Synthetic method of PARP1 inhibitor key intermediate

Abstract

The invention discloses a synthesis method of a PARP1 inhibitor key intermediate, and belongs to the technical field of medicines. The technical problem to be solved is to reduce the process synthesis cost of the key intermediate. According to the technical scheme, the method is characterized by comprising the following steps: firstly, synthesizing a nitrogen oxide intermediate, dissolving the nitrogen oxide intermediate in a solvent, sequentially adding trimethylamine and trifluoroacetic anhydride, and reacting at room temperature to quickly obtain a compound as shown in a formula II; the preparation method comprises the following steps: carrying out a heating reaction on a compound as shown in a formula II, acetonitrile and tetrabutylammonium fluoride without separation and purification, and introducing F atoms, so as to obtain the PARP1 inhibitor key intermediate with high yield.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a synthesis method of a PARP1 inhibitor key intermediate. BACKGROUND

[0002] For understanding the technical content of the application: Poly (ADP-ribose) polymerase (PARP) is a kind of nuclear enzyme closely related to DNA damage repair, and the PARP1 subtype accounts for more than 90% of repair tasks. PARP1 inhibitors are a kind of targeted drugs for poly (ADP-ribose) polymerase 1 (PARP1), which interfere with DNA damage repair by inhibiting the activity of PARP1, and show significant efficacy in the treatment of various cancers. In recent years, a number of PARP1 inhibitors have entered the clinical research stage, and PARP1 inhibitors have become one of the hotspots of tumor drug research and development. The PARP1 inhibitor represented by AZD5305 (chemical formula as shown below) has shown good biological activity.

[0003]

[0004] Among them, the structural formula of a PARP1 inhibitor key intermediate is as follows:

[0005] For the synthesis method of the above-mentioned PARP1 inhibitor key intermediate, the relevant patent documents searched are as follows: The disclosure country is China, the disclosure number is WO2024082654A1, and the disclosure date is April 25, 2024. The document discloses the synthesis path of the above-mentioned PARP1 inhibitor key intermediate: starting from 5-bromopyridine-2 carboxylate methyl ester, the key intermediate is obtained after two steps of reaction. This method is the current mainstream synthesis method of the key intermediate, but the expensive AgF2 is used in the first step, and the palladium catalysis is used in the second step, resulting in high cost.

[0006] The synthesis route is as follows: .

[0007] The disclosure country is the United Kingdom, the disclosure number is WO2024256377A1, and the disclosure date is December 19, 2024. Another method for synthesizing the key intermediate is disclosed, starting from 5-fluoro-6-bromo-pyridine-2-carboxylic acid, three steps of reaction, the main disadvantage of this route is that the starting material is expensive.

[0008] The synthesis route is as follows: .

[0009] In view of the deficiencies of the above routes, there is an urgent need in the art to provide a technical solution for synthesizing the intermediate in high yield from a large amount of inexpensive raw materials using conventional reagents, which has potential value for process amplification. SUMMARY

[0010] The purpose of the present application is to provide: A synthesis method of a PARP1 inhibitor key intermediate and related technologies aim to improve the synthesis yield of the PARP1 inhibitor key intermediate, reduce the process synthesis cost, and meet the demand for process production amplification.

[0011] Term explanation: Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, publications, and other documents referenced herein are hereby incorporated by reference in their entirety. If there is a plurality of definitions for a term herein, then the definitions in this section prevail.

[0012] It should be understood that the above brief summary and the following detailed description are illustrative and are not restrictive of the subject matter of the present application. In this application, unless otherwise indicated, the use of the singular includes the plural. It should also be noted that, as used in this application, the term "or" as used in the "and / or" is intended to mean "and / or" unless otherwise indicated. Furthermore, the use of the term "including" as well as other forms such as "include", "includes" and "included" is not limiting.

[0013] The definitions of standard chemical terms can be found in the reference "Organic Chemistry (Vols. 1 and 2), Qingshi Yi, Higher Education Press, 2005-06, 3rd edition".

[0014] Unless otherwise specified, conventional methods within the scope of the art are used, such as concentration, liquid-liquid separation, and column chromatography purification.

[0015] Unless a specific definition is provided, the use of each type of commercially available product used herein is in accordance with standard techniques. For example, the use of reagent kits can be carried out according to the manufacturer's instructions, or in accordance with ways known in the art or the instructions of the present application. In general, the above-mentioned techniques and methods can be carried out according to conventional methods well known in the art, according to the descriptions in the multiple summary and more specific literature cited and discussed in this specification.

[0016] The term "optional" or "optionally" means that the subsequent described event or circumstance can occur or can not occur, and the description includes the occurrence of the event or circumstance and the non-occurrence of the event or circumstance.

[0017] The term "column chromatography purification" as used herein refers to the separation of components in a mixture by taking advantage of the differences in adsorption-desorption equilibrium between the stationary phase (usually a solid adsorbent such as silica gel, alumina, etc.) and the mobile phase (eluent).

[0018] The term "liquid separation" as used herein refers to the separation of two immiscible liquids with different densities by taking advantage of the property of the two liquids to separate into layers after standing, and the operation process of separating them through a separatory funnel.

[0019] The term "slurry" as used herein refers to the process of mixing and stirring a solid product with a solvent to remove impurities and achieve purification by taking advantage of the difference in solubility of the product and impurities in a single solvent, and the solvent has good solubility for impurities and is essentially insoluble for the product.

[0020] In a first aspect, the present application provides: A nitroxide intermediate, the structural formula of which is as follows: .

[0021] In a second aspect, the present application provides: A synthesis method of a PARP1 inhibitor key intermediate, comprising the following steps: (1) first, the compound of formula I is reacted with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate of claim 1; (2) then, the nitroxide intermediate is sequentially added with a solvent, trimethylamine and trifluoroacetic anhydride, and reacted at room temperature to obtain the compound of formula II; (3) finally, the compound of formula II is dissolved in acetonitrile, and tetrabutylammonium fluoride is added for heating reaction to obtain the PARP1 inhibitor key intermediate, wherein, the structural formula of the compound of formula I, the compound of formula II and the PARP1 inhibitor key intermediate are as follows: 、 、 .

[0022] The technical features include: base, organic solvent, molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent, reaction conditions, slurry reagent, trimethylamine, temperature of adding solvent and trimethylamine, temperature of adding trifluoroacetic anhydride, molar volume ratio of trimethylamine and trifluoroacetic anhydride, reaction conditions at room temperature, tetrabutylammonium fluoride, volume ratio of acetonitrile and tetrabutylammonium fluoride, heating reaction conditions, liquid separation reagent, water washing process of organic phase and eluent for column chromatography purification, etc.

[0023] In step (1), the technical feature "base" is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide.

[0024] wherein the technical feature "base" is preferably: potassium carbonate, cesium carbonate, sodium tert-butoxide.

[0025] wherein the technical feature "base" is further preferably: potassium carbonate.

[0026] wherein in step (1), the technical feature "organic solvent" is selected from one or more of: N,N-dimethylformamide, tetrahydrofuran, and acetonitrile.

[0027] wherein the technical feature "organic solvent" is preferably: N,N-dimethylformamide, tetrahydrofuran, acetonitrile.

