Naphthyridinone derivative and preparation method thereof

Abstract

The invention relates to a naphthyridinone derivative and a preparation method thereof. According to the method, the defects in the prior art are overcome, the cost is greatly reduced, and the obtained product is good in purity, high in yield, high in process operability and high in process safety. Therefore, the method is suitable for industrial application.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a naphthyridone derivative and a preparation method and application thereof. Background Art

[0002] Poly(ADP-ribose) polymerases (PARP) are a superfamily of proteins that catalyze the ADP-ribosylation of proteins in eukaryotic cells, including at least 17 protein subtypes. PARP can catalyze the cleavage of the substrate nicotinamide adenine dinucleotide NAD+ into nicotinamide and ADP-ribose, and cause poly(ADP-ribosylation) of its target proteins. PARP is located in the cell nucleus and is a key enzyme in the repair of cellular DNA damage.

[0003] PARP1 is the earliest discovered and most studied PARP isoform, which includes three main domains, namely the DNA binding domain (DBD) at the N-terminus, the self-modification domain (AMD), and the catalytic domain at the C-terminus. PARP1 is an important functional protein in the process of DNA damage repair. PARP1 acts as a sensor for single-strand DNA damage. DNA damage can lead to PARP1 activation, poly ADP-ribosylation modification of its target proteins such as histones, and recruitment of related repair proteins to promote DNA damage repair. PARP1 is very important for the stability of the genome of normal cells, but in tumor treatment, PARP1 repairs the DNA of tumor cells damaged by radiotherapy and chemotherapy, which antagonizes the tumor-killing effect of radiotherapy and chemotherapy. Therefore, PARP1 inhibitors can be developed as sensitizers for tumor radiotherapy and chemotherapy.

[0004] Breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, which mainly has two subtypes: BRCA1 and BRCA2. BRCA plays an important role in the repair of double-stranded DNA breaks during DNA homologous recombination. Tumor cells often suffer from BRCA defects, which results in the loss of double-stranded DNA damage repair function. If PARP1 function is lost or inhibited at the same time, single-stranded DNA damage repair is also lost, which will eventually lead to tumor cell death and produce a "synthetic lethal" effect. Therefore, the use of PARP1 inhibitors to block the single-stranded DNA damage repair function has a selective killing effect on BRCA-deficient tumors.

[0005] PARP inhibitors have achieved great success in precision treatment of tumors, especially for tumors with BRCA mutations or defects. Currently available PARP inhibitors include Olaparib (AZD2281) from AstraZeneca, Rucaparib (CO-338) from Clovis, Niraparib (MK-4827) from Tesaro, and Talazoparib (BMN-673) from Pfizer. The indications are mainly for ovarian cancer and breast cancer with BRCA mutations, and there are many PARP inhibitors in the clinical research stage. PARP2 has the highest homology with PARP1 in the PARP family. Therefore, most of the PARP inhibitors currently available or in the clinical stage are non-selective PARP inhibitors, which have a strong inhibitory effect on both PARP1 and PARP2 subtypes. Studies have shown that PARP2 plays an important role in regulating the production of red blood cells, and the inhibition of PARP2 is closely related to the blood toxicity of PARP inhibitors in clinical practice, such as anemia and other side effects. Therefore, China has a huge market demand for PARP1 targets.

[0006] WO2022223025A1 discloses a PARP1 inhibitor, in which the patent uses ethyl 6-methyl-5-nitronicotinate and 5-bromomethylpyridinate as raw materials to prepare a PARP1 inhibitor compound. However, due to the long reaction route and harsh conditions, it requires multiple column chromatography and has a low yield, making it unsuitable for large-scale industrial production. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the inventors developed a method for preparing PARP1 inhibitors during a long-term research and development process.

[0008] The present invention provides a method for preparing a compound of general formula (VIII), comprising the steps of (a): reacting a compound of general formula (I-1-1) with a compound of general formula (VII) under the conditions of a base and a catalyst to obtain a compound of general formula (VIII);

[0009]

[0010] in,

[0011] X is halogen; preferably fluorine, chlorine or bromine;

[0012] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0013] R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0014] x is selected from 0, 1, 2, 3 or 4.

[0015] In certain embodiments of the present invention, in step (a), X is chlorine; R 1 is ethyl; x is 0.

[0016] In certain embodiments of the present invention, step (a) is carried out in the presence of a solvent, and the solvent is preferably a nitrile solvent, preferably one or more of acetonitrile, propionitrile, butyronitrile, benzyl cyanide and benzonitrile; more preferably acetonitrile.

[0017] In certain embodiments of the present invention, in step (a), the base is one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA and TEA; more preferably DIPEA.

[0018] In certain embodiments of the present invention, in step (a), the catalyst is an iodide; preferably NaI or KI.

[0019] In certain embodiments of the present invention, in step (a), the concentration of the compound of formula (I-1-1) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L (eg, 0.19 mol / L or 0.23 mol / L).

[0020] In certain embodiments of the present invention, in step (a), the concentration of the compound of formula (I-1-1) in the solvent is 0.2 mol / L.

[0021] In certain embodiments of the present invention, in step (a), the molar ratio of the compound of formula (I-1-1) to the compound of formula (VII) is 3:1 to 1:3; preferably 1:1 to 1:1.3 (eg 1:1.17).

[0022] In certain embodiments of the present invention, in step (a), the molar ratio of the compound of formula (I-1-1) to the compound of formula (VII) is 1:1.2.

[0023] In certain embodiments of the present invention, in step (a), the molar ratio of the compound of formula (I-1-1) to the base is 1:1 to 1:15; preferably 1:6 to 1:8 (eg 1:7.4).

[0024] In certain embodiments of the present invention, in step (a), the molar ratio of the compound of formula (I-1-1) to the base is 1:7 to 1:8 (e.g., 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9).

[0025] In certain embodiments of the present invention, in step (a), the molar ratio of the compound of formula (I-1-1) to the catalyst is 5:1 to 1:3; preferably 3.5:1 to 3:1 (eg 3.2:1).

[0026] In certain embodiments of the present invention, step (a) is carried out at 20-80°C; preferably at 50-60°C.

[0027] In certain embodiments of the present invention, the reaction time of step (a) is 1 to 5 hours, preferably 2 to 3 hours.

[0028] The present invention provides a method for preparing a compound of general formula (VII), characterized in that it comprises step (b): deprotecting a compound of general formula (IX) under acidic conditions to obtain a compound of general formula (VII);

[0029]

[0030] in,

[0031] GP is an amino protecting group; preferably Boc, Cbz, Fmoc, PMB or Bn; more preferably Boc;

[0032] R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0033] x is selected from 0, 1, 2, 3 or 4.

[0034] In certain embodiments of the present invention, in step (b), GP is Boc; x is 0.

[0035] In certain embodiments of the present invention, step (b) is carried out in the presence of a solvent, and the solvent is preferably a mixed solvent of an ester solvent and an ether solvent; the ester solvent is preferably one or more of methyl formate, ethyl acetate, ethyl formate and methyl acetate; the ether solvent is preferably one or more of diethyl ether, tetrahydrofuran and dioxane; the solvent is preferably a mixed solvent of ethyl acetate and dioxane.

[0036] In certain embodiments of the present invention, in step (b), the acid is HCl and / or trifluoroacetic acid; preferably HCl.

[0037] In certain embodiments of the present invention, in step (b), the concentration of the compound of formula (IX) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L (eg 0.22 mol / L).

[0038] In certain embodiments of the present invention, in step (b), the molar ratio of the compound of formula (IX) to the acid is 1:2 to 1:10; preferably 1:4 to 1:6 (eg 1:5).

[0039] In certain embodiments of the present invention, step (b) is carried out at 10-40°C; preferably at 20-25°C.

[0040] In certain embodiments of the present invention, the reaction time of step (b) is 10 to 25 hours, preferably 12 to 16 hours.

[0041] The present invention provides a method for preparing a compound of general formula (IX), characterized in that it comprises step (c): reacting a compound of general formula (X) with a compound of general formula (XI) to obtain a compound of general formula (IX);

[0042]

[0043] in,

[0044] GP is an amino protecting group; preferably Boc, Cbz, Fmoc, PMB or Bn; more preferably Boc;

[0045] X 1 is fluorine, chlorine or bromine; preferably bromine;

[0046] R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0047] R 6 Selected from

[0048] x is selected from 0, 1, 2, 3 or 4.

[0049] In certain embodiments of the present invention, in step (c), GP is Boc; X 1 is bromine; R 6 for x is 0.

[0050] In certain embodiments of the present invention, step (c) is carried out in the presence of a solvent, and the solvent is preferably a mixed solvent of an ether solvent and water; the ether solvent is preferably one or more of diethyl ether, tetrahydrofuran and dioxane.

[0051] In certain embodiments of the present invention, step (c) is carried out in the presence of a base, and the base is preferably a carbonate; more preferably one or more of potassium carbonate, sodium carbonate and cesium carbonate.

[0052] In certain embodiments of the present invention, step (c) is carried out in the presence of a catalyst, preferably Pd(PPh 3 ) 4 , Pd 2 (dba) 3 、NiCl 2 (dppf), PdCl 2 、Pd(dppf)Cl 2 、Pd(PPh 3 ) 2 Cl 2 and Pd(OAc) 2 One or more of; more preferably Pd(dppf)Cl 2 .

[0053] In certain embodiments of the present invention, step (c) is performed under the protection of nitrogen.

[0054] In certain embodiments of the present invention, in step (c), the concentration of the compound of formula (X) in the solvent is 0.01 to 1 mol / L; preferably 0.2 to 0.5 mol / L (eg 0.39 mol / L).

[0055] In certain embodiments of the present invention, step (c) is carried out at 80-110°C; preferably at 90-95°C.

[0056] In certain embodiments of the present invention, the reaction time of step (c) is 10 to 30 hours, preferably 16 to 20 hours.

[0057] The present invention provides a method for preparing a compound of general formula (XI), characterized in that it comprises step (d): reacting a compound of general formula (XII) with methylamine to obtain a compound of general formula (XI);

[0058]

[0059] in,

[0060] X 1 is fluorine, chlorine or bromine; preferably bromine.

[0061] In certain embodiments of the present invention, step (d) is carried out in the presence of a solvent, and the solvent is preferably an alcohol solvent; preferably one or more of methanol, ethanol, n-propanol, isopropanol and n-butanol.

[0062] In certain embodiments of the present invention, in step (d), the concentration of the compound of formula (XII) in the solvent is 0.1 to 3 mol / L; preferably 0.7 to 1.2 mol / L (eg 0.92 mol / L).

[0063] In certain embodiments of the present invention, step (d) is carried out at 10-40°C; preferably at 20-25°C.

[0064] In certain embodiments of the present invention, the reaction time of step (d) is 0.1 to 1 hour, preferably 0.5 to 1 hour.

[0065] The present invention provides a method for preparing a compound of the general formula (I-1-1), characterized in that it comprises step (e): reacting a compound of the general formula (I-1-4) with SOX 2 Or PgX' to obtain a compound of formula (I-1-1);

[0066]

[0067] in,

[0068] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0069] X is halogen; preferably fluorine, chlorine or bromine; more preferably chlorine;

[0070] Pg is a hydroxyl protecting group, preferably selected from methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl, p-toluenesulfonyl, nitrobenzenemethylsulfonyl, methanesulfonyl or trifluoromethanesulfonyl;

[0071] X' is halogen, preferably Cl or bromine.

[0072] In certain embodiments of the present invention, in step (e), R 1 is ethyl; X is chlorine.

[0073] In certain embodiments of the present invention, step (e) is carried out in the presence of a solvent, and the solvent is preferably a halogenated hydrocarbon solvent; preferably one or more of monochloromethane, dichloromethane and chloroform; more preferably dichloromethane.

[0074] In certain embodiments of the present invention, in step (e), the concentration of the compound of formula (I-1-4) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L (eg 0.23 mol / L).

[0075] In certain embodiments of the present invention, step (e) is carried out at 10-40°C; preferably at 20-25°C.

[0076] In certain embodiments of the present invention, the reaction time of step (e) is 1 to 3 hours or 15 to 30 hours; preferably 2 to 3 hours or 20 to 24 hours.

[0077] In certain embodiments of the present invention, step (e) optionally needs to react in the presence of a base, preferably the base is selected from one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA and TEA; preferably DIPEA; the molar ratio of the compound of general formula (I-1-4) to the base is 1:1 to 1:10; preferably 1:2 to 1:5; more preferably 1:3 to 1:4.

[0078] The present invention provides a method for preparing a compound of the general formula (I-1-4), characterized in that it comprises step (f): subjecting the compound of the general formula (I-1) to a reduction reaction to obtain a compound of the general formula (I-1-4);

[0079]

[0080] in,

[0081] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0082] R 7 Selected from hydrogen, deuterium, C 1-8 Alkyl or C 1-8 Halogenated alkyl; preferably C 1-8 Alkyl; more preferably ethyl.

[0083] In certain embodiments of the present invention, in step (f), R 1 is ethyl; R 7 It is ethyl.

[0084] In certain embodiments of the present invention, step (f) is carried out in the presence of a solvent, and the solvent is preferably an ether solvent; preferably one or more of diethyl ether, tetrahydrofuran and dioxane.

[0085] In certain embodiments of the present invention, the reducing agent in step (f) is sodium borohydride and / or LiAlH 4 ; LiAlH is preferred 4 .

[0086] In certain embodiments of the present invention, in step (f), the concentration of the compound of formula (I-1) in the solvent is 0.01 to 1 mol / L; preferably 0.1 to 0.3 mol / L (eg 0.2 mol / L).

[0087] In certain embodiments of the present invention, step (f) is carried out at -20 to 5°C; preferably at -5 to 5°C.

[0088] In certain embodiments of the present invention, the reaction time of step (f) is 0.1 to 1 hour, preferably 0.5 to 1 hour.

[0089] The present invention also provides a method for preparing a compound of the general formula (I-1), comprising step (h): reducing a compound of the general formula (III) with a reducing agent to obtain a compound of the general formula (II); step (g): catalyzing the compound of the general formula (II) with a catalyst to obtain a compound of the general formula (I-1);

[0090]

[0091] in,

[0092] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0093] R 7 Selected from hydrogen, deuterium, C 1-8 Alkyl or C 1-8 Halogenated alkyl; preferably C 1-8 Alkyl; more preferably ethyl.

[0094] The present invention also provides a method for preparing a compound of the general formula (I-1), comprising the step (g): catalyzing the compound of the general formula (II) with a catalyst to obtain a compound of the general formula (I-1);

[0095]

[0096] in,

[0097] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0098] R 7 Selected from hydrogen, deuterium, C 1-8 Alkyl or C1-8 Halogenated alkyl; preferably C 1-8 Alkyl; more preferably ethyl.

