Preparation method of PARP inhibitor and intermediate thereof

Abstract

The invention provides a synthetic method of a PARP inhibitor 6-fluoro-3-(1-isopropyl-4-methylpiperidine-4-yl)-4H-benzo [4, 5] imidazo [1, 2-b] pyrazole-8-formamide, an intermediate of the PARP inhibitor 6-fluoro-3-(1-isopropyl-4-methylpiperidine-4-yl)-4H-benzo [4, 5] imidazo [1, 2-b] pyrazole-8-formamide and a preparation method of the intermediate of the PARP inhibitor 6-fluoro-3-(1-isopropyl-4-methylpiperidine-4-yl)-4H-benzo [4, 5] imidazo [1, 2-b] pyrazole-8-formamide. And the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemical synthesis, and in particular, to a method for preparing a PARP inhibitor and an intermediate thereof. Background Art

[0002] 6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide is in the form of the free base of a novel highly active poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. PARP inhibitors are the first example of the practice of the synthetic lethality theory in clinical research. The concept of synthetic lethality was first proposed by geneticist Theodosius Dobzhansky in 1946. Based on the DNA damage response and repair system, it is a regulatory mechanism commonly present in various biological cells. The theoretical basis is that when multiple genes are mutated or damaged simultaneously, it will cause a more comprehensive blockage of the DNA damage response and repair process, resulting in the accumulation of DNA damage and triggering apoptosis. It is a new direction for the development of anti-tumor drugs since the molecular targeted therapy. The specific structure of 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide is as follows:

[0003]

[0004] Patent document CN104974161A reported a method for preparing a 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide compound. The reaction route is as follows:

[0005]

[0006] The following are the deficiencies of this preparation method: 1) The preparation route of this method is relatively long, the reaction cycle is long, and the operation is cumbersome. Although only 6 steps are shown in this route, in the actual preparation process, there are 4 actual operation steps from the preparation of A1 to A2, 2 actual operation steps from the preparation of A3 to A4, and 2 actual operation steps from A4 to A5. The actual total number of steps for the whole route is 11 steps; 2) In the process from A1 to A2, for the first step of introducing a methyl group with Grignard reagent and the fourth step of deprotonating with LDA to introduce a formyl group, the temperature also needs to be lowered to -70 °C, which requires relatively high requirements for the equipment in large-scale industrial production and results in high costs; 3) During the process from A3 to A4, dimethylamine will be decomposed, and the reaction between dimethylamine and the substrate will generate impurities, which requires column separation; during the process from A4 to A5, the secondary amine on the five-membered ring of the substrate will be oxidized to generate degradation impurities, increasing the separation difficulty; 4) During the production process from A5 to I, it is a strong acidic environment, and sodium cyanoborohydride is used, which has the risk of generating highly toxic hydrogen cyanide gas, and the safety is relatively low.

[0007] Patent document CN108137598B also reports another preparation method of 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide, and the reaction route is as follows:

[0008]

[0009] This type of preparation method also has deficiencies: 1) The preparation route of this method is also relatively long, and the actual total number of steps for the whole route is 10 steps; 2) For the second reaction, the temperature needs to be lowered to -50 °C to -40 °C multiple times, and for the fifth reaction, the temperature needs to be lowered to -60 °C. After rising to room temperature, the post-treatment still requires the temperature to be lowered to -30 °C to -20 °C, which requires relatively high requirements for the equipment in large-scale industrial production and the operation is cumbersome; 3) The total yield of this route is about 15.7%, and the material cost is relatively high.

[0010] Therefore, there is an urgent need to provide an improved preparation method to facilitate the preparation of 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide in a simpler, more efficient, more economical and / or safer manner, thereby facilitating large-scale production. Summary of the Invention

[0011] The object of the present invention is to provide a synthesis method of 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide, its intermediate and the preparation method of the intermediate, and the method has higher synthesis efficiency, simple process, low synthesis cost and is suitable for large-scale industrial production.

[0012] In the first aspect of the present invention, there is provided a method for preparing a compound of formula I, which is characterized by comprising the following steps: in a solvent, the compound of formula II undergoes a carbonylation coupling reaction as shown below in the presence of a metal catalyst, a ligand, a base, carbon monoxide and an ammonia source to obtain the compound of formula I;

[0013]

[0014] wherein X is a halogen;

[0015] The ammonia source is selected from bis(trimethylsilyl)amine (HMDS) and / or formamide.

[0016] In one embodiment of the present invention, in the carbonylation coupling reaction, the solvent is one or more of aprotic polar solvents, and the aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide and N,N-dimethylacetamide; the aprotic polar solvent is more preferably N,N-dimethylacetamide.

[0017] In one embodiment of the present invention, in the carbonylation coupling reaction, the metal catalyst is selected from palladium metal catalysts, platinum metal catalysts and / or copper metal catalysts. The palladium metal catalyst is preferably tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), dibenzylideneacetone palladium (Pd(dba) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium dichloride, dichloro-bis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)), bis(tris(o-tolyl)phosphine)dichloropalladium, 1,2-bis(diphenylphosphino)ethane dichloropalladium, etc.; the platinum metal catalyst is preferably platinum dioxide; the copper metal catalyst is preferably one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper, cuprous oxide; the catalyst is more preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)).

[0018] In one embodiment of the present invention, in the carbonylation coupling reaction, the ligand is selected from a phosphine-containing ligand coordinated with a palladium metal catalyst and / or a nitrogen-containing ligand coordinated with a copper metal catalyst. The phosphine-containing ligand coordinated with the palladium metal catalyst is preferably Xantphos, Sphos, Xphos, Ruphos, Brettphos; the nitrogen-containing ligand coordinated with the copper metal catalyst is preferably 1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, 1,10-phenanthroline; the ligand is more preferably Xantphos.

[0019] In one embodiment of the present invention, in the carbonylation coupling reaction, the base is selected from alkali metal bases, alkaline earth metal bases, organic bases and / or organometallic bases. The alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate; the alkaline earth metal base is preferably sodium hydride, potassium hydride, calcium hydride; the organic base is preferably triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the organometallic base is preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, aluminum isopropoxide; the base is more preferably triethylamine, N,N-diisopropylethylamine.

