Naphthyridine derivative and preparation method therefor

Abstract

Provided are a naphthyridine derivative and a preparation method therefor. The method overcomes the defects in the prior art and greatly reduces the cost. The obtained product exhibits good purity, high yield, high process operability, and high process safety. Therefore, the present invention is applicable to industrial uses.

Description

A naphthidine derivative and its preparation method Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a naphthidine derivative, its preparation method, and its application. Background Technology

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

[0003] PARP1 is the earliest discovered and most studied PARP isoform, comprising three main domains: the N-terminal DNA-binding domain (DBD), the self-modification domain (AMD), and the C-terminal catalytic domain. PARP1 is a crucial functional protein in DNA damage repair. As a sensor for single-strand DNA damage, PARP1 is activated by DNA injury, leading to poly-ADP-ribosylation of its target proteins, such as histones, and recruitment of related repair proteins to promote DNA damage repair. While PARP1 is essential for the stability of the genome in normal cells, in cancer treatment, its ability to repair DNA damaged by radiotherapy and chemotherapy can antagonize the tumor-killing effects of these treatments. Therefore, PARP1 inhibitors could be developed as sensitizers for radiotherapy and chemotherapy in cancer treatment.

[0004] The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, mainly consisting of two subtypes: BRCA1 and BRCA2. BRCA plays a crucial role in repairing double-strand DNA breaks during homologous recombination. Tumor cells frequently exhibit BRCA deficiency, resulting in the loss of double-strand DNA break repair function. If PARP1 function is simultaneously absent or inhibited, single-strand DNA break repair is also lost, ultimately leading to tumor cell death and producing a "synthetic lethality" effect. Therefore, using PARP1 inhibitors to block single-strand DNA break repair function has a selective killing effect on BRCA-deficient tumors.

[0005] PARP inhibitors have achieved great success in precision oncology, particularly for tumors with BRCA mutations or defects. Currently marketed PARP inhibitors include AstraZeneca's Olaparib (AZD2281), Clovis's Rucaparib (CO-338), Tesaro's Niraparib (MK-4827), and Pfizer's Talazoparib (BMN-673), primarily indicated for ovarian and breast cancers with BRCA mutations. Many other PARP inhibitors are also in clinical trials. PARP2 shares the highest homology with PARP1 within the PARP family; therefore, most marketed or clinically-developed PARP inhibitors are non-selective, exhibiting potent inhibitory effects on both PARP1 and PARP2 subtypes. Studies have shown that PARP2 plays a crucial role in regulating erythrocyte production, and inhibition of PARP2 is closely related to the hematologic toxicity of PARP inhibitors, such as anemia. Therefore, China has a significant market demand for PARP1 inhibitors.

[0006] WO2022223025A1 discloses a PARP1 inhibitor, in which a PARP1 inhibitor compound is prepared using ethyl 6-methyl-5-nitronicotinic acid ester and 5-bromomethylpyridinium ester as raw materials. However, due to the harsh reaction conditions and high cost, it requires multiple column chromatography processes, resulting in a low yield, which is not suitable 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 new intermediate during the long-term research and development process, which can be used to prepare PARP1 inhibitors.

[0008] The present invention provides a method for preparing a compound of formula I, comprising step s7) reacting a compound of formula II in the presence of a reducing agent to obtain a compound of formula I;

[0009] Among them, R1 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0010] In some embodiments of the present invention, the method further includes step s6) reacting compound III in the presence of sodium methoxide to obtain compound II.

[0011] Alternatively, it may include step s6'), where the compound of formula IV reacts with R1MgBr in the presence of a catalyst to obtain the compound of formula II.

[0012] In some embodiments of the present invention, the method further includes step s5), reacting compound V with R1MgBr in the presence of a catalyst to obtain compound II.

[0013] In some embodiments of the present invention, the method further includes step s4) reacting compound VI with NR6-SM in the presence of a reducing agent to obtain compound V'.

[0014] R2 is either methyl or ethyl.

[0015] In some embodiments of the present invention, the method further includes step s3) reacting compound VII in the presence of morpholine or silver nitrate to obtain compound VI;

[0016] In some embodiments of the present invention, the method further includes step s2) reacting compound VIII with tribromomethane in the presence of a base to obtain compound VII;

[0017] In some embodiments of the present invention, the method further includes step s1) reacting the compound of formula IX with sodium methoxide to obtain the compound of formula VIII;

[0018] R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0019] In some embodiments of the present invention, in step s1), the molar ratio of compound of formula IX to sodium methoxide is 1:1-5, preferably 1:1.5.

[0020] In some embodiments of the present invention, in step s1), the reaction solvent is methanol.

[0021] In some embodiments of the present invention, in step s1), the reaction temperature is 10-40°C, preferably 20-30°C.

[0022] In some embodiments of the present invention, in step s2), the base is selected from one or more of sodium alkoxide, potassium alkoxide, and lithium diisopropylamine, preferably potassium tert-butoxide or sodium tert-butoxide.

[0023] In some embodiments of the present invention, in step s2), the molar ratio of compound VIII to tribromomethane is 1:1-5, preferably 1:1.5.

[0024] In some embodiments of the present invention, in step s2), the reaction solvent is selected from one or more of diethyl ether, tetrahydrofuran, and dioxane, preferably tetrahydrofuran.

[0025] In some embodiments of the present invention, in step s2), the reaction temperature is -70 to -55°C.

[0026] In some embodiments of the present invention, in step s3), the temperature at which the compound of formula VII reacts in the presence of silver nitrate is 60-120°C, preferably 80-100°C, more preferably 75-85°C; the solvent is an alcohol solvent, preferably one or more of methanol, ethanol, n-propanol and isopropanol; the molar ratio of the compound of formula VII to silver nitrate is 1:1-10, preferably 1:1-3.

[0027] In some embodiments of the present invention, in step s3), when the compound of formula VII reacts in the presence of morpholine, a post-processing step s3-1) is also required to add hydrochloric acid to the reaction solution.

[0028] In some embodiments of the present invention, in step s3-1), the reaction solvent is dichloromethane.

[0029] In some embodiments of the present invention, in step s3-1), the reaction temperature is 10-40°C, preferably 20-30°C.

[0030] In some embodiments of the present invention, in step s4), the molar ratio of compound of formula VI to NR6-SM is 1:1-3, preferably 1:1-2, and more preferably 1:1.2.

