Preparation method of pyridazinone compound, deuterated pyridazinone compound and application thereof

Abstract

A preparation method of a pyridazinone compound, a deuterated pyridazinone compound and applications thereof, relating to the technical field of pharmacy. The preparation method comprises the following steps: under an inert atmosphere, mixing 3-cyanophenyl ethynyltetrazine, a base, dry methanol or deuterated methanol, and reacting to obtain an intermediate; and performing a demethylation reaction on the intermediate under an inert atmosphere to obtain a pyridazinone compound. This preparation method not only has mild reaction conditions and a short synthesis route, can effectively reduce the cost of industrial production of pyridazinone compounds and improve safety, but more importantly, this preparation method can prepare a deuterated pyridazinone compound, which can be further used to react with ((3-(5-(1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol to prepare deuterated tepotinib, effectively improving the metabolic stability, safety and efficacy of tepotinib.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmacy, and specifically relates to a preparation method of a pyridazinone compound, a deuterated pyridazinone compound prepared by using the preparation method, and deuterated tepotinib prepared by using the deuterated pyridazinone compound. Background Art

[0002] Tepotinib is a highly selective and potent MET tyrosine kinase inhibitor, mainly used for treating cancer patients carrying MET gene abnormalities. Currently, when using tepotinib, due to its possible rapid metabolism in the body, it has a short half-life and requires frequent dosing, resulting in poor patient compliance; in addition, toxic by-products may be produced during the metabolism of tepotinib, and the metabolic instability will also lead to fluctuations in blood drug concentration, affecting the efficacy.

[0003] As an isotope of hydrogen, deuterium is an ideal tracer and has no radioactivity. If tepotinib can be deuterated, the metabolic stability, safety and efficacy of tepotinib can be improved, providing an improvement plan for the possible problems of insufficient efficacy or side effects faced by patients with tepotinib indications, which has important scientific and clinical value.

[0004] Currently, tepotinib is mainly prepared by the bimolecular nucleophilic substitution reaction of a pyridazinone compound with (3-(5-1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol. The synthesis route is as follows:

[0005]

[0006] Among them, regarding the synthesis of the pyridazinone compound, the prior art discloses the synthesis using 3-acetylbenzonitrile or 3,6-dichloropyridazine as substrates. Patent CN119638633A discloses a synthesis method of a pyridazinone, which uses halogenated acetonitrile as a substrate and prepares the pyridazinone compound through Grignard reagent exchange, ring-opening reaction of succinic anhydride, ring-closing reaction, and oxidation reaction. However, the above-disclosed preparation methods of pyridazinone cannot prepare deuterated pyridazinone compounds, and correspondingly, they cannot further react with (3-(5-1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol to prepare deuterated tepotinib. Summary of the Invention

[0007] One object of the present invention is to provide a method for preparing a pyridazinone compound. This preparation method is based on the reaction of 3-cyanophenyl ethynyltetrazine with methanol or deuterated methanol, followed by demethylation to obtain a pyridazinone compound or a deuterated pyridazinone compound. This preparation method not only has mild reaction conditions and a short synthetic route, can effectively reduce the cost of industrial production of pyridazinone compounds and improve safety, but more importantly, this preparation method can obtain a deuterated pyridazinone compound, which can be further used to react with ((3-(5-1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol to obtain deuterated tepotinib, effectively improving the metabolic stability, safety and efficacy of tepotinib.

[0008] The above object of the present invention is achieved by the following technical solutions:

[0009] A method for preparing a pyridazinone compound, comprising the following steps:

[0010] Under an inert atmosphere, 3-cyanophenyl ethynyltetrazine, a base, and dry methanol or deuterated methanol are mixed and reacted to obtain an intermediate;

[0011] The intermediate is subjected to demethylation reaction under an inert atmosphere to obtain a pyridazinone compound shown in Formula I;

[0012] Formula I;

[0013] In Formula I, the group R is selected from hydrogen or deuterium.

[0014] In this technical solution, under an inert atmosphere, 3-cyanophenyl ethynyltetrazine is used as a reactant. Under basic conditions, 3-cyanophenyl ethynyltetrazine reacts with dry methanol MeOH to obtain an intermediate, and the intermediate is further demethylated to obtain a pyridazinone compound. The synthetic route is as follows:

[0015] ;

[0016]

[0017] In this technical solution, the reaction of 3-cyanophenyl ethynyltetrazine with methanol can be carried out at room temperature, and the reaction conditions are mild. In some embodiments, after the reaction is completed, the reaction solution is poured into water, extracted with dichloromethane DCM, dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography to obtain the corresponding intermediate.