[0020] In one embodiment of the present invention, the reaction temperature of the carbonylation coupling reaction is 70 °C to 120 °C, preferably 90 °C to 105 °C.

[0021] In one embodiment of the present invention, in the carbonylation coupling reaction, the pressure of carbon monoxide is 0.2 to 2.0 MPa, preferably 0.5 to 0.6 MPa.

[0022] In one embodiment of the present invention, the reaction time of the carbonylation coupling reaction is 12 to 48 h, preferably 27 h.

[0023] In one embodiment of the present invention, in the carbonylation coupling reaction, the reaction vessel is preferably an autoclave.

[0024] In one embodiment of the present invention, the method for preparing the compound of formula I further comprises the following steps:

[0025] and / or and / or and / or and / or and / or

[0026] Wherein, X is a halogen;

[0027] R 1 is selected from C1-5 Alkyl

[0028] In one embodiment of the present invention, the method for preparing the compound of formula I further comprises the following steps:

[0029] and / or and / or and / or and / or and / or

[0030] In one embodiment of the present invention, the method for preparing the compound of formula II comprises the following steps: In a solvent, the compound of formula III undergoes a ring-closing reaction as shown below in the presence of a palladium metal catalyst, a ligand, a base, and an inert gas to obtain the compound of formula II;

[0031]

[0032] wherein X is a halogen.

[0033] In one embodiment of the present invention, in the ring-closing reaction, the solvent is selected from one or more of ether solvents, alcohol solvents, aromatic hydrocarbon solvents, and aprotic polar solvents; the ether solvents are preferably one or two of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; the alcohol solvents are preferably ethanol and tert-butanol; the aromatic hydrocarbon solvents are preferably toluene and xylene; the aprotic polar solvents are preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the solvent is more preferably N,N-dimethylacetamide.

[0034] In one embodiment of the present invention, in the ring-closing reaction, the palladium metal catalyst is preferably tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), dibenzylideneacetone palladium (Pd(dba) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium dichloride, dichloro-bis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)), bis(tri-o-tolylphosphine)dichloropalladium, 1,2-bis(diphenylphosphino)ethane dichloropalladium; the palladium metal catalyst is more preferably Pd 2 (dba) 3 .

[0035] In one embodiment of the present invention, in the ring - closing reaction, the ligand is preferably a phosphine - containing ligand coordinated with a palladium metal catalyst; preferably, the phosphine - containing ligand coordinated with the palladium metal catalyst is Xantphos, Sphos, Xphos, Ruphos, Brettphos; most preferably, the phosphine - containing ligand coordinated with the palladium metal catalyst is Xantphos.

[0036] In one embodiment of the present invention, in the ring - closing reaction, the base is selected from alkali metal bases, alkaline earth metal bases, organic bases and / or organometallic bases. The alkali metal bases are preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate; the alkaline earth metal bases are preferably sodium hydride, potassium hydride, calcium hydride; the organic bases are preferably triethylamine, N,N - diisopropylethylamine, 4 - methylmorpholine, 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU); the organometallic bases are preferably sodium methoxide, sodium ethoxide, sodium tert - butoxide, lithium tert - butoxide, potassium tert - butoxide, aluminum isopropoxide; the base is more preferably cesium carbonate.

[0037] In one embodiment of the present invention, the reaction temperature of the ring - closing reaction is 80°C to 140°C, preferably 115°C to 125°C.

[0038] In one embodiment of the present invention, the reaction time of the ring - closing reaction is 2 - 12 h, preferably 7 h.

[0039] In one embodiment of the present invention, in the ring - closing reaction, the inert gas is selected from nitrogen, helium, neon, argon; the inert gas is preferably nitrogen.

[0040] In one embodiment of the present invention, the preparation method of the compound of formula III comprises the following steps: in a solvent, the compound of formula IV or its salt and the compound of formula V are subjected to the following - shown cyclization reaction in the presence of a base to obtain the compound of formula III;

[0041]

[0042] wherein, X is a halogen.

[0043] In one embodiment of the present invention, in the cyclization reaction, the solvent is preferably an alcohol solvent, more preferably ethanol.

[0044] In one embodiment of the present invention, in the cyclization reaction, after adding the compound of formula V, the reaction system needs to be adjusted to acidic conditions with an acid, and then the compound of formula IV or its salt is added. The acidic conditions are preferably pH = 5 - 6.

[0045] In one embodiment of the present invention, in the cyclization reaction, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, triethylamine, N,N - diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert - butoxide, lithium tert - butoxide, potassium tert - butoxide; the base is preferably sodium bicarbonate.

[0046] In one embodiment of the present invention, in the cyclization reaction, the acid preferably used when adjusting the reaction system to acidic is hydrochloric acid, hydrochloric acid - methanol, hydrochloric acid - ethanol; the acid more preferably used when adjusting the reaction system to acidic is hydrochloric acid - ethanol.

[0047] In one embodiment of the present invention, in the cyclization reaction, the compound of formula IV or its salt is preferably the compound of formula IV, the hydrochloride salt of the compound of formula IV.

[0048] In one embodiment of the present invention, the reaction temperature of the cyclization reaction is 10°C to 90°C, preferably 75°C to 85°C.

[0049] In one embodiment of the present invention, the reaction time of the cyclization reaction is 2 to 10 hours, preferably 7 hours.

[0050] In one embodiment of the present invention, the preparation method of the compound of formula III comprises the following operation steps: in the solvent, the compound of formula V is dissolved to obtain reaction solution 1, reaction solution 1 is adjusted with an acid to obtain reaction solution 2, the compound of formula IV or its salt is added to reaction solution 2 to obtain reaction solution 3, and a base is added to reaction solution 3 to obtain the compound of formula III.

[0051] In one embodiment of the present invention, the preparation method of the compound of formula III comprises the following operation steps: in the solvent, the compound of formula V is dissolved to obtain reaction solution 1, reaction solution 1 is adjusted to pH 5 - 6 with an acid to obtain reaction solution 2, the compound of formula IV or its salt is added to reaction solution 2 and stirred for 1 - 3 h to obtain reaction solution 3, a base is added to reaction solution 3, and the temperature is raised to 75°C - 85°C and reacted for 1 - 6 h to obtain the compound of formula III.