[0031] In some embodiments of the present invention, in step s4), the reducing agent is selected from stannous chloride dihydrate.

[0032] In some embodiments of the present invention, in step s4), the molar ratio of the compound of formula VI to the reducing agent is 1:1-10, preferably 1:1-5, and more preferably 1:4.

[0033] In some embodiments of the present invention, in step s4), the reaction solvent is an alcohol solvent, preferably one or more of methanol, ethanol, n-propanol, tert-butanol and isopropanol.

[0034] In some embodiments of the present invention, in step s4), the reaction temperature is 60-120°C, preferably 80-100°C, and more preferably 75-85°C.

[0035] In some embodiments of the present invention, in step s5), the molar ratio of compound V and R1MgBr is 1:1-10, preferably 1:1-3, and more preferably 1:2.5.

[0036] In some embodiments of the present invention, in step s5), the molar ratio of 1,3-bis(diphenylphosphine) nickel chloride to compound V is 1:100, preferably 1:50, and more preferably 1:10.

[0037] In some embodiments of the present invention, in step s5), the reaction solvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran and dioxane, preferably tetrahydrofuran.

[0038] In some embodiments of the present invention, the reaction temperature in step s5) is 40-100°C, preferably 50-70°C, and more preferably 55-65°C.

[0039] In some embodiments of the present invention, in step s5), R1MgBr can be replaced by one or more of R1B(OH)2, (R1)3B and (R1)2Zn.

[0040] In some embodiments of the present invention, in step s6), the molar ratio of compound III to sodium methoxide is 3-1:0.5-1, preferably 1:0.5-1, and more preferably 1:0.8-1.

[0041] In some embodiments of the present invention, in step s6), the reaction solvent is methanol.

[0042] In some embodiments of the present invention, in step s6), the reaction temperature is 40-100°C, preferably 50-70°C, and more preferably 55-65°C.

[0043] In some embodiments of the present invention, in step s6'), the catalyst is selected from one or more of zinc iodide, lithium chloride, copper chloride, copper bromide, cuprous iodide, zinc chloride, 1,3-bis(diphenylphosphine)dichloride, nickel chloride dimethoxyethane, 1,2-bis(diphenylphosphine)ethane nickel chloride, and 2,2'-bipyridine nickel chloride.

[0044] In some embodiments of the present invention, in step s6'), the molar ratio of compound of formula IV and R1MgBr is 1:1-10, preferably 1:1-3, and more preferably 1:2.5.

[0045] In some embodiments of the present invention, in step s6'), the molar ratio of 1,3-bis(diphenylphosphine) nickel chloride to the compound of formula IV is 1:100, preferably 1:50, and more preferably 1:10.

[0046] In some embodiments of the present invention, in step s6'), the reaction solvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran and dioxane, preferably tetrahydrofuran.

[0047] In some embodiments of the present invention, the reaction temperature in step s6') is 40-100°C, preferably 50-70°C, and more preferably 55-65°C.

[0048] In some embodiments of the present invention, in step s7), the reducing agent is one or more of NaBH4 / CaCl2, NaBH4 / MgCl2, NaBH4 / ZnCl2, LiAlH4, and borane.

[0049] In some embodiments of the present invention, in step s7), the molar ratio of the compound of formula II to the compound of formula I is 1:1-10, preferably 1:2-5, and more preferably 1:4.

[0050] In some embodiments of the present invention, in step s7), the reaction temperature is 10-45°C, preferably 20-25°C.

[0051] In some embodiments of the present invention, in step s7), the reaction solvent is an alcohol solvent, preferably one or more of methanol, ethanol, n-propanol and isopropanol.

[0052] The present invention also provides a method for preparing a compound of formula I-1, comprising step s8) reacting a compound of formula I with trifluoromethanesulfonic anhydride in the presence of a base to obtain a compound of formula I-1;

[0053] R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0054] In some embodiments of the present invention, in step s8), the base is one or more of an organic base or an inorganic base; preferably at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, DABCO, morpholine and pyridine, more preferably triethylamine.

[0055] In some embodiments of the present invention, in step s8), the molar ratio of the compound of formula I to trifluoromethanesulfonic anhydride is 1:1-5, preferably 1:3, and more preferably 1:1.2.

[0056] In some embodiments of the present invention, in step s8), the reaction solvent is DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, or dichloromethane; preferably dichloromethane.

[0057] In some embodiments of the present invention, in step s8), the reaction temperature is -10 to 10°C, preferably 0 to 5°C.

[0058] In some embodiments of the present invention, the method for preparing compound I-1 further includes the method for preparing compound I as described above.

[0059] The present invention also provides a method for preparing compound I-2, comprising step s8') reacting compound I with an oxidant to obtain compound I-2;

[0060] R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0061] In some embodiments of the present invention, in step s8'), the oxidant is one or more of the following: Des Martin reagent, PCC, PDC, MnO2, and Swern oxidation.

[0062] In some embodiments of the present invention, in step s8'), the molar ratio of the compound of formula I to the oxidant (such as the Des Martin reagent) is 1:1-5, preferably 1:3, and more preferably 1:1.2.

[0063] In some embodiments of the present invention, in step s8'), the reaction solvent is one or more of DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, and dichloromethane; preferably dichloromethane.

[0064] In some embodiments of the present invention, in step s8'), the reaction temperature is -10 to 10°C, preferably 0 to 5°C.

[0065] In some embodiments of the present invention, the method for preparing compound I-2 further includes the method for preparing compound I.

[0066] The present invention also provides a method for preparing compound I-3, comprising step s8”) reacting compound I with hydrobromic acid to obtain compound I-3;

[0067] R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0068] In some embodiments of the present invention, in step s8), the molar ratio of the compound of formula I to hydrobromic acid is 1:1-10, preferably 1:5, and more preferably 1:4.

[0069] In some embodiments of the present invention, in step s8), the reaction solvent is AcOH.

[0070] In some embodiments of the present invention, in step s8), the reaction temperature is 70-130°C, preferably 80-100°C, and more preferably 90°C.

[0071] The present invention also provides a method for preparing compound I-5, comprising step s10) reacting compound I-4 in the presence of an acid to obtain compound I-5;

[0072] In some embodiments of the present invention, the method further includes step s9) reacting compound I-1 with compound X or a salt thereof in the presence of a base and a catalyst to obtain compound I-4.