[0028] wherein the technical feature "organic solvent" is further preferably: N,N-dimethylformamide.

[0029] wherein in step (1), the technical feature "molar volume ratio of the compound of formula I to N-Boc piperazine, base, and organic solvent" is selected from: 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L.

[0030] wherein the technical feature "molar volume ratio of the compound of formula I to N-Boc piperazine, base, and organic solvent" is preferably: 2.8-3.2 mol:3-3.5 mol:6.2-8 mol:5.3-6 L.

[0031] wherein the technical feature "molar volume ratio of the compound of formula I to N-Boc piperazine, base, and organic solvent" is further preferably: 3.13 mol:3.44 mol:6.26 mol:5.3 L.

[0032] wherein in step (1), the technical feature "conditions of the reaction" includes "temperature of the reaction", "time of the reaction", and "after the reaction is completed, post-treatment is required, the process of the post-treatment includes: cooling the reaction solution to 20-30°C, filtering, concentrating, beating, and drying".

[0033] wherein the technical feature "temperature of the reaction" is selected from: 70-90°C.

[0034] wherein the technical feature "temperature of the reaction" is preferably: 75-85°C.

[0035] wherein the technical feature "temperature of the reaction" is further preferably: 75°C, 77°C, 80°C, 81°C, 83°C, 85°C.

[0036] wherein the technical feature "temperature of the reaction" is still further preferably: 80°C.

[0037] wherein the technical feature "time of the reaction" is selected from: 10-14 h.

[0038] wherein the technical feature "time of the reaction" is preferably: 10-12 h.

[0039] wherein the technical feature "time of the reaction" is further preferably: 10 h, 11 h, 12 h.

[0040] wherein the technical feature "time of the reaction" is even further preferably: 12 h.

[0041] wherein the technical feature "the filtration is performed using diatomaceous earth, the filter cake is eluted with ethyl acetate".

[0042] wherein the technical feature "agent for the slurry" is selected from: tetrahydrofuran, tert-butyl methyl ether or n-hexane.

[0043] wherein the technical feature "agent for the slurry" is preferably: tetrahydrofuran.

[0044] wherein the technical feature "time for the slurry" is selected from: 8-12 h.

[0045] wherein the technical feature "time for the slurry" is preferably: 8 h, 10 h, 12 h.

[0046] wherein the technical feature "time for the slurry" is further preferably: 12 h.

[0047] wherein in step (2) the technical feature "solvent" is selected from: one or more of dichloromethane, dichloroethane and tetrahydrofuran.

[0048] wherein the technical feature "solvent" is preferably: dichloromethane, dichloroethane.

[0049] wherein the technical feature "solvent" is further preferably: dichloromethane.

[0050] wherein in step (2) the technical feature "trimethylamine" is selected from: 1-3 M trimethylamine in tetrahydrofuran.

[0051] wherein the technical feature "trimethylamine" is preferably: 1.5-2.5 M trimethylamine in tetrahydrofuran.

[0052] wherein the technical feature "trimethylamine" is further preferably: 1.5 M trimethylamine in tetrahydrofuran, 1.8 M trimethylamine in tetrahydrofuran, 2 M trimethylamine in tetrahydrofuran, 2.2 M trimethylamine in tetrahydrofuran, 2.5 M trimethylamine in tetrahydrofuran.

[0053] wherein the technical feature "trimethylamine" is even further preferably: 2 M trimethylamine in tetrahydrofuran.

[0054] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is selected from 20-30 °C.

[0055] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is preferably 25-30 °C.

[0056] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is further preferably 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, or 30 °C.

[0057] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is still further preferably 25 °C.

[0058] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is selected from 20-30 °C.

[0059] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is preferably 25-30 °C.

[0060] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is further preferably 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, or 30 °C.

[0061] In step (2), the technical feature "temperature for adding the solvent and trimethylamine" is still further preferably 25 °C.

[0062] In step (2), the technical feature "temperature for adding the trifluoroacetic anhydride" is selected from 0-5 °C.

[0063] In step (2), the technical feature "temperature for adding the trifluoroacetic anhydride" is preferably 0-4 °C.

[0064] In step (2), the technical feature "temperature for adding the trifluoroacetic anhydride" is further preferably 0 °C, 1 °C, 2 °C, 3 °C, or 4 °C.

[0065] In step (2), the technical feature "temperature for adding the trifluoroacetic anhydride" is still further preferably 0 °C.

[0066] In step (2), the technical feature "molar volume ratio of the nitroxyl intermediate, the solvent, the trimethylamine, and the trifluoroacetic anhydride" is selected from 1-2 mol: 2-3 L: 3-5.5 L: 3-5.5 mol.

[0067] In step (2), the technical feature "molar volume ratio of the nitroxyl intermediate, the solvent, the trimethylamine, and the trifluoroacetic anhydride" is preferably 1-1.5 mol: 2.2-2.8 L: 3.2-5.3 L: 3.5-5.4 mol.

[0068] The molar volume ratio of the technical features "nitrogen oxide intermediate, solvent, trimethylamine, and trifluoroacetic anhydride" is further preferably 1.34 mol: 2.5 L: 5.3 L: 5.4 mol.

[0069] In step (2), the technical feature "room temperature reaction conditions" includes "room temperature reaction temperature", "room temperature reaction time", and "concentration after the room temperature reaction is monitored by TLC".

[0070] The technical feature "room temperature reaction temperature" is selected from 20-30°C.

[0071] The technical feature "room temperature reaction temperature" is preferably 25-30°C.

[0072] The technical feature "room temperature reaction temperature" is further preferably 25°C, 26°C, 27°C, 28°C, 29°C, 30°C.

[0073] The technical feature "room temperature reaction temperature" is further preferably 25°C.

[0074] The technical feature "room temperature reaction time" is selected from 0.5-1.5 h.

[0075] The technical feature "room temperature reaction time" is preferably 0.6-1.2 h.

[0076] The technical feature "room temperature reaction time" is further preferably 0.6 h, 0.8 h, 1 h, 1.2 h.

[0077] The technical feature "room temperature reaction time" is further preferably 1 h.

[0078] In step (3), the technical feature "tetrabutylammonium fluoride" is selected from 1-2 M tetrabutylammonium fluoride in tetrahydrofuran solution.

[0079] The technical feature "tetrabutylammonium fluoride" is preferably 1-1.5 M tetrabutylammonium fluoride in tetrahydrofuran solution.

[0080] The technical feature "tetrabutylammonium fluoride" is further preferably 1 M tetrabutylammonium fluoride in tetrahydrofuran solution, 1.1 M tetrabutylammonium fluoride in tetrahydrofuran solution, 1.2 M tetrabutylammonium fluoride in tetrahydrofuran solution, 1.3 M tetrabutylammonium fluoride in tetrahydrofuran solution, 1.4 M tetrabutylammonium fluoride in tetrahydrofuran solution, 1.5 M tetrabutylammonium fluoride in tetrahydrofuran solution.

[0081] The technical feature "tetrabutylammonium fluoride" is further preferably 1 M tetrabutylammonium fluoride in tetrahydrofuran solution.

[0082] wherein in step (3), the technical feature "volume ratio of acetonitrile and tetrabutylammonium fluoride" is selected from 1-3:6-7.

