Method for preparing pyridazinone compound and application of pyridazinone compound

Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a method for preparing a pyridazinone compound and application of the pyridazinone compound, and the method comprises the following steps: step 1, reacting a compound as shown in a formula V with a Grignard reagent to obtain a compound as shown in a formula IV; 2, reacting the compound shown in the formula IV with succinic anhydride to obtain a compound shown in a formula III; 3, reacting the compound shown in the formula III with hydrazine hydrate to obtain a compound shown in a formula II; 4, oxidizing the compound shown in the formula II to obtain a pyridazinone compound; the pyridazinone compound or the pharmaceutically acceptable salt or prodrug of the pyridazinone compound can be used for inhibiting the activity of MET protein kinase and the mutant form of the MET protein kinase, and especially can be used as a Tepotinib intermediate.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a pyridazinone compound and an application thereof. Background Art

[0002] Receptor tyrosine kinase c-Met, also known as hepatocyte growth factor receptor, is a transmembrane receptor with autonomous phosphorylation activity encoded by the MET gene. It is a unique subfamily in the receptor tyrosine kinase family and is mainly produced in epithelial cells. HGF is the only high-affinity ligand of c-Met and is widely present in various human tissues and organs. c-Met binds to HGF secreted by mesenchymal cells, triggering c-Met dimerization, which then undergoes transfer phosphorylation at the two catalytic sites Tyr1234 and Tyr1235 in the c-Met activation loop (A-loop), leading to autophosphorylation of Tyr1349 and Tyr1356 in its C-terminal multifunctional docking region, thereby recruiting a variety of cellular effectors, such as GAB1, GRB2, PLC, and SRC. GAB1 continues to recruit downstream effector molecules, such as SHP2, PI3K, CRKL, etc., to form a multi-protein signaling complex and activate a series of downstream signal transduction pathways, including RAS-MAPK, PI3K-AKT, and STATs pathways. c-Met / HGF has multiple biological functions, activates downstream signaling pathways, and plays a very important role in the occurrence, development, metastasis and angiogenesis of tumors.

[0003] Studies have found that c-Met is highly expressed in many tumor cells, such as hepatocellular carcinoma, gastric cancer, ovarian cancer, non-small cell lung cancer, renal cancer and other cancer cells. Overexpression of c-Met is closely related to the formation and prognosis of various tumors. Overactivation of the HGF / c-Met pathway will cause activation of downstream signaling pathways, thereby inducing cancer. In addition, overexpression of HGF and c-Met will also lead to resistance to related inhibitors in the EGFR, RAS-RAF-MEK and Akt-mTOR signaling pathways, which is an important mechanism for tumor cell escape. For example, in non-small cell lung cancer with EGFR active mutations, overexpression of HGF leads to phosphorylation of c-Met, thereby activating the downstream PI3K-Akt pathway, leading to cell resistance to EGFR inhibitors. Similarly, upregulation and secretion of HGF in the tumor microenvironment can lead to cell resistance to RAS inhibitors.

[0004] After blocking the abnormally activated HGF / c-Met signaling pathway in tumor cells, tumor cells will undergo a series of changes, including cell morphology changes, slowed proliferation, reduced tumorigenicity, and decreased invasive ability. Therefore, developing a highly active c-Met inhibitor can provide an effective treatment for a variety of primary c-Met signaling pathway abnormalities and drug-resistant c-Met abnormal expression tumors.

[0005] Currently, there are several main intervention therapies for the c-Met pathway: ① Therapeutic antibodies: bind to HGF or c-Met, and inhibit the c-Met pathway by interfering with the interaction between HGF and c-Met; ② Small molecule tyrosine kinase inhibitors: inhibit c-Met kinase activity or other kinases that play an important role in the progression of cancer; ③ Molecules similar to HS90 inhibitors: block the c-Met pathway by affecting the stability or expression of c-Met protein; ④ Functional molecules that interfere with the downstream effectors of the c-Met pathway.

[0006] As for c-Met small molecule inhibitors, the c-Met small molecule inhibitors currently under clinical development mainly include Crizotinib, Tepotinib, Capmatinib, Volitinib, Cabozantinib (XL-184) and ARQ-197, among which Tepotinib is a MET tyrosine kinase inhibitor with potential anti-tumor activity, which can be used to treat adult patients with metastatic non-small cell lung cancer (NSCLC) carrying MET exon 14 (METex14) skipping mutations; therefore, a method for large-scale synthesis of Tepotinib intermediates is urgently needed.

