Process for the synthesis of 4-aminopyridazine derivatives

Abstract

The present application relates to a synthesis method of 4-amino pyridazine derivatives, which comprises the following steps: reacting 3,4,6-trichloropyridazine with an amine compound of formula IV or a salt thereof, and then reacting with hydrogen in the presence of a hydrogenation catalyst to obtain a target compound; the present application can improve the reaction yield and efficiency, reduce the cost, optimize the operation steps, and is widely applied to the preparation of most pyridazine amine compounds, and is suitable for industrial application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 4-aminopyridazine derivatives. Background Technology

[0002] Pyridazinamine compounds, especially those with an amino group at the 4-position of the pyridazine structure, are important raw materials for the preparation of pyridazine-derived fine chemicals and are widely used in pharmaceutical and agricultural chemistry. For example, these pyridazinamine compounds have attracted considerable attention in drug research, showing potential for the treatment of Alzheimer's disease, depression, hypotension, and anxiety. Furthermore, pyridazinamine compounds are key intermediates in the preparation of pesticides containing pyridazine structures, such as 4-pyrazole-N-pyridazinamide compounds, which have been shown to be particularly effective in controlling invertebrate pests (see WO 2009 / 027393, WO 2010 / 034737, WO 2010 / 034738 and WO 2010 / 112177).

[0003] To further prepare halogen-free pyridazine amine compounds, a typical synthetic method, for example, WO 2011 / 038572 describes a mixture of 3,4,5-trichloropyridazine and an amine compound via a substitution reaction to obtain dichloropyridazine amines, followed by dehalogenation of the mixture in the presence of a hydrogenation catalyst (Pd / C) and a base (sodium hydroxide). Chinese patent application CN107592859A discloses a method for preparing 4-aminopyridazine compounds, using 3,4,5-trichloropyridazine as a starting material, and subjecting it to a dehalogenation / reduction reaction with a hydrogenation catalyst in the absence of a base.

[0004] However, methods for preparing dichloropyridazine amines from 3,4,5-trichloropyridazine require long reaction times or high temperatures, which are unfavorable for industrial applications in terms of reaction conditions, yield, and / or post-processing requirements. Specifically: 1. The raw material 3,4,5-trichloropyridazine is irritating and costly, making its preparation and solid-state processing particularly disadvantageous on an industrial scale. 2. Nucleophilic substitution reactions yield mixtures of dichloropyridazine amines, affecting the yield of dehalogenation reactions, and the overall yield needs further improvement. 3. Existing nucleophilic substitution reaction conditions are harsh, requiring long reaction times or high temperatures. CN107592859A optimizes the reaction conditions, but this is limited to the preparation of dichloropyridazine ethylamines and is difficult to widely apply to the preparation of most pyridazine amine compounds.

[0005] To reduce costs, improve reaction yield and efficiency, optimize operating procedures, and make the method applicable to the preparation of most 4-aminopyridazine derivatives, it is necessary to propose a new synthetic method for 4-aminopyridazine derivatives. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing 4-aminopyridazine derivatives, which can improve reaction yield and efficiency, reduce costs, optimize operation steps, and is widely applicable to most 4-aminopyridazine derivatives, suitable for industrial-scale production.

[0007] The synthesis method of 4-aminopyridazine derivatives specifically includes the following steps:

[0008] (1) The 3,4,6-trichloropyridazine of formula III reacts with the amine compound R-NH2 of formula IV or its salt to give the compound of formula II;

[0009] (2) Compound II reacts with hydrogen in the presence of a hydrogenation catalyst to obtain compound I.

[0010] In the amine compound of formula IV, the R substituent is selected from C1-C3 alkyl, C1-C3 alkyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, and C1-C3 alkyl-NR. e R f C1-C3 alkyl-S-C1-C3 alkyl, and may be substituted by one or more substituents, wherein the substituents are selected from C1-C3 alkyl, hydroxyl, cyano, nitro, and halogen;

[0011] R e R f The components are independently selected from hydrogen or C1-C4 alkyl groups.