[0083] wherein the technical feature "volume ratio of acetonitrile and tetrabutylammonium fluoride" is preferably 2-3:6.5-7.

[0084] wherein the technical feature "volume ratio of acetonitrile and tetrabutylammonium fluoride" is further preferably 2:6.7.

[0085] wherein in step (3), the technical feature "heating reaction conditions" includes "heating reaction temperature", "heating reaction time" and "after heating reaction, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, washed with water, dried and purified by column chromatography".

[0086] wherein the technical feature "heating reaction temperature" is selected from 50-70℃.

[0087] wherein the technical feature "heating reaction temperature" is preferably 55-65℃.

[0088] wherein the technical feature "heating reaction temperature" is further preferably 55℃, 57℃, 60℃, 61℃, 63℃, 65℃.

[0089] wherein the technical feature "heating reaction temperature" is still further preferably 60℃.

[0090] wherein the technical feature "heating reaction time" is selected from 0.5-1.5 h.

[0091] wherein the technical feature "heating reaction time" is preferably 0.5 h, 0.8 h, 1 h, 1.2 h, 1.5 h.

[0092] wherein the technical feature "heating reaction time" is further preferably 1 h.

[0093] wherein the technical feature "separation reagent" is selected from ethyl acetate.

[0094] wherein the technical feature "water washing organic phase process" is to wash with water and saturated brine in turn.

[0095] wherein the technical feature "eluent for column chromatography purification" is selected from a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1.

[0096] wherein the technical feature "eluent for column chromatography purification" is preferably a mixture of petroleum ether and ethyl acetate with a volume ratio of 2.5-3.5:1.

[0097] Preferably, the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 2.5:1, a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1, or a mixture of petroleum ether and ethyl acetate in a volume ratio of 3.5:1.

[0098] Preferably, the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0099] Based on further solving or simultaneously solving multiple technical problems of the technical problem of the present application, in the technical scheme provided by the second aspect of the present application, the preferred schemes include: The first preferred scheme: the base in step (1) is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0100] The second preferred scheme: the organic solvent in step (1) is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0101] The third preferred scheme: the molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent in step (1) is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0102] The fourth preferred scheme: the temperature of the reaction in step (1) is 70-90℃, and the reaction time is 10-14 h. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0103] The fifth preferred scheme: after the reaction in step (1) is completed, post-treatment is required, and the post-treatment process includes cooling the reaction liquid to 20-30℃, filtering, concentrating, beating and drying. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0104] The sixth priority scheme: the filtration uses diatomite, ethyl acetate is used to elute the filter cake, the pulping reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane, and the pulping time is 8-12 h. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0105] The seventh priority scheme: in step (2), the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane; and the trimethylamine is a 1-3 M trimethylamine solution in tetrahydrofuran. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0106] The eighth priority scheme: in step (2), the temperature for adding the solvent and the trimethylamine is 20-30°C, and the temperature for adding the trifluoroacetic anhydride is 0-5°C. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0107] The ninth priority scheme: in step (2), the temperature for the room temperature reaction is 20-30°C, the time for the room temperature reaction is 0.5-1.5 h, and after the room temperature reaction is monitored to end using TLC, concentration is performed. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0108] The tenth priority scheme: in step (2), the molar volume ratio of the intermediate, the solvent, the trimethylamine and the trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0109] The eleventh priority scheme: in step (2), the tetrabutylammonium fluoride is a 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran, and the volume ratio of the acetonitrile and the tetrabutylammonium fluoride is 1-3:6-7. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0110] The twelfth priority scheme: in step (3), the temperature for the heating reaction is 50-70°C, and the time for the heating reaction is 0.5-1.5 h. On the basis of solving the technical problem of "reducing cost", this technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor".

[0111] The thirteenth priority scheme: after the heating reaction in step (3) is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, the organic phase is washed with water, dried and purified by column chromatography. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0112] The fourteenth priority scheme: the reagent for separation is ethyl acetate, the process of washing the organic phase with water is to sequentially wash with water and saturated brine; the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1. This technical scheme further solves the technical problem of "increasing the yield of the key intermediate of the PARP1 inhibitor" on the basis of solving the technical problem of "reducing cost".

[0113] Examples 1-3 in the present application at least support the protection scope of claim 1.

[0114] For claim 1: The technical feature "nitroxide intermediate" is summarized from the foregoing explanation herein and / or the corresponding technical feature nitroxide intermediate (compound of formula I) in examples 1-3.

[0115] Examples 1-3 in the present application at least support the protection scope of claim 2.

[0116] For claim 2: The technical feature "(1) first react the compound of formula I with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate" is summarized by the common feature "(1) first react the compound of formula I with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate". Therefore, the person skilled in the art can reasonably determine that the subordinate concept of the technical feature "(1) first react the compound of formula I with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate", the basic equivalent technical means of the technical feature "(1) first react the compound of formula I with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate", and the technical means of the technical feature "(1) first react the compound of formula I with N-Boc piperazine, a base and an organic solvent to obtain the nitroxide intermediate" which can be replaced based on the existing technical level within the conventional technical means and common knowledge, shall all belong to the protection scope of claim 2.

[0117] The technical feature "adding solvent, trimethylamine and trifluoroacetic anhydride to the nitroxide intermediate in turn, reacting at room temperature to obtain the compound of formula II" is summarized by the aforementioned explanation herein and / or the corresponding technical feature in Examples 1-3. At 25°C, dichloromethane (DCM, 2.5 L) was added to a 10 L four-necked flask, and then the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol) were added in turn. The reaction system was cooled to 0°C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise thereto. After the dropwise addition was completed, the temperature was restored to 25°C, and the reaction was carried out for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II. At 25°C, dichloromethane (DCM, 2.5 L) was added to a 10 L four-necked flask, and then the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol) were added in turn. The reaction system was cooled to 0°C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise thereto. After the dropwise addition was completed, the temperature was restored to 25°C, and the reaction was carried out for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II. At 25°C, dichloromethane (DCM, 2.5 L) was added to a 10 L four-necked flask, and then the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol) were added in turn. The reaction system was cooled to 0°C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise thereto. After the dropwise addition was completed, the temperature was restored to 25°C, and the reaction was carried out for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II. Therefore, based on reasonable inference, one skilled in the art can determine that the subordinate concept of the technical features "adding solvent, trimethylamine and trifluoroacetic anhydride to the nitroxide intermediate in turn, reacting at room temperature to obtain the compound of formula II", the technical means substantially equivalent to the technical feature "adding solvent, trimethylamine and trifluoroacetic anhydride to the nitroxide intermediate in turn, reacting at room temperature to obtain the compound of formula II", and the technical means of "adding solvent, trimethylamine and trifluoroacetic anhydride to the nitroxide intermediate in turn, reacting at room temperature to obtain the compound of formula II" that can be replaced within the conventional technical means and common general knowledge based on the existing technical level, all should be within the protection scope of claim 2.