[0073] Alternatively, preferably, the method further includes step s9') reacting compound I-2 with compound X or a salt thereof in the presence of a reducing agent to obtain compound I-4.

[0074] R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

[0075] In some embodiments of the present invention, in step s9), the base is selected from one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA, and TEA; preferably DIPEA.

[0076] In some embodiments of the present invention, in step s9), the molar ratio of the compound of formula I-1 to the base is 1:1 to 1:15; preferably 1:6 to 1:10; more preferably 1:8 to 1:9.

[0077] In some embodiments of the present invention, in step s9), the molar ratio of compound I-1 to compound X is 1:1-5, preferably 1:1-3; more preferably 1:1.5.

[0078] In some embodiments of the present invention, in step s9), the catalyst is potassium iodide, preferably the molar ratio of potassium iodide to the compound of formula I-1 is 0.1-1:1, more preferably 0.3-0.5:1, and more preferably 0.35:1.

[0079] In some embodiments of the present invention, in step s9), the solvent is a nitrile solvent, preferably one or more of acetonitrile, propionitrile, butyronitrile, phenylacetonitrile, and benzonitrile; more preferably acetonitrile.

[0080] In some embodiments of the present invention, in step s9'), the reducing agent is sodium borohydride or sodium borohydride acetate, preferably sodium borohydride acetate.

[0081] In some embodiments of the present invention, in step s9'), the molar ratio of compound I-2 to compound X is 1:1-5, preferably 1:1-3; more preferably 1:1.2.

[0082] In some embodiments of the present invention, in step s9'), the molar ratio of the compound of formula I-2 to the reducing agent is 1:1-5, preferably 1:1-3; more preferably 1:2.

[0083] In some embodiments of the present invention, in step s9'), the reaction solvent is one or more of DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, and dichloromethane; preferably dichloromethane.

[0084] In some embodiments of the present invention, in step s9'), the reaction temperature is 10-40°C, preferably 20-30°C.

[0085] In some embodiments of the present invention, in step s10), the acid is an inorganic acid, preferably hydrochloric acid.

[0086] In some embodiments of the present invention, in step s10), the reaction solvent is water.

[0087] In some embodiments of the present invention, in step s10), the reaction temperature is 60-120°C, preferably 80-100°C.

[0088] In some embodiments of the present invention, the method further includes a method for preparing the compound of formula I-1 or formula I-2 as described above.

[0089] The present invention also provides a compound as shown below.

[0090] Among them, R1 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl

[0091] Preferably, the compound is selected from...

[0092] Compared with the prior art, the present invention has the following main advantages:

[0093] 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;

[0094] 2. The reaction raw materials are inexpensive and readily available, resulting in low cost;

[0095] 3. The separation and purification of products and intermediates by the method of the present invention are simpler, avoiding the need for multiple column chromatography in the prior art. The quality is stable, suitable for industrial scale-up, and better meets the requirements of safety and environmental protection.

[0096] Detailed description of the invention

[0097] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0098] "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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 their various branched isomers, etc.; the alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point;

[0099] "Deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium, wherein the definition of alkyl is as described above;

[0100] "Alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.

[0101] Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0102] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above; for example, trifluoromethyl.

[0103] "Haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above;

[0104] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, wherein the alkyl group is as defined above;

[0105] "Alcohol solvents" refer to alkane compounds containing hydroxyl groups in their molecules, such as methanol, ethanol, and isopropanol.

[0106] “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-butoxycarbonyl; “Cbz” refers to benzyloxycarbonyl; “Fmoc” refers to methoxycarbonyl; “PMB” refers to p-methoxybenzyl; “Bn” refers to benzyl; “PdCl2” refers to palladium chloride; “Pd(dppf)Cl2” refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; “Pd(PPh3)2Cl2” refers to bis(triphenylphosphine)palladium dichloride; “Pd(OAc)2” refers to palladium acetate; “LiAlH4” refers to lithium aluminum hydride; “DMF-DMA” refers to N,N-dimethylformamide dimethyl acetal.

[0107] In this invention, "multiple" or "various" refers to 1, 2, 3, 4, 5, 6, 7, etc.

[0108] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any one or more hydrogen atoms in the compounds of the embodiments of this invention can also be replaced by deuterium atoms. Detailed Implementation

[0109] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0110] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent, deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the internal standard, and tetramethylsilane (TMS) as the internal standard.

[0111] LC-MS analysis was performed using an Agilent 1260 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent ZORBAX SB-C18 column (4.6 × 150 mm, 5 μm). Other information is shown in the table below:

[0112] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0113] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0114] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, and in a dry solvent.

[0115] Example 1: Preparation of NR6-21

[0116] NR6-SM21 (900g, 1.0eq) was placed in a reaction flask, and methanol (9L) was added. The mixture was stirred, and a 30% sodium methoxide methanol solution (1023.8g, 1.5eq) was added dropwise while maintaining the temperature at 20-30℃. The mixture was stirred for 3-5 hours, and the reaction was confirmed to be complete by HPLC. Acetic acid (114.1g, 0.5eq) was added dropwise to adjust the pH to 6-8. The reaction solution was concentrated, and process water (13.5L) was added. The mixture was stirred for 3-5 hours, filtered, and the filter cake was washed with process water (1.8L). The filter cake was dried in a forced-air dryer at 50℃ for 10-12 hours to obtain 875.8g of white solid with a purity of 99.9%, a content of 99%, and a yield of 98% based on purity.

[0117] 1 H NMR (400MHz, DMSO) δ9.09(d,1H),8.82(d,1H),4.08(s,3H).