[0012]

[0013] In a preferred embodiment, the R substituent in the amine compound of formula IV is selected from methyl, ethyl, propyl, methoxy, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, and may be substituted by one or more substituents selected from fluorine, chlorine, methyl, hydroxyl, cyano, nitro, methylthio, ethylthio, N'N-dimethylamino, and cyclopropyl.

[0014] In a particularly preferred embodiment, the R substituent in the amine compound of formula IV is selected from ethyl, 2-mercaptoethyl, N,N-dimethylethylenedimethyl, 3-cyanoethyl, methoxy, cyclopropyl, 1-methyl-cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, and cyclopentyl.

[0015] The preferred reaction conditions for step (1) are as follows.

[0016] In this invention, the amine compound R-NH2 is selected from any substituted ethylamine, methoxyamine, cyclopropylamine, cyclopentylamine or cyclopropylmethylamine and their salts, preferably from ethylamine, 2-mercaptoethylamine, N,N-dimethylethylenediamine, 3-cyanoethylamine, methoxyamine hydrochloride, cyclopropylamine, 1-methyl-cyclopropylamine, cyclopropylmethylamine, (1-cyclopropylethyl)amine or cyclopentylamine.

[0017] In a preferred embodiment, an excess of the amine compound R-NH2 should be used.

[0018] In a preferred embodiment, the amine compound is added to the reaction in an amount of 1-10 mol / mol of compound III, preferably 1.5-6.0 mol / mol of compound III, and more preferably 1.5-3.0 mol / mol of compound III.

[0019] In a preferred embodiment, the solvent providing the amine compound R-NH2 is water, and a suitable concentration is 10-100% by weight, preferably 40-90% by weight, more preferably 60-80% by weight, and most preferably 65-75% by weight, based on the total weight of the solution.

[0020] In this invention, suitable solvents include aprotic solvents, such as dimethyl sulfoxide, N,N-dimethylformamide, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, carbon tetrachloride, etc., with ethyl acetate being preferred.

[0021] In this invention, the reaction temperature is 10-120℃, preferably 25-60℃, and more preferably 30-50℃.

[0022] In this invention, the reaction time can vary within a wide range, for example, from 1 hour to 4 days. Further, the reaction time is 1-24 hours, preferably 1-12 hours. More preferably, the reaction time is 1-5 hours, most preferably 2-5 hours.

[0023] The preferred reaction conditions for step (2) are as follows.

[0024] In this invention, step (2) can be carried out only in the presence of a hydrogenation catalyst, or in the presence of a hydrogenation catalyst and a base.

[0025] In this invention, the catalyst can be filtered out and reused after the reaction cycle of step (2) without significant loss of activity.

[0026] The hydrogenation catalyst includes any hydrogenation catalyst known in the art, such as heterogeneous and homogeneous hydrogenation catalysts, with heterogeneous catalysts being preferred. Preferably, the hydrogenation catalyst includes platinum, palladium, rhodium, ruthenium, nickel, or cobalt on a support such as carbon.

[0027] The bases include alkali metal and alkaline earth metal hydroxides, particularly selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal and alkaline earth metal oxides, particularly selected from lithium oxide, sodium oxide, calcium oxide and magnesium oxide; alkali metal and alkaline earth metal hydrides, particularly selected from lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal ammonides, particularly selected from lithium amino, sodium amino and potassium amino; alkali metal and alkaline earth metal carbonates, particularly selected from lithium carbonate and calcium carbonate; alkali metal bicarbonates, preferably sodium bicarbonate; alkali metal alkylates, particularly selected from methyl lithium, butyl lithium and phenyl lithium; alkyl magnesium halides, preferably methyl magnesium chloride; alkali metal and alkaline earth metal alkoxides, particularly selected from sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and magnesium dimethoxy; and nitrogen-containing bases, including tertiary amines, especially trimethylamine, triethylamine, diisopropylethylamine or N-methylpiperidine; pyridines, such as chloridine, rutidine and 4-dimethylaminopyridine; bicyclic amines, ammonia and primary amines.

[0028] In a preferred embodiment, the hydrogenation catalyst is selected from platinum or palladium on a support, ruanne nickel and ruanne cobalt, preferably platinum or palladium on carbon.