[0052] In one embodiment of the present invention, the preparation method of the compound of formula V comprises the following steps: in a solvent, the compound of formula VI and ethyl formate carry out the substitution reaction shown below in the presence of a base to obtain the compound of formula V;

[0053]

[0054] In one embodiment of the present invention, in the substitution reaction, the solvent is preferably an ether solvent, more preferably anhydrous tetrahydrofuran.

[0055] In one embodiment of the present invention, in the substitution reaction, the base is preferably LDA, n-BuLi, s-BuLi, NaH, LiHMDS, KHMDS; more preferably, the base is LDA.

[0056] In one embodiment of the present invention, the reaction temperature of the substitution reaction is -10°C to 30°C, preferably -10°C.

[0057] In one embodiment of the present invention, in the substitution reaction, a continuous flow reactor is used for the substitution reaction.

[0058] In one embodiment of the present invention, the method for preparing the compound of formula V comprises the following operating steps: in the solvent, the compound of formula VI is dissolved to obtain reaction solution 1, the base is reaction solution 2, ethyl formate is dissolved in the solvent to obtain reaction solution 3, reaction solution 1 is injected into the continuous flow reactor through the continuous flow pump 1, reaction solution 2 is injected into the continuous flow reactor through the continuous flow pump 2, reaction solution 3 is injected into the continuous flow reactor through the continuous flow pump 3, and the reaction temperature of the reactor is controlled to obtain the compound of formula V.

[0059] In one embodiment of the present invention, the method for preparing the compound of formula VI comprises the following steps: in the solvent, the compound of formula VII and the alkali metal halide undergo the decarboxylation reaction shown below to obtain the compound of formula VI;

[0060]

[0061] wherein, R 1 is selected from C 1-5 alkyl.

[0062] In one embodiment of the present invention, in the decarboxylation reaction, the solvent is one or more of an aprotic polar solvent, an ether solvent, an aromatic hydrocarbon solvent, and a mixed solvent of an organic solvent and water. The aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the ether solvent is preferably one or two of tetrahydrofuran and 2-methyltetrahydrofuran; the aromatic hydrocarbon solvent is preferably toluene; more preferably, the solvent is a mixed solvent of dimethyl sulfoxide and water.

[0063] In one embodiment of the present invention, in the decarboxylation reaction, the alkali metal halide is preferably LiCl, LiI, NaCl, NaBr; more preferably, the alkali metal halide is LiCl.

[0064] In one embodiment of the present invention, the reaction temperature of the decarboxylation reaction is 100°C to 180°C, preferably 120°C to 125°C.

[0065] In one embodiment of the present invention, the reaction time of the decarboxylation reaction is 2 to 24 h, preferably 12 h.

[0066] In one embodiment of the present invention, the method for preparing the compound of formula VII comprises the following steps: in a solvent, the compound of formula VIII, a Grignard reagent, and a copper catalyst are subjected to the following coupling reaction under an inert gas atmosphere to obtain the compound of formula VII;

[0067]

[0068] wherein, R 1 is selected from C 1-5 alkyl.

[0069] In one embodiment of the present invention, in the coupling reaction, the solvent is one or more of an aprotic polar solvent, an ether solvent, and an aromatic hydrocarbon solvent. The aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the ether solvent is preferably one or two of tetrahydrofuran and 2-methyltetrahydrofuran; the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably tetrahydrofuran.

[0070] In one embodiment of the present invention, in the coupling reaction, the Grignard reagent is preferably MeMgBr.

[0071] In one embodiment of the present invention, in the coupling reaction, the copper metal catalyst is preferably one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper, and cuprous oxide; the copper metal catalyst is more preferably cuprous iodide.

[0072] In one embodiment of the present invention, the reaction temperature of the coupling reaction is 0 °C to 20 °C, preferably 10 °C to 20 °C.

[0073] In one embodiment of the present invention, the inert gas in the coupling reaction is preferably nitrogen.

[0074] In one embodiment of the present invention, in the coupling reaction, the method for preparing the compound of formula VII comprises the following operating steps: in the solvent, the copper catalyst is slowly added dropwise with the Grignard reagent under an inert gas atmosphere to obtain reaction solution 1, the compound of formula VIII is dissolved in the solvent to obtain reaction solution 2, and reaction solution 2 is slowly added dropwise to reaction solution 1 to obtain the compound of formula VII.

[0075] In a certain embodiment of the present invention, in the coupling reaction, the preparation method of the compound of formula VII includes the following operating steps: in the solvent, cuprous iodide is slowly added dropwise with MeMgBr under an inert gas atmosphere, and stirred for 0.5 h to 2 h to obtain reaction solution 1. The compound of formula VIII is dissolved in the solvent to obtain reaction solution 2, and reaction solution 2 is slowly added dropwise to reaction solution 1 to obtain the compound of formula VII.

[0076] In a certain embodiment of the present invention, the preparation method of the compound of formula VIII includes the following steps: in the solvent, the compound of formula X and the compound of formula IX carry out the addition dehydration reaction as shown below to obtain the compound of formula VIII;

[0077]

[0078] wherein, R 1 is selected from C 1-5 alkyl.

[0079] In a certain embodiment of the present invention, in the addition dehydration reaction, the solvent is one or more of protic solvents; the protic solvent is preferably one or more of acetic acid, sulfuric acid, polyphosphoric acid and trifluoroacetic acid; the solvent is more preferably acetic acid.

[0080] In a certain embodiment of the present invention, the reaction temperature of the addition dehydration reaction is 0 °C to 40 °C, preferably 25 °C to 30 °C.

[0081] In a certain embodiment of the present invention, the preparation method of the compound of formula I further includes the following steps:

[0082] and / or;

[0083]

[0084] and / or; and / or;

[0085] and / or; and / or;

[0086]

[0087] wherein, X is a halogen;

[0088] R 1 is selected from C 1-5 alkyl;

[0089] The parameters and conditions in the preparation method of the compound of formula I are as described in the first aspect of the present invention.

