(dihydrogen phosphates); The compound of formula A3 is preferably The compound of formula A4 is preferably The compound of formula A5-L is preferably The compound of formula C1 is preferably

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