[0029] In a particularly preferred embodiment, the hydrogenation catalyst is platinum or palladium on carbon, wherein the platinum or palladium content is preferably 0.1-15% by weight, more preferably 1-5% by weight, based on the support material.

[0030] In a particularly preferred embodiment, the hydrogenation catalyst is palladium on carbon, wherein the palladium content is preferably 0.1-15 wt%, more preferably 0.5-10 wt%, based on the support material. Furthermore, it is particularly preferred that the amount of palladium used in reaction step (2) is 0.001-10 wt%, preferably 0.01-0.1 wt%, based on the starting material compound of formula II. Particularly preferred is 5-10% Pd / C used in an amount of 1-5 wt%, based on the amount of the starting material.

[0031] In another particularly preferred embodiment, the hydrogenation catalyst is platinum on carbon, wherein the platinum content is preferably 0.1-15% by weight, more preferably 0.5-10% by weight, based on the support material. Furthermore, the amount of platinum used in reaction step (2) is particularly preferred to be 0.001-1%, preferably 0.01-0.1% by weight, based on the starting material compound of formula II. Particularly preferred is 5-10% Pt / C used in an amount of 1-5% by weight based on the amount of the starting material.

[0032] In a preferred embodiment, the applied hydrogen pressure is 0.1-2 MPa, preferably 0.5-2 MPa, and more preferably 1-2 MPa.

[0033] In this invention, suitable solvents include protic solvents, preferably alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol.

[0034] In this invention, the reaction temperature is maintained in the range of 20-100°C, preferably 20-65°C. Preferably, the reaction mixture is heated to 30-40°C after the pressurized reactor in which the reaction is preferably carried out is filled with hydrogen. However, since the hydrogenation reaction is exothermic, it may be necessary to subsequently cool the reaction mixture to maintain a temperature preferably below 60°C. A reaction temperature of 30-60°C is particularly preferred.

[0035] In this invention, the reaction time can vary within a wide range. Preferably, the reaction time is 1-12 hours, more preferably 1-6 hours, for example 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours.

[0036] In existing technologies, methods for preparing dichloropyridazine amines from 3,4,5-trichloropyridazine require long reaction times or high temperatures, which are unfavorable for industrial applications in terms of reaction conditions, yield, and / or post-processing requirements. CN107592859A, through screening, found that using ethylamine as the nucleophile in nucleophilic substitution reactions is most effective for preparing dichloropyridazine amines, and ethylamino groups are also preferred in the dehalogenation reaction of dichloropyridazine amines. Therefore, the preparation and dehalogenation yield of dichloropyridazine amines are highly dependent on the nature of the amino substituent, and the reaction results of pyridazine amines with different amino substituents are unpredictable. However, even with the preferred ethylamino substituent, existing technologies still yield mixtures of dichloropyridazine amines.

[0037] Through extensive research, the applicant has discovered that the aminolysis of the starting material 3,4,5-trichloropyridazine exhibits poor selectivity at the reaction sites, leading to a mixture-like substitution reaction. In contrast, 3,4,6-trichloropyridazine shows high selectivity, directly yielding a monosubstituted aminolysis product without further separation or purification, resulting in a high reaction yield. Furthermore, when 3,4,6-trichloropyridazine is used instead of 3,4,5-trichloropyridazine, a single dichloropyridazine amine product can be obtained in high yield under mild reaction conditions, with simple operation, and it is also beneficial for subsequent dehalogenation reactions.

[0038] The advantages of this invention are as follows: It uses the inexpensive and readily available raw material 3,4,6-trichloropyridazine, which is widely available, ensures high safety in the reaction operation, and is beneficial for industrial-scale preparation. Furthermore, the raw material 3,4,6-trichloropyridazine can undergo highly efficient nucleophilic substitution reactions with most amines, and can prepare the vast majority of 4-aminopyridazine derivatives with high reaction selectivity. Simultaneously, it avoids the mixture of dichloropyridazine amines obtained from 3,4,5-trichloropyridazine, which can further improve the yield of the dehalogenation reaction, thereby comprehensively improving the overall reaction yield and efficiency. Detailed Implementation

[0039] Example 1: Synthesis of N-ethylpyridazine-4-amine

[0040]

[0041] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and 75% ethylamine (9.02 g, 150 mmol) was added. The mixture was reacted at 50 °C for 4 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to give 9.41 g of 3,6-dichloro-N-ethylpyridazine-4-amine, a pale yellow viscous substance, yield: 99%.