[0118] Example 2: Preparation of NR6-22

[0119] Under nitrogen protection, NR6-21 (700 g, 1.0 eq) and tribromomethane (1138.8 g, 1.5 eq) were added to tetrahydrofuran (3.5 L) to prepare solution 1. Hydrochloric acid (1.6 L) and methanol (1.6 L) were mixed to prepare solution 2. Potassium tert-butoxide (2359.6 g, 7 eq) was placed in a reaction flask, and tetrahydrofuran (7 L) was added. The mixture was stirred until dissolved, and nitrogen was purged three times. The temperature was lowered to -70 °C, and solution 1 was added dropwise while maintaining the temperature between -70 and -55 °C. The mixture was stirred for 2-3 hours. HPLC analysis confirmed the completion of the reaction. The reaction was quenched by adding the prepared solution 2 dropwise at -70 to -40℃. The mixture was allowed to rise naturally to room temperature. Water (14 L) and ethyl acetate (14 L) were added, and the mixture was stirred for 0.5-1 h. The organic phase was separated, and the aqueous phase was back-extracted with ethyl acetate (7 L). The organic phases were combined and washed with saturated sodium chloride aqueous solution (3.5 L). The organic phase was concentrated to dryness, and the residue was purified by Pad (it can be dissolved in dichloromethane (700 ml) for loading). The eluent was concentrated to dryness to obtain 893.7 g of yellow solid with a purity of 98.08% and a content of 95.26%, yielding a purity of 70%.

[0120] LCMS: MS m / z (ESI): 405.62 [M+H] +

[0121] 1 H NMR (400MHz, DMSO) δ8.71(s,1H),7.52(s,1H),4.16(s,3H).

[0122] Example 3 Preparation of NR6-5

[0123] Method 1

[0124] Step 1:

[0125] Prepare Solution 1 by mixing silver nitrate (440.6 g, 3.0 eq) and distilled water (700 ml). Place NR6-22 (350 g, 1.0 eq) in a reaction flask, add ethanol (3.5 L), heat to 80-85 °C, add Solution 1 dropwise, and stir at 78-83 °C for 5-8 hours. HPLC analysis indicates the reaction is complete. Cool to room temperature, filter through a diatomaceous earth sieve, rinse with ethanol (700 ml), concentrate the filtrate at <50 °C, and add distilled water (3.5 L) and ethyl acetate. Extract (5.25L), separate the organic phase, add saturated sodium bicarbonate (1.05L) to the aqueous phase to adjust pH to 6-8, add ethyl acetate (2.8L), stir for 0.5-1h, filter through diatomaceous earth, wash with ethyl acetate (700ml), allow the filtrate to stand and separate, combine the organic phases, wash with saturated sodium chloride aqueous solution (3.5L), concentrate the organic phase to dryness, add ethanol (1.05L) with distillation, concentrate to dryness, the residue is a yellow oily substance, directly used in the next step, yield 100%.

[0126] Step 2:

[0127] Place the residue from the previous step in a reaction flask, add ethanol (7L), stir to dissolve, add ethyl 3,3-diethoxypropionate (197.4g, 1.2eq) and stannous chloride dihydrate (780.3g, 4.0eq), heat to 78-83℃, stir for 2-4h, and check the reaction is complete by HPLC. Concentrate the reaction solution to 2-3V at 45℃, add ethyl acetate (7L), stir well, add 1M hydrochloric acid (3.5L)*3 times to wash, separate the organic phase, add saturated sodium bicarbonate (1.75L) to adjust the pH to 7-8, and add diatomaceous earth (1... 750g), stir for 0.5-1h, filter through diatomaceous earth, wash with ethyl acetate (1050ml), wash the filtrate with saturated sodium chloride aqueous solution (3.5L), separate the organic phase, concentrate at 45℃, distill twice with ethanol, concentrate, add ethanol (1.75L), heat to 80℃ and reflux, stir to dissolve, slowly cool to 25℃, control the temperature at 20-30℃ and stir for 5-7h, filter, wash with ethanol (700ml), dry the filter cake to obtain 190.2g of yellow solid with a purity of 99.29%, content of 99%, and yield of 70% (based on content).

[0128] Method 2

[0129] Place NR6-22 (350g, 1.0eq) in a reaction flask, add morpholine (1.4L), heat to 60℃ and stir for 1-2h. HPLC detection indicates the reaction is complete. Cool to room temperature, add dichloromethane (2.8L), stir for 0.5-1h, filter, wash the filter cake with dichloromethane (700ml), and add the filtrate dropwise to 4M hydrochloric acid (10.5L) at 0-10℃. Allow to cool naturally to room temperature, stir for 1-2h, and HPLC detection indicates the reaction is complete. Allow to stand and separate the phases. Extract the aqueous phase twice with dichloromethane (3.5L), combine the organic phases, wash with saturated sodium chloride aqueous solution (3.5L), concentrate the organic phase to dryness, add ethanol (1.05L) and distill, concentrate to dryness. The residue is a yellow oily substance, which can be used directly in the next step.

[0130] Place the residue NR6-6-4 in a reaction flask, add ethanol (7L), stir to dissolve, add ethyl 3,3-diethoxypropionate (197.4g, 1.2eq) and stannous chloride dihydrate (780.3g, 4.0eq), heat to 78-83℃, stir for 2-4h, and check the reaction is complete by HPLC. Concentrate the reaction solution at 45℃, add ethyl acetate (7L), stir well, add 1M hydrochloric acid (3.5L)*3 times to wash, separate the organic phase, add saturated sodium bicarbonate (1.75L) to adjust the pH to 7-8, and add diatomaceous earth (1... 750g), stir for 0.5-1h, filter through diatomaceous earth, wash with ethyl acetate (1050ml), wash the filtrate with saturated sodium chloride aqueous solution (3.5L), separate the organic phase, concentrate at 45℃, distill twice with ethanol, concentrate, add ethanol (1.75L), heat to 80℃ and reflux, stir to dissolve, slowly cool to 25℃, control the temperature at 20-30℃ and stir for 5-7h, filter, wash with ethanol (700ml), dry the filter cake to obtain 190.2g of yellow solid with a purity of 99.29%, content of 99%, and yield of 60% of the content.

[0131] LCMS: MS m / z (ESI): 311.98 [M+H] +

[0132] 1 H NMR (400MHz, CDCl3) δ9.34(d,1H),8.78(s,1H),8.58(s,1H),4.50(q,2H),4.20(s,3H),1.48(t,3H).