[0118] The technical feature "finally dissolving the compound of formula II in acetonitrile, adding tetrabutylammonium fluoride, and then heating to obtain the key intermediate of PARP1 inhibitor" is summarized as follows: the solid is dissolved in acetonitrile (2 L), tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) is added, and then the reaction is carried out at 60°C for 1 h. After the reaction is completed, the reaction solution is cooled to 25°C, and the reaction solution is concentrated and dried to obtain a crude product. The crude product is separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase is collected. The organic phase is washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. The filtrate is concentrated to obtain a crude product, which is purified by column chromatography (PE:EtOAc=3:1, v / v) to obtain the key intermediate of PARP1 inhibitor. The solid is dissolved in acetonitrile (2.5 L), tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) is added, and then the reaction is carried out at 60°C for 1 h. After the reaction is completed, the reaction solution is cooled to 25°C, and the reaction solution is concentrated and dried to obtain a crude product. The crude product is separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase is collected. The organic phase is washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. The filtrate is concentrated to obtain a crude product, which is purified by column chromatography (PE:EtOAc=3:1, v / v) to obtain the key intermediate of PARP1 inhibitor. The solid is dissolved in tetrahydrofuran (2 L), tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) is added, and then the reaction is carried out at 60°C for 1 h. After the reaction is completed, the reaction solution is cooled to 25°C, and the reaction solution is concentrated and dried to obtain a crude product. The crude product is separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase is collected. The organic phase is washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. The filtrate is concentrated to obtain a crude product, which is purified by column chromatography (PE:EtOAc=3:1, v / v) to obtain the key intermediate of PARP1 inhibitor. Therefore, based on the reasonable presumption, the sub-concept of the technical feature "finally dissolving the compound of formula II in acetonitrile, adding tetrabutylammonium fluoride, and then heating to obtain the key intermediate of PARP1 inhibitor", the basic equivalent technical means of the technical feature "finally dissolving the compound of formula II in acetonitrile, adding tetrabutylammonium fluoride, and then heating to obtain the key intermediate of PARP1 inhibitor", and the technical means of "finally dissolving the compound of formula II in acetonitrile, adding tetrabutylammonium fluoride, and then heating to obtain the key intermediate of PARP1 inhibitor" which can be replaced based on the existing technical level within the conventional technical means and common knowledge, should all belong to the protection scope of claim 2.

[0119] The embodiments 1-3 in the present application at least support the protection scope of claim 3.

[0120] For claim 3: The technical feature "the base is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide" is generalized from the aforementioned explanation herein and / or the corresponding technical feature potassium carbonate in the embodiments 1-3 via the common feature "base". Therefore, the person skilled in the art can reasonably infer that the subordinate concept of the technical feature "the base is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide", the substantially equivalent technical means of the technical feature "the base is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide", and the technical means of "the base is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide" that can be replaced within the conventional technical means and common general knowledge based on the existing technical level, all should belong to the protection scope of claim 3, for example, the technical feature "the base is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide" is replaced by potassium carbonate and cesium carbonate, cesium carbonate and sodium tert-butoxide, etc., which still belongs to the protection scope of claim 3 of the present application.

[0121] The embodiments 1-3 in the present application at least support the protection scope of claim 4.

[0122] For the claim 4: The technical feature "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile" is generalized from the aforementioned explanation herein and / or the corresponding technical feature N,N-dimethylformamide in the embodiments 1-3 via the common feature "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile". Therefore, the person skilled in the art can reasonably infer that the subordinate concept of the technical feature "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile", the substantially equivalent technical means of the technical feature "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile", and the technical means of "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile" that can be replaced within the conventional technical means and common general knowledge based on the existing technical level, all should belong to the protection scope of claim 4, for example, the technical feature "the organic solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile" is replaced by N,N-dimethylformamide and tetrahydrofuran, tetrahydrofuran and acetonitrile, etc., which still belongs to the protection scope of claim 4 of the present application.

[0123] The embodiments 1-3 in the present application at least support the protection scope of claim 5.

[0124] For the claim 5: The technical feature "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L" is summarized from the previous explanations and / or the corresponding technical features in Examples 1-3, i.e. the molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 3.13 mol:3.44 mol:6.26 mol:5.3 L, the molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.92 mol:3.21 mol:6.42 mol:6 L, the molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 3.13 mol:3.44 mol:7.82 mol:5.3 L, etc. Therefore, according to the reasonable presumption of the skilled person, the subordinate concept of the technical feature "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L", the technical means substantially equivalent to "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L", and the technical means of "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L" that can be replaced within the conventional technical means and common general knowledge based on the prior art level, should all belong to the protection scope of claim 5, for example, under the condition that other technical features remain unchanged, replacing "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L" with "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 3.5 mol:4 mol:8 mol:6 L", "molar volume ratio of the compound of formula I, N-Boc piperazine, base and organic solvent is 2.5 mol:3 mol:6 mol:5 L", etc., still belongs to the protection scope of claim 5 of the present application.

[0125] Examples 1-3 in the present application at least support the protection scope of claim 6.

[0126] For claim 6: The technical feature "the temperature of the reaction is 70-90°C" is generalized from the aforementioned explanations and / or the corresponding technical features 70°C, 80°C, 90°C, etc. in Examples 1-3 by the common feature "the temperature of the reaction is 70-90°C". Therefore, the person skilled in the art can reasonably infer that the technical feature "the temperature of the reaction is 70-90°C", the subordinate concept of "the temperature of the reaction is 70-90°C", the substantially equivalent technical means of "the temperature of the reaction is 70-90°C", and the technical means of "the temperature of the reaction is 70-90°C" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 6, for example, "the temperature of the reaction is 70-90°C" is replaced by 75°C, 81°C, etc. without changing other technical features, which still belongs to the protection scope of claim 6 of the present application.

[0127] The technical feature "the reaction time is 10-14 h" is generalized from the aforementioned explanations and / or the corresponding technical features 10 h, 12 h, etc. in Examples 1-3 by the common feature "the reaction time is 10-14 h". Therefore, the person skilled in the art can reasonably infer that the technical feature "the reaction time is 10-14 h", the subordinate concept of "the reaction time is 10-14 h", the substantially equivalent technical means of "the reaction time is 10-14 h", and the technical means of "the reaction time is 10-14 h" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 6, for example, "the reaction time is 10-14 h" is replaced by 11 h, etc. without changing other technical features, which still belongs to the protection scope of claim 6 of the present application.

[0128] Examples 1-3 in the present application at least support the protection scope of claim 7.

[0129] For the claim 7 involves: The technical feature "the post-treatment after the reaction is completed, the process of the post-treatment includes: after the reaction solution is cooled to 20-30 DEG C, filtering, concentrating, beating and drying" is summarized by the common feature "the post-treatment after the reaction is completed, the process of the post-treatment includes: after the reaction solution is cooled to 20-30 DEG C, filtering, concentrating, beating and drying" from the foregoing explanation and / or the corresponding technical features in embodiments 1-3. Therefore, the person skilled in the art can reasonably infer that the subordinate concept of the technical feature "the post-treatment after the reaction is completed, the process of the post-treatment includes: after the reaction solution is cooled to 20-30 DEG C, filtering, concentrating, beating and drying", the basic equivalent technical means of "the post-treatment after the reaction is completed, the process of the post-treatment includes: after the reaction solution is cooled to 20-30 DEG C, filtering, concentrating, beating and drying", and the technical means of "the post-treatment after the reaction is completed, the process of the post-treatment includes: after the reaction solution is cooled to 20-30 DEG C, filtering, concentrating, beating and drying" which can be replaced within the conventional technical means and public common knowledge based on the existing technical level should all belong to the protection scope of claim 7.