[0099] In certain embodiments of the present invention, in step (g), R 1 is ethyl; R 7 It is ethyl.

[0100] In certain embodiments of the present invention, in step (g), the catalyst is a phosphine-containing catalyst; preferably methyl phosphine, triethyl phosphine, tripropyl phosphine, tri-tert-butyl phosphine, triphenyl phosphine or tributyl phosphine.

[0101] In certain embodiments of the present invention, in step (g), the reaction is carried out in the presence of an acid, which can be selected from an organic acid or an inorganic acid; preferably a carboxylic acid (R-COOH), a sulfonic acid (R-SO 3 H), sulfinic acid (R-SOOH), thiocarboxylic acid (R-SH), hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; more preferably acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid.

[0102] In certain embodiments of the present invention, in step (g), the reaction is carried out in a solvent, preferably an organic solvent; the concentration of the compound of formula (II) in the solvent is 0.05 g / ml to 0.5 g / ml.

[0103] In certain embodiments of the present invention, in step (g), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably dioxane.

[0104] The present invention also provides a method for preparing a compound of general formula (II), comprising step (h): reducing a compound of general formula (III) with a reducing agent to obtain a compound of general formula (II);

[0105]

[0106] in,

[0107] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0108] R 7 Selected from hydrogen, deuterium, C1-8 Alkyl or C 1-8 Halogenated alkyl; preferably C 1-8 Alkyl; more preferably ethyl.

[0109] In certain embodiments of the present invention, in step (h), R 1 is ethyl; R 7 It is ethyl.

[0110] In certain embodiments of the present invention, in step (h), the reducing agent is selected from a metal reducing agent or a non-metal reducing agent; the metal reducing agent is selected from iron powder or zinc powder, preferably iron powder; the non-metal reducing agent is selected from tin chloride, ferrous chloride or zinc chloride.

[0111] In certain embodiments of the present invention, in step (h), the reaction is carried out in a solvent, and the solvent is preferably a mixed solvent; the concentration of the compound of formula (III) in the mixed solvent is preferably 0.05 g / ml to 0.5 g / ml.

[0112] In certain embodiments of the present invention, in step (h), the mixed solvent is selected from methanol, ethanol, isopropanol, tert-butanol, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or a mixed solvent of dichloromethane and water; preferably a mixed solvent of ethanol and water, wherein the volume content of water is 1% to 50%.

[0113] In certain embodiments of the present invention, in step (h), the reaction temperature of the reaction is 0 to 100°C; preferably 70 to 80°C.

[0114] The present invention also provides a method for preparing a compound of general formula (III), comprising the steps (i): subjecting a compound of general formula (IV) to a Wittig reaction in the presence of a phosphorus ylide reagent to obtain a compound of general formula (III);

[0115]

[0116] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0117] R 7 Selected from hydrogen, deuterium, C 1-8 Alkyl or C 1-8 Halogenated alkyl; preferably C1-8 Alkyl; more preferably ethyl.

[0118] In certain embodiments of the present invention, in step (i), R 1 is ethyl; R 7 It is ethyl.

[0119] In certain embodiments of the present invention, in step (i), the phosphorus ylide reagent is selected from triethyl 2-butyl acrylate, trimethyl 2-butyl acrylate, tripropyl 2-butyl acrylate; preferably triethyl 2-butyl acrylate.

[0120] In certain embodiments of the present invention, in step (i), the reaction is optionally carried out in an organic solvent, and the concentration of the compound of formula (IV) in the solvent is 0.05 g / ml to 0.5 g / ml.

[0121] In certain embodiments of the present invention, in step (i), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran.

[0122] In certain embodiments of the present invention, in step (i), the reaction is optionally carried out in the presence of a base, and the base is one or more of an organic base or an inorganic base; preferably at least one of sodium hydrogen sulfide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, DBU, and DABCO.

[0123] In certain embodiments of the present invention, in step (i), the molar ratio of the base to the compound of formula (IV) is 1 to 10:1; preferably 1:1.

[0124] In certain embodiments of the present invention, in step (i), the reaction temperature of the reaction is -70 to 50°C; preferably -70 to -50°C.

[0125] The present invention also provides a method for preparing a compound of general formula (IV), comprising steps (j-1) and (j-2): in step (j-1), a compound of general formula (VI) reacts with DMF-DMA in an organic solvent to obtain a compound of general formula (V); in step (j-2), the compound of general formula (V) undergoes an oxidation reaction in the presence of an oxidant to obtain a compound of general formula (IV);

[0126]

[0127] R 7 Selected from hydrogen, deuterium, C 1-8 Alkyl or C 1-8 Halogenated alkyl, preferably C 1-8 Alkyl, more preferably ethyl.

[0128] In certain embodiments of the present invention, in step (j-1), the molar ratio of DMF-DMA to the compound of formula (VI) is 1 to 30:1; preferably 1 to 20:1; more preferably 1 to 10:1; further preferably 1 to 5:1; and further preferably 2:1.

[0129] In certain embodiments of the present invention, in step (j-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably DMF.

[0130] In certain embodiments of the present invention, in step (j-1), the concentration of the compound of formula (VI) is 0.05 g / ml to 0.5 g / ml.

[0131] In certain embodiments of the present invention, in step (j-1), the reaction is carried out in the presence of a base, and the base is one or more organic bases or inorganic bases; preferably at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, and DABCO.

[0132] In certain embodiments of the present invention, in step (j-1), the molar ratio of the base to the compound of formula (VI) is 0.1 to 10:1.

[0133] In certain embodiments of the present invention, in step (j-1), the reaction temperature is 0 to 100°C; preferably 35 to 45°C.

[0134] In certain embodiments of the present invention, in step (j-2), the oxidant is selected from perchlorate, permanganate, dichromate, peroxide or gaseous oxidant; preferably sodium dichromate, potassium dichromate, potassium permanganate, sodium perchlorate, oxygen or chlorine.

[0135] In certain embodiments of the present invention, in step (j-2), the oxidation reaction is carried out in an organic solvent, and the concentration of the compound of formula (V) is 0.05 g / ml to 0.5 g / ml.

[0136] In certain embodiments of the present invention, in step (j-2), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran.

[0137] In certain embodiments of the present invention, in step (j-2), the temperature of the oxidation reaction is -20 to 100°C; preferably 25 to 35°C.

[0138] In certain embodiments of the present invention, the method for preparing the compound of general formula (VIII) further comprises the above-mentioned step (b); optionally, it further comprises the above-mentioned step (c); optionally, it further comprises the above-mentioned step (d); optionally, it further comprises the above-mentioned step (e); optionally, it further comprises the above-mentioned step (f); optionally, it further comprises the above-mentioned step (h) and the above-mentioned step (g); optionally, it further comprises the above-mentioned step (i); optionally, it further comprises the above-mentioned steps (j-1) and (j-2).

[0139] In certain embodiments of the present invention, the method for preparing the compound of formula (VII) further comprises step (c); optionally, it further comprises step (d).

[0140] The present invention provides a method for preparing a compound of general formula (VIII), characterized in that it comprises step (a-1): reacting a compound of general formula (I-1-2) with a compound of general formula (VII) to obtain a compound of general formula (VIII);

[0141]

[0142] R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0143] R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0144] x is selected from 0, 1, 2, 3 or 4.

[0145] In certain embodiments of the present invention, in step (a-1), R 1 is ethyl; x is 0.

[0146] In certain embodiments of the present invention, step (a-1) is carried out in the presence of a solvent, and the solvent is preferably a mixed solvent of an alcohol solvent and a halogenated hydrocarbon solvent; the alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol; the halogenated hydrocarbon solvent is preferably one or more of monochloromethane, dichloromethane and chloroform; preferably, the solvent is a mixed solvent of methanol and dichloromethane.

[0147] In certain embodiments of the present invention, step (a-1) is carried out in the presence of a base, wherein the base is preferably acetate; more preferably one or more of sodium acetate, potassium acetate and calcium acetate; further preferably sodium acetate.

[0148] In certain embodiments of the present invention, step (a-1) is carried out in the presence of a water absorbing agent, and the water absorbing agent is preferably a molecular sieve, a water absorbing inorganic salt, trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, Ti(OiPr) 4 、Ti(OEt) 4 or TiCl(OiPr) 3 .

[0149] In certain embodiments of the present invention, step (a-1) is carried out in the presence of a reducing agent, and the reducing agent is preferably one or more of sodium triacetyloxyborohydride and sodium borohydride; more preferably sodium borohydride.

[0150] In certain embodiments of the present invention, in step (a-1), the concentration of the compound of formula (I-1-2) in the solvent is 0.01 to 0.2 mol / L; preferably 0.05 to 0.1 mol / L (eg 0.07 mol / L).

[0151] In certain embodiments of the present invention, step (a-1) is carried out at 10-40°C; preferably at 20-30°C.

[0152] In certain embodiments of the present invention, the molar ratio of the compound of formula (I-1-2) to the compound of formula (VII) is 3:1 to 1:3; preferably 1:1 to 1:1.3; more preferably 1:1.2.

[0153] In certain embodiments of the present invention, the reaction time of step (a-1) is 10 to 30 hours, preferably 17 to 20 hours.

[0154] The present invention provides a method for preparing a compound of the general formula (I-1-2), characterized in that it comprises the step (b-1): reacting a compound of the general formula (XIV) with N,N-dimethylformamide to obtain a compound of the general formula (I-1-2);

[0155]

[0156] X 2 is halogen; preferably fluorine, chlorine or bromine;

[0157] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0158] In certain embodiments of the present invention, in step (b-1), X 2 is bromine; R 1 It is ethyl.

[0159] In certain embodiments of the present invention, step (b-1) is carried out in the presence of a solvent, and the solvent is preferably an ether solvent; preferably one or more of diethyl ether, tetrahydrofuran and dioxane.

[0160] In certain embodiments of the present invention, step (b-1) is carried out in the presence of a base, preferably n-butyllithium.

[0161] In certain embodiments of the present invention, in step (b-1), the concentration of the compound of formula (VIX) in the solvent is 0.01 to 0.5 mol / L; preferably 0.15 to 0.25 mol / L (eg 0.2 mol / L).

[0162] In certain embodiments of the present invention, step (b-1) is carried out at -70 to -50°C; preferably at -65 to -60°C.

[0163] In certain embodiments of the present invention, the reaction time of step (b-1) is 1 to 6 hours, preferably 2 to 4 hours.

[0164] The present invention also provides a method for preparing a compound of the general formula (I-2), comprising step (c-1): catalyzing the compound of the general formula (II-1) with a catalyst to obtain a compound of the general formula (I-2); step (d-1): reducing the compound of the general formula (III-1) with a reducing agent to obtain a compound of the general formula (II-1);

[0165]

[0166] in,

[0167] R 1 Selected from hydrogen, deuterium, halogen, cyano, C1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0168] X 2 is halogen; preferably fluorine, chlorine or bromine.

[0169] The present invention also provides a method for preparing a compound of the general formula (I-2), comprising step (c-1): catalyzing the compound of the general formula (II-1) with a catalyst to obtain a compound of the general formula (I-2);

[0170]

[0171] Among them, R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0172] X 2 is halogen; preferably fluorine, chlorine or bromine.

[0173] In certain embodiments of the present invention, in step (c-1), R 1 is ethyl; X 2 For bromine.

[0174] In certain embodiments of the present invention, in step (c-1), the catalyst is a phosphine-containing catalyst; preferably methyl phosphine, triethyl phosphine, tripropyl phosphine, tri-tert-butyl phosphine, triphenyl phosphine or tributyl phosphine.

[0175] In certain embodiments of the present invention, in step (c-1), the reaction is carried out in the presence of an acid, which can be selected from an organic acid or an inorganic acid; preferably a carboxylic acid (R-COOH), a sulfonic acid (R-SO 3 H), sulfinic acid (R-SOOH), thiocarboxylic acid (R-SH), hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; more preferably acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid.

[0176] In certain embodiments of the present invention, in step (c-1), the reaction is carried out in a solvent, preferably an organic solvent; the concentration of the compound of formula (II-1) in the solvent is 0.05 g / ml to 0.5 g / ml.

[0177] In certain embodiments of the present invention, in step (c-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably dioxane.

[0178] The present invention also provides a method for preparing a compound of the general formula (II-1), comprising step (d-1): reducing the compound of the general formula (III-1) with a reducing agent to obtain the compound of the general formula (II-1);

[0179]

[0180] Among them, R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0181] X 2 is halogen; preferably fluorine, chlorine or bromine.

[0182] In certain embodiments of the present invention, in step (d-1), R 1 is ethyl; X 2 For bromine.

[0183] In certain embodiments of the present invention, in step (d-1), the reducing agent is selected from a metal reducing agent or a non-metal reducing agent; the metal reducing agent is selected from iron powder or zinc powder, preferably iron powder; the non-metal reducing agent is selected from tin chloride, ferrous chloride or zinc chloride.

[0184] In certain embodiments of the present invention, in step (d-1), the reaction is carried out in a solvent, and the solvent is preferably a mixed solvent; the concentration of the compound of formula (III-1) in the mixed solvent is preferably 0.05 g / ml to 0.5 g / ml.

[0185] In certain embodiments of the present invention, in step (d-1), the mixed solvent is selected from methanol, ethanol, isopropanol, tert-butanol, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or a mixed solvent of dichloromethane and water; preferably a mixed solvent of ethanol and water, wherein the volume content of water is 1% to 50%.

[0186] In certain embodiments of the present invention, in step (d-1), the reaction temperature of the reaction is 0 to 100°C; preferably 70 to 80°C.

[0187] The present invention also provides a method for preparing a compound of the general formula (III-1), comprising step (e-1): subjecting the compound of the general formula (IV-1) to a Wittig reaction in the presence of a phosphorus ylide reagent to obtain a compound of the general formula (III-1);

[0188]

[0189] R 1 Selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl;

[0190] X 2 is halogen; preferably fluorine, chlorine or bromine; preferably bromine.

[0191] In certain embodiments of the present invention, in step (e-1), R 1 is ethyl; X 2 For bromine.

[0192] In certain embodiments of the present invention, in step (e-1), the phosphorus ylide reagent is selected from triethyl 2-butyl propylene ester, trimethyl 2-butyl propylene ester, tripropyl 2-butyl propylene ester; preferably triethyl 2-butyl propylene ester (triethyl 2-phosphonobutyrate);

[0193] In certain embodiments of the present invention, in step (e-1), the reaction is optionally carried out in an organic solvent, and the concentration of the compound of formula (IV-1) in the solvent is 0.05 g / ml to 0.5 g / ml.