[0090] In one embodiment of the present invention, X is selected from halogens.

[0091] In one embodiment of the present invention, X is selected from bromine and chlorine.

[0092] In one embodiment of the present invention, R1 is selected from C 1-5 alkyl.

[0093] In one embodiment of the present invention, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0094] In one embodiment of the present invention, the method for preparing the compound of formula I further comprises the following steps:

[0095] and / or; and / or; and / or; and / or; and / or;

[0096]

[0097] The parameters and conditions in the method for preparing the compound of formula I are as described in the first aspect of the present invention.

[0098] The present invention also provides the compound of formula II-1, the compound of formula III-1, the compound of formula V, the compound of formula VI, or the compound of formula VII-1 as shown below:

[0099]

[0100] The present invention also provides the use of the compound of formula II-1, the compound of formula III-1, the compound of formula V, the compound of formula VI, or the compound of formula VII-1 as described above in the preparation of the compound of formula I.

[0101] Terms and Definitions

[0102] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention.

[0103] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope recorded in the specification of this application.

[0104] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by those skilled in the art to which the claimed subject matter pertains. All patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference unless otherwise indicated. If there are multiple definitions of a term herein, the definitions in this chapter shall prevail.

[0105] It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention. In this application, the singular form also includes the plural unless specifically stated otherwise. It must be noted that, unless clearly stated otherwise in the text, the singular forms used in this specification and the claims include the plural forms of the indicated items. It should also be noted that, unless otherwise indicated, the terms "or" and "or" mean "and / or". In addition, the term "comprising" and other forms, such as "including", "containing", and "having" are not restrictive.

[0106] Definitions of standard chemical terms can be found in references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless otherwise specifically defined, the terms used in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions provided by the manufacturer for a kit can be utilized, or reactions and purifications can be carried out in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in accordance with conventional methods well known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0107] The chapter headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals of operations, and theses, are incorporated herein by reference in their entirety.

[0108] Except as aforesaid, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings set forth below.

[0109] In the present application, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use in patients) acid. The pharmaceutically acceptable acids include inorganic acids and organic acids. For details, reference can be made to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0110] In the present application, the error of the reaction temperature during the synthesis process is ±10 °C.

[0111] In the present application, the error of the reaction time during the synthesis process is ±1 h.

[0112] In the present application, the error of the reaction pressure during the synthesis process is ±0.2 MPa.

[0113] The compounds provided herein, including the intermediates that can be used to prepare the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include their protected derivatives. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, etc., as well as isotopes, etc. Suitable protecting groups for amino and amido groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for hydroxyl groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.

[0114] For the reactions in each step, the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc. After the reaction in each step is completed, the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Without affecting the next reaction, the target compound can also directly enter the next reaction without separation and purification.

[0115] Based on the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0116] The reagents and raw materials used in the present invention are all commercially available.

[0117] The positive and progressive effects of the present invention are as follows. The present application provides a preparation method of a PARP inhibitor 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide that is completely different from the prior art. In the preparation method, the piperidine is not protected by an amino protecting group, and there is no need to remove the amino protecting group. The reaction steps are shortened to 7 steps, and the total yield is increased to 30.5%. The synthesis efficiency is higher and the material cost is lower. In the step of preparing the compound of formula V from the compound of formula VI, a continuous flow reactor is used, which solves the problems of high equipment requirements, high energy consumption and potential safety risks in the amplification process, and has significant economic benefits. The post-treatment of the reaction does not require cumbersome process steps such as column chromatography for separation, and has one or more advantages such as simpler operation, strong practicability, and the ability to achieve large-scale and industrial production. Detailed implementation manners

[0118] The following further illustrates the present invention with specific examples. It should be understood that the following description is only the most preferred implementation manner of the present invention and should not be considered as a limitation on the protection scope of the present invention. On the basis of fully understanding the present invention, for the experimental methods without specific conditions noted in the following examples, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be regarded as being included in the protection scope of the present invention.

[0119] The present application has the following definitions:

[0120] Symbol or unit:

[0121] M: mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) represents an n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L.

[0122] Reagent:

[0123] HMDS: bis(trimethylsilyl)amine

[0124] Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium

[0125] Pd(dba) 2 : dibenzylideneacetone palladium(II)

[0126] Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium

[0127] PdCl 2(dppf): Dichloropalladium(II) bis(1,1'-bis(diphenylphosphino)ferrocene)

[0128] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0129] Sphos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

[0130] Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0131] Ruphos: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0132] Brettphos: 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl

[0133] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0134] LDA: Lithium diisopropylamide

[0135] n-BuLi: n-Butyllithium

[0136] s-BuLi: sec-Butyllithium

[0137] NaH: Sodium hydride

[0138] LiHMDS: Lithium bis(trimethylsilyl)amide

[0139] KHMDS: Potassium bis(trimethylsilyl)amide

[0140] LiCl: Lithium chloride

[0141] MeMgBr: Methylmagnesium bromide

[0142] THF: Tetrahydrofuran

[0143] CuI: Copper(I) iodide

[0144] DMA: N,N-Dimethylacetamide

[0145] DMSO: Dimethyl sulfoxide

[0146] Test method:

[0147] LCMS: Liquid chromatography–mass spectrometry

[0148] Example 1: Synthesis of 6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

[0149]

[0150] Step 1: Preparation of Ethyl 2-cyano-2-(1-isopropylpiperidin-4-yl)acetate

[0151]

[0152] Add N-isopropyl-4-piperidone (42.00 kg), ethyl cyanoacetate (33.60 kg), and acetic acid (1.0 kg) into the reaction kettle in sequence, and stir at 25 - 30 °C for 1 h. After the reaction is complete, dilute with dichloromethane (280.00 kg), and wash the organic phase twice with 3% potassium carbonate (80 L) and saturated brine (40 L) respectively. Collect the organic phase and concentrate to obtain 72.00 kg of crude product. Yield: 102.4%.