[0042] 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),6.77–6.56(m,1H),2.32–2.09(m,2H).1.48–1.23(m,3H).

[0043] LC-MS: (M+1)m / z = 191.2.

[0044] Step 2: The 3,6-dichloro-N-ethylpyridazine-4-amine (9.41 g, 49.5 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.94 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, purged three times with hydrogen, and pressurized to 2 MPa. The reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, the reactor was purged with nitrogen, and Pd / C was removed by filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The mixture was stirred for 3 h, and insoluble matter was removed by filtration. The filtrates were combined, concentrated under reduced pressure, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product N-ethylpyridazine-4-amine (5.91 g, 98% purity), yield: 95.0%.

[0045] 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.76–8.68(m,1H),8.64(s,1H),7.06–6.96(m,1H),1.41–1.04(m,5H).

[0046] LC-MS: (M+1)m / z = 124.1.

[0047] Example 2: Synthesis of 3-(pyridazine-4-ylamino)propionitrile

[0048]

[0049] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and 3-aminopropionitrile (10.5 g, 150 mmol) was added. The mixture was reacted at 50 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 10.48 g of 3-(3,6-dichloropyridazine-4-yl)amino)propionitrile, a yellow viscous substance, yield: 97%.

[0050] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),6.53–6.46(m,1H),2.95–2.63(m,2H),2.28–2.21(m,2H).

[0051] LC-MS: (M+1)m / z = 217.2.

[0052] Step 2: 3-(3,6-dichloropyridazin-4-yl)amino)propionitrile (8.64 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor. 10% Pd / C (0.86 g, 1%) was added, followed by nitrogen purging for 1 minute and hydrogen replacement three times. The reactor was pressurized to 2 MPa and reacted at 50 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, the pressure was released, nitrogen purging was performed, and Pd / C was removed by filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The mixture was stirred at room temperature for 3 h, and insoluble matter was removed by filtration. The mixture was concentrated under reduced pressure, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain 3-(pyridazin-4-yl)propionitrile (5.68 g, purity 96%), yield: 92.0%.

[0053] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=2.9Hz,1H),8.55(d,J=5.9Hz,1H),7.32(s,1H),6.79–6.70(m,1H),3.24–3.18(m,2H),2.77(t,J=6.5Hz,2H).

[0054] LC-MS: (M+1)m / z = 149.1.

[0055] Example 3: Synthesis of N-cyclopropylpyridazine-4-amine

[0056]

[0057] Step 1: 3,4,6-Trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and cyclopropylamine (8.55 g, 150 mmol) was added. The mixture was reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 9.85 g of 3,6-dichloro-N-cyclopropylpyridazine-4-amine, a pale yellow viscous substance, yield: 97%.

[0058] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.09(s,1H),2.57–2.46(m,1H),1.25–0.93(m,4H).

[0059] LC-MS: (M+1)m / z = 204.1.

[0060] Step 2: The 3,6-dichloro-N-cyclopropylpyridazine-4-amine (8.12 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.81 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, and subjected to three hydrogen purgings. The pressure was increased to 1.8 MPa, and the reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by filtration. The mixture was concentrated under reduced pressure, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain N-cyclopropylpyridazine-4-amine (5.13 g, 96% purity), yield: 91.1%.

[0061] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.73(s,1H),8.50(s,1H),7.24(s,1H),2.77–2.58(m,1H),1.05–0.23(m,4H).

[0062] LC-MS: (M+1)m / z = 136.1.