[0194] In certain embodiments of the present invention, in step (e-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran.

[0195] In certain embodiments of the present invention, in step (e-1), the reaction is optionally carried out in the presence of a base, and the base is one or more organic bases or inorganic bases; preferably at least one of sodium hydrogen sulfide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, DBU, and DABCO.

[0196] In certain embodiments of the present invention, in step (e-1), the molar ratio of the base to the compound of formula (IV-1) is 1 to 10:1; preferably 1.5:1 or preferably 1:1.

[0197] In certain embodiments of the present invention, in step (e-1), the reaction temperature of the reaction is -70 to 50°C; preferably -70 to -50°C.

[0198] The present invention also provides a method for preparing a compound of the general formula (IV-1), comprising steps (f-1) and (f-2): in step (f-1), the compound of the general formula (VI-1) reacts with DMF-DMA in an organic solvent to obtain a compound of the general formula (V-1); in step (f-2), the compound of the general formula (V-1) undergoes an oxidation reaction in the presence of an oxidant to obtain a compound of the general formula (IV-1);

[0199]

[0200] X 2 is halogen, preferably fluorine, chlorine or bromine, preferably bromine.

[0201] In certain embodiments of the present invention, in step (f-1), the molar ratio of DMF-DMA to the general formula (VI-1) is 1 to 30:1; preferably 1 to 20:1; more preferably 1 to 10:1; further preferably 1 to 5:1; and further preferably 2:1.

[0202] In certain embodiments of the present invention, in step (f-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably DMF.

[0203] In certain embodiments of the present invention, in step (f-1), the concentration of the compound of formula (VI-1) is 0.05 g / ml to 0.5 g / ml.

[0204] In certain embodiments of the present invention, in step (f-1), the reaction is carried out in the presence of a base, and the base is one or more organic bases or inorganic bases; preferably at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, and DABCO.

[0205] In certain embodiments of the present invention, in step (f-1), the molar ratio of the base to the compound of formula (VI-1) is 0.1 to 10:1.

[0206] In certain embodiments of the present invention, in step (f-1), the reaction temperature is 0 to 100°C; preferably 35 to 45°C.

[0207] In certain embodiments of the present invention, in step (f-2), the oxidant is selected from periodate, perchlorate, permanganate, dichromate, peroxide or gaseous oxidant; preferably sodium periodate, sodium dichromate, potassium dichromate, potassium permanganate, sodium perchlorate, oxygen or chlorine.

[0208] In certain embodiments of the present invention, in step (f-2), the oxidation reaction is carried out in an organic solvent, and the concentration of the compound of formula (V-1) is 0.05 g / ml to 0.5 g / ml.

[0209] In certain embodiments of the present invention, in step (f-2), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran.

[0210] In certain embodiments of the present invention, in step (f-2), the temperature of the oxidation reaction is -20 to 100°C; preferably 20 to 25°C or preferably 25 to 35°C.

[0211] The present invention also provides a method for preparing a compound of the general formula (IV-1), comprising step (f'-1): in the presence of an oxidant, subjecting the compound of the general formula (VI-1) to an oxidation reaction to obtain a compound of the general formula (IV-1)

[0212]

[0213] In certain embodiments of the present invention, in step (f'-1), the oxidizing agent is selenium dioxide.

[0214] In certain embodiments of the present invention, in step (f'-1), the reaction is carried out in an organic solvent selected from 1,4-dioxane, DMF, N-methylpyrrolidone, DMSO, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably 1,4-dioxane.

[0215] In certain embodiments of the present invention, in step (f'-1), the reaction temperature is 80-200°C; preferably 100-110°C.

[0216] In certain embodiments of the present invention, in step (f'-1), the molar ratio of the compound of formula (VI-1) to the oxidant is 1:1-1:5, preferably 1:1.5.

[0217] In certain embodiments of the present invention, the method for preparing the compound of general formula (VIII) comprises step (a-1) and further comprises step (b-1); optionally, further comprises step (c-1); optionally, further comprises step (d-1); optionally, further comprises step (e-1); optionally, further comprises steps (f-1) and (f-2).

[0218] In certain embodiments of the present invention, the preparation method of the compound of formula (VIII) is as follows:

[0219]

[0220] or:

[0221]

[0222] Compared with the prior art, the present invention has the following main advantages:

[0223] 1. Avoid using expensive raw materials such as highly toxic selenium dioxide, DDQ and precious metal catalysts, which is more in line with the requirements of green chemistry;

[0224] 2. The reaction raw materials are cheap and easy to obtain, and the cost is low;

[0225] 3. The reaction conditions are mild and the yield is high. For example, step (a) can be carried out at 50-60°C;

[0226] 4. The reaction for synthesizing the compound of the general formula (I-1-1) and the compound of the general formula (I-1-2) eliminates the hydrogenation reduction and aromatization of the double bond, shortens the steps, and improves the atom economy;

[0227] 5. The separation and purification of the products and intermediates of the method of the present invention are simpler, avoiding the multiple column chromatography of the prior art, and can be scaled up from g level to kg level, with stable quality, suitable for industrial scale-up, and more in line with safety and environmental protection requirements.

[0228] Detailed description of the invention

[0229] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0230] "Alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc.; alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment;

[0231] "deuterated alkyl" means an alkyl group in which one or more hydrogen atoms are replaced by deuterium, wherein alkyl is as defined above;

[0232] "Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl) wherein alkyl is as defined above.

[0233] Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0234] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above; for example, trifluoromethyl;

[0235] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above;

[0236] "Hydroxyalkyl" means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above;

[0237] "Alcohol solvents" refer to alkane compounds containing hydroxyl groups in the molecule, such as methanol, ethanol, and isopropanol.

[0238] "DIPEA" refers to N,N-diisopropylethylamine; "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; "DABCO" refers to 1,4-diazabicyclo[2.2.2]octane; "Boc" refers to tert-butyloxycarbonyl; "Cbz" refers to benzyloxycarbonyl; "Fmoc" refers to methyloxycarbonyl; "PMB" refers to p-methoxybenzyl; "Bn" refers to benzyl; "PdCl" refers to methyl 2 "Pd(dppf)Cl 2 " refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; "Pd(PPh 3 ) 2 Cl 2 " refers to bistriphenylphosphine palladium dichloride; "Pd(OAc) 2 " refers to palladium acetate; "LiAlH 4 ” refers to lithium aluminum hydride; “DMF-DMA” refers to N,N-dimethylformamide dimethyl acetal.

[0239] In the present invention, the "many" in the "plurality" or "multiple" refers to 1, 2, 3, 4, 5, 6, 7, etc.;

[0240] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any one or more hydrogen atoms in the example compounds of the present invention can also be replaced by deuterium atoms. DETAILED DESCRIPTION

[0241] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0242] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) The internal standard was tetramethylsilane (TMS).

[0243] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 Infinity Series mass spectrometer. HPLC was performed using an Agilent ZORBAX SB-C18 column (4.6×150 mm, 5 μm). Other information is shown in the following table:

[0244]

[0245] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0246] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0247] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent.

[0248] Example 1 Preparation of 5-nitro-6-(2-dimethylamino)vinylnicotinate

[0249]

[0250] Add 5-nitro-6-methylnicotinic acid ethyl ester (50g, 0.24mol) and DMF (400ml) into a 1L three-necked flask and protect with nitrogen. Add triethylamine (10ml) at room temperature, add DMF-DMA (56.7g, 0.48mol) dropwise, heat the oil bath to 35-40℃ and react for 5-6 hours. HPLC detection shows that the raw materials react completely. Turn off the heating, add 400ml of water dropwise, stir at room temperature for 1-2 hours; filter, wash the filter cake with 250ml of water, and vacuum dry it with an oil pump to constant weight to obtain 5-nitro-6-(2-dimethylamino)vinylnicotinic acid ethyl ester (53g, red solid), with a yield of 84% and a HPLC purity of 98.7%. MS (ESI) m / z: 266 [M+1] + .

[0251] 1 H NMR (400 MHz, DMSO-d 6 )δ8.79(d,J=2.0Hz,1H),8.52(d,J=2.1Hz,1H),8.36(d,J=12.1Hz,1H),6.13(d,J=1 2.1Hz, 1H), 4.31 (q, J = 7.1Hz, 2H), 3.24 (s, 3H), 2.97 (s, 3H), 1.32 (t, J = 7.1Hz, 3H).

[0252] 13 C NMR (101 MHz, DMSO-d 6)δ164.19(s),155.75(s),154.57(s),153.37(s),135.83(s),135.18(s),116.36(s),91.30(s),61.27(s),14.63(s).

[0253] Example 2 Preparation of 5-nitro-6-(2-dimethylamino)vinylnicotinate

[0254]

[0255] Add 5-nitro-6-methylnicotinic acid ethyl ester (98g, 0.466mol) and DMF (800ml) into a 2L three-necked flask and protect with nitrogen. Add triethylamine (20ml) at room temperature, add DMF-DMA (111g, 0.931mol) dropwise, heat the oil bath to 35-40℃ and react for 5-6 hours. HPLC detection shows that the raw materials react completely. Turn off the heating, add 800ml of water dropwise, stir at room temperature for 1-2 hours; filter, wash the filter cake with 200ml of water, and vacuum dry it with an oil pump to constant weight to obtain 5-nitro-6-(2-dimethylamino)vinylnicotinic acid ethyl ester (107g, red solid), with a yield of 86% and a HPLC purity of 98.5%. MS (ESI) m / z: 266 [M+1] + .

[0256] 1 H NMR (400 MHz, DMSO-d 6 )δ8.79(d,J=2.0Hz,1H),8.52(d,J=2.1Hz,1H),8.36(d,J=12.1Hz,1H),6.13(d,J=1 2.1Hz, 1H), 4.31 (q, J = 7.1Hz, 2H), 3.24 (s, 3H), 2.97 (s, 3H), 1.32 (t, J = 7.1Hz, 3H).

[0257] 13 C NMR (101 MHz, DMSO-d 6 )δ164.19(s),155.75(s),154.57(s),153.37(s),135.83(s),135.18(s),116.36(s),91.30(s),61.27(s),14.63(s).

[0258] Example 3 Preparation of 6-formyl-5-nitronicotinic acid ethyl ester

[0259]

[0260] Add 5-nitro-6-(2-dimethylamino)vinylnicotinate (35.8 g, 0.134 mol) and THF (350 ml) into a 1L three-necked reaction flask, and the solid is completely dissolved. Sodium periodate (85 g, 0.4 mol) and water (350 ml) are prepared into a solution, and added dropwise to the reaction system, and the temperature is controlled not to exceed 25°C. After 1 to 2 hours, the raw material was sampled for HPLC detection. The reaction was complete. The filter cake was washed with EA (150 ml). The filtrate was separated and the aqueous phase was extracted once with EA (250 ml). The organic phases were combined and washed once with 5% sodium bicarbonate solution (250 ml) and once with 10% sodium thiosulfate solution (250 ml). The KI test paper did not change color. The organic phase was washed once with brine (200 ml) and dried with anhydrous sodium sulfate (100 g). The filtrate was concentrated to dryness under reduced pressure and dried to constant weight under oil pump vacuum to obtain ethyl 6-formyl-5-nitronicotinate (30 g, black oily substance). The yield was 99.2%. The purity was 97% after HPLC detection. MS (ESI) m / z: 225 [M+1] + .

[0261] 1 H NMR (400 MHz, DMSO-d 6 )δ9.75(s,1H),9.68(d,J=2.9Hz,1H),9.29(d,J=2.9Hz,1H),4.29(q,J=11.8Hz,2H),1.30(t,J=11.8Hz,3H).

[0262] Example 4 Preparation of 6-formyl-5-nitronicotinic acid ethyl ester

[0263]

[0264] Add 5-nitro-6-(2-dimethylamino)vinylnicotinate (104 g, 0.392 mol) and THF (1040 ml) into a 3L three-necked reaction flask, and the solid is completely dissolved. Sodium periodate (251.5 g, 1.176 mol) and water (1040 ml) are prepared into a solution, and added dropwise to the reaction system, and the temperature is controlled not to exceed 25°C. After 1 to 2 hours, the raw material was sampled for HPLC detection. The reaction was complete. The filter cake was washed with EA (650 ml), the filtrate was separated, and the aqueous phase was extracted once with EA (650 ml); the organic phases were combined, washed once with 5% sodium bicarbonate solution (750 ml), washed once with 10% sodium thiosulfate solution (750 ml), and the KI test paper did not change color. The mixture was washed once with brine (600 ml) and dried with anhydrous sodium sulfate (100 g); the filtrate was concentrated to dryness under reduced pressure and dried to constant weight under oil pump vacuum to obtain 6-formyl-5-nitronicotinic acid ethyl ester (87.2 g, black oily substance) with a yield of 98.4%. The HPLC detection result showed that the purity was 97%. MS (ESI) m / z: 225 [M+1] + .

[0265] 1 H NMR (400 MHz, DMSO-d 6 )δ9.75(s,1H),9.68(d,J=2.9Hz,1H),9.29(d,J=2.9Hz,1H),4.29(q,J=11.8Hz,2H),1.30(t,J=11.8Hz,3H).

[0266] Example 5 Preparation of a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate

[0267]

[0268] Add THF (150ml) and NaH (mass content 60%wt, 8.0g, 0.2mol) to a 1L three-necked reaction flask, protect with nitrogen, and cool to 0-5°C in an ice-water bath. Add triethyl 2-butyl acrylate (47.2g, 0.187mol) dropwise, and release gas obviously. After adding, heat to 20-25°C and react for 1-2 hours. Cool to below -60°C in a dry ice bath, and add a THF (150ml) solution of ethyl 6-formyl-5-nitronicotinate (30g, 0.134mol) dropwise, and control the temperature not to exceed -60°C. After adding, keep warm and stir for 30-60 minutes. Take a sample for HPLC detection, and the raw material reaction is complete. The reaction solution was slowly poured into a saturated ammonium chloride solution (600 ml) under stirring, stirred for 20 to 30 minutes, allowed to stand, separated, the aqueous phase was extracted once with EA (200 ml), the organic phases were combined, washed once with saturated brine (200 ml), dried over anhydrous sodium sulfate (100 g), filtered, the filtrate was concentrated to dryness under reduced pressure, and dried to constant weight under oil pump vacuum to obtain 66 g of black oily substance, which was separated by silica gel column chromatography using EA:PE with a volume ratio of 1:10 as the mobile phase to obtain a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate (32 g, light yellow oily liquid), with a yield of 75%. HPLC detection showed that the purity was 99%. MS (ESI) m / z: 323 [M+1] + .