[0133] Example 4: Preparation of NR6-5-Me

[0134] At room temperature, NR6-22 (15.0 g, 1.0 eq) and morpholine (60 mL) were placed in a reaction flask and stirred at 58–63 °C for 1–2 h. The reaction was monitored by HPLC to confirm completion (Note: Intermediates are unstable and may appear in multiple states on HPLC; the disappearance of the starting material is used as the intermediate control standard). The temperature was lowered to 20–30 °C, 120 mL of dichloromethane was added, and the mixture was stirred for 30 min. The reaction solution was filtered, and the filter cake was washed with 30 mL of dichloromethane. 4 M HCl aqueous solution (450 mL) was added to another reaction flask, and the temperature was maintained at 0–10 °C. The filtered dichloromethane solution was then added dropwise to the 4 M HCl solution. In an aqueous HCl solution, the temperature is naturally raised to 20–30°C, and the mixture is stirred for 1–2 hours. HPLC analysis confirms the reaction is complete (a single main peak appears on HPLC). The mixture is allowed to stand for 0.5–1 hours, then separated. The organic phase (lower layer) and the aqueous phase (upper layer) are extracted once more with dichloromethane. The organic phases are combined and washed with a saturated sodium chloride solution. The organic phase is then concentrated, isopropanol is added, and the mixture is concentrated again for use in the next stage of the reaction. Isopropanol (300 mL) is added and stirred until dissolved. Methyl 3,3-dimethoxypropionate (6.59 g, 1.2 eq) and stannous chloride dihydrate (33.44 g, 4.0 eq) are added. The mixture is stirred at 78–83°C for 2–4 hours. HPLC analysis confirms the reaction is complete. The temperature is lowered to 45°C and maintained below 45°C. The mixture is concentrated under reduced pressure. Ethyl acetate (300 mL) is added and stirred until homogeneous. The mixture is then washed three times with 150 mL of 1M hydrochloric acid solution to remove tin salts. The organic phase is then separated. Adjust the pH of the organic phase to 7-8 with 75 mL of saturated sodium bicarbonate solution, then add diatomaceous earth and stir for 0.5-1 h. Filter the mixture through a diatomaceous earth filter, wash the filter cake with ethyl acetate, stir the filtrate for 0.5-1 h, allow it to stand, and separate the organic phase. Wash the organic phase once with 10 mL of saturated sodium chloride solution, keeping the temperature ≤45℃. Concentrate the organic phase, then add ethanol, concentrate again, add ethanol, heat to 80℃ and reflux, stir for 0.5-1 h, slowly cool (4-5 h) to 25℃, precipitating a large amount of solid. Stir at 20-30℃ for 5-7 h, then filter. Wash the filter cake with ethanol, and dry the filter cake at 45℃ for 10-12 h to obtain 5.6 g of yellow solid with a purity of 99.02% and a content of 94%. The three-step yield is 53%.

[0135] 1 H NMR (400MHz, CDCl3) δ9.33(d,1H),8.78(d,1H),8.57(s,1H),4.19(s,3H),4.04(s,3H).

[0136] Example 5 Preparation of NR6-6

[0137] Zinc chloride (643 ml, 1 M in THF) was placed in a reaction flask, purged with nitrogen three times, and ethyl magnesium bromide (643 ml, 1 M in THF) was added dropwise at -5-5℃. The mixture was purged with nitrogen three times, and stirred at -5-5℃ for 0.5 h. 1,3-bis(diphenylphosphine propane) nickel dichloride (13.94 g, 0.1 eq) and NR6-5 (80 g, 1.0 eq) were added, purged with nitrogen three times, and the temperature was raised to 58-63℃. The mixture was stirred for 16-20 h, and the reaction was confirmed by HPLC. The mixture was cooled to room temperature, and 1 M hydrochloric acid (800 ml) was added dropwise. The mixture was concentrated at 45℃, extracted three times with ethyl acetate (800 ml), and the organic phases were combined. Water (400 ml) was added, and the pH was adjusted to 400 ml with saturated sodium bicarbonate aqueous solution. 7-8. Allow to stand and separate the liquid. Wash the organic phase with saturated sodium chloride aqueous solution (400 ml), separate the organic phase, filter through diatomaceous earth, rinse with ethyl acetate (160 ml, 2V), concentrate the organic phase to dryness, distill twice with 160-240 ml of ethanol, concentrate to dryness, add ethanol (320 ml), heat to 80℃ and reflux, stir to dissolve, slowly cool to 25℃, maintain temperature at 20-30℃ and stir for 5-7 hours, filter, wash with ethanol (80 ml), dry the filter cake to obtain 54.15 g of yellow solid with a purity of 99.07% and a content of 99%, yielding 80% of the total content.

[0138] LCMS: MS m / z (ESI): 261.18 [M+H] +

[0139] 1 H NMR (400MHz, CDCl3) δ9.40–9.14(m,1H),8.87–8.65(m,1H),8.06(d,1H),4.49(dt,2H),4.13(d,3H),2.81(qd,2H),1.47(q,3H),1.38–1.30(m,3H).

[0140] Example 6 Preparation of NR6-6-Me

[0141] At room temperature, NR6-6 (42.0 g, 1.0 eq) and methanol (420 ml) were placed in a reaction flask, and nitrogen was purged three times. MeONa in MeOH (42.0 g, 0.8 eq) was added, and the mixture was stirred at 60 °C for 1-2 h. The reaction was confirmed by HPLC. The mixture was then cooled to room temperature and kept below 30 °C. 6 ml of glacial acetic acid was added to adjust the pH to 8. Subsequently, the mixture was concentrated under reduced pressure, and 420 ml of water was added. The mixture was stirred for 1-4 h, filtered, and the filter cake was washed three times with 84 ml of water. The filter cake was then vacuum dried at 40-50 °C for 15-20 h to obtain 36.8 g of the title compound with a purity of 98.34%, an content of 91.74%, and a yield of 85% (based on purity).