[0063] Example 4: Synthesis of N-(cyclopropylmethyl)pyridazine-4-amine

[0064]

[0065] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and cyclopropylmethylamine (10.65 g, 150 mmol) was added. The mixture was reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 10.42 g of 3,6-dichloro-N-(cyclopropylmethyl)pyridazine-4-amine, a pale yellow viscous substance, yield: 96%.

[0066] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),6.945–6.39(m,1H),2.98–2.66(m,2H),0.83(dt,J=7.8,2.7Hz,1H),0.34–0.29(m,2H),0.18–0.09(m,2H).

[0067] LC-MS: (M+1)m / z = 218.2.

[0068] Step 2: The 3,6-dichloro-N-(cyclopropylmethyl)pyridazin-4-amine (8.7 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.87 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, purged three times with hydrogen, and pressurized to 2 MPa. The reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, the reactor was purged with nitrogen, and Pd / C was removed by filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by filtration. The mixture was concentrated under reduced pressure, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain N-(cyclopropylmethyl)pyridazin-4-amine (5.54 g, 97% purity), yield: 90.1%.

[0069] 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.29(s,1H),7.46(s,1H),6.46(s,1H),2.95–2.6 3(m,2H),0.78(dt,J=7.8,2.7Hz,1H),0.28–0.22(m,2H),0.08(dd,J=4.6,1.8Hz,2H).

[0070] LC-MS: (M+1)m / z=150.1.

[0071] Example 5: Synthesis of N-(1-cyclopropylethyl)pyridazine-4-amine

[0072]

[0073] Step 1: 3,4,6-Trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, followed by the addition of 1-cyclopropylethane-1-amine hydrochloride (18.15 g, 150 mmol), and then triethylamine (15.15 g, 150 mmol). The reaction was carried out at 50 °C for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure to give 11.43 g of the product 3,6-dichloro-N-(1-cyclopropylethyl)pyridazine-4-amine, a yellow viscous substance, yield: 99%.

[0074] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),6.78(s,1H),2.96(td,J=8.7,6.4Hz,1H),1.02( d,J=6.5Hz,3H),0.96(dt,J=8.4,5.5Hz,1H),0.35–0.15(m,2H),0.13–-0.06(m,2H).

[0075] LC-MS: (M+1)m / z = 232.1.

[0076] Step 2: The 3,6-dichloro-N-(1-cyclopropylethyl)pyridazin-4-amine (9.24 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.92 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, purged three times with hydrogen, and pressurized to 2 MPa. The reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain N-(1-cyclopropylethyl)pyridazin-4-amine (6.2 g, purity 96%), yield: 91.2%.

[0077] 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.29(s,1H),7.46(s,1H),6.46(s,1H),2.95–2.6 3(m,2H),0.78(dt,J=7.8,2.7Hz,1H),0.28–0.22(m,2H),0.08(dd,J=4.6,1.8Hz,2H).

[0078] LC-MS: (M+1)m / z = 164.0.

[0079] Example 6: Synthesis of N-cyclopentylpyridazine-4-amine

[0080]

[0081] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and cyclopentanamine (12.75 g, 150 mmol) was added. The mixture was reacted at 50 °C for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure to give 11.43 g of the product 3,6-dichloro-N-cyclopentylpyridazine-4-amine, a yellow viscous substance, yield: 97%.

[0082] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),4.78(s,1H),2.96(td,J=8.7,6.4Hz,1H),1.35–1.15(m,2H),0.93–0.86(m,2H).

[0083] LC-MS: (M+1)m / z = 232.2.

[0084] Step 2: The 3,6-dichloro-N-cyclopentylpyridazin-4-amine (9.24 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.92 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, and subjected to three hydrogen purgings. The pressure was increased to 1.5 MPa, and the reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product N-cyclopentylpyridazin-4-amine (6.16 g, purity 96%), yield: 90.6%.

[0085] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,J=7.9Hz,1H),8.28(s,1H),7.14(s,1H),4.73(s,1H) ,3.56–3.36(m,1H),2.01(d,J=14.1Hz,2H),1.92–1.86(m,4H),1.73(d,J=9.0Hz,2H).

[0086] LC-MS: (M+1)m / z = 164.0.