[0269] 1 H NMR (400 MHz, DMSO-d 6 )δ9.28(d,J=2.9Hz,1H),9.02(d,J=3.1Hz,1H),7.64(t,J=2.0Hz,1H),4.29(q,J=11.8Hz,2H),4.08(q,J=11.8 Hz,2H),2.44(qd,J=13.4,1.9Hz,2H),1.30(t,J=11.8Hz,3H),1.16(t,J=11.8Hz,3H),1.07(t,J=13.4Hz,3H).

[0270] Example 6 Preparation of a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate

[0271]

[0272] Add THF (420ml) and NaH (mass content 60%wt, 22.4g, 0.561mol) to a 2L three-necked reaction flask, protect with nitrogen, and cool to 0-5°C in an ice-water bath. Add triethyl 2-butyl acrylate (132.0g, 0.523mol) dropwise, and release gas obviously. After adding, heat to 20-25°C and react for 1-2 hours. Cool to below -60°C in a dry ice bath, and add a THF (440ml) solution of 6-formyl-5-nitronicotinic acid ethyl ester (83.8g, 0.374mol) dropwise, and control the temperature not to exceed -60°C. After adding, keep warm and stir for 30-60 minutes. Take a sample for HPLC detection, and the raw material reaction is complete. The reaction solution was slowly poured into a saturated ammonium chloride solution (1700 ml) under stirring, stirred for 20 to 30 minutes, allowed to stand, and separated. The aqueous phase was extracted once with EA (500 ml), the organic phases were combined, washed once with saturated brine (600 ml), dried over anhydrous sodium sulfate (200 g), filtered, and the filtrate was concentrated to dryness under reduced pressure and dried to constant weight using an oil pump vacuum to obtain 175.6 g of a black oil (theoretical amount: 120.54 g). HPLC detection showed that the purity was 86%, which was directly used in the next step reaction.

[0273] About 100 mg of black oil was taken and separated by silica gel column chromatography using EA:PE volume ratio of 1:10 as mobile phase to obtain about 50 mg of a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate for structural identification and confirmation. MS (ESI) m / z: 323 [M+1] + .

[0274] 1 H NMR (400 MHz, DMSO-d 6 )δ9.28(d,J=2.9Hz,1H),9.02(d,J=3.1Hz,1H),7.64(t,J=2.0Hz,1H),4.29(q,J=11.8Hz,2H),4.08(q,J=11.8 Hz,2H),2.44(qd,J=13.4,1.9Hz,2H),1.30(t,J=11.8Hz,3H),1.16(t,J=11.8Hz,3H),1.07(t,J=13.4Hz,3H).

[0275] Example 7 Preparation of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate

[0276]

[0277] A mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate (33g, 0.1mol), ethanol (330ml), water (66ml), ammonium chloride (54.6g, 1.0mol) and iron powder (57.2g, 1.0mol) were added to a 1L three-necked flask, heated to 75-80°C in an oil bath for 1-2 hours, and the reaction of the raw materials was complete after HPLC detection. Turn off the heating, add diatomaceous earth (38g), cool to room temperature and filter, wash the filter cake with ethanol (200ml), and concentrate the filtrate to dryness under reduced pressure. The filter cake was slurried with DCM / MeOH=10:1 (500ml) for 30 minutes, filtered, washed, and the filtrate was combined with the filtrate from the first concentration, and the inorganic salt was removed by filtration. The filtrate was concentrated to dryness under reduced pressure to obtain a mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (30 g, yellow solid). HPLC analysis showed that the combined HPLC purity of the two was about 95%, and the yield was 99%.

[0278] Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0279]

[0280] A mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (30g, 0.1mol), dioxane (300ml), acetic acid (12g, 0.2mol) and tributylphosphine (41g, 0.2mol) were added to a 1L three-necked flask, heated to 60°C in an oil bath for 12 hours, and the reaction of the raw materials was complete by HPLC detection. The mixture was concentrated to dryness under reduced pressure, ethyl acetate (150ml) was added for pulping, and filtered to obtain 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (22.3g, off-white solid). HPLC detection showed a purity of 99% and a yield of 88.2%. MS (ESI) m / z: 247 [M+1] + .

[0281] 1 H NMR (400 MHz, DMSO-d 6 6) δ12.31(s,1H),8.60(s,1H),7.92(s,1H),7.90(s,1H),4.33(m,2H),2.55(m,2H),1.32(t,J=7.1Hz,3H),0.94(t,J=7.4Hz,3H).

[0282] Example 8 Preparation of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate

[0283]

[0284] Add a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate (173.6 g crude product, theoretical amount 120.5 g, 0.374 mol), ethanol (1200 ml), water (240 ml), ammonium chloride (100 g, 1.87 mol) and iron powder (104.5 g, 1.87 mol) into a 3L three-necked flask, heat to 75-80°C in an oil bath for 1-2 hours, and HPLC detection shows that the raw materials react completely. Turn off the heating, add diatomaceous earth (50 g), cool to room temperature and filter, wash the filter cake with ethanol (500 ml), and concentrate the filtrate to dryness under reduced pressure. The filter cake was slurried with DCM / MeOH=10:1 (1500 ml) for 30 minutes, filtered, washed, and the obtained filtrate was combined with the filtrate from the first concentration, and the inorganic salts were removed by filtration. The filtrate was concentrated to dryness under reduced pressure to obtain a mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (150 g, black oil, theoretical amount 109.5 g). HPLC detection showed that the HPLC purity of the two added was about 86%, which was directly used for the next step reaction.

[0285] Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0286]

[0287] A mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (148 g, theoretical amount 109.3 g, 0.374 mol), dioxane (1000 ml), acetic acid (45 g, 0.748 mol) and tributylphosphine (151.7 g, 0.748 mol) were added to a 2L three-necked flask, heated to 60°C in an oil bath for 12 to 16 hours, and the reaction of the raw materials was complete by HPLC detection. The mixture was concentrated under reduced pressure to remove about 700 g of dioxane, stirred and slurried at room temperature for 1 hour, filtered, and the filter cake was washed with 100 ml of EA, drained, and dried under vacuum with an oil pump to constant weight to obtain 47.8 g of off-white solid. The solid HPLC detection showed that the purity was 99%, and the total molar yield of the four-step reaction (oxidation / wittig / reduction / cyclization) was about 50%. MS (ESI) m / z: 247 [M+1] + .

[0288] 1 H NMR (400 MHz, DMSO-d 6 )δ12.31(s,1H),8.60(s,1H),7.92(s,1H),7.90(s,1H),4.33(m,2H),2.55(m,2H),1.32(t,J=7.1Hz,3H),0.94(t,J=7.4Hz,3H).

[0289] Example 9 Preparation of 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one

[0290]

[0291] 7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (8.5 g, 0.0345 mol) and THF (170 ml) were added to a 500 ml three-necked flask. The solid was insoluble. Nitrogen was used as protection. The temperature was cooled to -5 to 5 °C in an ice-water bath. LiAlH 4Solution (1.0M, 0.045mol), the solid gradually dissolved and then precipitated, the temperature was controlled not to exceed 5℃, and the mixture was stirred for 30 to 60 minutes after addition; sampling HPLC detection, the raw material reaction was complete. First, water (1.7g) was added dropwise, then 15% NaOH solution (1.7g) was added dropwise, and finally water (5.1g) was added dropwise, and stirred for 1 hour after addition. Filter, wash the filter cake with EA (50ml), the solid purity was 97.2%, containing product and aluminum salt; filtrate 84.6%, 0.3g after concentration. The filter cake was slurried three times with MeOH / DCM=1:1 solution (250ml) at 40℃, filtered, and the filtrate was collected. The three filtrates were combined, concentrated under reduced pressure to remove DCM, and the solid was precipitated. It was washed with methanol twice, and about methanol (70ml) remained at the end. EA (70ml) was added dropwise under stirring, and the temperature was cooled to 0~5℃ in an ice-water bath, and stirred for 30~60 minutes. Filter, wash the filter cake with a small amount of ice methanol, drain, and dry under oil pump vacuum to constant weight to obtain 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (5.3 g, off-white solid), with a yield of 75.2% and a purity of 98.7%. MS (ESI) m / z: 205 [M+1] + .

[0292] 1 H NMR (400 MHz, DMSO-d 6 )δ12.1(s,1H),8.48(s,1H),7.85(s,1H),7.83(s,1H),5.17(s,1H),4.61(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0293] Example 10 Preparation of 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one

[0294]

[0295] 7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (35 g, 0.142 mol) and THF (700 ml) were added to a 2L three-necked flask. The solid was insoluble. Nitrogen was protected and the temperature was cooled to -5 to 5°C in an ice-water bath. LiAlH 4Solution (1.0M / L THF solution, 170ml, 0.170mol), the solid first gradually dissolved and then precipitated, the temperature was controlled not to exceed 5℃, and the addition was completed and stirred for 30-60 minutes; sampling HPLC detection, the raw material reaction was complete. First, water (6.5g) was added dropwise, then 15% NaOH solution (6.5g) was added dropwise, and finally water (19.5g) was added dropwise, and stirred for 1 hour after addition. Filter, wash the filter cake with EA (150ml), the solid purity was about 95%, containing product and aluminum salt; the product accounted for about 80% in the filtrate, and it was about 2.6g after concentration. The filter cake was slurried three times with MeOH / DCM=1:1 solution (1000ml) at 40℃, filtered, and the filtrate was collected. The three filtrates were combined, concentrated under reduced pressure to remove DCM, precipitated solids, and taken with methanol twice, and finally concentrated to about 145g, EA (145ml) was added dropwise while stirring, and the temperature was cooled to 0-5℃ in an ice-water bath, and stirred for 60 minutes. Filter, wash the filter cake with a small amount of ice methanol, drain, and dry under vacuum with an oil pump to constant weight to obtain 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (22.6 g, off-white solid), with a yield of 78% and a purity of 98.5%. MS (ESI) m / z: 205 [M+1] + .

[0296] 1 H NMR (400 MHz, DMSO-d 6 )δ12.1(s,1H),8.48(s,1H),7.85(s,1H),7.83(s,1H),5.17(s,1H),4.61(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0297] Example 11 Preparation of 5-bromo-3-nitropyridinecarboxaldehyde

[0298]

[0299] Add 5-bromo-2-methyl-3-nitropyridine (20g, 92.2mmol) and 1,4-dioxane (100mL) into a 250mL three-necked flask, stir to dissolve, replace with nitrogen 3-4 times, add selenium dioxide (15.3g, 138.2mmol) solid under nitrogen protection, control the temperature at 15-25℃, and there is no obvious temperature rise. The system is turbid liquid. Heat to 105-110℃ and stir for 24h. TLC detection shows that the raw material is basically reacted. Cool to room temperature, filter, rinse the filter cake with ethyl acetate (200mL), concentrate the filtrate to dryness, and purify on a silica gel column (gradient elution of petroleum ether / ethyl acetate volume ratio from 5:1 to 3:1) to obtain 5-bromo-3-nitropyridine carboxaldehyde (15.3g, brick red solid), yield: 72%, HPLC purity is 94.4%. MS (ESI) m / z: 232 [M+1] +

[0300] 1 H NMR (400 MHz, DMSO-d 6 ): δ / ppm 10.08(s,1H),9.22(s,1H),8.95(s,1H).

[0301] 13 C NMR (400 MHz, DMSO-d 6 ): δ / ppm 189.49,154.48,145.80,143.75,135.22,124.58.

[0302] Example 12 Preparation of 5-bromo-3-nitropyridinecarboxaldehyde

[0303]

[0304] Add 5-bromo-2-methyl-3-nitropyridine (20g, 92.2mmol) and DMF (160mL) into a three-necked flask and protect with nitrogen. Add triethylamine (4ml) at room temperature, dropwise add DMF-DMA (22g, 184.4mmol), heat the oil bath to 35-40℃ and react for 5-6 hours. HPLC detection shows that the raw materials react completely. Turn off the heating, dropwise add 400ml of water, stir at room temperature for 1-2 hours; filter, wash the filter cake with 250ml of water, and vacuum dry it with an oil pump to constant weight to obtain about 21g of red solid, with a yield of 84% and a HPLC purity of 98%.

[0305] The obtained red solid was added to a 1L three-necked reaction bottle, and then THF (210ml) was added to completely dissolve the solid. Sodium periodate (32g, 0.15mol) and water (130ml) were prepared into a solution, and then added dropwise to the reaction system, and the temperature was controlled not to exceed 25°C. After 1 to 2 hours, a sample was taken for HPLC detection, and the raw material reaction was complete, filtered, the filter cake was washed with EA (100ml), the filtrate was separated, and the aqueous phase was extracted once with EA (200ml); the organic phases were combined, washed once with 5% sodium bicarbonate solution (200ml), washed once with 10% sodium thiosulfate solution (200ml), and the KI test paper did not change color, and then washed once with brine (100ml), and dried with anhydrous sodium sulfate (50g); filtered, the filtrate was concentrated to dryness under reduced pressure, and dried to constant weight with an oil pump vacuum to obtain 5-bromo-3-nitropyridinecarboxaldehyde (14.2g, brick red solid), with a yield of 82% and a HPLC purity of 95%. MS (ESI) m / z: 232 [M+1] +

[0306] 1 H NMR (400 MHz, DMSO-d 6 ): δ / ppm 10.08(s,1H),9.22(s,1H),8.95(s,1H).

[0307] 13 C NMR (400 MHz, DMSO-d 6 ): δ / ppm 189.49,154.48,145.80,143.75,135.22,124.58.

[0308] Example 13 Preparation of 7-bromo-3-ethyl-1,5-naphthyridin-2-one

[0309]

[0310] Add sodium hydride (4.3g, 64.5mmol, 60% content) and tetrahydrofuran (50mL) into a 500mL three-necked flask, stir evenly, replace with nitrogen 3-4 times, and cool to 0-5℃ under nitrogen protection. Add triethyl 2-phosphonobutyrate (15.3g, 60.7mmol) to the reaction flask at 0-5℃, add the solution to room temperature, and stir for 1-2 hours. Then cool to -60℃, slowly add the pre-prepared solution of 5-bromo-3-nitropyridinecarboxaldehyde (10.0g, 43.3mmol) in tetrahydrofuran (100mL) to the reaction flask, add the solution to -60℃, and stir for 0.5-1 hour. TLC detects that the reaction of the raw materials is complete. The temperature was controlled below 30°C, and the reaction solution was added to a pre-prepared saturated ammonium chloride solution (200 mL). After the addition was completed, the mixture was stirred for 30 minutes, allowed to stand, and separated. The aqueous phase was extracted once with ethyl acetate (100 mL), and the organic phases were combined, washed twice with a saturated aqueous sodium bicarbonate solution (100 mL), washed once with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate (30 g), filtered, and the filtrate was concentrated to dryness to obtain a crude product of intermediate 1 (20 g, brown oil, mixture of cis and trans isomers) with an HPLC purity of 95.0%.