[0130] Embodiments 1-3 in the application support at least the protection scope of claim 8.

[0131] For claim 8: The technical feature "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane" is summarized by the common feature "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane" from the foregoing explanation and / or the corresponding technical features in embodiments 1-3. Therefore, the person skilled in the art can reasonably infer that the subordinate concept of the technical feature "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane", the basic equivalent technical means of "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane", and the technical means of "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane" which can be replaced within the conventional technical means and public common knowledge based on the existing technical level should all belong to the protection scope of claim 8, for example, under the condition that other technical features remain unchanged, replacing "the beating reagent is tetrahydrofuran, methyl tert-butyl ether or n-hexane" with methyl tert-butyl ether, n-hexane, etc., still belongs to the protection scope of claim 8 of the application.

[0132] The technical feature "the beating time is 8-12 h" is generalized from the aforementioned explanation herein and / or the corresponding technical feature "the beating time is 12 h" in Embodiments 1-3 by the common feature "the beating time is 8-12 h". Therefore, according to a reasonable presumption of a person skilled in the art, it can be determined that the technical feature "the beating time is 8-12 h", the sub-concept of "the beating time is 8-12 h", the substantially equivalent technical means of "the beating time is 8-12 h", and the technical means of "the beating time is 8-12 h" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, all should be within the protection scope of claim 8, for example, replacing "the beating time is 8-12 h" with 8 h, 11 h, etc. while keeping other technical features unchanged, which is still within the protection scope of claim 8 of the present application.

[0133] Embodiments 1-3 in the present application at least support the protection scope of claim 9.

[0134] For claim 9: The technical feature "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane" is generalized from the aforementioned explanation herein and / or the corresponding technical feature "dichloromethane, dichloroethane, etc." in Embodiments 1-3 by the common feature "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane". Therefore, according to a reasonable presumption of a person skilled in the art, it can be determined that the technical feature "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane", the sub-concept of "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane", the substantially equivalent technical means of "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane", and the technical means of "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, all should be within the protection scope of claim 9, for example, replacing "the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane" with dichloromethane and tetrahydrofuran, dichloroethane and tetrahydrofuran, etc. while keeping other technical features unchanged, which is still within the protection scope of claim 9 of the present application.

[0135] The technical feature "the temperature for adding the solvent and trimethylamine is 20-30°C" is generalized from the technical features "the temperature for adding the solvent and trimethylamine is 25°C", "the temperature for adding the solvent and trimethylamine is 27°C", "the temperature for adding the solvent and trimethylamine is 29°C", "the temperature for adding the solvent and trimethylamine is 30°C" and the like in the foregoing explanations and / or Examples 1-3 by the common feature "the temperature for adding the solvent and trimethylamine is 20-30°C". Therefore, the person skilled in the art can reasonably deduce that the technical feature "the temperature for adding the solvent and trimethylamine is 20-30°C", the lower concept of "the temperature for adding the solvent and trimethylamine is 20-30°C", the substantially equivalent technical means of "the temperature for adding the solvent and trimethylamine is 20-30°C", and the technical means of "the temperature for adding the solvent and trimethylamine is 20-30°C" that can be replaced within the conventional technical means and common general knowledge based on the existing technical level, should all belong to the protection scope of claim 10, for example, "the temperature for adding the solvent and trimethylamine is 20-30°C" is replaced by 26°C, 28°C and the like, which still belongs to the protection scope of claim 10 of the present application.

[0136] Examples 1-3 in the present application at least support the protection scope of claim 10.

[0137] For claim 10: The technical feature "the temperature for adding the solvent and trimethylamine is 20-30°C" is generalized from the technical features "the temperature for adding the solvent and trimethylamine is 25°C", "the temperature for adding the solvent and trimethylamine is 27°C", "the temperature for adding the solvent and trimethylamine is 29°C", "the temperature for adding the solvent and trimethylamine is 30°C" and the like in the foregoing explanations and / or Examples 1-3 by the common feature "the temperature for adding the solvent and trimethylamine is 20-30°C". Therefore, the person skilled in the art can reasonably deduce that the technical feature "the temperature for adding the solvent and trimethylamine is 20-30°C", the lower concept of "the temperature for adding the solvent and trimethylamine is 20-30°C", the substantially equivalent technical means of "the temperature for adding the solvent and trimethylamine is 20-30°C", and the technical means of "the temperature for adding the solvent and trimethylamine is 20-30°C" that can be replaced within the conventional technical means and common general knowledge based on the existing technical level, should all belong to the protection scope of claim 10, for example, "the temperature for adding the solvent and trimethylamine is 20-30°C" is replaced by 26°C, 28°C and the like, which still belongs to the protection scope of claim 10 of the present application.

[0138] The technical feature "the temperature for adding trifluoroacetic anhydride is 0-5℃" is generalized from the previous explanation and / or the corresponding technical features in Examples 1-3, i.e. the temperature for adding trifluoroacetic anhydride is 0℃, 2℃, 4℃, 5℃, etc. by the common feature "the temperature for adding trifluoroacetic anhydride is 0-5℃". Therefore, according to the reasonable presumption of the person skilled in the art, it can be determined that the subordinate concept of the technical feature "the temperature for adding trifluoroacetic anhydride is 0-5℃", the substantially equivalent technical means of "the temperature for adding trifluoroacetic anhydride is 0-5℃", and the technical means of "the temperature for adding trifluoroacetic anhydride is 0-5℃" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 10. For example, under the condition that other technical features remain unchanged, replacing "the temperature for adding trifluoroacetic anhydride is 0-5℃" with 1℃, 3℃, etc. still belongs to the protection scope of claim 10 of the present application.

[0139] Examples 1-3 in the present application at least support the protection scope of claim 11.

[0140] For claim 11: The technical feature "the temperature for room temperature reaction is 20-30℃" is generalized from the previous explanation and / or the corresponding technical features in Examples 1-3, i.e. the temperature for room temperature reaction is 25℃, 28℃, 30℃, etc. by the common feature "the temperature for room temperature reaction is 20-30℃". Therefore, according to the reasonable presumption of the person skilled in the art, it can be determined that the subordinate concept of the technical feature "the temperature for room temperature reaction is 20-30℃", the substantially equivalent technical means of "the temperature for room temperature reaction is 20-30℃", and the technical means of "the temperature for room temperature reaction is 20-30℃" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 11. For example, under the condition that other technical features remain unchanged, replacing "the temperature for room temperature reaction is 20-30℃" with 26℃, 27℃, etc. still belongs to the protection scope of claim 11 of the present application.