[0087] Example 7: Synthesis of N-(1-methylcyclopropyl)pyridazine-4-amine

[0088]

[0089] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, followed by the addition of 1-methylcyclopropane-1-amine hydrochloride (16.05 g, 150 mmol), and then triethylamine (15.15 g, 150 mmol). The reaction was carried out at 50 °C for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure to give 10.63 g of the product 3,6-dichloro-N-(1-methylcyclopropyl)pyridazine-4-amine, a yellow viscous substance, yield: 98%.

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),5.78(s,1H),1.96(td,J=8.7,6.4Hz,3H),0.85–0.76(m,2H),0.13–0.05(m,2H).

[0091] LC-MS: (M+1)m / z = 218.2.

[0092] Step 2: The 3,6-dichloro-N-(1-methylcyclopropyl)pyridazin-4-amine (8.68 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.87 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, purged three times with hydrogen, and pressurized to 2 MPa. The reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product N-(1-methylcyclopropyl)pyridazin-4-amine (5.66 g, purity 96%), yield: 91.1%.

[0093] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.56(s,2H),5.05(s,1H),1.36(s,3H),0.93–0.58(m,4H).

[0094] LC-MS: (M+1)m / z=150.1.

[0095] Example 8: Synthesis of N-(tetrahydrofuran-3-yl)pyridazine-4-amine

[0096]

[0097] Step 1: 3,4,6-Trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and tetrahydrofuran-3-amine hydrochloride (18.45 g, 150 mmol) was added, followed by triethylamine (15.15 g, 150 mmol). The reaction was carried out at 50 °C for 5 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to give 10.63 g of the product 3,6-dichloro-N-(tetrahydrofuran-3-yl)pyridazine-4-amine, a yellow viscous substance, yield: 97%.

[0098] 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),5.78(s,1H),3.96(td,J=8.7,6.4Hz,2H),3.85–3.76(m,4H),3.13–3.05(m,1H).

[0099] LC-MS: (M+1)m / z = 234.1.

[0100] Step 2: The 3,6-dichloro-N-(tetrahydrofuran-3-yl)pyridazin-4-amine (9.32 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.93 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, and subjected to three hydrogen purgings. The pressure was increased to 2 MPa, and the reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product N-(tetrahydrofuran-3-yl)pyridazin-4-amine (6.34 g, purity 96%), yield: 92.2%.

[0101] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.56(s,1H),7.43(s,1H),5.05(s,1H),4.93–4.88(m,2H).

[0102] 3.93–3.76(m,4H).2.93–2.76(m,1H).

[0103] LC-MS: (M+1)m / z = 166.2.

[0104] Example 9: Synthesis of O-methyl-N-(pyridazin-4-yl)hydroxylamine

[0105]

[0106] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, followed by the addition of methoxyamine hydrochloride (12.45 g, 150 mmol), and then triethylamine (15.15 g, 150 mmol). The mixture was refluxed at 70 °C for 8–12 h. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure to give 9.46 g of the product N-(3,6-dichloropyridazine-4-yl)-O-methylhydroxylamine, a yellow viscous substance, yield: 98%.

[0107] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),5.28(s,1H),3.58(s,3H).

[0108] LC-MS: (M+1)m / z = 194.3.

[0109] Step 2: The N-(3,6-dichloropyridazin-4-yl)-O-methylhydroxylamine (7.72 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.77 g, 1% L) was added. The reactor was then purged with nitrogen for 1 minute, and subjected to three hydrogen purgings. The pressure was increased to 1.8 MPa, and the reaction was carried out at 50 °C for 2.5 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product O-methyl-N-(pyridazin-4-yl)hydroxylamine (4.75 g, purity 96%), yield: 91.1%.

[0110] 1 H NMR (400MHz, DMSO-d6) δ9.63(s,1H),8.53(s,1H),7.83(s,1H),5.72(s,1H),3.78(s,3H).

[0111] LC-MS: (M+1)m / z = 126.1.