[0007] Chinese patent application CN102264727A discloses the following two synthesis methods:

[0008]

[0009] The substrate 3-acetobenzonitrile used in method one is relatively expensive, and glyoxylic acid is highly toxic and harmful to the human body; the second step of method two uses a palladium catalyst, which is relatively expensive, and both methods have a long reaction time and low preparation efficiency. Overall, they are not suitable for large-scale production. Summary of the invention

[0010] The purpose of the present invention is to provide a method for preparing a pyridazinone compound and its application, which greatly reduces the cost and reaction time.

[0011] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0012] According to a first aspect of an embodiment of the present invention, a method for preparing a pyridazinone compound is provided, wherein the pyridazinone compound has a structural formula of the following formula I:

[0013]

[0014] The method comprises: subjecting a compound having the following formula II to an oxidation reaction to obtain the pyridazinone compound;

[0015]

[0016] wherein n1 is selected from 0, 1, 2 or 3, n1 R1s are the same or different from each other, and R1 is selected from hydroxyl, nitro, cyano, amino, substituted or unsubstituted C1-C 30 Alkyl, substituted or unsubstituted C2-C 30 Alkenyl, substituted or unsubstituted C2-C 30 Alkynyl, substituted or unsubstituted C1-C 30 Alkoxy, substituted or unsubstituted C1-C 10 Cycloalkoxy, substituted or unsubstituted C3-C 30 Cycloalkyl, substituted or unsubstituted C6-C 30 aryl, substituted or unsubstituted 3-30 membered heterocyclyl, substituted or unsubstituted 5-30 membered heteroaryl.

[0017] Preferably, the compound of formula II is prepared by the following steps:

[0018]

[0019] Step 1: reacting the compound of formula V with a Grignard reagent to obtain a compound of formula IV;

[0020] Step 2: reacting the compound of formula IV with succinic anhydride to obtain a compound of formula III;

[0021] Step 3: reacting the compound of formula III with hydrazine hydrate to obtain the compound of formula II; wherein n1 and R1 are as defined above, and X1 is selected from a halogen atom.

[0022] Preferably, the compound of formula I is prepared by the following steps:

[0023]

[0024] Step 1: reacting a compound of formula V with a Grignard reagent to obtain a compound of formula IV; Step 2: reacting the compound of formula IV with succinic anhydride to obtain a compound of formula III; Step 3: reacting the compound of formula III with hydrazine hydrate to obtain a compound of formula II; Step 4: oxidizing the compound of formula II to obtain the pyridazinone compound; wherein n1 and R1 are defined as above, and X1 is selected from a halogen atom.

[0025] Preferably, n1 is selected from 0, and the pyridazinone compound has the structural formula of the following formula I-1:

[0026]

[0027] Preferably, the pyridazinone compound of formula I-1 is prepared by the following steps:

[0028]

[0029] Step 1-1: reacting the compound of formula V-1 with a Grignard reagent to obtain a compound of formula IV-1;

[0030] Step 2-1: reacting the compound of formula IV-1 with succinic anhydride to obtain 4-(3-cyanophenyl)-4-oxobutanoic acid;

[0031] Step 3-1: reacting the 4-(3-cyanophenyl)-4-oxobutanoic acid with hydrazine hydrate to obtain 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile;

[0032] Step 4-1: subjecting the 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to an oxidation reaction to obtain the pyridazinone compound of formula I-1.

[0033] Preferably, X1 is selected from Br.

[0034] Preferably, in step 1-1, the molar ratio of the compound of formula V-1 to the Grignard reagent is 1:1.1-2; further preferably, in step 1-1, the molar ratio of the compound of formula V-1 to the Grignard reagent is 1:1.3.

[0035] Preferably, in step 1-1, the Grignard reagent is selected from isopropylmagnesium chloride-lithium chloride.

[0036] Preferably, in step 2-1, the molar ratio of the compound of formula IV-1 to succinic anhydride is 1:1.1-2; further preferably, in step 2-1, the molar ratio of the compound of formula IV-1 to succinic anhydride is 1:1.5.

[0037] Preferably, in step 3-1, the molar ratio of 4-(3-cyanophenyl)-4-oxobutanoic acid to hydrazine hydrate is 1:0.9-1.1; further preferably, in step 3-1, the molar ratio of 4-(3-cyanophenyl)-4-oxobutanoic acid to hydrazine hydrate is 1:1.

[0038] Preferably, in step 4-1, the oxidant of the oxidation reaction is cupric chloride;

[0039] Preferably, in step 4-1, the molar ratio of 3-(6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)benzonitrile to copper chloride is 1:1.8-2.2; further preferably, in step 4-1, the molar ratio of 3-(6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)benzonitrile to copper chloride is 1:2.