[0141] The technical feature "the time of the room temperature reaction is 0.5-1.5 h" is summarized from the aforementioned explanation and / or the corresponding technical feature "the time of the room temperature reaction is 1 h, 1.2 h, etc." in the embodiments 1-3 by the common feature "the time of the room temperature reaction is 0.5-1.5 h". Therefore, the person skilled in the art can reasonably infer that the technical feature "the time of the room temperature reaction is 0.5-1.5 h", the sub-concept of "the time of the room temperature reaction is 0.5-1.5 h", the basic equivalent technical means of "the time of the room temperature reaction is 0.5-1.5 h", and the technical means that can replace "the time of the room temperature reaction is 0.5-1.5 h" based on the prior art level within the conventional technical means and common general knowledge should all belong to the protection scope of claim 11. For example, "the time of the room temperature reaction is 0.5-1.5 h" is replaced by 0.6 h, 0.8 h, etc. without changing other technical features, which still belongs to the protection scope of claim 11 of the present application.

[0142] The embodiments 1-3 in the present application at least support the protection scope of claim 12.

[0143] For the claim 12: The technical feature "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol" is generalized from the aforementioned explanations and / or the corresponding technical features in Examples 1-3, i.e. molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1.34 mol:2.5 L:5.3 L:5.4 mol, molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1.34 mol:2.5 L:3.55 L:3.55 mol, molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1.34 mol:2.5 L:4 L:4 mol, etc. by the common feature "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol". Therefore, according to the reasonable presumption of the skilled in the art, the subordinate concept of the technical feature "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol", the basic equivalent technical means of "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol", and the technical means of "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol" which can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 12, for example, replacing "molar volume ratio of nitroxyl intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol:2-3 L:3-5.5 L:3-5.5 mol" with 1 mol:2 L:3 L:3 mol, 2 mol:3 L:5.5 L:5.5 mol, etc. while other technical features remain unchanged, still belongs to the protection scope of claim 12 of the present application.

[0144] Examples 1-3 in the present application support at least the protection scope of claim 13.

[0145] For claim 13: The technical feature "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran" is generalized from the corresponding technical features 1 M tetrabutylammonium fluoride solution in tetrahydrofuran, 1.1 M tetrabutylammonium fluoride solution in tetrahydrofuran, 1.2 M tetrabutylammonium fluoride solution in tetrahydrofuran, 1.3 M tetrabutylammonium fluoride solution in tetrahydrofuran, etc. in the foregoing explanations and / or Examples 1-3 by the common feature "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran". Therefore, a person skilled in the art can reasonably deduce that the technical feature "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran", the sub-concept of "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran", the substantially equivalent technical means of "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran", and the technical means of "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 13. For example, "tetrabutylammonium fluoride is 1-2 M tetrabutylammonium fluoride solution in tetrahydrofuran" is replaced by 1.4 M tetrabutylammonium fluoride solution in tetrahydrofuran, 1.5 M tetrabutylammonium fluoride solution in tetrahydrofuran, etc. without changing other technical features, which still belongs to the protection scope of claim 13 of the present application.

[0146] The technical feature "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7" is generalized from the corresponding technical features the volume ratio of acetonitrile and tetrabutylammonium fluoride is 2:6.7, **, **, etc. in the foregoing explanations and / or Examples 1-3 by the common feature "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7". Therefore, a person skilled in the art can reasonably deduce that the technical feature "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7", the sub-concept of "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7", the substantially equivalent technical means of "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7", and the technical means of "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 13. For example, "the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1-3:6-7" is replaced by the volume ratio of acetonitrile and tetrabutylammonium fluoride is 1:6, the volume ratio of acetonitrile and tetrabutylammonium fluoride is 3:7, etc. without changing other technical features, which still belongs to the protection scope of claim 13 of the present application.

[0147] Examples 1-3 in the present application at least support the protection scope of claim 14.

[0148] For the claim 14: The technical feature "the temperature of the heating reaction is 50-70°C" is generalized from the aforementioned explanation and / or the corresponding technical features in Examples 1-3, i.e. the temperature of the heating reaction is 55°C, 57°C, 60°C, 61°C, etc. via the common feature "the temperature of the heating reaction is 50-70°C". Therefore, according to the reasonable presumption of the person skilled in the art, it can be determined that the subordinate concept of the technical feature "the temperature of the heating reaction is 50-70°C", the substantially equivalent technical means of "the temperature of the heating reaction is 50-70°C", and the technical means of "the temperature of the heating reaction is 50-70°C" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 14. For example, under the condition that other technical features remain unchanged, replacing "the temperature of the heating reaction is 50-70°C" with 63°C, 65°C, etc. still belongs to the protection scope of claim 14 of the present application.

[0149] The technical feature "the time of the heating reaction is 0.5-1.5 h" is generalized from the aforementioned explanation and / or the corresponding technical features in Examples 1-3, i.e. the time of the heating reaction is 1 h, 1.2 h, 1.5 h, etc. via the common feature "the time of the heating reaction is 0.5-1.5 h". Therefore, according to the reasonable presumption of the person skilled in the art, it can be determined that the subordinate concept of the technical feature "the time of the heating reaction is 0.5-1.5 h", the substantially equivalent technical means of "the time of the heating reaction is 0.5-1.5 h", and the technical means of "the time of the heating reaction is 0.5-1.5 h" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claim 14. For example, under the condition that other technical features remain unchanged, replacing "the time of the heating reaction is 0.5-1.5 h" with 0.5 h, 0.8 h, etc. still belongs to the protection scope of claim 14 of the present application.

[0150] Examples 1-3 in the present application at least support the protection scope of claim 15.

[0151] For the claim 15: The technical feature "after the heating reaction is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, washed with water, dried and purified by column chromatography" is summarized from the foregoing explanations and / or the corresponding technical features in Examples 1-3. Therefore, by reasonable inference, one skilled in the art can determine that the subordinate concept of the technical feature "after the heating reaction is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, washed with water, dried and purified by column chromatography", the basic equivalent technical means of "after the heating reaction is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, washed with water, dried and purified by column chromatography", and the technical means of "after the heating reaction is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, washed with water, dried and purified by column chromatography" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all be within the protection scope of claim 15.

[0152] Examples 1-3 in the present application at least support the protection scope of claim 16.

[0153] For claim 16: The technical feature "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1" is summarized from the foregoing explanations and / or the corresponding technical features in Examples 1-3, such as a mixture of petroleum ether and ethyl acetate with a volume ratio of 2.5:1, a mixture of petroleum ether and ethyl acetate with a volume ratio of 3:1, etc. by the common feature "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1". Therefore, by reasonable inference, one skilled in the art can determine that the subordinate concept of the technical feature "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1", the basic equivalent technical means of "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1", and the technical means of "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1" that can be replaced within the conventional technical means and common knowledge based on the existing technical level, should all be within the protection scope of claim 16, such as replacing "the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 2-4:1" with a mixture of petroleum ether and ethyl acetate with a volume ratio of 3.5:1, etc. while other technical features remain unchanged, which is still within the protection scope of claim 16 of the present application.

[0154] The present application has the following beneficial effects: The present application has at least the following beneficial effects: Compared with the prior art, the present application has better technical effects in yield, cost, etc.

[0155] According to experimental tests, the present application can synthesize the key intermediate of the PARP1 inhibitor in high yield from a large amount of inexpensive raw materials using conventional reagents, and the overall cost is reduced by more than 40% compared with the prior art route.