[0142] Method 2

[0143] Zinc chloride (643 ml, 1 M in THF) was placed in a reaction flask, purged with nitrogen three times, and ethyl magnesium bromide (643 ml, 1 M in THF) was added dropwise at -5-5℃. The mixture was purged with nitrogen three times, and stirred at -5-5℃ for 0.5 h. 1,3-bis(diphenylphosphine propane) nickel dichloride (13.94 g, 0.1 eq) and NR6-5-Me (80 g, 1.0 eq) were added, purged with nitrogen three times, and the temperature was raised to 58-63℃. The mixture was stirred for 16-20 h, and the reaction was confirmed by HPLC. The mixture was cooled to room temperature, and 1 M hydrochloric acid (800 ml) was added dropwise. The mixture was concentrated at 45℃, extracted three times with ethyl acetate (800 ml), and the organic phases were combined. Water (400 ml) was added, and the pH was adjusted with saturated sodium bicarbonate aqueous solution (400 ml). H=7-8, allow to stand and separate, wash the organic phase with saturated sodium chloride aqueous solution (400ml), separate the organic phase, filter through diatomaceous earth, rinse with ethyl acetate (160ml), concentrate the organic phase to dryness, distill twice with 160-240ml of ethanol, concentrate to dryness, add ethanol (320ml), heat to 80℃ and reflux, stir to dissolve, slowly cool to 25℃, maintain temperature at 20-30℃ and stir for 5-7h, filter, wash with ethanol (80ml), dry the filter cake to obtain 54.15g of yellow solid, purity 99.07%, content 99%, yield 80.1%.

[0144] LCMS: MS m / z (ESI): 247.16 [M+H] +

[0145] 1 H NMR (400MHz, DMSO) δ9.14(t,1H),8.49(dd,1H),8.10(d,1H),4.06(s,3H),3.95(s,3H),2.73(qd,2H),1.35–1.14(m,3H).

[0146] Example 7 Preparation of NR6-7

[0147] At room temperature, NR6-6-Me (36.0 g, 1.0 eq) and ethanol (720 ml) were placed in a reaction flask, and CaCl2 (22.12 g, 2.0 eq) was added. Nitrogen gas was purged three times, and the mixture was stirred at room temperature for 1-3 h. NaBH4 (22.12 g, 4.0 eq) was added to the reaction flask at a controlled temperature of 20-30 °C, and the mixture was stirred at 20-25 °C for 10-20 h. The reaction was confirmed to be complete by HPLC. Methanol (72 ml) was added to the reaction flask at a controlled temperature of 25 °C. The temperature was then kept below 25 °C, and saturated NH4Cl solution (180 ml) was added. The mixture was then concentrated under reduced pressure. Add water (720 ml) and ethyl acetate (1080 ml), stir for 1 h, then allow to stand and separate the liquid. Separate the upper organic phase and extract the lower aqueous phase twice with ethyl acetate (1080 ml). Combine the organic phases, dry with anhydrous Na2SO4, then concentrate under reduced pressure. Add n-heptane (360 ml), stir at 15-25 °C for 10-15 h, filter, wash the filter cake three times with n-heptane (72 ml), and dry the filter cake under vacuum at 40-50 °C for 15-20 h to obtain 31.1 g of the title compound with a purity of 93.01%, an abundance of 75.2%, and a yield of 80% (based on purity).

[0148] 1 H NMR (400MHz, DMSO) δ8.72(d,1H),8.12–7.93(m,2H),5.00(s,1H),4.72(d,2H),4.04(s,3H),2.83–2.60(m,2H),1.25(dd,3H).

[0149] Example 8 Preparation of ADI2

[0150] At room temperature, NR6-7 (27.5 g, 1.0 eq) was placed in a reaction flask, and 275 mL of HBr in AcOH (4.0 eq) was added. The mixture was then stirred at 90 °C for 15-20 h. The reaction was confirmed by HPLC. The mixture was cooled to room temperature and kept below 50 °C. The mixture was concentrated under reduced pressure, and water (138 mL) was added. The temperature was kept below 30 °C, and 5% Na2CO3 solution (28 mL) was added to adjust the pH to 7. The mixture was stirred at 15-25 °C for 3-7 h. The mixture was filtered, and the filter cake was washed three times with water (55 mL). The filter cake was then vacuum dried at 40-50 °C for 15-20 h to obtain 31.1 g of the yellow-brown title compound, which is a single molecule of hydrobromide with a purity of 96.03%, an abundance of 75.2%, and a yield of 85%.

[0151] LCMS: MS m / z (ESI): 268.11 [M+H] +

[0152] 1H NMR (400MHz, DMSO) δ12.03(d,1H),8.52(dd,1H),7.75(d,1H),7.69(d,1H),4.85(s,2H),2.60–2.53(m,2H),1.32–1.07(m,3H).

[0153] Example 9 Preparation of ADI2-1

[0154] NR6-7 (21.80 g, 1.0 eq) and dichloromethane (218 mL) were added to the reactor, followed by triethylamine (20.40 g, 2.0 eq). Nitrogen was purged three times, and the mixture was stirred. The reactor was cooled to 0°C–5°C in an ice-water bath. Trifluoromethanesulfonic anhydride (33.84 g, 1.2 eq) was added dropwise to the reactor, maintaining the reactor temperature below 5°C. After the addition was complete, the reactor was stirred for another 30 minutes at the same temperature. The reaction was monitored by HPLC until it ended. The reaction was quenched with process water (5 mL). The organic phase was extracted with saturated sodium bicarbonate solution (200 mL), process water (200 mL), and saturated sodium chloride solution (200 mL), respectively. The organic phase was dried with sodium sulfate and concentrated to obtain 34.2 g of a white solid with a purity of 97.12%. The crude product was used directly in the next reaction step.

[0155] LCMS: MS m / z (ESI): 351.06 [M+H] +

[0156] Example 10 Preparation of ADI2-2

[0157] NR6-7 (21.83 g, 1.0 eq.) and dichloromethane (436 mL) were added to the reactor. Nitrogen was purged three times, and stirring was started. The reactor was cooled to 0–5 °C in an ice-water bath, and the reaction temperature was maintained constant. Dess-Martin reagent (50.90 g, 1.2 eq.) was added to the reaction system. After the addition was complete, nitrogen was purged three times, and the reaction continued at the same temperature for 1–2 hours. HPLC monitoring confirmed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution (218 mL), and the phases separated. The aqueous phase was extracted three times with dichloromethane (218 mL). The organic phases were combined and washed once each with saturated sodium thiosulfate solution (436 mL), process water (436 mL), and saturated brine (436 mL). After drying and vacuum concentration, 20.31 g of a white solid with a purity of 98.43% was obtained. The crude product was used directly in the next reaction step.