[0040] Preferably, the pyridazinone compound of formula I-1 is prepared by the following steps:

[0041]

[0042] Step 1-2: 3-bromobenzonitrile is reacted with a Grignard reagent, isopropylmagnesium chloride-lithium chloride, to obtain (3-cyanophenyl)magnesium bromide;

[0043] Step 2-2: reacting the (3-cyanophenyl)magnesium bromide with succinic anhydride to obtain 4-(3-cyanophenyl)-4-oxobutanoic acid;

[0044] Step 3-2: reacting the 4-(3-cyanophenyl)-4-oxobutanoic acid with hydrazine hydrate to obtain 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile;

[0045] Step 4-2: subjecting the 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to an oxidation reaction to obtain the pyridazinone compound of formula I-1.

[0046] Preferably, the pyridazinone compound is prepared by the following steps:

[0047] Step 1-2: 3-bromobenzonitrile is mixed with tetrahydrofuran, and the mixture is cooled to -20°C after nitrogen substitution, and a Grignard reagent isopropylmagnesium chloride-lithium chloride is added dropwise thereto while controlling the temperature at -20±2°C. After the addition is complete, the temperature is kept constant and stirred for 1-4 hours to obtain (3-cyanophenyl)magnesium bromide;

[0048] Step 2-2: Succinic anhydride and tetrahydrofuran are mixed, and the mixture is cooled to -60°C after nitrogen replacement. The temperature is kept constant, and the (3-cyanophenyl)magnesium bromide obtained in step 1-2 is transferred thereto. After the transfer is completed, the mixture is stirred for 1-3 hours to obtain 4-(3-cyanophenyl)-4-oxobutanoic acid;

[0049] Step 3-2: The 4-(3-cyanophenyl)-4-oxobutanoic acid is mixed with ethanol, hydrazine hydrate is added thereto, and after nitrogen replacement, the temperature is raised to 80° C. and refluxed for 2 h to obtain 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile;

[0050] Step 4-2: Mix the 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile with acetonitrile, add copper chloride, heat to 85° C. and reflux for 50 min, then cool until a solid precipitates, and obtain the pyridazinone compound of formula I-1 after filtration and recrystallization.

[0051] Preferably, in step 1-2, a sampling and monitoring process is also included: after sampling, dry ice is used for quenching, and LC-MS is sent to monitor the residual raw material, and stirring is terminated after confirming that the residual raw material is less than 5%.

[0052] Preferably, in step 2-2, after the stirring is completed, the step of quenching the reaction with hydrochloric acid is also included: 7M hydrochloric acid is added to the reaction bottle, after nitrogen replacement, the temperature is cooled to 0°C, and then the stirred reaction solution is transferred to the reaction bottle for quenching, and the temperature is controlled between 0-10°C during the process.

[0053] Preferably, in step 2-2, after quenching the reaction with hydrochloric acid, the process further comprises concentrating, extracting and separating the liquids to obtain 4-(3-cyanophenyl)-4-oxobutanoic acid.

[0054] Preferably, in step 3-2, after the temperature reaction is completed, the reaction system is cooled to room temperature, and then continued to be cooled with ice water until a large amount of yellow flocculent solid is precipitated, and 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile is obtained after filtration.

[0055] Preferably, n1 is selected from 1, and the pyridazinone compound has the structural formula of the following formula I-2:

[0056]

[0057] Preferably, the pyridazinone compound of formula I-2 is prepared by the following steps:

[0058]

[0059] Step 1-1: reacting the compound of formula V-2 with a Grignard reagent to obtain a compound of formula IV-2;

[0060] Step 2-1: reacting the compound of formula IV-2 with succinic anhydride to obtain 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid;

[0061] Step 3-1: reacting the 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid with hydrazine hydrate to obtain 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile;

[0062] Step 4-1: subjecting the 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile to an oxidation reaction to obtain the pyridazinone compound of formula I-2;

[0063] X1 is halogen.

[0064] Preferably, in step 1-1, the molar ratio of the compound of formula V-2 to the Grignard reagent is 1:1.1-2;

[0065] Preferably, in step 1-1, the Grignard reagent is selected from isopropylmagnesium chloride-lithium chloride;

[0066] Preferably, in step 2-1, the molar ratio of the compound of formula IV-2 to succinic anhydride is 1:1.1-2;

[0067] Preferably, in step 3-1, the molar ratio of 4-(3-cyanophenyl)-4-oxobutanoic acid to hydrazine hydrate is 1:0.9-1.1;

[0068] Preferably, in step 4-1, the oxidant of the oxidation reaction is copper chloride; the molar ratio of 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to copper chloride is 1:1.8-2.2;

[0069] Preferably, X1 is Br.