[0018] In this technical solution, the demethylation of the intermediate can be achieved by adding dry DCM and BBr3 solution to the intermediate under an inert atmosphere and refluxing. In some embodiments, after the reaction is completed, the reaction is quenched with saturated NaHCO3 solution, adjusted to a weakly alkaline pH, extracted three times with DCM, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain the pyridazinone compound.

[0019] In some embodiments, the inert atmosphere can be nitrogen protection or argon protection.

[0020] In some embodiments, the base used in the reaction can be sodium carbonate, potassium carbonate, etc.

[0021] In this technical solution, the reaction conditions of the preparation process for preparing the pyridazinone compound based on 3-cyanophenyl ethynyltetrazine are mild, the synthesis route is short, the yield can reach over 70%, which can effectively reduce the cost of industrial production of the pyridazinone compound and improve safety. More importantly, in this preparation method, after replacing methanol with deuterated methanol, a deuterated pyridazinone compound can be prepared.

[0022] Specifically, under an inert atmosphere, using 3-cyanophenyl ethynyltetrazine as a reactant, under alkaline conditions, after 3-cyanophenyl ethynyltetrazine reacts with dry deuterated methanol CD3OD, an intermediate is obtained, and after further demethylation of the intermediate, a deuterated pyridazinone compound can be obtained. Its synthesis route is as follows:

[0023] ;

[0024]

[0025] This deuterated pyridazinone compound can further react with ((3-(5-(1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol to obtain deuterated tepotinib, thereby realizing the tracing of tepotinib, which is beneficial to understanding the metabolic stability, safety and efficacy of tepotinib during the medication process, and is expected to solve the problems of insufficient efficacy or side effects that patients with tepotinib indications may face. Among them, the synthesis route of deuterated tepotinib is as follows:

[0026]

[0027] In this technical solution, the preparation of 3-cyanophenyl ethynyltetrazine can be carried out by using the preparation method of ethynyltetrazine compounds disclosed by the inventor's team in Patent CN112812074B.

[0028] As a preferred preparation method of 3-cyanophenyl ethynyltetrazine in this invention, specifically, it includes the following steps:

[0029] S1: Under an inert atmosphere, 3-cyanobenzoic acid and 3-methyl-3-hydroxymethyloxetane are mixed and reacted to obtain (3-methyloxetane-3-yl) 3-cyanobenzoate;

[0030] S2: Add boron trifluoride ether solution to the (3-methyloxetane-3-yl) 3-cyanobenzoate for reaction. After the (3-methyloxetane-3-yl) 3-cyanobenzoate reacts completely, add methylthiohydrazine iodide salt, and heat the reaction under an inert atmosphere. After the reaction is completed and cooled, add iodobenzene diacetate to the reaction solution to obtain 3-cyanophenylthiomethyltetrazine;

[0031] S3: The 3-cyanophenylthiomethyltetrazine is heated and reacted with tributyl(trimethylsilylethynyl)tin under an inert atmosphere to obtain TMS-substituted 3-cyanophenyl ethynyltetrazine. After the TMS-substituted 3-cyanophenyl ethynyltetrazine undergoes an elimination reaction, the 3-cyanophenyl ethynyltetrazine is obtained.

[0032] In this technical solution, in step S1, (3-methyloxetane-3-yl) 3-cyanobenzoate is obtained by mixing and reacting 3-cyanobenzoic acid and 3-methyl-3-hydroxymethyloxetane. The synthesis route is as follows:

[0033]

[0034] In some preferred embodiments, 3-cyanobenzoic acid is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP), and dry DCM is added under an inert atmosphere. Subsequently, 3-methyl-3-hydroxymethyloxetane is added at a low temperature, and the (3-methyloxetane-3-yl) 3-cyanobenzoate is obtained by reaction.

[0035] In one or more embodiments, 3-methyl-3-hydroxymethyloxetane is added at -5°C to 5°C. After addition, the reaction solution is continuously stirred at this temperature for several minutes, and then the reaction solution is stirred and reacted at room temperature.