[0156] In addition, based on the case of the present application: Based on the comparison of Examples 1-3 and Comparative Examples 1-3, the present application adopts a combination of specific technical means such as trimethylamine equivalent, tetrabutylammonium fluoride equivalent, and trifluoroacetic anhydride equivalent, which achieves new technical effects, i.e., further improves the yield of the key intermediate of the PARP1 inhibitor on the basis of reducing cost. The technical effect after combination is more superior than the sum of the effect of each technical means. BRIEF DESCRIPTION OF DRAWINGS

[0157] Figure 1 The nuclear magnetic hydrogen spectrum of the compound of formula I.

[0158] Figure 2 The nuclear magnetic hydrogen spectrum of the nitroxide intermediate.

[0159] Figure 3 The nuclear magnetic hydrogen spectrum of the key intermediate of the PARP1 inhibitor.

[0160] Figure 4 The HPLC chart of the key intermediate of the PARP1 inhibitor. DETAILED DESCRIPTION

[0161] The following non-limiting examples can enable those skilled in the art to have a more comprehensive understanding of the present application, but do not limit the present application in any way. The following content is only an exemplary description of the scope of the present application, and those skilled in the art can make various changes and modifications to the present application based on the disclosed content, and it should also belong to the scope of the present application.

[0162] The present application will be further described in the following specific examples. The various instruments, devices, equipment, reagents, products, etc. used in the examples of the present application are obtained through conventional commercial channels unless otherwise specified.

[0163] The synthesis method of the compound of formula I is as follows: (1) 25 °C, into a 10 L four-necked flask, add methanol (MeOH, 6.4 L) and 5-fluoro-2-pyridinecarboxylic acid (800 g, 5.67 mol), open the stirring (80 rpm), drop in the thionyl chloride (SOCl2, 809 g), after the drop is completed, 70 °C reflux for 12 h. After the reaction is completed, remove the methanol under reduced pressure to obtain a solid residue. Dilute with dichloromethane (5 L), wash the organic phase with saturated aqueous sodium bicarbonate solution, water and saturated brine successively, dry over anhydrous sodium sulfate. After rotary evaporation, the crude product is obtained, which is slurried with petroleum ether for 2 h, filtered and dried to obtain 730 g of compound of formula III, white solid, yield 83%.

[0164] (2) 25 °C, into a 10 L four-necked flask, add 1,2-dichloroethane (DCE, 6.4 L) and compound of formula III (800 g, 5.157 mol), add mCPBA (1.33 kg, 7.73 mol) in batches under stirring. React for 24 h. After the reaction is completed, pour the reaction solution into saturated sodium thiosulfate solution (3 L), stir for 30 min, and filter the mixture through diatomite. Extract the filtrate with dichloromethane for 3 times, combine the organic phase, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, the crude product is purified by column chromatography (PE:EtOAc = 2:1, v / v) to obtain 547 g of compound of formula I, yellow oil, yield 62%. The nuclear magnetic resonance spectrum of hydrogen of compound of formula I is shown in Figure 1

[0165] The synthesis route is as follows:

[0166] Example 1 A synthesis method of a key intermediate of a PARP1 inhibitor, the steps are as follows: (1) 25 °C, into a 10 L four-necked flask, add N,N-dimethylformamide (DMF, 5.3 L), compound of formula I (536 g, 3.13 mol), N-Boc piperazine (642 g, 3.44 mol) and potassium carbonate (K2CO3, 866 g, 6.26 mol) successively. The system is heated to 80 °C for 12 h. After the reaction is completed, cool the reaction solution to 25 °C, filter through diatomite, and elute the filter cake with ethyl acetate. Concentrate the filtrate to dryness to obtain a yellowish solid crude product. Slurry the crude product with tetrahydrofuran for 12 h, filter and dry to obtain 760 g of nitroxide intermediate, yellowish solid, yield 72%, purity 99.5%, the nuclear magnetic resonance spectrum of hydrogen of the nitroxide intermediate is shown in Figure 2

[0167] ​​(2) At 25 °C, a 10 L four-necked flask was charged with dichloromethane (DCM, 2.5 L), the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol) was added successively. The reaction system was cooled to 0 °C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise. After the dropwise addition was completed, the reaction was resumed to 25 °C for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II, a light yellow solid. The solid was dissolved in acetonitrile (2 L), and tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) was added, followed by reaction at 60 °C for 1 h. After the reaction was completed, the reaction solution was cooled to 25 °C, and the reaction solution was concentrated and dried to obtain the crude product. The crude product was separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase was collected. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (PE:EtOAc = 3:1, v / v) to obtain 295 g of the PARP1 inhibitor key intermediate, a white solid, with a yield of 65%, a purity of 99.3%, and the nuclear magnetic resonance hydrogen spectrum of the PARP1 inhibitor key intermediate is shown in Figure 3 , and the HPLC chart is shown in Figure 4 .

[0168] The synthesis route is as follows:

[0169] Example 2 (1) At 25 °C, a 10 L four-necked flask was charged with tetrahydrofuran (THF, 6 L), the compound of formula I (500 g, 2.92 mol), N-Boc piperazine (597 g, 3.21 mol) and potassium carbonate (K2CO3, 886 g, 6.42 mol) was added successively. The system was warmed to 90 °C for 12 h. After the reaction was completed, the reaction solution was cooled to 25 °C, filtered with diatomite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to dryness to obtain a light yellow solid crude product. The crude product was slurried with tetrahydrofuran for 12 h, filtered and dried to obtain the nitroxide intermediate 690 g, a light yellow solid, with a yield of 70%.

[0170] (2) At 25 °C, a 10 L four-necked flask was charged with dichloroethane (DCE, 2.5 L), and the nitrogen oxide intermediate (452 g, 1.34 mol) and trimethylamine (1.5 M in THF, 5.3 L, 8 mol) were added successively. The reaction system was cooled to 0 °C, and trifluoroacetic anhydride (TFAA, 1.1 kg, 5.4 mol) was added dropwise. After the dropwise addition was completed, the reaction was resumed at 25 °C for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II, a light yellow solid. The solid was dissolved in acetonitrile (2.5 L), and tetrabutylammonium fluoride (1 M TBAF in THF, 6.7 L) was added, followed by reaction at 60 °C for 1 h. After the reaction was completed, the reaction solution was cooled to 25 °C, and the reaction solution was concentrated and dried to obtain a crude product. The crude product was separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase was collected. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a crude product, which was purified by column chromatography (PE:EtOAc = 3:1, v / v) to obtain 309 g of the PARP1 inhibitor key intermediate, a white solid, with a yield of 68%.

[0171] Example 3 (1) At 25 °C, a 10 L four-necked flask was charged with N,N-dimethylacetamide (DMAc, 5.3 L), the compound of formula I (536 g, 3.13 mol), N-Boc piperazine (642 g, 3.44 mol), and potassium carbonate (K2CO3, 1.08 kg, 7.82 mol) were added successively. The system was warmed to 80 °C for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to 25 °C, and the reaction solution was filtered through diatomite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to dryness to obtain a light yellow solid crude product. The crude product was slurried in tetrahydrofuran for 12 h, filtered, and dried to obtain the nitrogen oxide intermediate 791 g, a light yellow solid, with a yield of 75%.