[0070] According to a second aspect of an embodiment of the present invention, a pharmaceutical composition is provided, characterized in that the pharmaceutical composition comprises the pyridazinone compound prepared by the aforementioned method, or a pharmaceutically acceptable salt or prodrug of the pyridazinone compound, and a pharmaceutically acceptable carrier.

[0071] According to a third aspect of an embodiment of the present invention, there is provided use of the pyridazinone compound prepared by the aforementioned method or the pharmaceutical composition in synthesizing a drug for inhibiting the activity of MET protein kinase and its mutant forms.

[0072] Preferably, the drug that inhibits the activity of MET protein kinase and its mutant forms is Tepotinib.

[0073] Preferably, the pyridazinone compound prepared by the aforementioned method, or a pharmaceutically acceptable salt or prodrug of the pyridazinone compound, can be used as a Tepotinib intermediate.

[0074] The beneficial effects of the present invention are:

[0075] (1) The raw materials used in the preparation method provided by the present invention are cheaper than those used in the prior art, which effectively reduces the production cost.

[0076] (2) The preparation method provided by the present invention takes less time than the prior art and can effectively improve the preparation efficiency.

[0077] (3) The reaction conditions of the preparation method provided by the present invention are milder, and the operation is safe and simple.

[0078] (4) The yield of each step of the preparation method provided by the present invention is high, and a product of high purity can be obtained without purification by column chromatography. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 This is the H NMR spectrum data of the product obtained in step 2 of Example 1 of the present invention.

[0080] Figure 2 This is the H NMR spectrum data of the product obtained in step 3 of Example 1 of the present invention.

[0081] Figure 3 This is the H NMR spectrum data of the product obtained in step 4 of Example 1 of the present invention. DETAILED DESCRIPTION

[0082] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0083] In the present invention, the term "alkyl" refers to an aliphatic hydrocarbon group, which can be straight or branched. Branched refers to one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkyl chain. "Lower alkyl" refers to a group containing about 1 to about 6 carbon atoms in the chain, which can be straight or branched.

[0084] In the present invention, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be straight or branched. Branched refers to one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkenyl chain. "Lower alkenyl" refers to a group containing about 2 to about 6 carbon atoms in the chain, which can be straight or branched.

[0085] In the present invention, the term "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be straight or branched. Branched refers to one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkynyl chain. "Lower alkynyl" refers to containing about 2 to about 6 carbon atoms in the chain, which can be straight or branched. Non-limiting examples of alkynyl include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl and decynyl.

[0086] In the present invention, the term "aryl" refers to an aromatic monocyclic or polycyclic ring system. The aryl group may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

[0087] In the present invention, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system in which one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen or sulfur, either alone or in combination, preferably containing about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents", which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name indicates that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of the heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyrazinyl, furanyl, thiophenyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl, and the like.

[0088] In the present invention, the term "amino" refers to a -NR'R" group. The amino group may be optionally substituted. In an unsubstituted amino group, R' and R" are hydrogen. In a substituted amino group, R' and R" may each independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl or heteroaryl, provided that R' and R" are not both hydrogen. In a substituted amino group, R' and R" may be cyclized to form a cyclic amino group, such as a pyrrolidinyl or piperidinyl group. Such cyclic amino groups may incorporate other heteroatoms, for example to form piperazine or morpholine groups. Such cyclic amino groups may be optionally substituted, for example, by amino, hydroxyl or oxo groups.

[0089] In the present invention, the term "alkoxy" refers to -O-alkyl. Alkoxy can refer to a straight chain, branched or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and pentoxy. Alkoxy can be optionally substituted with one or more alkoxy substituents ("substituted alkoxy").

[0090] In the present invention, the term "cycloalkyl" refers to a non-aromatic mono- or polycyclic ring system, and the preferred cycloalkyl ring contains about 5 to about 7 ring atoms. The cycloalkyl group may be optionally substituted with one or more "ring system substituents", which may be the same or different and are defined as above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl, etc. In the present invention, the term "cycloalkoxy" refers to a group in which one or more carbons in a mono- or polycyclic ring system of a "cycloalkyl" are replaced by oxygen atoms.

[0091] In the present invention, the term "heterocyclyl" refers to a non-aromatic saturated monocyclic or polycyclic ring system, wherein one or more ring atoms in the ring system are elements other than carbon, such as nitrogen, oxygen or sulfur, either alone or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system, and preferred heterocycles contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name indicates that at least one nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. The heterocyclyl may be optionally substituted with one or more "ring system substituents", which are the same or different and are defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolane, 1,4-dioxacyclohexyl, tetrahydrofuranyl, tetrahydrophenylthio, tetrahydrothiopyranyl, etc.