[0311] E-form intermediate 1: MS (ESI) m / z: 330 [M+1] +

[0312] 1 H NMR (400 MHz, CDCl 3 ): δ / ppm 8.94(d,1H),8.47(d,1H),7.76(s,1H),4.33-4.28(q,2H),2.63-2.58(q,2H),1.37-1.34(t,3H),1.12-1.09(t,3H).

[0313] 13 C NMR (400MHz, CDCl 3 ): δ / ppm 167.20,153.98,148.00,145.23,142.29,134.81,130.20,119.14,61.31,21.52,14.24,13.59.

[0314] Z intermediate 1: MS (ESI) m / z: 330 [M+1] +

[0315] 1 H NMR (400 MHz, CDCl 3): δ / ppm 8.77(d,1H),8.47(d,1H),7.00(s,1H),4.16-4.11(q,2H),2.56-2.50(q,2H),1.23-1.19(t,3H),1.18-1.15(t,3H).

[0316] 13 C NMR (400MHz, CDCl 3 ): δ / ppm 168.60,153.47,148.16,144.12,143.85,134.84,125.07,118.38,60.86,27.96,13.99,12.15.

[0317] Add the crude product (20 g) from the previous step, ethanol (200 mL), water (40 mL), iron powder (24.2 g) and ammonium chloride (23.3 g) into a 1 L three-necked flask, heat to 75-80°C, and stir for 2-3 hours. TLC indicates that the reaction of the raw material is complete. The temperature was lowered to 30-40°C, diatomaceous earth (25 g) was added to the reaction solution, stirred for 30 minutes, diatomaceous earth pad was spread, filtered, the filter cake was rinsed with ethanol (200 mL), and then the filter cake was rinsed with the prepared dichloromethane methanol solution (dichloromethane: methanol = 10: 1, 400 mL), the filtrate was combined, concentrated to 1-2V, and dichloromethane methanol solution (dichloromethane: methanol = 10: 1, 400 mL) was added, stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated to dryness to obtain the crude product of intermediate 2 (14.6 g, brown solid, mixture of cis isomers and ring-closed products), HPLC purity was 95.0% (the sum of the two).

[0318] E-form intermediate 2: MS (ESI) m / z: 300 [M+1] + .

[0319] 1 H NMR (400 MHz, CDCl 3 ): δ / ppm 8.11(d,1H),7.42(s,1H),7.16(d,1H),4.31-4.25(q,2H),3.94(s,2H),2.70-2.64(q,2H),1.36-1.32(t,3H),1.10-1.06(t,3H).

[0320] 13 C NMR (400MHz, CDCl 3 ): δ / ppm 168.08,142.29,140.08,140.03,138.84,130.43,124.29,120.23,60.98,21.16,14.29,13.74.

[0321] The crude product (14.6 g) of the previous step, 1,4-dioxane (150 mL), acetic acid (5.7 g, 95.0 mmol) and tributylphosphine (14.4 g, 71.2 mmol) were added to a 1L three-necked flask, heated to 60-65°C, and stirred for 18-20 hours. TLC detected that the raw materials were basically reacted. The reaction solution was concentrated to 50-70 mL, cooled to 20-25°C, stirred for 1-2 hours, filtered, and the filter cake was rinsed with ethyl acetate (10-20 mL) and dried to obtain the product 7-bromo-3-ethyl-1,5-naphthyridine-2 (monohydro) ketone (6.8 g, off-white flocculent solid), with a three-step yield of 62% and a HPLC purity of 98.2%. MS (ESI) m / z: 254 [M+1] + .

[0322] 1 H NMR (400 MHz, DMSO-d 6 ): δ / ppm 10.21(s,1H),8.51(s,1H),7.83(s,1H),7.73(s,1H),2.52(q,2H),1.18(t,3H).

[0323] 13 C NMR (400 MHz, DMSO-d 6 ): δ / ppm 161.61,145.02,140.87,136.38,135.54,134.91,124.37,119.58,23.54,12.76.

[0324] Example 14 Preparation of 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carbaldehyde

[0325]

[0326] 7-Bromo-3-ethyl-1,5-naphthyridin-2-one (1.0 g, 3.95 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask, stirred evenly, and replaced with nitrogen 3-4 times if not dissolved. Under nitrogen protection, the temperature was cooled to -65 to -60 ° C in a dry ice acetone bath, and the temperature was controlled at -65 to -60 ° C. n-butyl lithium (4.8 mL, 12.00 mmol, 2.5 M / hexane) was added dropwise. After the addition was completed, the temperature was controlled at -65 to -60 ° C, and stirred for 1-2 hours; the temperature was controlled at -65 to -60 ° C, and the pre-prepared tetrahydrofuran solution (5 mL) of N, N-dimethylformamide (0.58 g, 7.90 mmol) was slowly added dropwise to the reaction flask, and the temperature rose significantly. The system gradually became thinner during the process. After the addition was completed, the temperature was stirred at -65 to -60 ° C for 1-2 hours. TLC detected that the raw material reaction was complete. The temperature was controlled below 30°C, and the reaction solution was added to a pre-prepared saturated ammonium chloride solution (20 mL). After the addition was completed, the reaction mixture was stirred for 30 minutes, allowed to stand, and separated. The aqueous phase was extracted once with ethyl acetate (20 mL), and the organic phases were combined, washed twice with water (20 mL), washed once with a saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate (3 g), filtered, and the filtrate was concentrated to dryness. The mixture was slurried with a petroleum ether ethyl acetate solution (1:1, 4 mL) at 40-50°C for 30 minutes, cooled to room temperature, stirred for 30 minutes, filtered, and dried to obtain 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxaldehyde (0.4 g, yellow solid), with a yield of 50% and a HPLC purity of 88.0%. MS (ESI) m / z: 203 [M+1] + .

[0327] 1 H NMR (400MHz, DMSO-d6): δ / ppm 12.18(s,1H),10.16(s,1H),8.91(s,1H),8.03(s,1H),7.83(s,1H),2.58(q,2H),1.22(t,3H).

[0328] 13 C NMR (400 MHz, DMSO-d 6 ): δ / ppm 192.46,161.76,145.90,143.73,141.34,135.50,133.94,130.74,122.20,23.73,12.69.

[0329] Example 15 Preparation of 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one

[0330]

[0331] 7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxaldehyde (0.5 g, 2.5 mmol) and THF (5 ml) were added to a three-necked flask. The solid was insoluble. Nitrogen was used as protection. The temperature was cooled to -5 to 5 °C in an ice-water bath. LiAlH 4 Solution (1.0M, 3ml, 3mmol), the solid gradually dissolved and then precipitated, the temperature was controlled not to exceed 5℃, and the mixture was stirred for 30-60 minutes after addition; sampling was performed for HPLC detection, and the raw material reaction was complete. First, water (120mg) was added dropwise, then 15% NaOH solution (120mg) was added dropwise, and finally water (360mg) was added dropwise, and the mixture was stirred for 1 hour after addition. Filter, wash the filter cake with EA (5ml), and collect the solid.

[0332] The filter cake was slurried three times with MeOH / DCM=1:1 solution (20ml) at 40℃, filtered, and the filtrate was collected. The three filtrates were combined, concentrated under reduced pressure, methanol (1.5ml) was added, EA (1.5ml) was added dropwise with stirring, the temperature was cooled to 0~5℃ in an ice-water bath, and stirred for 30 minutes. Filter, wash the filter cake with a small amount of ice methanol, drain, and dry it under oil pump vacuum to constant weight to obtain 3-ethyl-7-hydroxymethyl-1,5-naphthyridine-2(1H)-one (412mg, off-white solid), with a yield of 82% and a purity of 98%. MS(ESI)m / z:205[M+1] + .

[0333] 1 H NMR (400 MHz, DMSO-d 6 )δ12.1(s,1H),8.48(s,1H),7.85(s,1H),7.83(s,1H),5.17(s,1H),4.61(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0334] Example 16 Preparation of N-methyl-5-bromopicolinamide

[0335]

[0336] Add 5-bromopyridine-2-carboxylic acid methyl ester (50g, 0.23mol) and methanol (250ml) into a 1L three-necked flask, stir until the solid does not dissolve, add methylamine aqueous solution (250ml, methylamine content is 25-30wt%), the solid gradually dissolves, add it in 15 minutes, react for 30-60 minutes, and HPLC detection shows that the raw material reacts completely. The reaction solution is directly concentrated to dryness under reduced pressure and dried to constant weight with an oil pump to obtain N-methyl-5-bromopyridinecarboxamide (49.8g, white solid), with a yield of 100% and a HPLC purity of 98%. MS (ESI) m / z: 215 [M+1] + .

[0337] 1 H NMR (400 MHz, DMSO-d 6 )δ8.76(d,J=15.0Hz,1H),8.73(d,J=2.9Hz,1H),8.30(dd,J=15.0,3.1Hz,1H),6.42(s,1H),2.85(s,3H).

[0338] Example 17 Preparation of N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydro)-6-N-methyl-formamide

[0339]

[0340] N-methyl-5-bromopicolinamide (42.5 g, 0.2 mol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (61.2 g, 0.2 mol), dioxane (425 ml), water (85 ml) and cesium carbonate (129 g, 0.4 mol) were added to a 1L three-necked flask and replaced with nitrogen three times; Pd(dppf)Cl 2 (4.2g, 5.7mmol), nitrogen replacement three times again; oil bath temperature raised to 90-95℃ for 16-20 hours; sample HPLC detection, the raw material reaction is complete; reaction solution is concentrated to dryness under reduced pressure, EA (250ml) and water (250ml) are added, stirred and allowed to stand for stratification, the aqueous phase is extracted once with EA (250ml), the organic phases are combined, washed once with brine, and dried with anhydrous sodium sulfate; 90g silica gel pad is used for filtration, and the filter cake is rinsed with EA:PE=1:1 solution (1.5L), and the filtrate is concentrated to dryness under reduced pressure to obtain N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydro)-6-N-methyl-formamide (61g, brown oily liquid), the yield is 97.3%, and the HPLC detection result shows that the purity is 93.8%. MS (ESI) m / z:318[M+1] + .

[0341] 1 H NMR (400 MHz, DMSO-d 6)δ8.57(d,J=2.9Hz,1H),8.37(d,J=15.0Hz,1H),8.14(dd,J=15.0,2.9Hz,1H),6.38(s,1H),6.13(tt,J=12.5,1.9Hz,1H),4.86( d,J=12.5Hz,1H),3.91(dd,J=24.2,12.0Hz,2H),3.61(t,J=11.5Hz,1H),2.85(s,3H),2.62(td,J=11.6,1.9Hz,2H),1.42(s,9H).

[0342] Example 18 Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride

[0343]

[0344] Add N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydro)-6-N-methyl-formamide (61g, 0.19mol) and EA (610ml) to a 1L three-necked flask, stir until completely dissolved, add hydrochloric acid dioxane solution (240ml, 4.0M, 0.96mol) dropwise, and a yellow solid is immediately precipitated. Stir for 12 to 16 hours after the addition. HPLC detection shows that the raw material is completely reacted and the solid color is off-white. Filter, wash the filter cake with EA (100ml) and then drain, and vacuum dry with an oil pump to constant weight to obtain N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-formamide hydrochloride (52.5g, off-white solid), with a yield of 94%. HPLC detection shows that the purity is 95%. MS (ESI) m / z: 218 [M+1] + .

[0345] 1 H NMR (400 MHz, DMSO-d 6 )δ8.57(d,J=2.9Hz,1H),8.37(d,J=15.0Hz,1H),8.14(dd,J=15.0,2.9Hz,1H),6.39(s,1H),6.11(tt,J=12 .4,2.0Hz,1H),3.39(d,J=12.4Hz,2H),2.98(t,J=11.6Hz,2H),2.85(s,3H),2.37(td,J=11.6,1.9Hz,2H).

[0346] Example 19 Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0347]

[0348] 3-Ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (4.7 g, 0.023 mol) and DCM (100 ml) were added to a 250 ml three-necked flask. The solid was insoluble. Nitrogen was protected and the temperature was cooled to 0-10°C in an ice-water bath. SOCl was added dropwise. 2 (16.4g, 0.14mol), after adding, the temperature was raised to 20-25℃ and reacted for 20-24 hours; sampling HPLC detection, the raw material reaction was complete, filtered, and the filter cake was vacuum dried with an oil pump to constant weight; 7-(chloromethyl)-3-ethyl-1,5-naphthyridine-2(1H)-one hydrochloride (5.9g, off-white solid) was obtained, the yield was 100%, and the HPLC detection results showed that the purity was 97%. MS (ESI) m / z: 223[M+1] + .

[0349] 1 H NMR (400 MHz, DMSO-d 6 )δ8.21(d,J=2.9Hz,1H),7.53(d,J=3.1Hz,1H),7.46(t,J=2.0Hz,1H),4.79(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0350] Example 20 Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0351]

[0352] 3-Ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (19.0 g, 0.093 mol) and DCM (400 ml) were added to a 1L three-necked flask. The solid was insoluble. Nitrogen was protected and the temperature was cooled to 0-10°C in an ice-water bath. SOCl was added dropwise. 2 (66.3g, 0.558mol), after adding, the temperature was raised to 20-25℃ and reacted for 20-24 hours; sampling HPLC detection, the raw material reaction was complete, filtered, and the filter cake was vacuum dried with an oil pump to constant weight; 7-(chloromethyl)-3-ethyl-1,5-naphthyridine-2(1H)-one hydrochloride (24.2g, off-white solid) was obtained, the yield was 100%, and the HPLC detection results showed that the purity was 97%. MS (ESI) m / z: 223[M+1] + .

[0353] 1 H NMR (400 MHz, DMSO-d 6)δ8.21(d,J=2.9Hz,1H),7.53(d,J=3.1Hz,1H),7.46(t,J=2.0Hz,1H),4.79(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0354] Example 21 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0355]

[0356] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.9 g, 0.023 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (8.0 g, 0.027 mol) and KI (1.2 g, 7.2 mmol) were added into a 500 ml three-necked flask. The solid was insoluble. DIPEA (22.2 g, 0.17 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 120ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 50ml acetonitrile: water = 1: 1 solution, then wash with 100ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (7.7g, off-white solid), yield 83%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0357] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0358] Example 22 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0359]

[0360] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (6.7 g, 0.023 mol) and KI (1.0 g, 5.8 mmol) were added into a 250 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 75-85°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 100ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 25ml acetonitrile: water = 1: 1 solution, then wash with 25ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (4.2g, off-white solid), yield 54%, HPLC detection, the result shows that the purity is 97%. MS (ESI) m / z: 404 [M+1] + .