[0112] Example 10: Synthesis of 2-(pyridazine-4-ylamino)ethane-1-thiol

[0113]

[0114] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and 2-aminoethane-1-thiol (11.55 g, 150 mmol) was added. The reaction was carried out at 45 °C for 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to give 10.93 g of the product 2-(3,6-dichloropyridazine-4-yl)amino)ethane-1-thiol, a yellow viscous substance, yield: 98%.

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),4.75(s,1H),3.56–3.45(m,2H),2.91–2.83(m,2H),1.63-1.59(m,1H).

[0116] LC-MS: (M+1)m / z = 224.1.

[0117] Step 2: 2-(3,6-dichloropyridazin-4-yl)amino)ethane-1-thiol (9.24 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor. 10% Pd / C (1.85 g, 2%) was added, followed by nitrogen purging for 1 minute and hydrogen replacement three times. The reactor was pressurized to 1.5 MPa and reacted at 50 °C for 3 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, nitrogen purging was performed, and Pd / C was removed by vacuum filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation. The solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product 2-(pyridazin-4-ylamino)ethane-1-thiol (5.97 g, purity 96%), yield: 92.3%.

[0118] 1 H NMR (400MHz, DMSO-d6) δ9.56(s,1H),8.17(s,1H),7.11(s,1H),5.62(s,1H),3.56–3.36(m,2H),2.92–2.86(m,2H),1.43(d,J=9.0Hz,1H).

[0119] LC-MS: (M+1)m / z = 156.1.

[0120] Example 11: Synthesis of N-(2-(ethylthio)ethyl)pyridazine-4-amine

[0121]

[0122] Step 1: 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and 2-(ethylthio)ethylamine (15.75 g, 150 mmol) was added. The reaction was carried out at 50 °C for 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to give 12.42 g of the product 3,6-dichloro-N-(2-(ethylthio)ethyl)pyridazine-4-amine, a yellow viscous substance, yield: 99%.

[0123] 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 5.78 (s, 1H), 3.41–3.09 (m, 4H), 2.02–1.75 (m, 2H), 1.82 (d, J = 9.0Hz, 3H).

[0124] LC-MS: (M+1)m / z = 252.2.

[0125] Step 2: The 3,6-dichloro-N-(2-(ethylthio)ethyl)pyridazine-4-amine (10.04 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (2 g, 2%) was added. The reactor was then purged with nitrogen for 1 minute, and subjected to three hydrogen purgings. The pressure was increased to 1.8 MPa, and the reaction was carried out at 55 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation, and the solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain the product N-(2-(ethylthio)ethyl)pyridazine-4-amine (7.03 g, purity 96%), yield: 92.1%.

[0126] 1 H NMR(400MHz,DMSO-d6)δ9.80(d,J=7.9Hz,1H),8.28(s,1H),7.14(s,1H),5.73(s,1H) ,3.56–3.16(m,4H),2.01(d,J=14.1Hz,2H),1.92–1.86(m,2H),1.73(d,J=9.0Hz,3H).

[0127] LC-MS: (M+1)m / z = 184.3.

[0128] Example 12: N 1 N 1 -dimethyl-N 2Synthesis of 1,2-(pyridazine-4-yl)ethane-1,2-diamine

[0129]

[0130] Step 1: Place 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) in a 250 mL reaction flask, and add N2O2. 1 N 1 -Dimethylethane-1,2-diamine (13.2 g, 150 mmol) was reacted at 50 °C for 5 h. After the reaction was complete as monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure to give product N. 1 -(3,6-Dichloropyridazine-4-yl)-N 2 N 2 -Dimethylethane-1,2-diamine, 11.47 g of yellow viscous substance, yield: 98%.

[0131] 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 4.69 (s, 1H), 3.96 (td, J = 8.7, 6.4Hz, 2H), 3.35–3.15 (m, 2H), 2.36 (m, 6H).

[0132] LC-MS: (M+1)m / z = 235.1.