[0092] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0093] Example 1

[0094] The following steps are involved:

[0095] Step 1: Grignard exchange

[0096]

[0097] 3-Bromobenzonitrile (5.4 g, 30 mmol, 1.0 eq.) and tetrahydrofuran (33 mL) were mixed in a 100 mL jacketed reaction bottle, and the temperature was lowered to -20 °C after nitrogen replacement. Then iPrMgCl was added dropwise . LiCl (1.3 eq.) was added and the temperature was controlled at -20±2°C. After the addition was completed, the mixture was stirred at the temperature for 2 hours, during which time a sample was taken and quenched with dry ice and then sent to LC-MS to monitor the residual raw material. After confirming that the residual raw material was less than 5%, the subsequent operation was performed to obtain (3-cyanophenyl)magnesium bromide.

[0098] Step 2: Ring opening using succinic anhydride

[0099]

[0100] Succinic anhydride (4.5 g, 45 mmol, 1.5 eq.) and tetrahydrofuran (22 mL) were mixed in a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to -60 ° C. After that, the Grignard reagent prepared in the first step was transferred to this reaction bottle using a double-ended needle under temperature control. After the transfer was completed, the reaction was stirred and reacted for 1.5 hours under temperature control, and a sample was taken and quenched with dry ice and sent to LC-MS for monitoring. After confirming that the reaction was completed, the 7M hydrochloric acid (24 mL) prepared in advance was added to a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to 0 ° C, and then the above reaction solution was transferred to this reaction bottle through a double-ended needle for quenching, and the temperature was controlled between 0-10 ° C during the process. The quenched solution was vacuum concentrated to remove tetrahydrofuran, and the aqueous phase was extracted with ethyl acetate, and then the pH was adjusted to 9-10 with 10% sodium bicarbonate solution, and then the liquid was separated. The aqueous phase was then adjusted to pH 2-3 with concentrated hydrochloric acid, and the temperature was controlled between 0-10°C. Afterwards, it was extracted twice with ethyl acetate, the organic phases were combined, and then concentrated in vacuo to obtain the compound 4-(3-cyanophenyl)-4-oxobutanoic acid (5.5 g, yield 90%). Its H NMR spectrum data is as follows: Figure 1 shown.

[0101] 1H NMR (400MHz, CDCl3) δ8.29-8.28(1H), 8.24-8.22(1H), 7.90-7.87(1H), 7.67-7.64(1H), 3.34-3.31(2H), 2.89-2.86(2H).

[0102] Step 3: Ring closure reaction

[0103]

[0104] 4-(3-Cyanophenyl)-4-oxobutanoic acid (1.0 g, 4.9 mmol) and ethanol (15 mL) were mixed in a 50 mL three-necked flask, and hydrazine hydrate (0.3 mL, 4.9 mmol, 1 eq.) with a content of 80% was added. After nitrogen substitution, the temperature was raised to 80°C and refluxed for 2 h. The sampling point was controlled at the central control board. After confirming that the reaction was completed, the reaction system was cooled to room temperature and continued to be cooled with ice water until a large amount of yellow flocculent solid was precipitated. The compound 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile (0.83 g, yield 85%) was obtained by filtration. Its H NMR spectrum data are shown as follows: Figure 2 shown.

[0105] 1 H NMR (400MHz, DMSO) δ11.09(1H),8.14-8.13(1H),8.10-8.09(1H),8.08-8.07(1H),7.89-7.63(1H),3.01-2.97(2H),1.08-1.04(2H).

[0106] Step 4: Oxidation reaction

[0107]

[0108] 3-(6-Oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile and acetonitrile (10 mL) were mixed in a 25 mL three-necked flask, copper chloride (1.4 g, 10.0 mmol, 2 eq.) was added, the temperature was raised to 85°C, refluxed for 50 min, and after the reaction was confirmed to be complete by the sampling point control panel, the reaction system was cooled to room temperature, and then continued to be cooled with ice water until a large amount of solid precipitated. The obtained solid was filtered and recrystallized with isopropanol to obtain compound 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (0.94 g, yield 95%). Its H NMR spectrum data are shown as follows: Figure 3 shown.

[0109] 1H NMR (400MHz, DMSO) δ13.36(1H),8.32-8.31(1H),8.22-8.19(1H),8.15-8.12(1H),7.93-7.91(1H),7.72-7.68(1H),7.06-7.03(1H).