[0036] In this technical solution, in step S2, boron trifluoride ether solution is added to the (3-methyloxetane-3-yl) 3-cyanobenzoate for reaction. After the (3-methyloxetane-3-yl) 3-cyanobenzoate reacts completely, methylthiohydrazine iodide salt is added, and the reaction is heated under an inert atmosphere. After cooling, iodobenzene diacetate is added to the reaction solution, and 3-cyanophenylthiomethyltetrazine is obtained by reaction. The synthesis route is as follows:

[0037]

[0038] In some preferred embodiments, dry DCM is added to the (3-methyloxetane-3-yl) 3-cyanobenzoate, and then boron trifluoride ether solution is slowly added for reaction. After the (3-methyloxetane-3-yl) 3-cyanobenzoate is completely reacted, pyridine is added to quench the reaction.

[0039] In some preferred embodiments, methylthiohydrazine iodide salt and DMF are added to the reaction solution. Subsequently, DCM is removed under vacuum, and the reaction solution is heated under an inert atmosphere. After the reaction is completed, iodobenzene diacetate is added at a low temperature, and the reaction is carried out at room temperature to obtain 3-cyanophenylthiomethyltetrazine.

[0040] In one or more embodiments, the temperature of the heating reaction is 60-90 °C. After the reaction is completed, the reaction solution is cooled to -5 °C to 5 °C, and iodobenzene diacetate (PIDA) is added slowly in batches.

[0041] In the present technical solution, in step S3, 3-cyanophenylthiomethyltetrazine and tributyl(trimethylsilylethynyl)tin are heated and reacted under an inert atmosphere to obtain TMS-substituted 3-cyanophenyl ethynyltetrazine. After the elimination reaction of the TMS-substituted 3-cyanophenyl ethynyltetrazine, the 3-cyanophenyl ethynyltetrazine is obtained. The synthesis route is as follows:

[0042] ;

[0043]

[0044] In some preferred embodiments, 3-cyanophenylthiomethyltetrazine, PdCl2(PPh3)2 and CuI are dissolved in dry 1,4-dioxane, tributyl(trimethylsilylethynyl)tin is added, and the reaction is carried out under an inert atmosphere to obtain TMS-substituted 3-cyanophenyl ethynyltetrazine.

[0045] In some preferred embodiments, the TMS-substituted 3-cyanophenyl ethynyltetrazine is dissolved in methanol, and after adding potassium carbonate, the reaction is carried out at room temperature to obtain the 3-cyanophenyl ethynyltetrazine.

[0046] Another object of the present invention is to provide a deuterated pyridazinone compound, which is prepared by any of the foregoing preparation methods. The deuterated pyridazinone compound has the structural formula shown in Formula II:

[0047] Formula II.

[0048] Furthermore, the present invention also provides an application of a deuterated pyridazinone compound. Using any of the foregoing deuterated pyridazinone compounds, the deuterated pyridazinone compound is used to prepare deuterated tepotinib shown in Formula III

[0049] Formula III.

[0050] Another object of the present invention is to provide a deuterated tepotinib having a structural formula shown in Formula III, and the deuterated tepotinib is prepared by reacting a deuterated pyridazinone compound shown in Formula II with (3-(5-1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol;

[0051] Formula II; Formula III.

[0052] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0053] 1. The reaction conditions of the preparation process of the pyridazinone compound based on 3-cyanophenyl ethynyltetrazine in the present invention are mild, the synthesis route is short, the yield can reach more than 70%, which can effectively reduce the cost of industrial production of the pyridazinone compound and improve safety;

[0054] 2. The preparation method of the present invention can prepare a deuterated pyridazinone compound, which can be further reacted to prepare a deuterated tepotinib, and has wide application value;

[0055] 3. The deuterated tepotinib prepared by the present invention introduces deuterium as a tracer, and is expected to master the metabolic stability, safety and efficacy of tepotinib during medication, and provide an improvement plan for the problems of insufficient efficacy or side effects that patients with tepotinib indications may face. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The drawings described herein are used to provide a further understanding of the embodiments of the present invention, form a part of this application, and do not constitute a limitation on the embodiments of the present invention. In the drawings:

[0057] Figure 1 is a process flow block diagram of the preparation method of the pyridazinone compound and tepotinib in a specific embodiment of the present invention;

[0058] Figure 2 is a process flow block diagram of the preparation method of 3-cyanophenyl ethynyltetrazine in a specific embodiment of the present invention; DETAILED DESCRIPTION OF THE EMBODIMENTS

[0059] In order to make the purpose, technical solution and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the embodiments and the drawings. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and do not constitute a limitation on the present invention.