[0158] Example 11 Preparation of ADI5

[0159] Method 1

[0160] Acetonitrile (472 mL), ADI2-1 (31.52 g, 1.0 eq.), ADI4 (38.77 g, 1.5 eq.), and potassium iodide (5.23 g, 0.35 eq.) were added to a reactor and stirred. Simultaneously, N,N-diisopropylethylamine (123.3 g, 9.0 eq.) was added dropwise. After the addition was complete, the temperature was raised to 50–60 °C, and the reaction was allowed to proceed for 2–3 hours. The reaction was monitored by HPLC until completion. Process water (472 mL) was added dropwise to the reactor, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filter cake was collected. The filter cake was pulped with petroleum ether (315 mL), filtered, and dried to obtain ADI5 (32.5 g), with a purity of 96.52% and a content of 92.49%, resulting in a two-step yield of 78.12%.

[0161] Method 2

[0162] Dichloromethane (400 mL), ADI2 (19.44 g, 1.0 eq.), and ADI4 (31.34 g, 1.2 eq.) were added to a reactor and stirred. Sodium borohydride acetate (38.15 g, 2.0 eq.) was added, and the reaction was carried out at room temperature for 12–18 hours. After the reaction was completed by HPLC monitoring, saturated sodium bicarbonate solution (300 mL) was added to quench the reaction, and the phases separated. The aqueous phase was extracted three times with dichloromethane (150 mL), and the organic phases were combined. The organic phase was washed once with saturated brine (300 mL), dried, and concentrated under vacuum to obtain a white solid. After slurrying with petroleum ether (300 mL), the solid was filtered and dried to obtain ADI5 (33.76 g), with a purity of 93.47% and a content of 86.25%. The two-step yield was 69.74%.

[0163] LCMS: MS m / z (ESI): 418.22 [M+H] +

[0164] Example 12 Preparation of ADI6

[0165] 6M hydrochloric acid (500 mL) was added to the reactor, and ADI5 (25.00 g, 1.0 eq.) was added under stirring. The mixture was heated to reflux and reacted for 8–12 hours. The mixture was then cooled to 0°C, and the pH was adjusted to 6–7 using 20% ​​sodium hydroxide solution. The mixture was filtered, and the filter cake was collected. After drying, 20.59 g of product was obtained, with a purity of 98.33%, a content of 91.04%, and a yield of 83.91% (based on purity).

[0166] LCMS: MS m / z (ESI): 404.21 [M+H] +

Claims

1. A process for the preparation of a compound of formula I, characterized in that, comprising the step of reacting a compound of formula II in the presence of a reducing agent to obtain a compound of formula I; wherein R1is selected from C 1-8 alkyl, C 1-8 alkyl, C 1-8 alkyl, C 1-8 alkyl, C 1-8 haloalkyl or C 1-3 haloalkyl or C 1-3 haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

2. The production method according to claim 1, wherein The method also comprises a step s6) of reacting the compound of formula III in the presence of sodium methoxide to obtain the compound of formula II or further comprising the step s6') reacting the compound of formula IV with R1MgBr in the presence of a catalyst to obtain the compound of formula II Preferably, the process further comprises a step s5) of reacting the compound of formula V with R1MgBr in the presence of a catalyst to give the compound of formula II Preferably, the process further comprises a step s4) of reacting the compound of formula VI with NR6-SM in the presence of a reducing agent to give a compound of formula V'; Wherein, R2 is methyl or ethyl; Preferably, the process further comprises a step s3) of reacting the compound of formula VII in the presence of morpholine or silver nitrate to obtain the compound of formula VI; Preferably, the process further comprises a step s2) of reacting the compound of formula VIII with tribromomethane in the presence of a base to give the compound of formula VII; Preferably, the process further comprises the step s1) of reacting the compound of formula IX with sodium methoxide to obtain the compound of formula VIII; R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

3. The preparation method according to claim 1 or 2, characterized in that, In step s1), the molar ratio of compound IX to sodium methoxide is 1:1-5; preferably 1:1.

5. In step s1), the reaction solvent is methanol; In step s1), the reaction temperature is 10-40℃; preferably 20-30℃. In step s2), the base is selected from one or more of sodium alkoxide, potassium alkoxide, and lithium diisopropylamine, preferably potassium tert-butoxide or sodium tert-butoxide; In step s2), the molar ratio of compound VIII to tribromomethane is 1:1-5; preferably 1:1.

5. In step s2), the reaction solvent is selected from one or more of diethyl ether, tetrahydrofuran, and dioxane; tetrahydrofuran is preferred. In step s2), the reaction temperature is -70 to 55°C; In step s3), the reaction temperature of compound VII in the presence of silver nitrate is 60-120°C, preferably 80-100°C, more preferably 75-85°C; the solvent is an alcohol solvent; preferably one or more of methanol, ethanol, n-propanol and isopropanol; the molar ratio of compound VII to silver nitrate is 1:1-10; preferably 1:1-3. In step s3), when compound VII reacts in the presence of morpholine, a post-treatment step s3-1) is required to add hydrochloric acid to the reaction solution; In step s3-1), the reaction solvent is dichloromethane; In step s3-1), the reaction temperature is 10-40℃; preferably 20-30℃. In step s4), the molar ratio of compound VI to NR6-SM is 1:1-3; preferably 1:1-2; more preferably 1:1.2; In step s4), the reducing agent is selected from stannous chloride dihydrate; In step s4), the molar ratio of compound VI to reducing agent is 1:1-10; preferably 1:1-5; more preferably 1:4; In step s4), the reaction solvent is an alcohol solvent, preferably one or more of methanol, ethanol, n-propanol, tert-butanol and isopropanol; In step s4), the reaction temperature is 60-120℃, preferably 80-100℃, and more preferably 75-85℃; In step s5), the molar ratio of compound V to R1MgBr is 1:1-10, preferably 1:1-3, and more preferably 1:2.5; In step s5), the molar ratio of 1,3-bis(diphenylphosphine) nickel chloride to compound V is 1:100, preferably 1:50, and more preferably 1:

10. In step s5), R1MgBr can be replaced by one or more of R1B(OH)2, (R1)3B and (R1)2Zn; In step s5), the reaction solvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran and dioxane, preferably tetrahydrofuran; The reaction temperature in step s5) is 40-100℃, preferably 50-70℃, and more preferably 55-65℃; In step s6), the molar ratio of compound III to sodium methoxide is 3-1:0.5-1, preferably 1:0.5-1, and more preferably 1:0.8-1; In step s6), the reaction solvent is methanol; In step s6), the reaction temperature is 40-100℃, preferably 50-70℃, and more preferably 55-65℃; In step s6'), the catalyst is selected from one or more of zinc chloride, zinc iodide, lithium chloride, copper chloride, copper bromide, cuprous iodide, 1,3-bis(diphenylphosphine propane) nickel chloride, nickel chloride dimethoxyethane, 1,2-bis(diphenylphosphine) ethane nickel chloride and 2,2'-bipyridine nickel chloride; In step s6'), the molar ratio of compound IV to R1MgBr is 1:1-10, preferably 1:1-3, and more preferably 1:2.5; In step s6'), the molar ratio of 1,3-bis(diphenylphosphine) nickel chloride to compound IV is 1:100, preferably 1:50, and more preferably 1:

10. In step s6'), the reaction solvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran and dioxane, preferably tetrahydrofuran; The reaction temperature in step s6') is 40-100℃, preferably 50-70℃, and more preferably 55-65℃; In step s7), the reducing agent is one or more of NaBH4 / CaCl2, NaBH4 / MgCl2, NaBH4 / ZnCl2, LiAlH4, and borane; In step s7), the molar ratio of the compound of formula II to the compound of formula I is 1:1-10, preferably 1:2-5, and more preferably 1:4; In step s7), the reaction temperature is 10-45℃, preferably 20-25℃; In step s7), the reaction solvent is an alcohol solvent, preferably one or more of methanol, ethanol, n-propanol and isopropanol.

4. A process for the preparation of a compound of formula 1-1 characterized in that, comprising the step s8) reacting a compound of formula I with triflic anhydride in the presence of a base to give a compound of formula I-1 ; R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

5. The production method according to claim 4, wherein In step s8), the base is one or more of organic or inorganic bases; preferably at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, DABCO, morpholine and pyridine, more preferably triethylamine; In step s8), the molar ratio of compound I to trifluoromethanesulfonic anhydride is 1:1-5, preferably 1:3, and more preferably 1:1.

2. In step s8), the reaction solvent is DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, or dichloromethane; dichloromethane is preferred. In step s8), the reaction temperature is -10 to 10°C, preferably 0 to 5°C.

6. A process for the preparation of a compound of formula I-2, characterized by, comprising the step s8') reacting a compound of formula I with an oxidizing agent to obtain a compound of formula I-2; R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

7. The production method according to claim 6, wherein In step s8'), the molar ratio of the compound of formula I to the oxidant (such as the Des Martin reagent) is 1:1-5, preferably 1:3, more preferably 1:1.2; In step s8'), the oxidant is one or more of the following: Des Martin reagent, PCC, PDC, MnO2, and Swern oxidation. In step s8'), the reaction solvent is one or more of DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, and dichloromethane; preferably dichloromethane. In step s8'), the reaction temperature is -10 to 10°C, preferably 0 to 5°C.

8. The production method according to any one of claims 4 to 7, wherein The method further includes a method for preparing the compound of formula I as described in any one of claims 1-3.

9. A process for the preparation of a compound of formula I-3, characterized by, comprising the step s8") reacting the compound of formula I with hydrobromic acid to obtain a compound of formula I-3; R1 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkyl or C 1-8 Halogenated alkoxy group; preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

10. The production method according to claim 9, wherein In step s8), the molar ratio of compound I to hydrobromic acid is 1:1-10, preferably 1:5, more preferably 1:4; In step s8), the reaction solvent is AcOH; In step s8), the reaction temperature is 70-130℃, preferably 80-100℃, and more preferably 90℃.

11. A process for the preparation of a compound of formula I-5, characterized by, comprising the step s10) reacting a compound of formula I-4 in the presence of an acid to obtain a compound of formula I-5; Preferably, the process further comprises a step s9) of reacting the compound of formula I-1 with a compound of formula X or a salt thereof in the presence of a base and a catalyst to give a compound of formula I-4 or preferably, the method further comprises a step s9') reacting the compound of formula I-2 with a compound of formula X or a salt thereof in the presence of a reducing agent to give a compound of formula I-4 wherein R1is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkyl or C 1-8 haloalkoxy; preferably C 1-3 alkyl or C 1-3 haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl.

12. The preparation method according to claim 11, characterized in that, In step s9), the base is selected from one or more of pyridine, methylamine, ethylenediamine, diisopropylamine, DIPEA, and TEA; preferably DIPEA; In step s9), the molar ratio of the compound of formula I-1 to the base is 1:1-1:15; preferably 1:6-1:10; more preferably 1:8-1:9; In step s9), the molar ratio of compound I-1 to compound X is 1:1-5, preferably 1:1-3; more preferably 1:1.

5. In step s9), the catalyst is potassium iodide, preferably the molar ratio of potassium iodide to the compound of formula I-1 is 0.1-1:1, more preferably 0.3-0.5:1, and more preferably 0.35:1; In step s9), the solvent is a nitrile solvent, preferably one or more of acetonitrile, propionitrile, butyronitrile, phenylacetonitrile, and benzonitrile; more preferably acetonitrile. In step s9'), the reducing agent is sodium borohydride or sodium borohydride acetate, preferably sodium borohydride acetate; In step s9'), the molar ratio of compound I-2 to compound X is 1:1-5, preferably 1:1-3; more preferably 1:1.

2. In step s9'), the molar ratio of compound I-2 to reducing agent is 1:1-5, preferably 1:1-3; more preferably 1:2; In step s9'), the reaction solvent is one or more of DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, thiomethylbenzene, ethyl acetate, and dichloromethane; preferably dichloromethane. In step s9'), the reaction temperature is 10-40℃, preferably 20-30℃; In step s10), the acid is an inorganic acid, preferably hydrochloric acid; In step s10), the reaction solvent is water; In step s10), the reaction temperature is 60-120℃, preferably 80-100℃.

13. The production method according to claim 11 or 12, characterized by, The method further includes a method for preparing the compound of formula I-1 or formula I-2 as described in any one of claims 4-7.

14. A compound as shown below wherein, R1is selected from C 1-8 alkyl, C 1-8 deuteroalkyl, C 1-8 alkoxy, C 1-8 haloalkyl or C 1-8 haloalkoxy; preferably C 1-3 alkyl or C 1-3 haloalkyl; more preferably methyl, ethyl, trifluoromethyl or trifluoroethyl Preferably, the compound is selected from

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