[0110] Example 2

[0111] The following steps are included:

[0112] Step 1: Grignard exchange

[0113]

[0114] 3-Bromo-5-methylbenzonitrile (5.9 g, 30 mmol, 1.0 eq.) and tetrahydrofuran (35 mL) were mixed in a 100 mL jacketed reaction bottle, and the temperature was lowered to -20 °C after nitrogen replacement. Then iPrMgCl was added dropwise . LiCl (1.3 eq.) was added and the temperature was controlled at -20±2°C. After the addition was completed, the mixture was stirred at the controlled temperature for 2 hours, during which time a sample was taken and quenched with dry ice and then sent to LC-MS to monitor the residual raw material. After confirming that the residual raw material was less than 5%, the subsequent operation was performed to obtain (3-cyano-5-methylphenyl)magnesium bromide.

[0115] Step 2: Ring opening using succinic anhydride

[0116]

[0117] Succinic anhydride (4.5 g, 45 mmol, 1.5 eq.) and tetrahydrofuran (22 mL) were mixed in a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to -60 ° C. After that, the Grignard reagent prepared in the first step was transferred to this reaction bottle using a double-ended needle under temperature control. After the transfer was completed, the reaction was stirred and reacted for 1.5 hours under temperature control, and a sample was taken and quenched with dry ice and sent to LC-MS for monitoring. After confirming that the reaction was completed, the 7M hydrochloric acid (24 mL) prepared in advance was added to a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to 0 ° C, and then the above reaction solution was transferred to this reaction bottle through a double-ended needle for quenching, and the temperature was controlled between 0-10 ° C during the process. The quenched solution was vacuum concentrated to remove tetrahydrofuran, and the aqueous phase was extracted with ethyl acetate, and then the pH was adjusted to 9-10 with 10% sodium bicarbonate solution, and then the liquid was separated. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and the temperature was controlled between 0-10° C. Afterwards, it was extracted twice with ethyl acetate, the organic phases were combined and then concentrated in vacuo to obtain compound 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid (5.3 g, yield 87%).

[0118] Step 3: Ring closure reaction

[0119]

[0120] 4-(3-Cyano-5-methylphenyl)-4-oxobutanoic acid (1.0 g, 4.9 mmol) and ethanol (15 mL) were mixed in a 50 mL three-necked flask, and 80% hydrazine hydrate (0.3 mL, 4.9 mmol, 1 eq.) was added. After nitrogen substitution, the temperature was raised to 80 ° C. and refluxed for 2 h. The sampling point was controlled at the central control board. After confirming that the reaction was completed, the reaction system was cooled to room temperature, and then continued to cool with ice water until a large amount of yellow flocculent solid precipitated. The compound 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile (0.88 g, yield 85%) was obtained by filtration.

[0121] Step 4: Oxidation reaction

[0122]

[0123] 3-Methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile (1.0 g, 5.0 mmol) and acetonitrile (10 mL) were mixed in a 25 mL three-necked flask, copper chloride (1.4 g, 10.0 mmol, 2 eq.) was added, the temperature was raised to 85°C, refluxed for 50 min, and after the sampling point board central control confirmed the completion of the reaction, the reaction system was cooled to room temperature, and then continued to cool with ice water until a large amount of solid precipitated, the obtained solid was filtered and recrystallized with isopropanol to obtain the compound 3-methyl-5-(6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile (1.0 g, yield 95%).

[0124] Comparative Example 1

[0125] The following steps are involved:

[0126] Step 1: Grignard reagent exchange, adjust to iPrMgCl Grignard reagent

[0127]

[0128] 3-Bromobenzonitrile (5.4 g, 30 mmol) and tetrahydrofuran (32 mL) were mixed in a 100 mL jacketed reaction bottle, and the temperature was lowered to -20°C after nitrogen replacement. Then iPrMgCl (1.3 eq.) was added dropwise, and the temperature was controlled at -20±2°C. After the addition was completed, the temperature was controlled and stirred for 2 hours. During this period, samples were taken and quenched with dry ice and sent to LC-MS to monitor the residual raw materials. After confirming that the residual raw materials were less than 5%, the subsequent operation was carried out to obtain (3-cyanophenyl) magnesium bromide.

[0129] Step 2: Ring opening using succinic anhydride

[0130]

[0131] Succinic anhydride (4.5 g, 45 mmol, 1.5 eq.) and tetrahydrofuran (22 mL) were mixed in a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to -60 ° C. After that, the Grignard reagent prepared in the first step was transferred to this reaction bottle using a double-ended needle under temperature control. After the transfer was completed, the reaction was stirred and reacted for 1.5 hours under temperature control, and a sample was taken and quenched with dry ice and sent to LC-MS for monitoring. After confirming that the reaction was completed, the 7M hydrochloric acid (24 mL) prepared in advance was added to a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to 0 ° C, and then the above reaction solution was transferred to this reaction bottle through a double-ended needle for quenching, and the temperature was controlled between 0-10 ° C during the process. The quenched solution was vacuum concentrated to remove tetrahydrofuran, and the aqueous phase was extracted with ethyl acetate, and then the pH was adjusted to 9-10 with 10% sodium bicarbonate solution, and then the liquid was separated. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and the temperature was controlled between 0-10° C. Then, it was extracted twice with ethyl acetate, and the organic phases were combined and concentrated in vacuo to obtain compound 4-(3-cyanophenyl)-4-oxobutanoic acid (2.5 g, yield 40%).