[0060] There are no particular restrictions on the sources of all raw materials of the present invention, and they can be purchased on the market or prepared by conventional methods well-known to those skilled in the art. There are no particular restrictions on the purity of all raw materials of the present invention, and the present invention preferably uses analytically pure or the purity requirements conventional in the pharmaceutical field. For all raw materials of the present invention, their trade names and abbreviations are all conventional trade names and abbreviations in the art, and each trade name and abbreviation is clear and definite within the field of its relevant uses. Those skilled in the art can obtain them from the market or prepare them by conventional methods according to the trade name, abbreviation and corresponding uses.

[0061] The present invention has no particular restrictions on the expression modes of the substituents, and all use the expression modes well-known to those skilled in the art. Based on common sense, those skilled in the art can correctly understand their meanings according to their expression modes.

[0062] In the present invention, the term "connection" can be directly connected or indirectly connected via other groups without special explanation.

[0063] I. Preparation of 3-cyanophenyl ethynyltetrazine, and the preparation method is as Figure 2 shown.

[0064]

Example 1

[0065]

[0066] (1) Weigh 3-cyanobenzoic acid (1.0 equiv.), EDCI (1.2 equiv.) and DMAP (0.1 equiv.) into a round-bottom flask. Under argon protection, add dry DCM (DCM, 1.0 M), then place the reaction at 0 °C, and add 3-methyl-3-hydroxymethyloxetane (1.2 equiv.). After stirring at 0 °C for 10 minutes, then stir at room temperature overnight. After the reaction is completed, quench the reaction with saturated NaHCO3 solution, extract three times with DCM, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The obtained mixture is purified by silica gel column chromatography to obtain the corresponding (3-methyloxetane-3-yl) 3-cyanobenzoate.

[0067]

[0068] (2) Weigh (3 - methyloxetan - 3 - yl) 3 - cyanobenzoate into a round - bottom flask, then evacuate and replace the gas with argon three times. Place the round - bottom flask in an ice - salt bath, add dry DCM (1.0 M), and stir for 10 minutes. Then add boron trifluoride etherate solution (1.2 equiv.) dropwise, and stir the reaction under this condition until the ester compound completely reacts monitored by TLC. Then add pyridine (3.0 equiv.) to quench the reaction, then add methylthiocarbazide iodide salt (0.7 equiv.) and N,N - dimethylformamide (DMF, 1.0 M), and remove DCM under vacuum. Then, under the protection of argon, heat and stir at 80 °C for 60 minutes. After that, cool the reaction solution to 0 °C, slowly add iodobenzene diacetate (PIDA, 0.7 equiv.) in batches, stir at room temperature for 60 minutes, quench the reaction with saturated NaHCO3 solution, extract three times with DCM, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The obtained mixture is dissolved in ethyl acrylate EA, and then washed three times with saturated brine. The organic phase is dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 3 - cyanophenylthiomethyltetrazine. Red solid, yield 64%.

[0069] 1 H NMR(400 MHz, CDCl3) δ 8.83 (t, J = 1.7 Hz, 1H), 8.76 (dt, J = 8.1, 1.5Hz, 1H), 7.88 (dt, J = 7.7, 1.4 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 2.81 (s, 3H).

[0070] 13 C NMR(101 MHz, CDCl3) δ 176.6, 160.9, 135.4, 133.2, 131.4, 131.0,130.3, 118.1, 113.9, 13.6.

[0071] HRMS(ESI) calculated for C 10 H8N5S + [M + H] + m / z 230.0495, found230.0497.

[0072]

[0073] (3) Inside the glove box, 3-cyanophenylthiomethyltetrazine (0.2 mmol), PdCl2(PPh3)2 (0.04 mmol), and CuI (0.4 mmol) were successively added to a 4 mL reaction flask, then dry 1,4-dioxane (2 mL) was added to dissolve, and then tributyl(trimethylsilylethynyl)tin (0.4 mmol) was added. Under nitrogen conditions, the reaction solution was heated at 50 °C for 12 hours. After the reaction was completed, it was filtered, the reaction solution was concentrated, and purified by silica gel column chromatography to obtain TMS-substituted 3-cyanophenylethynyltetrazine.