[0361] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0362] Example 23 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0363]

[0364] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (6.7 g, 0.023 mol) and KI (1.0 g, 5.8 mmol) were added into a 250 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 35-45°C and the reaction was carried out for 6-8 hours. Sampling HPLC detection showed that the raw material was not completely reacted; the temperature was lowered to 20-25°C, 100 ml of water and 200 ml of ethyl acetate were added, extracted, the organic phase was retained, and concentrated to obtain a crude product, which was separated by column chromatography to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (2.8 g, off-white solid), with a yield of 36%. HPLC detection showed that the purity was 98%. MS (ESI) m / z: 404 [M+1] + .

[0365] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0366] Example 24 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0367]

[0368] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (6.7 g, 0.023 mol) and KI (1.0 g, 5.8 mmol) were added into a 500 ml three-necked flask. The solid was insoluble. DIPEA (12.4 g, 0.10 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection showed that the raw material was not completely reacted; the temperature was lowered to 20-25°C, 120 ml of water was added dropwise, and the mixture was stirred for 1 hour after addition; the filter cake was washed with 50 ml of acetonitrile: water = 1:1 solution, and then with 100 ml of water, and then dried to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (4.4 g, off-white solid), with a yield of 57%. HPLC detection showed that the purity was 97%. MS (ESI) m / z: 404 [M+1] + .

[0369] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0370] Example 25 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0371]

[0372] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (200 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (6.7 g, 0.023 mol) and KI (1.0 g, 5.8 mmol) were added into a 500 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection showed that the raw material was not completely reacted; the temperature was lowered to 20-25°C, 120 ml of water was added dropwise, and the mixture was stirred for 1 hour after addition; the filter cake was washed with 50 ml of acetonitrile: water = 1:1 solution, and then with 100 ml of water, and after drying, 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (3.6 g, off-white solid) was obtained, with a yield of 46%. HPLC detection showed that the purity was 95%. MS (ESI) m / z: 404 [M+1] + .

[0373] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0374] Example 26 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0375]

[0376] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (6.0 g, 0.021 mol) and KI (1.0 g, 5.8 mmol) were added into a 250 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 100ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 25ml acetonitrile: water = 1: 1 solution, then wash with 25ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (5.9g, off-white solid), yield 76%, HPLC detection, the result shows that the purity is 96%. MS (ESI) m / z: 404 [M+1] + .

[0377] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0378] Example 27 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0379]

[0380] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (5.6 g, 0.019 mol) and KI (1.0 g, 5.8 mmol) were added into a 250 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 100ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 25ml acetonitrile: water = 1: 1 solution, then wash with 25ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (5.2g, off-white solid), yield 67%, HPLC detection, the result shows that the purity is 96%. MS (ESI) m / z: 404 [M+1] + .

[0381] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0382] Example 28 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0383]

[0384] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (5.0 g, 0.019 mol), acetonitrile (100 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (11.2 g, 0.038 mol) and KI (1.0 g, 5.8 mmol) were added into a 250 ml three-necked flask. The solid was insoluble. DIPEA (17.4 g, 0.135 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cooling to 20 ~ 25 ℃, adding 100ml water and 200ml ethyl acetate, extraction, retaining the organic phase, concentrating to obtain a crude product, column chromatography separation to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (2.0g, off-white solid), yield 26%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0385] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0386] Example 29 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0387]

[0388] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (22.6 g, 0.087 mol), acetonitrile (450 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (30.3 g, 0.105 mol) and KI (4.3 g, 26 mmol) were added to a 1L three-necked flask. The solid was insoluble. DIPEA (84.4 g, 0.653 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 450ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 100ml acetonitrile: water = 1: 1 solution, then wash with 100ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (29.2g, off-white solid), yield 83%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0389] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0390] Example 30 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0391]

[0392] 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (200.0 g, 0.77 mol), acetonitrile (4000 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (267.7 g, 0.92 mol) and KI (38.2 g, 0.23 mol) were added into a 1L three-necked flask. The solid was insoluble. DIPEA (744.2 g, 5.77 mol) was added dropwise under nitrogen protection. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 4000ml water dropwise, stir for 1 hour after addition; filter, wash the filter cake with 1000ml acetonitrile: water = 1: 1 solution, then wash with 1000ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (283.0g, off-white solid), yield 91%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0393] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0394] Example 31 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-nitrogen-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0395]

[0396] 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxaldehyde (monohydrochloride, 400 mg, 1.68 mmol), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (dihydrochloride, 0.58 g, 2.0 mmol), anhydrous sodium acetate (0.40 g, 5.0 mmol), trimethyl orthoformate (3.6 g, 33.6 mmol), anhydrous methanol (16 mL) and dichloromethane (12 mL) were added to a 100 mL three-necked flask, stirred evenly, and the mixture was replaced with nitrogen 3-4 times. Under nitrogen protection, the mixture was stirred at 20-30°C for 16-18 hours, and the temperature was controlled at 20-30°C. Sodium triacetyloxyborohydride (0.71 g, 3.36 mmol) was added, and the mixture was stirred for 1-2 hours. HPLC detection showed that the product accounted for about 75%. The temperature was controlled at 20-30°C, saturated sodium bicarbonate aqueous solution (50 mL) was added, and ethyl acetate (50 mL) was used for extraction three times. The organic phases were combined, washed once with water, washed once with saturated sodium chloride, and dried over anhydrous sodium sulfate. The crude product of the concentrated filtrate was separated by silica gel column chromatography to obtain the product 1'-((7-ethyl-6-oxygen-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-nitrogen-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.5 g, white solid), yield: 75%, HPLC purity: 97%. MS (ESI) m / z: 404.2 [M+1] + .

[0397] 1 H NMR (400 MHz, CDCl 3 ):δ / ppm 11.57(s,1H),8.57(dd,2H),8.16(d,1H),7.96(m,1H),7.87(s,1H),7.76-7.87(m,2H),6.23(t,1H),3 .83(s,2H),3.31(s,2H),3.05(d,3H),2.84(s,2H),2.71-2.78(q,2H),2.63(s,2H),1.26-1.33(t,3H).

[0398] 13 C NMR (400MHz, CDCl 3 ):δ / ppm 161.91,163.61,148.50,146.20,144.85,139.71,138.11,137.52,136.71,136.28,133.22, 133.18,132.13,122.97,122.92,121.80,60.41,59.34,53.14,49.64,26.13,23.41,12.32.

[0399] Example 32 Preparation of 7-(sulfonate)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0400]

[0401] 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (1.0 g, 4.9 mmol) and DCM (20 ml) were added to a 100 mL three-necked flask, and the mixture was protected by nitrogen and cooled to 0-10°C in an ice-water bath; DIPEA (1.9 g, 14.7 mmol) was added, and MsCl (0.84 g, 7.4 mmol) was added dropwise under temperature control. After the addition, the temperature was raised to 20-25°C and the mixture was reacted for 2 hours; the raw materials were sampled for HPLC detection, and the reaction was complete. The crude product was concentrated and directly carried out to the next step. MS (ESI) m / z: 283 [M+1] + .

[0402] Example 33 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0403]

[0404] In a 100 ml three-necked flask, 7-(sulfonate)-3-ethyl-1,5-naphthyridin-2(1H)-one (crude product, 4.9 mmol) obtained in the previous step, acetonitrile (20 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (1.7 g, 5.8 mmol) and KI (0.25 g, 1.5 mmol) were added. The solid was insoluble. Under nitrogen protection, DIPEA (4.6 g, 35 mmol) was added dropwise. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 20ml water dropwise, stir for half an hour after addition; filter, wash the filter cake with 20ml acetonitrile: water = 1: 1 solution, then wash with 20ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (1.0g, off-white solid), the two-step reaction yield is about 51%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0405] 1 H NMR (400 MHz, DMSO-d 6)δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0406] Example 34 Preparation of 7-(p-Toluenesulfonate)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0407]

[0408] 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (1.0 g, 4.9 mmol) and DCM (20 ml) were added to a 100 mL three-necked flask, and the mixture was protected by nitrogen and cooled to 0-10°C in an ice-water bath; DIPEA (1.9 g, 14.7 mmol) was added, and TsCl (1.0 g, 5.2 mmol) was added dropwise under temperature control. After the addition, the temperature was raised to 20-25°C and the mixture was reacted for 2 hours; the raw materials were sampled for HPLC detection, and the reaction was complete. The crude product was concentrated and directly carried out to the next step. MS (ESI) m / z: 359 [M+1] + .

[0409] Example 35 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0410]

[0411] In a 100 ml three-necked flask, 7-(p-toluenesulfonate)-3-ethyl-1,5-naphthyridin-2(1H)-one (crude product, 4.9 mmol) obtained in the previous step, acetonitrile (20 ml), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (1.7 g, 5.8 mmol) and KI (0.25 g, 1.5 mmol) were added. The solid was insoluble. Under nitrogen protection, DIPEA (4.6 g, 35 mmol) was added dropwise. After the addition, the temperature was raised to 50-60°C and the reaction was carried out for 1-2 hours. Sampling HPLC detection, the raw material reaction is complete; cool to 20 ~ 25 ℃, add 20ml water dropwise, stir for half an hour after addition; filter, wash the filter cake with 20ml acetonitrile: water = 1: 1 solution, then wash with 20ml water, and drain to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.9g, off-white solid), the two-step reaction yield is about 46%, HPLC detection, the result shows that the purity is 98%. MS (ESI) m / z: 404 [M+1] + .

[0412] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

[0413] Example 36 Preparation of 5-nitro-6-(2-dimethylamino)vinylnicotinate

[0414]

[0415] Add DMF (36L), 5-nitro-6-methylnicotinate (4.5kg, 21.4mol), triethylamine (0.9L) and DMF-DMA (5.1kg, 42.8mol) to the reaction kettle in sequence. After the addition, heat to 35-45℃ and react for 5-6 hours. HPLC detection shows that the raw materials react completely. Control the temperature to ≤30℃ and drop 36L of purified water into the kettle. After the addition, control the temperature to 15-25℃ and stir for 2-3 hours. Filter, wash the filter cake with 10L of water and dry to obtain 5-nitro-6-(2-dimethylamino)vinylnicotinate (5.01kg, red solid), with a yield of 88% and a HPLC purity of 98.5%.

[0416] MS (ESI) m / z: 266 [M+1] + .

[0417] 1 H NMR (400 MHz, DMSO-d 6 )δ8.79(d,J=2.0Hz,1H),8.52(d,J=2.1Hz,1H),8.36(d,J=12.1Hz,1H),6.13(d,J=1 2.1Hz, 1H), 4.31 (q, J = 7.1Hz, 2H), 3.24 (s, 3H), 2.97 (s, 3H), 1.32 (t, J = 7.1Hz, 3H).

[0418] 13 C NMR (101 MHz, DMSO-d 6 )δ164.19(s),155.75(s),154.57(s),153.37(s),135.83(s),135.18(s),116.36(s),91.30(s),61.27(s),14.63(s).

[0419] Example 37 Preparation of 6-formyl-5-nitronicotinic acid ethyl ester

[0420]

[0421] Add 50L of tetrahydrofuran and 5-nitro-6-(2-dimethylamino)vinyl nicotinate (5.01kg, 18.9mol) to the reactor in sequence. Control the temperature at 20-30°C, add sodium periodate aqueous solution (12.12kg of sodium periodate, 50L of purified water), and control the temperature at 20-40°C during the addition. After the addition is completed, control the temperature at 20-40°C and stir for 2-3 hours. After HPLC detection of the complete reaction of the raw materials, filter, wash the filter cake with 40L of ethyl acetate, and let the filtrate stand for stratification. The aqueous phase is extracted with ethyl acetate twice (40L each time) and then combined with the organic phase. The combined organic phase is washed with 10% sodium bicarbonate solution, 10% sodium thiosulfate solution and saturated brine in sequence, and then added with anhydrous sodium sulfate for drying. Filter, and concentrate the filtrate under reduced pressure to obtain 6-formyl-5-nitronicotinate (3.78kg, black oily substance), with a yield of 89%. HPLC detection shows that the purity is 97%. MS (ESI) m / z: 225 [M+1] + .

[0422] 1 H NMR (400 MHz, DMSO-d 6 )δ9.75(s,1H),9.68(d,J=2.9Hz,1H),9.29(d,J=2.9Hz,1H),4.29(q,J=11.8Hz,2H),1.30(t,J=11.8Hz,3H).

[0423] Example 38 Preparation of a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate

[0424]

[0425] Under nitrogen protection, add 19L of tetrahydrofuran and 1.02kg of sodium hydride to the reactor in sequence. After cooling to 0-10°C, add triethyl 2-butyl acrylate (5.94kg, 23.5mol) dropwise. After addition, heat to 20-30°C and keep warm for 1-2 hours. Then cool to -70--60°C, and add a solution of 6-formyl-5-nitronicotinic acid ethyl ester (3.78kg, 16.9mol) in tetrahydrofuran (19L). After addition, keep warm and stir for 0.5-1 hour. After HPLC detection of the complete reaction of the raw materials, add the resulting reaction solution to an aqueous solution of ammonium chloride (60L of purified water, 18kg of ammonium chloride) under stirring. After addition, stir evenly and stand for stratification. The aqueous phase is extracted twice with ethyl acetate (30L each time) and then combined with the organic phase. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated to dryness under reduced pressure, and purified by column with petroleum ether / ethyl acetate = 10 / 1 to petroleum ether / ethyl acetate = 5 / 1 to obtain a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate (3.4 kg brown oil), yield: 62.4%. MS (ESI) m / z: 323 [M+1] + .

[0426] 1 H NMR (400 MHz, DMSO-d 6 )δ9.28(d,J=2.9Hz,1H),9.02(d,J=3.1Hz,1H),7.64(t,J=2.0Hz,1H),4.29(q,J=11.8Hz,2H),4.08(q,J=11.8 Hz,2H),2.44(qd,J=13.4,1.9Hz,2H),1.30(t,J=11.8Hz,3H),1.16(t,J=11.8Hz,3H),1.07(t,J=13.4Hz,3H).