[0172] (2) At 25 °C, a 10 L four-necked flask was charged with tetrahydrofuran (THF, 2.5 L), and then the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 3.35 L, 6.7 mol) were added successively. The reaction system was cooled to 0 °C, and then trifluoroacetic anhydride (TFAA, 703 g, 3.35 mol) was added dropwise. After the dropwise addition was completed, the reaction was resumed at 25 °C for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II, a light yellow solid. The solid was dissolved in tetrahydrofuran (2 L), and then tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) was added. Then the reaction was carried out at 60 °C for 1 h. After the reaction was completed, the reaction solution was cooled to 25 °C, and then the reaction solution was concentrated and rotary evaporated to obtain a crude product. The crude product was separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase was collected. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a crude product, which was purified by column chromatography (PE:EtOAc = 3:1, v / v) to obtain 275 g of the PARP1 inhibitor key intermediate, a white solid, with a yield of 61%.

[0173] Comparative Example 1 Compared with Example 1, the only difference is that the amount of trimethylamine in step (2) is different, which is as follows: At 25 °C, a 10 L four-necked flask was charged with dichloromethane (DCM, 2.5 L), and then the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 2.68 L, 5.36 mol) were added successively. The reaction system was cooled to 0 °C, and then trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise. After the dropwise addition was completed, the reaction was resumed at 25 °C for 1 h. After TLC showed that the starting material disappeared, the reaction solution was directly concentrated to obtain the compound of formula II, a light yellow solid. The solid was dissolved in acetonitrile (2 L), and then tetrabutylammonium fluoride (1M TBAF in THF, 6.7 L) was added. Then the reaction was carried out at 60 °C for 1 h. After the reaction was completed, the reaction solution was cooled to 25 °C, and then the reaction solution was concentrated and rotary evaporated to obtain a crude product. The crude product was separated by liquid-liquid extraction with ethyl acetate and water, and the organic phase was collected. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a crude product, which was purified by column chromatography (PE:EtOAc = 3:1, v / v) to obtain 160 g of the PARP1 inhibitor key intermediate, a white solid, with a yield of 35%.

[0174] Comparative Example 2 Compared with Example 1, the only difference is that the amount of tetrabutylammonium fluoride added in step (2) is different, which is as follows: To a 10 L four-necked flask was added dichloromethane (DCM, 2.5 L) at 25 °C, followed by the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol). The reaction system was cooled to 0 °C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise. After the addition was completed, the reaction was resumed to 25 °C for 1 h. TLC showed that the starting material disappeared, and the reaction solution was directly concentrated to obtain the compound of formula II, a light yellow solid. The solid was dissolved in acetonitrile (2 L), and tetrabutylammonium fluoride (1M TBAF in THF, 5.36 L) was added, followed by reaction at 60 °C for 1 h. TLC showed that obvious impurities appeared above the product spot, which was difficult to separate by column chromatography.

[0175] Comparative Example 3 Compared with Example 1, the only difference was the equivalent of trifluoroacetic anhydride in step (2), which was as follows: To a 10 L four-necked flask was added dichloromethane (DCM, 2.5 L) at 25 °C, followed by the nitroxide intermediate (452 g, 1.34 mol) and trimethylamine (2M in THF, 4 L, 8 mol). The reaction system was cooled to 0 °C, and trifluoroacetic anhydride (TFAA, 844 g, 4 mol) was added dropwise. After the addition was completed, the reaction was resumed to 25 °C for 1 h. TLC showed that most of the starting material remained.

[0176] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A nitrogen oxide intermediate, the structural formula of which is shown below; 。 2. A method for synthesizing a key intermediate of a PARP1 inhibitor, characterized in that, Includes the following steps: (1) The compound of formula I is first reacted with N-Boc piperazine, a base and an organic solvent to obtain the nitrogen oxide intermediate of claim 1; (2) Add solvent, trimethylamine and trifluoroacetic anhydride to the nitride intermediate in sequence, and react at room temperature to obtain compound II; (3) Finally, the compound of formula II was dissolved in acetonitrile, tetrabutylammonium fluoride was added, and the mixture was heated to obtain the key intermediate of the PARP1 inhibitor. The structural formulas of compounds of formula I, formula II, and key intermediates of PARP1 inhibitors are shown below: 、 、 。 3. The synthesis method according to claim 2, characterized in that, In step (1), the alkali is selected from one or more of potassium carbonate, cesium carbonate and sodium tert-butoxide.

4. The synthesis method according to claim 2, characterized in that, The organic solvent mentioned in step (1) is selected from one or more of N,N-dimethylformamide, tetrahydrofuran and acetonitrile.

5. The synthesis method according to claim 2, characterized in that, The molar volume ratio of the compound of formula I in step (1) to N-Boc piperazine, base and organic solvent is 2.5-3.5 mol:3-4 mol:6-8 mol:5-6 L.

6. The synthesis method according to claim 2, characterized in that, In step (1), the reaction temperature is 70-90℃ and the reaction time is 10-14 h.

7. The synthesis method according to claim 2, characterized in that, In step (1), after the reaction is completed, post-processing is required. The post-processing process includes: cooling the reaction solution to 20-30°C, filtering, concentrating, pulping and drying.

8. The synthesis method according to claim 7, characterized in that, The filtration process uses diatomaceous earth, and the filter cake is washed with ethyl acetate. The slurrying reagent is tetrahydrofuran, methyl ether, or n-hexane, and the slurrying time is 8-12 h.

9. The synthesis method according to claim 2, characterized in that, In step (2), the solvent is selected from one or more of dichloromethane, dichloroethane and dioxane; the trimethylamine is a tetrahydrofuran solution of 1-3 M trimethylamine.

10. The synthesis method according to claim 2, characterized in that, In step (2), the temperature at which the solvent and trimethylamine are added is 20-30°C, and the temperature at which trifluoroacetic anhydride is added is 0-5°C.

11. The synthesis method according to claim 2, characterized in that, In step (2), the room temperature reaction temperature is 20-30℃ and the room temperature reaction time is 0.5-1.5 h. After the room temperature reaction is completed by monitoring with TLC, concentration is carried out.

12. The synthesis method according to claim 2, characterized in that, In step (2), the molar volume ratio of the nitrogen oxide intermediate, solvent, trimethylamine and trifluoroacetic anhydride is 1-2 mol: 2-3 L: 3-5.5 L: 3-5.5 mol.

13. The synthesis method according to claim 12, characterized in that, In step (3), the tetrabutylammonium fluoride is a 1-2 M tetrabutylammonium fluoride tetrahydrofuran solution; the volume ratio of acetonitrile to tetrabutylammonium fluoride is 1-3:6-7.

14. The synthesis method according to claim 2, characterized in that, In step (3), the temperature of the heating reaction is 50-70℃ and the heating reaction time is 0.5-1.5 h.

15. The synthesis method according to claim 2, characterized in that, In step (3), after the heating reaction is completed, the reaction solution needs to be cooled to 20-30℃, then concentrated, separated, the organic phase washed with water, dried and purified by column chromatography.

16. The synthesis method according to claim 15, characterized in that, The reagent for the separation is ethyl acetate; the process of washing the organic phase with water involves washing with water and saturated brine sequentially; the eluent for column chromatography purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 2-4:1.

Images