[0153] 1 H NMR(400MHz,CDCl 3 )δ4.29 - 4.15(m,2H),3.14 - 3.04(m,2H),2.81 - 2.72(m,3H),2.69 - 2.63(s,2H),2.59(t,J = 5.8Hz,2H),2.44 - 2.36(m,1H),1.37 - 1.25(m,3H),1.01(dd,J = 12.7,6.6Hz,6H)

[0154] LCMS[M+H] + :237.2

[0155] Step 2: Preparation of Ethyl 2-cyano-2-(1-isopropyl-4-methylpiperidin-4-yl)acetate

[0156]

[0157] Under nitrogen protection, add THF (400.00 kg) and CuI (90.00 kg) into the reaction kettle. Cool the reaction solution to 0 - 10 °C, and slowly add MeMgBr (326.00 kg, 3 M) dropwise to the reaction solution. After the addition is complete, stir for 1 h. Then, add a solution of ethyl 2-cyano-2-(1-isopropylpiperidin-4-yl)acetate (80.00 kg) in THF (142.00 kg) dropwise into the reaction system at 0 - 10 °C. After the addition is complete, heat up to 10 - 20 °C and stir for 1 h. After the reaction is complete, at 0 - 10 °C, drop the reaction solution into a saturated ammonium chloride (1125 L) solution, filter with diatomaceous earth (75 kg), wash the filter residue with ethyl acetate (180.00 kg), extract the filtrate three times with ethyl acetate (100.00 kg), combine the organic phases, wash twice with saturated brine (150 L), concentrate and dry to obtain 68.00 kg of ethyl 2-cyano-2-(1-isopropyl-4-methylpiperidin-4-yl)acetate. Yield: 91.6%.

[0158] 1 H NMR(400MHz,CDCl 3 )δ4.30-4.17(m,3H),3.45(d,J=9.1Hz,1H),2.80-2.66(m,2H),2.66-2.55(m,2H),2.53-2.39(m,2H),1.78(ddd,J=13.2,8.2,3.4Hz,2H),1.69(dddd,J=13.5,5.6,3.4,1.9Hz,1H),1.61-1.51(m,1H),1.32-1.26(m,3H),1.13(s,3H),1.03(t,J=5.4Hz,6H)

[0159] LCMS[M+H] + :253.2

[0160] Step 3: Preparation of (1-isopropyl-4-methylpiperidin-4-yl)acetonitrile

[0161]

[0162] Ethyl 2-cyano-2-(1-isopropyl-4-methylpiperidin-4-yl)acetate (130.00 kg), DMSO (395.00 kg), LiCl (26.00 kg), and water (30.00 kg) were successively added to the reaction kettle, and the temperature was raised to 120 - 125 °C and stirred for 12 h. After the reaction was complete, the temperature was lowered to below 40 °C, and the reaction solution was slowly added to a mixed solution of water (750.00 kg) and acetic acid (26.00 kg). After stirring for 0.5 h, it was allowed to stand for 30 minutes, and then liquid separation was carried out. The aqueous layer was extracted with ethyl acetate (130.00 kg), and after liquid separation, the organic phase was discarded. The aqueous layer was then adjusted to pH 9 - 10 by adding solid potassium carbonate (65.00 kg), and then the aqueous phase was extracted three times with ethyl acetate (130.00 kg). The organic layers were combined, washed once with drinking water (130.00 kg) and once with saturated brine (130.00 kg). The organic layers were combined, concentrated and dried to obtain (1-isopropyl-4-methylpiperidin-4-yl)acetonitrile (60.10 kg). Yield: 65.0%.

[0163] 1 H NMR(400MHz,CDCl 3 )δ2.69(dt,J=13.1,6.6Hz,1H),2.52 - 2.41(m,4h),2.27(s,2H),1.56(dd,J=6.7,4.6Hz,4H),1.10(s,3H),1.03(d,J=6.5Hz,6H)

[0164] LCMS[M+H] + :181.2

[0165] Step 4: Preparation of 2-formyl-2-(1-isopropyl-4-methylpiperidin-4-yl)acetonitrile

[0166]

[0167] (1-Isopropyl-4-methylpiperidin-4-yl)acetonitrile (7.00 kg) was dissolved in anhydrous THF (14 L), denoted as Solution 1; the LDA (33 L, 2 M) solution was denoted as Solution 2; the anhydrous THF (6.03 L) solution of ethyl formate (6.03 kg) was denoted as Solution 3. Solution 1 was injected into the continuous flow reactor through the continuous flow pump 1; Solution 2 was injected into the continuous flow reactor through the continuous flow pump 2; Solution 3 was injected into the continuous flow reactor through the continuous flow pump 3; the reaction temperature of the reactor was controlled at about -10 °C for the reaction. The specific data is as follows:

[0168] Pump 1 (mL / min) Pump 2 (mL / min) Pump 3 (mL / min) Flow rate 40 62 11.2

[0169] Collect the liquid flowing out of the continuous flow reactor. At 10 - 20 °C, add water (1.44 kg) to the reaction solution to quench the reaction, and the reaction system becomes clear. Concentrate the reaction solution at about 20 °C to remove about 2 / 3 of its volume, then add n - heptane (70 L) and stir for 1 h. Filter to obtain the wet product, and dry it at 45 - 50 °C for 2 h to obtain 13.70 kg of 2 - formyl - 2 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl)acetonitrile.