[0427] Example 39 Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0428]

[0429] Add 35L of anhydrous ethanol, 7L of purified water, a mixture of (E)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and (Z)-5-nitro-6-(2,2-ethoxycarbonylethyl)vinylnicotinate (3.4kg, 10.6mol), ammonium chloride (2.83kg, 52.9mol) and iron powder (2.96kg, 52.9mol) to the reactor. After the addition, heat to 70-80℃ and keep warm for 1-2 hours. After HPLC detection of the complete reaction of the raw materials, cool to ≤30℃ and filter through diatomaceous earth. The filter cake is slurried twice with a mixed solvent of DCM / MeOH=10:1. The filtrate is concentrated under reduced pressure to obtain a concentrated solution. Combine the slurry from the two times with the concentrated solution, stir evenly and let stand to separate. The organic phase is washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to dryness to obtain a mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl)vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (2.89 kg, brown oil), with a yield of 93.2%.

[0430]

[0431] Add 25L of 1,4-dioxane, a mixture of (E)-5-amino-6-(2,2-ethoxycarbonylethyl) vinylnicotinate and 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (2.89kg, 9.9mol), tributylphosphine (3.99kg, 19.8mol) and glacial acetic acid (1.2L, 19.8mol) to the reactor in sequence, raise the temperature to 55-65°C, and keep the temperature to react for 12-14 hours. After HPLC detection of the complete reaction of the raw materials, the reaction solution is concentrated to dryness under reduced pressure. After adding 9L of ethyl acetate and stirring to dissolve, 9L of n-heptane is added dropwise within 1-1.5 hours. After the addition is completed, the temperature is controlled at 10-30°C and stirred for 2-3 hours. Filter, wash the filter cake with n-heptane, collect the filter cake, and dry to obtain ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.035 kg, brown solid). Yield: 83.4%. HPLC detection, purity: 98.6%. MS (ESI) m / z: 247 [M+1] + .

[0432] 1 H NMR (400 MHz, DMSO-d 6 )δ12.31(s,1H),8.60(s,1H),7.92(s,1H),7.90(s,1H),4.33(m,2H),2.55(m,2H),1.32(t,J=7.1Hz,3H),0.94(t,J=7.4Hz,3H).

[0433] Example 40 Preparation of 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one

[0434]

[0435] Add 33L of tetrahydrofuran and ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1.64kg, 6.66mol) to the reactor in sequence, and replace with nitrogen three times. After cooling to -15~-5℃, add 8L of LiAlH4 solution dropwise, and control the temperature ≤5℃ during the addition process. After the addition is completed, control the temperature to -15~-5℃ and stir for 1~1.5 hours. After HPLC detects that the raw materials have reacted completely, control the temperature ≤5℃ and add 304g of purified water dropwise. After the addition is completed, add sodium hydroxide aqueous solution (45.6g of sodium hydroxide, 260g of purified water) and 912g of purified water dropwise. After the addition is completed, stir for 1~1.5 hours, add 1.6kg of diatomaceous earth, stir for 10~20 minutes and filter. Wash the filter cake with ethyl acetate and then reflux and slurry it with a mixed solvent of dichloromethane and methanol in a ratio of 1:1 for 3 times. The three pulping filtrates were combined and concentrated under reduced pressure, and 5L of anhydrous methanol and 5L of ethyl acetate were added to cool to -5~5℃ for crystallization. Filter and dry the filter cake to obtain 3-ethyl-7-hydroxymethyl-1,5-naphthyridin-2(1H)-one (983.5g, light brown solid), with a yield of 72.3% and a purity of 96.4%. MS (ESI) m / z: 205[M+1] + .

[0436] 1 H NMR (400 MHz, DMSO-d 6 )δ12.1(s,1H),8.48(s,1H),7.85(s,1H),7.83(s,1H),5.17(s,1H),4.61(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0437] Example 41 Preparation of N-methyl-5-bromopicolinamide

[0438]

[0439] Add 5-bromopyridine-2-carboxylic acid methyl ester (1.8kg, 8.33mol) to methanol (9L), add 3.6L methylamine aqueous solution dropwise while stirring, control the temperature at 10-30°C after the addition, and stir to react for 0.5-1 hour. After HPLC detection of the complete reaction of the raw materials, the reaction solution is concentrated to dryness under reduced pressure. Add 9L n-heptane, control the temperature at 10-30°C, stir for 1-2 hours, and filter. The filter cake is dried to obtain N-methyl-5-bromopyridinecarboxamide (1.55kg, white solid), with a yield of 86.5% and an HPLC purity of 99.7%. MS (ESI) m / z: 215 [M+1] + .

[0440] 1 H NMR (400 MHz, DMSO-d 6 )δ8.76(d,J=15.0Hz,1H),8.73(d,J=2.9Hz,1H),8.30(dd,J=15.0,3.1Hz,1H),6.42(s,1H),2.85(s,3H).

[0441] Example 42 Preparation of N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydro)-6-N-methyl-formamide

[0442]

[0443] Under nitrogen protection, add N-methyl-5-bromopyridine carboxamide (1.5kg, 6.98mol), N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester (2.26kg, 7.31mol) and 2kg of anhydrous potassium carbonate to 15L 1,4-dioxane and 3L purified water. Add 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (150g, 0.2mol) under stirring. After the addition, heat to 90-100℃ and keep warm for 20-22 hours. After the reaction is completed by HPLC detection, the reaction solution is concentrated to dryness under reduced pressure, 7.5L ethyl acetate and 7.5L purified water are added, stirred evenly, and then allowed to stand for stratification. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and washed with brine. After drying over anhydrous sodium sulfate, dilute with n-heptane, and then filter through 1.5kg silica gel pad, and the filter cake is rinsed with a mixed solution of n-heptane: ethyl acetate = 1:1. The eluent was added to the filtrate and concentrated under reduced pressure to obtain N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydrogen)-6-N-methyl-formamide (2.83 kg, brown oily liquid), which was directly used in the next step. MS (ESI) m / z: 318 [M+1] + .

[0444] 1 H NMR (400 MHz, DMSO-d6 )δ8.57(d,J=2.9Hz,1H),8.37(d,J=15.0Hz,1H),8.14(dd,J=15.0,2.9Hz,1H),6.38(s,1H),6.13(tt,J=12.5,1.9Hz,1H),4.86( d,J=12.5Hz,1H),3.91(dd,J=24.2,12.0Hz,2H),3.61(t,J=11.5Hz,1H),2.85(s,3H),2.62(td,J=11.6,1.9Hz,2H),1.42(s,9H).

[0445] Example 43 Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride

[0446]

[0447] Add 25L ethyl acetate and N-Boc-3',6'-dihydro-[3,4'-bipyridine]-1'(2'hydrogen)-6-N-methyl-formamide (2.82kg, 8.88mol) to the reactor, stir for 20-30 minutes, then add 8.8L hydrogen chloride\ethyl acetate solution (4.0M). After the dropwise addition, control the temperature to 30-40℃ and keep the reaction for 18-20 hours. After HPLC detection of the complete reaction of the raw materials, cool the reaction solution to 20-30℃ and filter. After the filter cake is slurried with ethyl acetate, dry it to obtain N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-formamide hydrochloride (1.92kg, off-white solid). The yield is 74.5%, and the HPLC detection results show that the purity is 95.4%. MS (ESI) m / z: 218 [M+1] + .

[0448] 1 H NMR (400 MHz, DMSO-d 6 )δ8.57(d,J=2.9Hz,1H),8.37(d,J=15.0Hz,1H),8.14(dd,J=15.0,2.9Hz,1H),6.39(s,1H),6.11(tt,J=12 .4,2.0Hz,1H),3.39(d,J=12.4Hz,2H),2.98(t,J=11.6Hz,2H),2.85(s,3H),2.37(td,J=11.6,1.9Hz,2H).

[0449] Example 44 Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0450]

[0451] Add 3-ethyl-7-hydroxymethyl-1,5-naphthyridine-2(1H)-one (965g, 4.73mol), 20L dichloromethane and 20.6L thionyl chloride to the reactor. After the addition, heat to 30-40°C and keep warm for 20-22 hours. After HPLC detection of the complete reaction of the raw materials, cool the reaction solution to 20-30°C and filter. The filter cake is slurried with dichloromethane and filtered and dried to obtain 7-(chloromethyl)-3-ethyl-1,5-naphthyridine-2(1H)-one hydrochloride (1.21kg, light yellow-brown solid), with a yield of 98.4%. HPLC detection shows that the purity is 96%. MS (ESI) m / z: 223 [M+1] + .

[0452] 1 H NMR (400 MHz, DMSO-d 6 )δ8.21(d,J=2.9Hz,1H),7.53(d,J=3.1Hz,1H),7.46(t,J=2.0Hz,1H),4.79(s,2H),2.44(qd,J=13.4,1.9Hz,2H),1.07(t,J=13.4Hz,3H).

[0453] Example 45 Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0454]

[0455] Add 24L acetonitrile, 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one hydrochloride (1.19kg, 4.59mol), N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (1.60kg, 5.5mol) and 230g potassium iodide (230g, 1.39mol) to the reactor. After the addition is completed, DIPEA (4.5kg, 34.8mol) is added dropwise under stirring. After the addition is completed, the temperature is raised to 50-60℃ and the reaction is carried out for 2-3 hours. After HPLC detection of the complete reaction of the raw materials, 24L purified water is added dropwise at a temperature of 50-60℃. After the addition is completed, the temperature is lowered to 20-30℃ after stirring for 3-4 hours and then filtered after stirring for 3-4 hours. The filter cake was treated with acetonitrile / water (1 / 1) mixed solution and water in turn, and then dried to obtain 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (1.12 kg, off-white solid), with a yield of 94.2%. HPLC detection showed that the purity was 98.2%. MS (ESI) m / z: 404 [M+1] +。

[0456] 1 H NMR (400 MHz, DMSO-d 6 )δ11.85(s,1H),8.71(d,J=9.3Hz,2H),8.42(s,1H),8.04–7.95(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3. 73(s,2H),3.16(s,2H),2.82(d,J=4.7Hz,3H),2.70(d,J=5.1Hz,2H),2.54(d,J=7.4Hz,4H),1.19(t,J=7.4Hz,3H).

Claims

1. A method for preparing a compound of general formula (VIII), characterized in that: It includes the steps Method 1 (a): The compound of general formula (I-1-1) reacts with the compound of general formula (VII) in the presence of a base and a catalyst to obtain a compound of general formula (VIII); Method 2 (a-1): The compound of general formula (I-1-2) reacts with the compound of general formula (VII) to obtain the compound of general formula (VIII); in, X is halogen; preferably fluorine, chlorine or bromine; or X is selected from OH or OPg; Pg is a hydroxyl protecting group, preferably selected from methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl, p-toluenesulfonyl, nitrobenzenemethylsulfonyl, methanesulfonyl or trifluoromethanesulfonyl; R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; x is selected from 0, 1, 2, 3 or 4.

2. The preparation method according to claim 1, characterized in that The base in step (a) is selected from one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA and TEA; preferably DIPEA; the molar ratio of the compound of formula (I-1-1) to the base is 1:1 to 1:15; preferably 1:6 to 1:8; more preferably 1:7 to 1:8; Step (a-1) is carried out in the presence of a base, wherein the base is preferably acetate; more preferably one or more of sodium acetate, potassium acetate and calcium acetate; further preferably sodium acetate.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The catalyst in step (a) is an iodide; preferably NaI or KI; the molar ratio of the compound of general formula (I-1-1) to the catalyst is 5:1 to 1:3; preferably 3.5:1 to 3:

1.

4. The preparation method according to any one of claims 1 to 3, characterized in that: Step (a) is carried out in the presence of a solvent, wherein the solvent is a nitrile solvent; preferably one or more of acetonitrile, propionitrile, butyronitrile, benzyl cyanide and benzonitrile; more preferably acetonitrile; the concentration of the compound of formula (I-1-1) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L, more preferably 0.2 mol / L; Step (a-1) is carried out in the presence of a solvent, wherein the solvent is preferably a mixed solvent of an alcohol solvent and a halogenated hydrocarbon solvent; the alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol; the halogenated hydrocarbon solvent is preferably one or more of methyl chloride, dichloromethane and chloroform; preferably, the solvent is a mixed solvent of methanol and dichloromethane; In step (a-1), the concentration of the compound of formula (I-1-2) in the solvent is 0.01 to 0.2 mol / L; preferably 0.05 to 0.1 mol / L; Step (a-1) is carried out in the presence of a water absorbing agent, wherein the water absorbing agent is preferably a molecular sieve, a water absorbing inorganic salt, trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, Ti(OiPr)4, Ti(OEt)4 or TiCl(OiPr)3; Step (a-1) is carried out in the presence of a reducing agent, and the reducing agent is preferably one or more of sodium triacetyloxyborohydride and sodium borohydride.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The molar ratio of the compound of general formula (I-1-1) to the compound of general formula (VII) is 3:1 to 1:3; preferably 1:1 to 1:1.3; more preferably 1:1.2; Step (a) is carried out at 20 to 80° C.; preferably at 50 to 60° C.; The reaction time of step (a) is 1 to 5 hours; preferably 2 to 3 hours; The molar ratio of the compound of general formula (I-1-2) to the compound of general formula (VII) is 3:1 to 1:3; preferably 1:1 to 1:1.3; more preferably 1:1.2; Step (a-1) is carried out at 10 to 40°C, preferably at 20 to 30°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The preparation method further comprises the step (b): deprotecting the compound of the general formula (IX) under acidic conditions to obtain the compound of the general formula (VII); Optionally, it further comprises step (c): reacting a compound of general formula (X) with a compound of general formula (XI) to obtain a compound of general formula (IX); Optionally, it further comprises step (d): reacting the compound of general formula (XII) with methylamine to obtain the compound of general formula (XI); Optionally, it further comprises step (e): reacting the compound of general formula (I-1-4) with SOX2 or PgX' to obtain the compound of general formula (I-1-1); Wherein, Pg is a hydroxyl protecting group, preferably selected from methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl, p-toluenesulfonyl, nitrobenzenemethylsulfonyl, methanesulfonyl or trifluoromethanesulfonyl; X' is halogen, preferably Cl or bromine; Optionally, it further comprises step (f): the compound of general formula (I-1) undergoes a reduction reaction to obtain a compound of general formula (I-1-4); Optionally, it further comprises steps (h) and (g): Step (h): reducing the compound of formula (III) with a reducing agent to obtain a compound of formula (II); Step (g): catalyzing the compound of formula (II) with a catalyst to obtain a compound of formula (I-1); Optionally, it further comprises the step (i): the compound of the general formula (IV) undergoes a Wittig reaction in the presence of a phosphorus ylide reagent to obtain a compound of the general formula (III); Optionally, it further comprises steps (j-1) and (j-2): In step (j-1): the compound of formula (VI) reacts with DMF-DMA in an organic solvent to obtain a compound of formula (V); In step (j-2): the compound of formula (V) undergoes oxidation reaction in the presence of an oxidant to obtain a compound of formula (IV); in, X is halogen; preferably fluorine, chlorine or bromine; more preferably chlorine; X1 is fluorine, chlorine or bromine; more preferably bromine; GP is an amino protecting group; preferably Boc, Cbz, Fmoc, PMB or Bn; more preferably Boc; R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Halogenated alkoxy, preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R7 is selected from hydrogen, deuterium, C 1-8 Alkyl or C 1-8 Halogenated alkyl; preferably C 1-8 Alkyl; more preferably ethyl; R6 is selected from x is selected from 0, 1, 2, 3 or 4.