[0132] Comparative Example 2

[0133] Changing the molar ratio of the raw materials in step 1-4 to a ratio outside the protection range, theoretically, the yield is lower than that of Example 1-2.

[0134] Step 1: Grignard exchange

[0135]

[0136] 3-Bromo-5-methylbenzonitrile (3.9 g, 20 mmol) and tetrahydrofuran (23 mL) were mixed in a 100 mL jacketed reaction bottle, and the temperature was cooled to -20 °C after nitrogen replacement. Then iPrMgCl was added dropwise . LiCl (1.0 eq.) was added and the temperature was controlled at -20±2°C. After the addition was completed, the mixture was stirred at the temperature for 2 hours, during which time a sample was taken and quenched with dry ice and then sent to LC-MS to monitor the residual raw material. After confirming that the residual raw material was less than 5%, the subsequent operation was performed to obtain (3-cyano-5-methylphenyl)magnesium bromide.

[0137] Step 2: Ring opening using succinic anhydride

[0138]

[0139] Succinic anhydride (2.0 g, 20 mmol, 1.0 eq.) and tetrahydrofuran (10 mL, 5.0 Vol.) were mixed in a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to -60 ° C. After that, the Grignard reagent prepared in the first step was transferred to this reaction bottle under temperature control using a double-ended needle. After the transfer was completed, the reaction was stirred and reacted for 1.5 h under temperature control, and a sample was taken and quenched with dry ice and sent to LC-MS for monitoring. After confirming that the reaction was completed, the 7M hydrochloric acid (11 mL) prepared in advance was added to a 100 mL jacketed bottle, and after nitrogen replacement, the temperature was lowered to 0 ° C, and then the above reaction solution was transferred to this reaction bottle through a double-ended needle for quenching, and the temperature was controlled between 0-10 ° C during the process. The quenched solution was vacuum concentrated to remove tetrahydrofuran, and the aqueous phase was extracted with ethyl acetate, and then the pH was adjusted to 9-10 with 10% sodium bicarbonate solution, and then the liquid was separated. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and the temperature was controlled between 0-10° C. Afterwards, it was extracted twice with ethyl acetate, the organic phases were combined and then concentrated in vacuo to obtain compound 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid (2.9 g, yield 66%).

[0140] Step 3: Ring closure reaction

[0141]

[0142] 4-(3-Cyano-5-methylphenyl)-4-oxobutanoic acid (1.0 g, 4.9 mmol) and ethanol (15 mL, 15.0 Vol.) were mixed in a 50 mL three-necked flask, and 80% hydrazine hydrate (0.24 mL, 3.9 mmol, 0.8 eq.) was added. After nitrogen substitution, the temperature was raised to 80 ° C. and refluxed for 2 h. The sampling point was controlled at the central control board. After confirming that the reaction was completed, the reaction system was cooled to room temperature, and then continued to cool with ice water until a large amount of yellow flocculent solid precipitated. The compound 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile (0.43 g, yield 42%) was obtained by filtration.

[0143] Step 4: Oxidation reaction

[0144]

[0145] 3-Methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile (1.0 g, 5.0 mmol) and acetonitrile (10 mL, 10.0 Vol.) were mixed in a 25 mL three-necked flask, copper chloride (1.1 g, 7.5 mmol, 1.5 eq.) was added, the temperature was raised to 85 ° C, refluxed for 50 min, and after the sampling point board central control confirmed the completion of the reaction, the reaction system was cooled to room temperature, and then continued to cool with ice water until a large amount of solid precipitated, the obtained solid was filtered and recrystallized with isopropanol to obtain the compound 3-methyl-5-(6-oxo-1,6-dihydropyridazine-3-yl)benzonitrile (0.9 g, yield 85%).

[0146] Those skilled in the art will readily appreciate other embodiments of the present invention after considering the specification and practicing the disclosure disclosed herein. The present invention is intended to cover any variations, uses or adaptations of the present invention that follow the general principles of the present invention and include common knowledge or customary techniques in the art that are not disclosed by the present invention. The description and examples are to be considered exemplary only, and the true scope and spirit of the present invention is indicated by the claims.