[0170] 1 H NMR(400MHz,D 2 O)δ7.79(s,1H),3.76(t,J=6.7Hz,1H),2.78 - 2.72(m,1H),2.69(d,J=15.9Hz,2H),2.55(d,J=9.9Hz,2H),1.84(d,J=14.6Hz,2H),1.60 - 1.51(m,2H),1.11(s,3H),1.08(t,J=5.2Hz,6H)

[0171] LCMS[M + H] + :209.2

[0172] Step 5: Preparation of 2 - (2,6 - dibromo - 4 - fluorophenyl) - 4 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl)pyrazol - 3 - amine

[0173]

[0174] At 10 - 20 °C, add ethanol (3.90 kg) and 2 - formyl - 2 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl)acetonitrile (1.00 kg) to the reaction kettle, adjust the pH to 5 - 6 with hydrochloric acid ethanol. Within 0.5 h, add 2,6 - dibromo - 4 - fluorophenylhydrazine hydrochloride (1.076 kg) to the reaction system, and react the reaction solution at 10 - 20 °C for 1 h. Then add sodium bicarbonate (1.20 kg) to the reaction solution, raise the temperature to 75 - 85 °C, and react for 6 h. After the reaction is completed, concentrate and dry the reaction solution under reduced pressure at 40 - 50 °C. Add ethyl acetate (7.20 kg) and 10% potassium carbonate solution (11.88 kg) to the obtained residue, stir for 30 minutes, and filter. The filtrate is separated into layers, and the lower aqueous phase is extracted three times with ethyl acetate (3.60 kg). Combine the organic phases, wash with water (2.00 kg) once, collect the organic phase, concentrate and dry it under reduced pressure at 40 - 50 °C. Stir the residue in the kettle with ethyl acetate (0.35 kg) and n - heptane (4.00 kg) at 20 - 30 °C for 1 - 2 h, filter, and dry to obtain 1.25 kg of 2 - (2,6 - dibromo - 4 - fluorophenyl) - 4 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl)pyrazol - 3 - amine. The total yield of the two - step reaction is 91.3%.

[0175] 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.43 (d, J = 1.4 Hz, 2H), 3.45 (s, 3H), 2.72 - 2.65 (m, 1H), 2.65 - 2.56 (m, 2H), 2.56 - 2.48 (m, 2H), 2.23 - 2.08 (m, 2H), 1.76 - 1.61 (m, 2H), 1.03 (t, J = 5.6 Hz, 6H)

[0176] LCMS [M + H] + : 473.0

[0177] Step 6: Preparation of 8 - bromo - 6 - fluoro - 3 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl) - 4H - benzo[4,5]imidazo[1,2 - b]pyrazole

[0178]

[0179] Charge DMA (5.60 kg) into the reaction kettle, and successively add 2 - (2,6 - dibromo - 4 - fluorophenyl) - 4 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl)pyrazol - 3 - amine (1.00 kg), cesium carbonate (2.06 kg), Pd 2 (dba) 3 (0.05 kg), XantPhos (0.10 kg), displace with nitrogen 3 times, heat to an internal temperature of 115 - 125 °C, and stir for 7 h. After the reaction is completed, cool down to 20 - 30 °C. Filter the reaction solution and collect the filtrate directly for the next step of the reaction.

[0180] 1H NMR (400 MHz, DMSO) δ 7.63 (s, 1H), 7.28 (dd, J = 9.4, 2.3 Hz, 1H), 7.21 (dd, J = 9.0, 2.3 Hz, 1H), 2.62 (s, 1H), 2.55 (s, 2H), 2.34 (s, 2H), 1.71 - 1.59 (m, 2H), 1.23 (s, 3H), 0.92 (d, J = 6.5 Hz, 6H)

[0181] LCMS [M + H] + : 393.1

[0182] Step 7: Preparation of 6 - fluoro - 3 - (1 - isopropyl - 4 - methylpiperidin - 4 - yl) - 4H - benzo[4,5]imidazo[1,2 - b]pyrazole - 8 - carboxamide

[0183]

[0184] The DMA solution of 8-bromo-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole was added to an autoclave, and HMDS (1.09 kg), N,N-diisopropylethylamine (0.56 kg), Pd(dppf)Cl 2 (0.005 kg), XantPhos (0.01 kg) were added in sequence. After purging with nitrogen three times, CO (0.5 - 0.6 MPa) was introduced, the temperature was raised to 95 - 105 °C, and the mixture was stirred for 27 h. After the reaction solution was cooled to 20 - 30 °C, it was filtered, the filter residue was washed with ethyl acetate (1.00 kg), the organic phase was collected, and at 0 - 10 °C, purified water (6.00 kg) was added and stirred for 1 h to precipitate a solid, and the crude product 1 wet product was obtained by filtration. Ethyl acetate (3.00 kg) was added to the crude product 1 wet product, and the mixture was stirred at 20 - 30 °C for 0.5 h, and the crude product 2 wet product was obtained by filtration. Then the crude product 2 wet product was slurried with ethanol (3.16 kg) for 0.5 h, the crude product 3 wet product was collected, and dried at 75 - 85 °C for 2 - 3 h to obtain 0.41 kg of 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide. The total yield of the two steps was 55.0%.

[0185] 1 H NMR (400 MHz, DMSO) δ 10.60 (s, 2H), 8.08 (s, 1H), 7.76 (s, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.49 - 7.33 (m, 1H), 2.60 (dd, J = 21.5, 15.2 Hz, 3H), 2.35 (s, 2H), 2.08 (s, 2H), 1.75 - 1.59 (m, 2H), 1.26 (s, 3H), 0.92 (d, J = 6.4 Hz, 6H)

[0186] LCMS [M+H] + : 486.1

[0187] The compounds described in the present invention can be prepared by the synthetic methods described above, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the present invention rather than limit the scope of its subject matter and the compounds claimed for these examples.

Claims

1. A method for preparing a compound of formula I, characterized in that, it comprises the following steps: in a solvent, the compound of formula II undergoes a carbonylation coupling reaction as shown below in the presence of a metal catalyst, a ligand, a base, carbon monoxide and an ammonia source to obtain the compound of formula I; wherein X is a halogen; the ammonia source is selected from bis(trimethylsilyl)amine (HMDS) and / or formamide.