[0074]

[0075] (4) Dissolve TMS-substituted 3-cyanophenylethynyltetrazine in MeOH (5 mL), add K2CO3 (0.02 mmol), and stir at room temperature. After monitoring the reaction by TLC until it was completed, the reaction solution was quickly poured into water, extracted three times with DCM, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purified by silica gel column chromatography to obtain 3-cyanophenylethynyltetrazine. Red solid, yield 70%.

[0076] 1 H NMR(400 MHz, DMSO- d 6) δ 8.95 (t, J = 1.7 Hz, 1H), 8.88 (dt, J = 8.1,1.5 Hz, 1H), 7.95 (dt, J = 7.7, 1.4 Hz, 1H), 7.77 (t, J = 7.9 Hz, 1H), 3.83 (s,1H).

[0077] 13 C NMR(101 MHz, DMSO- d 6) δ 160.7, 156.8, 136.4, 132.6, 132.5, 132.1,130.6, 117.9, 114.3, 87.2, 77.1.

[0078] HRMS(ESI) calculated for C 11 H6N5 + [M + H] +m / z 208.0618, found 208.0626.

[0079] II. Preparation of pyridazinone compounds and tepotinib, the preparation method is as Figure 1 shown.

[0080]

Example 2

[0081]

[0082] (1) Weigh 3-cyanophenyl ethynyltetrazine and K2CO3 (0.1 equiv.) into a round-bottom flask, then evacuate and replace the gas with argon three times, add dry MeOH (0.1 M), and stir at room temperature. After monitoring the reaction by TLC until it is completed, concentrate under reduced pressure. The intermediate I is obtained by separation and purification through silica gel column chromatography (petroleum ether: ethyl acetate = 8:1~5:1). White solid, yield 88%.

[0083] 1 H NMR(400 MHz, CDCl3) δ 8.36–8.23 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H),7.74 (dt, J = 7.7, 1.4 Hz, 1H), 7.62 (td, J = 7.7, 0.7 Hz, 1H), 7.11 (d, J = 9.2Hz, 1H), 4.21 (s, 3H).

[0084] 13 C NMR(101 MHz, CDCl3) δ 164.9, 153.3, 137.6, 132.8, 130.8, 130.2,130.0, 126.9, 118.6, 118.2, 113.4, 55.3.

[0085] HRMS(ESI) calculated for C 12 H 10 N3O + [M + H] + m / z 212.0818, found212.0820.

[0086]

[0087] (2) Weigh intermediate I into a round-bottom flask, then evacuate and replace the gas with argon three times. Add dry DCM (0.1 M), add BBr3 solution, and reflux. After monitoring the reaction by TLC until it is completed, quench the reaction with saturated NaHCO3 solution, adjust the pH to weakly alkaline, extract three times with DCM, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The pyridazinone compound is obtained by separation and purification through silica gel column chromatography (dichloromethane:methanol = 10:1), as a white solid with a yield of 95%.

[0088] 1 H NMR(400 MHz, DMSO- d 6) δ 13.35 (s, 1H), 8.31 (t, J = 1.7 Hz, 1H), 8.20(dt, J = 8.1, 1.6 Hz, 1H), 8.13 (d, J = 9.9 Hz, 1H), 7.91 (dt, J = 7.7, 1.3 Hz,1H), 7.70 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 9.9, 1.8 Hz, 1H).

[0089] 13 C NMR(101 MHz, DMSO- d 6) δ 160.2, 142.1, 135.8, 132.7, 131.3, 130.3,130.21, 130.20, 129.3, 118.5, 112.1.

[0090] HRMS (ESI) calculated for C 11 H8N3O + [M + H] + m / z 198.0662, found198.0668.

[0091]

[0092] Furthermore, tepotinib is synthesized based on the pyridazinone compound. Specifically, the pyridazinone compound and (3-(5-(1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol (1.5 equiv.) are weighed and placed in a round-bottom flask. PPh3 is added inside the glove box and dissolved with THF. After taking it out, diisopropyl azodicarboxylate is dissolved in THF and dropped into the reaction solution under ice bath conditions. After adding, the ice bath is removed and it is naturally raised to room temperature. The reaction is carried out for 18 hours. After monitoring the end of the reaction by TLC, it is concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and then decocted with tert-butyl methyl ether, and vacuum dried to obtain tepotinib.