7. The preparation method according to any one of claims 1 to 5, characterized in that: The preparation method further comprises step (b-1): The compound of general formula (XIV) is reacted with N,N-dimethylformamide to obtain a compound of general formula (I-1-2); X2 is halogen; preferably fluorine, chlorine or bromine; R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl; Optionally, the method further comprises step (c-1): catalyzing the compound of formula (II-1) with a catalyst to obtain a compound of formula (I-2); Optionally, the method further comprises step (d-1): reducing the compound of formula (III-1) with a reducing agent to obtain the compound of formula (II-1); Optionally, the method further comprises step (e-1): subjecting the compound of formula (IV-1) to a Wittig reaction in the presence of a phosphorus ylide reagent to obtain a compound of formula (III-1); Optionally, the method further comprises steps (f-1) and (f-2): in step (f-1), the compound of formula (VI-1) reacts with DMF-DMA in an organic solvent to obtain a compound of formula (V-1); in step (f-2), the compound of formula (V-1) undergoes an oxidation reaction in the presence of an oxidant to obtain a compound of formula (IV-1); 8. A method for preparing a compound of general formula (VII), characterized in that: The method comprises the step (b): removing the protecting group of the compound of the general formula (IX) under acidic conditions to obtain the compound of the general formula (VII); in, GP is an amino protecting group; preferably Boc, Cbz, Fmoc, PMB or Bn; more preferably Boc; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; x is selected from 0, 1, 2, 3 or 4; The acid is HCl and / or trifluoroacetic acid; preferably HCl; Optionally, the preparation method further comprises step (c): reacting the compound of general formula (X) with the compound of general formula (XI) to obtain the compound of general formula (IX); Optionally, it further comprises step (d): reacting the compound of general formula (XII) with methylamine to obtain the compound of general formula (XI); in, GP is an amino protecting group; preferably Boc, Cbz, Fmoc, PMB or Bn; more preferably Boc; X1 is fluorine, chlorine or bromine; more preferably bromine; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or C 1-8 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R6 is selected from x is selected from 0, 1, 2, 3 or 4.

9. The preparation method according to claim 6 or 8, characterized in that: In step (b), GP is Boc; x is 0; Step (b) is carried out in the presence of a solvent, wherein the solvent is a mixed solvent of an ester solvent and an ether solvent; the ester solvent is preferably one or more of methyl formate, ethyl acetate, ethyl formate and methyl acetate; the ether solvent is one or more of diethyl ether, tetrahydrofuran and dioxane; the solvent is a mixed solvent of ethyl acetate and dioxane; In step (b), the concentration of the compound of formula (IX) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L; In step (b), the molar ratio of the compound of formula (IX) to the acid is 1:2 to 1:10; preferably 1:4 to 1:6; Step (b) is carried out at 10 to 40°C; preferably at 20 to 25°C; The reaction time of step (b) is 10 to 25 hours, preferably 12 to 16 hours.

10. The preparation method according to claim 6 or 8, characterized in that: In step (c), GP is Boc; X1 is bromine; R6 is x is 0; Step (c) is carried out in the presence of a solvent, wherein the solvent is a mixed solvent of an ether solvent and water; the ether solvent is one or more of diethyl ether, tetrahydrofuran and dioxane; Step (c) is carried out in the presence of a base, wherein the base is a carbonate; more preferably one or more of potassium carbonate, sodium carbonate and cesium carbonate; Step (c) is carried out in the presence of a catalyst, wherein the catalyst is one or more of Pd(PPh3)4, Pd2(dba)3, NiCl2(dppf), PdCl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2 and Pd(OAc)2; preferably Pd(dppf)Cl2; Step (c) is carried out under the protection of nitrogen; In step (c), the concentration of the compound of formula (X) in the solvent is 0.01 to 1 mol / L; preferably 0.2 to 0.5 mol / L; Step (c) is carried out at 80-110°C, preferably at 90-95°C; The reaction time of step (c) is 10 to 30 hours, preferably 16 to 20 hours; Step (d) is carried out in the presence of a solvent, wherein the solvent is an alcohol solvent; preferably one or more of methanol, ethanol, n-propanol, isopropanol and n-butanol; In step (d), the concentration of the compound of formula (XII) in the solvent is 0.1 to 3 mol / L; preferably 0.7 to 1.2 mol / L; Step (d) is carried out at 10 to 40°C; preferably at 20 to 25°C; The reaction time of step (d) is 0.1 to 1 hour, preferably 0.5 to 1 hour.

11. The preparation method according to claim 6, characterized in that: In step (e), R1 is ethyl; X is chlorine; Step (e) is carried out in the presence of a solvent, wherein the solvent is a halogenated hydrocarbon solvent, preferably one or more of methyl chloride, dichloromethane and chloroform; more preferably dichloromethane; In step (e), the concentration of the compound of general formula (I-1-4) in the solvent is 0.01 to 1 mol / L; preferably 0.15 to 0.35 mol / L; Step (e) is carried out at 10 to 40° C.; preferably at 20 to 25° C.; The reaction time of step (e) is 1 to 3 hours or 15 to 30 hours; preferably 2 to 3 hours or 20 to 24 hours; Step (e) optionally needs to react in the presence of a base, preferably the base is selected from one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA and TEA; preferably DIPEA; the molar ratio of the compound of formula (I-1-4) to the base is 1:1 to 1:10; preferably 1:2 to 1:5; more preferably 1:3 to 1:4; In step (f), R1 is ethyl; R7 is ethyl; Step (f) is carried out in the presence of a solvent, wherein the solvent is an ether solvent; preferably one or more of diethyl ether, tetrahydrofuran and dioxane; The reducing agent in step (f) is sodium borohydride and / or LiAlH4; preferably LiAlH4; In step (f), the concentration of the compound of formula (I-1) in the solvent is 0.01 to 1 mol / L; preferably 0.1 to 0.3 mol / L; Step (f) is carried out at -20 to 5°C; preferably at -5 to 5°C; The reaction time of step (f) is 0.1 to 1 hour; preferably 0.5 to 1 hour; In step (g), R1 is ethyl; R7 is ethyl; In step (g), the catalyst is a phosphine-containing catalyst; preferably methyl phosphine, triethyl phosphine, tripropyl phosphine, tri-tert-butyl phosphine, triphenyl phosphine or tributyl phosphine; In step (g), the reaction is carried out in the presence of an acid, and the acid is selected from an organic acid or an inorganic acid; preferably carboxylic acid (R-COOH), sulfonic acid (R-SO3H), sulfinic acid (R-SOOH), thiocarboxylic acid (R-SH), hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; more preferably acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; In step (g), the reaction is carried out in a solvent, the solvent is an organic solvent, and the concentration of the compound of formula (II) in the solvent is 0.05 g / ml to 0.5 g / ml; In step (g), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably dioxane; In step (h), R1 is ethyl; R7 is ethyl; In step (h), the reducing agent is selected from a metal reducing agent or a non-metal reducing agent; the metal reducing agent is selected from iron powder or zinc powder; preferably iron powder; the non-metal reducing agent is selected from tin chloride, ferrous chloride or zinc chloride; In step (h), the reaction is carried out in a solvent, the solvent is a mixed solvent, and the concentration of the compound of formula (III) in the mixed solvent is 0.05 g / ml to 0.5 g / ml; In step (h), the mixed solvent is selected from methanol, ethanol, isopropanol, tert-butanol, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or a mixed solvent of dichloromethane and water; preferably a mixed solvent of ethanol and water, wherein the volume content of water is 1% to 50%; In step (h), the reaction temperature is 0 to 100°C; preferably 70 to 80°C; In step (i), R1 is ethyl; R7 is ethyl; In step (i), the phosphorus ylide reagent is selected from triethyl 2-butyl acrylate, trimethyl 2-butyl acrylate or tripropyl 2-butyl acrylate; preferably triethyl 2-butyl acrylate; In step (i), the reaction is optionally carried out in an organic solvent, wherein the concentration of the compound of formula (IV) in the solvent is 0.05 g / ml to 0.5 g / ml; In step (i), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran; In step (i), the reaction is optionally carried out in the presence of a base, wherein the base is one or more organic bases or inorganic bases; preferably at least one of sodium hydrogen sulfide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, DBU, and DABCO; In step (i), the molar ratio of the base to the compound of formula (IV) is 1 to 10:1; preferably 1:1; In step (i), the reaction temperature is -70 to 50°C; preferably -70 to -50°C; In step (j-1), the molar ratio of DMF-DMA to the general formula (VI) is 1 to 30:1; preferably 1 to 20:1; more preferably 1 to 10:1; further preferably 1 to 5:1; further preferably 2:1; In step (j-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably DMF; In step (j-1), the concentration of the compound of formula (VI) is 0.05 g / ml to 0.5 g / ml; In step (j-1), the reaction is carried out in the presence of a base, wherein the base is one or more organic bases or inorganic bases; and is selected from at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, and DABCO; In step (j-1), the molar ratio of the base to the compound of formula (VI) is 0.1 to 10:1; In step (j-1), the reaction temperature is 0 to 100°C; preferably 35 to 45°C; In step (j-2), the oxidant is selected from perchlorate, permanganate, dichromate, peroxide or gaseous oxidant; preferably sodium dichromate, potassium dichromate, potassium permanganate, sodium perchlorate, oxygen or chlorine; In step (j-2), the oxidation reaction is carried out in an organic solvent, and the concentration of the compound of formula (V) is 0.05 g / ml to 0.5 g / ml; In step (j-2), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran; In step (j-2), the temperature of the oxidation reaction is -20 to 100°C; preferably 25 to 35°C.

12. The preparation method according to claim 7, characterized in that: Step (b-1) is carried out in the presence of a solvent, and the solvent is preferably an ether solvent; preferably one or more of diethyl ether, tetrahydrofuran and dioxane; Step (b-1) is carried out in the presence of a base, and the base is preferably n-butyl lithium; In step (b-1), the concentration of the compound of formula (XVI) in the solvent is 0.01 to 0.5 mol / L; preferably 0.15 to 0.25 mol / L; Step (b-1) is carried out at -70 to -50°C; preferably at -65 to -60°C; The reaction time of step (b-1) is 1 to 6 hours; preferably 2 to 4 hours; In step (c-1), R1 is ethyl; X2 is bromine; In step (c-1), the catalyst is a phosphine-containing catalyst; preferably methyl phosphine, triethyl phosphine, tripropyl phosphine, tri-tert-butyl phosphine, triphenyl phosphine or tributyl phosphine; In step (c-1), the reaction is carried out in the presence of an acid, and the acid can be selected from an organic acid or an inorganic acid; preferably carboxylic acid (R-COOH), sulfonic acid (R-SO3H), sulfinic acid (R-SOOH), thiocarboxylic acid (R-SH), hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; more preferably acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid or phosphoric acid; In step (c-1), the reaction is carried out in a solvent, and the solvent is preferably an organic solvent; the concentration of the compound of formula (II-1) in the solvent is 0.05 g / ml to 0.5 g / ml; In step (c-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably dioxane; In step (d-1), R1 is ethyl; X2 is bromine; In step (d-1), the reducing agent is selected from a metal reducing agent or a non-metal reducing agent; the metal reducing agent is selected from iron powder or zinc powder, preferably iron powder; the non-metal reducing agent is selected from tin chloride, ferrous chloride or zinc chloride; In step (d-1), the reaction is carried out in a solvent, and the solvent is preferably a mixed solvent; the concentration of the compound of formula (III-1) in the mixed solvent is preferably 0.05 g / ml to 0.5 g / ml; In step (d-1), the mixed solvent is selected from methanol, ethanol, isopropanol, tert-butanol, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or a mixed solvent of dichloromethane and water; preferably a mixed solvent of ethanol and water, wherein the volume content of water is 1% to 50%; In step (d-1), the reaction temperature is 0 to 100°C; preferably 70 to 80°C; In step (e-1), R1 is ethyl; X2 is bromine; In step (e-1), the phosphorus ylide reagent is selected from triethyl 2-butyl acrylate, trimethyl 2-butyl acrylate, tripropyl 2-butyl acrylate; preferably triethyl 2-butyl acrylate; In step (e-1), the reaction is optionally carried out in an organic solvent, and the concentration of the compound of formula (IV-1) in the solvent is 0.05 g / ml to 0.5 g / ml; In step (e-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran; In step (e-1), the reaction is optionally carried out in the presence of a base, wherein the base is one or more organic bases or inorganic bases; preferably at least one of sodium hydrogen sulfide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, DBU, and DABCO; In step (e-1), the molar ratio of the base to the compound of formula (IV-1) is 1 to 10:1; preferably 1.5:1 or preferably 1:1; In step (e-1), the reaction temperature is -70 to 50°C; preferably -70 to -50°C; In step (f-1), the molar ratio of DMF-DMA to the general formula (VI-1) is 1 to 30:1; preferably 1 to 20:1; more preferably 1 to 10:1; further preferably 1 to 5:1; further preferably 2:1; In step (f-1), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably DMF; In step (f-1), the concentration of the compound of formula (VI-1) is 0.05 g / ml to 0.5 g / ml; In step (f-1), the reaction is carried out in the presence of a base, wherein the base is one or more organic bases or inorganic bases; preferably at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, and DABCO; In step (f-1), the molar ratio of the base to the compound of formula (VI-1) is 0.1 to 10:1; In step (f-1), the reaction temperature is 0 to 100°C; preferably 35 to 45°C; In step (f-2), the oxidant is selected from periodate, perchlorate, permanganate, dichromate, peroxide or gaseous oxidant; preferably sodium periodate, sodium dichromate, potassium dichromate, potassium permanganate, sodium perchlorate, oxygen or chlorine; In step (f-2), the oxidation reaction is carried out in an organic solvent, and the concentration of the compound of formula (V-1) is 0.05 g / ml to 0.5 g / ml; In step (f-2), the organic solvent is selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate or dichloromethane; preferably tetrahydrofuran; In step (f-2), the temperature of the oxidation reaction is -20 to 100°C; preferably 20 to 25°C or preferably 25 to 35°C.

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