Claims

1. A method for preparing a pyridazinone compound, characterized in that: The pyridazinone compound has the structural formula I below: The method comprises: subjecting a compound having the following formula II to an oxidation reaction to obtain the pyridazinone compound; wherein n1 is selected from 0, 1, 2 or 3, n1 R1s are the same or different from each other, and R1 is selected from hydroxyl, nitro, cyano, amino, substituted or unsubstituted C1-C 30 Alkyl, substituted or unsubstituted C2-C 30 Alkenyl, substituted or unsubstituted C2-C 30 Alkynyl, substituted or unsubstituted C1-C 30 Alkoxy, substituted or unsubstituted C1-C 10 Cycloalkoxy, substituted or unsubstituted C3-C 30 Cycloalkyl, substituted or unsubstituted C6-C 30 aryl, substituted or unsubstituted 3-30 membered heterocyclyl, substituted or unsubstituted 5-30 membered heteroaryl.

2. The method according to claim 1, characterized in that The compound of formula II is prepared by the following steps: Step 1: reacting the compound of formula V with a Grignard reagent to obtain a compound of formula IV; Step 2: reacting the compound of formula IV with succinic anhydride to obtain a compound of formula III; Step 3: reacting the compound of formula III with hydrazine hydrate to obtain the compound of formula II; wherein n1 and R1 are as defined in claim 1, and X1 is selected from halogen atoms.

3. The method according to claim 1 or 2, characterized in that: n1 is selected from 0, and the pyridazinone compound has the structural formula of the following formula I-1:

4. The method according to claim 3, characterized in that The pyridazinone compound of formula I-1 is prepared by the following steps: Step 1-1: reacting the compound of formula V-1 with a Grignard reagent to obtain a compound of formula IV-1; Step 2-1: reacting the compound of formula IV-1 with succinic anhydride to obtain 4-(3-cyanophenyl)-4-oxobutanoic acid; Step 3-1: reacting the 4-(3-cyanophenyl)-4-oxobutanoic acid with hydrazine hydrate to obtain 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile; Step 4-1: subjecting the 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to an oxidation reaction to obtain the pyridazinone compound of formula I-1; X1 is halogen.

5. The method according to claim 4, characterized in that The method meets at least one of the following requirements: 1) In step 1-1, the molar ratio of the compound of formula V-1 to the Grignard reagent is 1:1.1-2; 2) In step 1-1, the Grignard reagent is selected from isopropylmagnesium chloride-lithium chloride; 3) In step 2-1, the molar ratio of the compound of formula IV-1 to succinic anhydride is 1:1.1-2; 4) In step 3-1, the molar ratio of 4-(3-cyanophenyl)-4-oxobutanoic acid to hydrazine hydrate is 1:0.9-1.1; 5) In step 4-1, the oxidant of the oxidation reaction is copper chloride; the molar ratio of 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to copper chloride is 1:1.8-2.2; 6) X1 is Br.

6. The method according to claim 1 or 2, characterized in that: n1 is selected from 1, and the pyridazinone compound has the structural formula of the following formula I-2:

7. The method according to claim 3, characterized in that The pyridazinone compound of formula I-2 is prepared by the following steps: Step 1-1: reacting the compound of formula V-2 with a Grignard reagent to obtain a compound of formula IV-2; Step 2-1: reacting the compound of formula IV-2 with succinic anhydride to obtain 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid; Step 3-1: reacting the 4-(3-cyano-5-methylphenyl)-4-oxobutanoic acid with hydrazine hydrate to obtain 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile; Step 4-1: subjecting the 3-methyl-5-(6-oxo-1,4,5,6-tetrahydropyrazin-3-yl)benzonitrile to an oxidation reaction to obtain the pyridazinone compound of formula I-2; X1 is halogen.

8. The method according to claim 7, characterized in that The method meets at least one of the following requirements: 1) In step 1-1, the molar ratio of the compound of formula V-2 to the Grignard reagent is 1:1.1-2; 2) In step 1-1, the Grignard reagent is selected from isopropylmagnesium chloride-lithium chloride; 3) In step 2-1, the molar ratio of the compound of formula IV-2 to succinic anhydride is 1:1.1-2; 4) In step 3-1, the molar ratio of 4-(3-cyanophenyl)-4-oxobutanoic acid to hydrazine hydrate is 1:0.9-1.1; 5) In step 4-1, the oxidant of the oxidation reaction is copper chloride; the molar ratio of 3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzonitrile to copper chloride is 1:1.8-2.2; 6) X1 is Br.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the pyridazinone compound prepared by the method according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or prodrug of the pyridazinone compound, and a pharmaceutically acceptable carrier.

10. Use of the pyridazinone compound prepared by the method according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in synthesizing a drug for inhibiting the activity of MET protein kinase and its mutant forms.

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