[0093] 1 H NMR(400 MHz, DMSO- d 6) 8.63 (s, 2H), 8.41–8.34 (m, 2H), 8.27–8.20(m, 2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93 (dt, J = 7.8, 1.3 Hz, 1H), 7.72 (t, J = 7.9Hz, 1H), 7.48 (dd, J = 4.9, 1.3 Hz, 2H), 7.16 (d, J = 9.7 Hz, 1H), 5.44 (s, 2H),4.03 (d, J = 6.0 Hz, 2H), 2.84–2.70 (m, 2H), 2.15 (s, 3H), 1.85 (td, J = 11.6,2.2 Hz, 2H), 1.79–1.62 (m, 3H), 1.47–1.11 (m, 3H).

[0094] 13 C NMR(101 MHz, DMSO- d 6) δ 158.8, 155.8, 151.7, 144.2, 142.0, 137.4,137.0, 135.5, 132.9, 130.9, 130.4, 130.3, 130.2, 129.7, 129.5, 129.0, 126.9,126.4, 118.5, 112.2, 73.0, 54.8, 54.6, 46.2, 34.8, 28.4.

[0095] HRMS (ESI) calculated for C 29 H 29 N6O2 + [M + H] + m / z 493.2347, found 493.2354.

[0096]

Example 3

[0097]

[0098] (1)Weigh ethynyltetrazine and K2CO3 (0.1 equiv.) into a round-bottom flask, then evacuate and replace the gas with argon three times, add CD3OD (0.1 M), and stir at room temperature. After monitoring the reaction by TLC until it is completed, concentrate under reduced pressure. The corresponding intermediate II is obtained by separation and purification through silica gel column chromatography. White solid, with a yield of 90%. According to 1H NMR analysis, the deuteration rate of the two deuteriums on the pyridazine ring is 98% each, and the deuteration rate of the deuterium on the methoxy group is 99%.

[0099] 1 1H NMR(400 MHz, CDCl3) δ 8.35–8.22 (m, 2H), 7.79 (s, 0.02H), 7.74 (dt, J = 7.7, 1.3 Hz, 1H), 7.66–7.58 (m, 1H), 7.11 (s, 0.02H), 4.20 (s, 0H).

[0100]

[0101] (2)Weigh intermediate II into a round-bottom flask, then evacuate and replace the gas with argon three times, add dry DCM (0.1 M), add BBr3 solution, and reflux. After monitoring the reaction by TLC until it is completed, quench the reaction with saturated NaHCO3 solution, adjust to weakly alkaline pH, extract three times with DCM, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The corresponding deuterated pyridazinone compound is obtained by separation and purification through silica gel column chromatography. White solid, with a yield of 90%. According to 1H NMR analysis, the deuteration rate of each deuterium is 98%.

[0102] 1 1H NMR(400 MHz, DMSO- d 6) δ 13.35 (s, 1H), 8.31 (t, J = 1.7 Hz, 1H),8.24–8.17 (m, 1H), 8.13 (s, 0.02H), 7.91 (dt,J = 7.7, 1.4 Hz, 1H), 7.70 (t, J =7.9 Hz, 1H), 7.04 (s, 0.02H).

[0103]

[0104] Further, deuterated tepotinib was synthesized based on the deuterated pyridazinone compound. Specifically, the deuterated pyridazinone compound and (3-(5-(1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol (1.5 equiv.) were weighed and placed in a round-bottom flask. PPh3 was added in a glove box and dissolved in THF. After taking it out, diisopropyl azodicarboxylate was dissolved in THF and dropped into the reaction solution under ice bath conditions. After adding, the ice bath was removed and the temperature was naturally raised to room temperature. The reaction was carried out for 18 hours. After monitoring the reaction by TLC and completion, it was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography and then decocted with tert-butyl methyl ether, and dried in vacuo to obtain deuterated tepotinib. According to the analysis of 1H NMR, the deuteration rate of each deuterium was 95%.

[0105] 1 1H NMR(400 MHz, DMSO- d 6) 8.63 (s, 2H), 8.41–8.34 (m, 2H), 8.28–8.20(m, 2H), 8.17 (s, 0.05H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 7.72 (t, J = 7.9 Hz,1H), 7.48 (dd, J = 4.9, 1.3 Hz, 2H), 7.16 (s, 0.05H), 5.44 (s, 2H), 4.04 (d, J =5.7 Hz, 2H), 2.87–2.78 (m, 2H), 2.19 (s, 3H), 1.96–1.87 (m, 2H), 1.75 (dt, J =13.9, 3.7 Hz, 3H), 1.40–1.28 (m, 3H).