2. The preparation method according to claim 1, characterized in that, it satisfies one or more of the following conditions: 1) In the carbonylation coupling reaction, the solvent is one or more of aprotic polar solvents, and the aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide and N,N-dimethylacetamide; the aprotic polar solvent is more preferably N,N-dimethylacetamide; 2) In the carbonylation coupling reaction, the metal catalyst is selected from palladium metal catalysts, platinum metal catalysts, and / or copper metal catalysts. The palladium metal catalyst is preferably tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), bis(dibenzylideneacetone)palladium (Pd(dba) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 )) 4 ), palladium acetate, palladium dichloride, dichloro-bis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (PdCl 2 (dppf)), bis(tri-o-tolylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane dichloride, or one or more thereof; the platinum metal catalyst is preferably platinum dioxide; the copper metal catalyst is preferably cuprous iodide, cuprous bromide, cuprous chloride, copper, cuprous oxide, or one or more thereof; the catalyst is more preferably dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (PdCl 2 (dppf)); 3) In the carbonylation coupling reaction, the ligand is selected from a phosphine-containing ligand coordinated with a palladium metal catalyst and / or a nitrogen-containing ligand coordinated with a copper metal catalyst. The phosphine-containing ligand coordinated with the palladium metal catalyst is preferably Xantphos, Sphos, Xphos, Ruphos, Brettphos; the nitrogen-containing ligand coordinated with the copper metal catalyst is preferably 1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, 1,10-phenanthroline; the ligand is more preferably Xantphos; 4) In the carbonylation coupling reaction, the base is selected from alkali metal bases, alkaline earth metal bases, organic bases and / or organometallic bases. The alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate; the alkaline earth metal base is preferably sodium hydride, potassium hydride, calcium hydride; the organic base is preferably triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the organometallic base is preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, aluminum isopropoxide; the base is more preferably triethylamine, N,N-diisopropylethylamine; 5) In the carbonylation coupling reaction, the reaction temperature is 70°C to 120°C, preferably 90°C to 105°C; 6) In the carbonylation coupling reaction, the pressure of carbon monoxide is 0.2 to 2.0 MPa, preferably 0.5 to 0.6 MPa; 7) In the carbonylation coupling reaction, the reaction time is 12 to 48 h, preferably 27 h; 8) The carbonylation coupling reaction vessel is preferably an autoclave.

3. The preparation method according to claim 1, characterized in that, it comprises the following steps: and / or and / or and / or and / or and / or wherein X is a halogen; R 1 selected from C 1-5 alkyl group.

4. The preparation method according to claim 3, characterized in that, it comprises the following steps: and / or and / or and / or and / or and / or 5. The preparation method according to claim 3, characterized in that, it comprises the following steps: in a solvent, the compound of formula III undergoes a ring-closing reaction as shown below in the presence of a palladium metal catalyst, a ligand, a base and an inert gas to obtain the compound of formula II; wherein X is a halogen, preferably bromine or chlorine; Preferably, the preparation method of the compound of formula II satisfies one or more of the following conditions: 1) In the ring-closing reaction, the solvent is selected from one or more of ether solvents, alcohol solvents, aromatic hydrocarbon solvents, and aprotic polar solvents; the ether solvents are preferably one or two of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; the alcohol solvents are preferably ethanol and tert-butanol; the aromatic hydrocarbon solvents are preferably toluene and xylene; the aprotic polar solvents are preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the solvent is more preferably N,N-dimethylacetamide; 2) In the said ring-closing reaction, the palladium metal catalyst is preferably tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), dibenzylideneacetone palladium (Pd(dba) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 )) 4 ), palladium acetate, palladium dichloride, dichloro-bis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (PdCl 2 (dppf)), bis(tris(o-tolyl)phosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane dichloride, or one or more thereof; the palladium metal catalyst is more preferably Pd 2 (dba) 3 ; 3) In the ring-closing reaction, the ligand is preferably a phosphine-containing ligand coordinated with a palladium metal catalyst; preferably, the phosphine-containing ligand coordinated with the palladium metal catalyst is Xantphos, Sphos, Xphos, Ruphos, Brettphos; most preferably, the phosphine-containing ligand coordinated with the palladium metal catalyst is Xantphos; 4) In the ring-closing reaction, the base is selected from alkali metal bases, alkaline earth metal bases, organic bases, and / or organometallic bases. The alkali metal bases are preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium phosphate; the alkaline earth metal bases are preferably sodium hydride, potassium hydride, and calcium hydride; the organic bases are preferably triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the organometallic bases are preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, and aluminum isopropoxide; the base is more preferably cesium carbonate; 5) In the ring-closing reaction, the reaction temperature is 80°C to 140°C, preferably 115°C to 125°C; 6) In the ring-closing reaction, the reaction time is 2 - 12 h, preferably 7 h; 7) In the ring-closing reaction, the inert gas is selected from nitrogen, helium, neon, and argon; the inert gas is preferably nitrogen.

6. The preparation method according to claim 3, characterized in that it comprises the following steps: In a solvent, the compound of formula IV or its salt and the compound of formula V undergo the following cyclization reaction in the presence of a base to obtain the compound of formula III; Among them, R 1 is selected from C 1-5 alkyl; Preferably, the preparation method of the compound of formula III satisfies one or more of the following conditions: 1) In the cyclization reaction, the solvent is preferably an alcohol solvent, more preferably ethanol; 2) After adding the compound of formula V in the cyclization reaction, the reaction system needs to be adjusted to acidic conditions with an acid, and then the compound of formula IV or its salt is added. The acidic conditions are preferably pH = 5 - 6; 3) In the cyclization reaction, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide; the base is preferably sodium bicarbonate; 4) In the cyclization reaction, the acid used to adjust the reaction system to acidic is preferably hydrochloric acid, hydrochloric acid in methanol, or hydrochloric acid in ethanol; more preferably, the acid used to adjust the reaction system to acidic is hydrochloric acid in ethanol. 5) In the cyclization reaction, the compound of formula IV or its salt is preferably the compound of formula IV or the hydrochloride of the compound of formula IV. 6) The reaction temperature of the cyclization reaction is 10°C to 90°C, preferably 75°C to 85°C. 7) The reaction time of the cyclization reaction is 2 to 10 h, preferably 7 h. 8) The preparation method of the compound of formula III includes the following operation steps: In the solvent, the compound of formula V is dissolved to obtain reaction solution 1, reaction solution 1 is adjusted with an acid to obtain reaction solution 2, the compound of formula IV or its salt is added to reaction solution 2 to obtain reaction solution 3, and a base is added to reaction solution 3 to obtain the compound of formula III. 9) The preparation method of the compound of formula III includes the following operation steps: In the solvent, the compound of formula V is dissolved to obtain reaction solution 1, reaction solution 1 is adjusted to pH 5 to 6 with an acid to obtain reaction solution 2, the compound of formula IV or its salt is added to reaction solution 2 and stirred for 1 to 3 h to obtain reaction solution 3, a base is added to reaction solution 3, and the temperature is raised to 75°C to 85°C and reacted for 1 to 6 h to obtain the compound of formula III.