[0106] The specific embodiments described above have further elaborated on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above description is only the specific embodiments of the present invention and is not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a pyridazinone compound, characterized in that: The following steps are involved: Under an inert atmosphere, 3-cyanophenylethynyl tetrazine, a base, and dry methanol or deuterated methanol are mixed and reacted to obtain the intermediate shown in Formula I; The intermediate is subjected to a demethylation reaction under an inert atmosphere to obtain a pyridazinone compound; In formula I, the group R is selected from hydrogen or deuterium.

2. A method for preparing a pyridazinone compound according to claim 1, characterized in that: Preparation of the 3-cyanophenylethynyl tetrazine The following steps are involved: S1: Under an inert atmosphere, 3-cyanobenzoic acid and 3-methyl-3-hydroxymethyloxetane are mixed and reacted to obtain (3-methyloxetane-3-yl) 3-cyanobenzoate; S2: adding boron trifluoride ether solution to the (3-methyloxetane-3-yl) 3-cyanobenzoate to react, and after the (3-methyloxetane-3-yl) 3-cyanobenzoate reacts completely, adding methylthiocarbazide iodide, heating to react under an inert atmosphere, and after the reaction is completed and cooled, adding iodophenyldiacetic acid to the reaction solution to obtain 3-cyanophenylthiomethyltetrazine; S3: The 3-cyanophenylthiomethyl tetrazine is heated to react with tributyl(trimethylsilylethynyl)tin under an inert atmosphere to obtain trimethylsilyl-substituted 3-cyanophenylethynyl tetrazine, and the trimethylsilyl-substituted 3-cyanophenylethynyl tetrazine is subjected to an elimination reaction to obtain the 3-cyanophenylethynyl tetrazine.

3. The method for preparing a pyridazinone compound according to claim 2, wherein: In step S1, 3-cyanobenzoic acid is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, and then dry dichloromethane is added under an inert atmosphere, followed by the addition of 3-methyl-3-hydroxymethyloxetane to react and obtain the (3-methyloxetane-3-yl) 3-cyanobenzoate.

4. The method for preparing a pyridazinone compound according to claim 2, wherein: In step S2, dry dichloromethane is added to the (3-methyloxetane-3-yl) 3-cyanobenzoate, and then boron trifluoride ether solution is slowly added to react. After the (3-methyloxetane-3-yl) 3-cyanobenzoate reacts completely, pyridine is added to quench the reaction.

5. The method for preparing a pyridazinone compound according to claim 4, wherein In step S2, methylthiocarbazide iodide and N,N-dimethylformamide are added to the reaction solution, and then dichloromethane is removed in vacuo. The reaction solution is heated under an inert atmosphere for reaction. After the reaction is completed, iodophenyldiacetic acid is added, and the reaction is carried out at room temperature to obtain 3-cyanophenylthiomethyltetrazine.

6. The method for preparing a pyridazinone compound according to claim 2, wherein: In step S3, 3-cyanophenylthiomethyltetrazine, PdCl2(PPh3)2 and CuI are dissolved in dry 1,4-dioxane, tributyl(trimethylsilylethynyl)tin is added, and the mixture is reacted under an inert atmosphere to obtain trimethylsilyl-substituted 3-cyanophenylethynyltetrazine.

7. The method for preparing a pyridazinone compound according to claim 2, wherein: In step S3, the trimethylsilyl-substituted 3-cyanophenylethynyl tetrazine is dissolved in methanol, and potassium carbonate is added thereto and reacted at room temperature to obtain the 3-cyanophenylethynyl tetrazine.

8. A deuterated pyridazinone compound, characterized in that Prepared by the preparation method of a pyridazinone compound according to any one of claims 1 to 7, the deuterated pyridazinone compound has the structural formula shown in Formula II:

9. A use of a deuterated pyridazinone compound, characterized in that: The deuterated pyridazinone compound according to claim 8 is used to prepare the deuterated tepotinib shown in formula III 10. A deuterated tepotinib, characterized in that: The deuterated tepotinib has the structural formula shown in Formula III, and the deuterated tepotinib is prepared by reacting a deuterated pyridazinone compound shown in Formula II with (3-(5-1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)methanol;

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