7. The preparation method according to any one of claims 3 or 4, characterized in that, it includes the following steps: In the solvent, the compound of formula VI and ethyl formate are subjected to the substitution reaction shown below in the presence of a base to obtain the compound of formula V; Preferably, the preparation method of the compound of formula V satisfies one or more of the following conditions: 1) In the substitution reaction, the solvent is preferably an ether solvent, more preferably anhydrous tetrahydrofuran. 2) In the substitution reaction, the base is preferably LDA, n-BuLi, s-BuLi, NaH, LiHMDS, KHMDS; more preferably, the base is LDA. 3) The reaction temperature of the substitution reaction is -10°C to 30°C, preferably -10°C. 4) The substitution reaction uses a continuous flow reactor. 5) The preparation method of the compound of formula V includes the following operation steps: In the solvent, the compound of formula VI is dissolved to obtain reaction solution 1, the base is reaction solution 2, ethyl formate is dissolved in the solvent to obtain reaction solution 3, reaction solution 1 is injected into the continuous flow reactor through a continuous flow pump 1, reaction solution 2 is injected into the continuous flow reactor through a continuous flow pump 2, reaction solution 3 is injected into the continuous flow reactor through a continuous flow pump 3, and the reaction temperature of the reactor is controlled to obtain the compound of formula V.

8. The preparation method according to claim 3, characterized in that, it includes the following steps: In the solvent, the compound of formula VII and an alkali metal halide are subjected to the decarboxylation reaction shown below to obtain the compound of formula VI; wherein, R 1 is selected from C 1-5 alkyl; Preferably, the preparation method of the compound of formula VI satisfies one or more of the following conditions: 1) In the decarboxylation reaction, the solvent is one or more of an aprotic polar solvent, an ether solvent, an aromatic hydrocarbon solvent, and a mixed solvent of an organic solvent and water. The aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the ether solvent is preferably one or two of tetrahydrofuran and 2-methyltetrahydrofuran; the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably a mixed solvent of dimethyl sulfoxide and water; 2) In the decarboxylation reaction, the alkali metal halide is preferably LiCl, LiI, NaCl, NaBr; the alkali metal halide is more preferably LiCl; 3) The reaction temperature of the decarboxylation reaction is 100°C to 180°C, preferably 120°C to 125°C 4) The reaction time of the decarboxylation reaction is 2 to 24 h, preferably 12 h.

9. The preparation method according to claim 3, characterized in that, it comprises the following steps: In a solvent, the compound of formula VIII, a Grignard reagent, and a copper catalyst are subjected to the following coupling reaction under an inert gas atmosphere to obtain the compound of formula VII; wherein, R 1 is selected from C 1-5 alkyl; Preferably, the preparation method of the compound of formula VII satisfies one or more of the following conditions: 1) In the coupling reaction, the solvent is one or more of an aprotic polar solvent, an ether solvent, and an aromatic hydrocarbon solvent. The aprotic polar solvent is preferably one or two of dimethyl sulfoxide, acetone, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the ether solvent is preferably one or two of tetrahydrofuran and 2-methyltetrahydrofuran; the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably tetrahydrofuran; 2) In the coupling reaction, the Grignard reagent is preferably MeMgBr; 3) In the coupling reaction, the copper metal catalyst is preferably one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper, and cuprous oxide; the copper metal catalyst is more preferably cuprous iodide; 4) The reaction temperature of the coupling reaction is 0°C to 20°C, preferably 10°C to 20°C; 5) The inert gas in the coupling reaction is preferably nitrogen; 6) The preparation method of the compound of formula VII comprises the following operating steps: In the solvent, the copper catalyst slowly drops the Grignard reagent under an inert gas atmosphere to obtain reaction solution 1, dissolves the compound of formula VIII in the solvent to obtain reaction solution 2, and slowly drops reaction solution 2 into reaction solution 1 to obtain the compound of formula VII; 7) The preparation method of the compound of formula VII comprises the following operating steps: In the solvent, cuprous iodide slowly drops MeMgBr under an inert gas atmosphere, stirs for 0.5 h to 2 h to obtain reaction solution 1, dissolves the compound of formula VIII in the solvent to obtain reaction solution 2, and slowly drops reaction solution 2 into reaction solution 1 to obtain the compound of formula VII.

10. The preparation method according to claim 3, characterized in that, It includes the following steps: In a solvent, the compound of formula X and the compound of formula IX undergo the addition dehydration reaction as shown below to obtain the compound of formula VIII; Among them, R 1 is selected from C 1-5 alkyl; Preferably, the preparation method of the compound of formula VIII satisfies one or more of the following conditions: 1) In the addition dehydration reaction, the solvent is one or more of protic solvents; the protic solvent is preferably one or more of acetic acid, sulfuric acid, polyphosphoric acid, and trifluoroacetic acid; the solvent is more preferably acetic acid; 2) The reaction temperature of the addition dehydration reaction is 0°C to 40°C, preferably 25°C to 30°C.

11. The preparation method according to claim 1, characterized in that it includes the following steps: and / or; and / or; and / or; and / or; and / or; wherein X is a halogen; R 1 selected from C 1-5 alkyl; The parameters and conditions in the preparation method of the compound of formula I are as described in any one of claims 1-10.

12. The preparation method according to claim 11, characterized in that it includes the following steps: and / or; and / or; and / or; and / or; and / or; The parameters and conditions in the preparation method of the compound of formula I are as described in any one of claims 1-10.

13. The compound of formula II-1, the compound of formula III-1, the compound of formula V, the compound of formula VI, or the compound of formula VII-1:

14. Use of the compound according to claim 13 in the preparation method according to any one of claims 1-12.

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