[0133] Step 2: The 3,6-dichloro-N-(2-(ethylthio)ethyl)pyridazine-4-amine (10.04 g, 40 mmol) obtained in Step 1 and anhydrous ethanol (100 mL) were placed in a high-pressure reactor. 10% Pd / C (1 g, 1%) was added, followed by nitrogen purging for 1 minute and hydrogen replacement three times. The reactor was pressurized to 2 MPa and reacted at 50 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, the pressure was released, nitrogen purging was performed, and Pd / C was removed by vacuum filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The mixture was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The solvent was removed by rotary evaporation. The solid was precipitated using an ethanol / methyl tert-butyl ether system to obtain product N. 1 N 1 -dimethyl-N 2 -(pyridazine-4-yl)ethane-1,2-diamine (6.25 g, purity 95%), yield: 90.2%.

[0134] 1H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.28(s,1H),7.14(s,1H),5.73(s,1H),3.56–3.36(m,2H),3.01(d,J=14.1Hz,2H),2.33(s,6H).

[0135] LC-MS: (M+1)m / z = 167.1.

[0136] Comparative Example 1

[0137] 3,4,5-Trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and 75% ethylamine (9.02 g, 150 mmol) was added. The reaction was carried out at 45 °C for 5 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine. The reaction mixture was cooled to 10 °C and the product was filtered off. The mother liquor was then concentrated and the crude material was recrystallized from MTBE to separate the remaining product.

[0138] The mixture of the two substances and anhydrous ethanol (100 mL) was placed in a high-pressure reactor, and then 10% Pd / C (0.94 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, followed by three hydrogen purgings. The pressure was increased to 0.2 bar, and the reaction was carried out at 55 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The mixture was stirred for 3 h, and insoluble matter was removed by vacuum filtration. The filtrates were combined, concentrated under reduced pressure, and 4.31 g of solid product with a purity of 90% was obtained. The overall yield of the two steps was 63%.

[0139] Comparative Example 2

[0140] 3,4,5-Trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and cyclopropylamine (8.55 g, 150 mmol) was added. The reaction mixture was reacted at 45 °C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a mixture of 3,4-dichloro-5-cyclopropylaminopyridazine and 3,5-dichloro-4-cyclopropylaminopyridazine. The reaction mixture was cooled to 10 °C and the product was filtered off. The mother liquor was then concentrated and the crude material was recrystallized from MTBE to separate the remaining product.

[0141] The mixture obtained in the first step and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and 10% Pd / C (0.81 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, followed by three hydrogen purgings. The pressure was increased to 0.5 bar, and the reaction was carried out at 55 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, the pressure was released, and the reactor was purged with nitrogen. Pd / C was removed by vacuum filtration, and the filtrates were combined. The filtrate was placed in another reaction flask, and K₂CO₃ (13.8 g, 100 mmol) was added. The mixture was stirred at room temperature for 3 h, and insoluble matter was removed by vacuum filtration. The mixture was concentrated under reduced pressure to give 3.45 g of a brown solid with a purity of 88%. The overall yield of the two steps was 45%.

[0142] Comparative Example 3: Changing the reaction pressure

[0143] 3,4,6-trichloropyridazine (10 g, 50 mmol) and ethyl acetate (100 mL) were placed in a 250 mL reaction flask, and cyclopropylmethylamine (10.65 g, 150 mmol) was added. The mixture was reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 10.09 g of 3,6-dichloro-N-(cyclopropylmethyl)pyridazine-4-amine, a pale yellow viscous substance, yield: 93%.

[0144] The 3,6-dichloro-N-(cyclopropylmethyl)pyridazin-4-amine (8.7 g, 40 mmol) obtained in the first step and anhydrous ethanol (100 mL) were placed in a high-pressure reactor, and then 10% Pd / C (0.87 g, 1%) was added. The reactor was then purged with nitrogen for 1 minute, purged three times with hydrogen, and pressurized to 1 MPa. The reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reactor was cooled to room temperature, the pressure was released, the reactor was purged with nitrogen, and Pd / C was removed by filtration. The filtrates were combined. The filtrate was placed in another reaction flask, and K2CO3 (13.8 g, 100 mmol) was added. The reactor was stirred at room temperature for 3 h, and insoluble matter was removed by filtration. The mixture was concentrated under reduced pressure and crystallized with a mixed solvent of dichloromethane / ethyl acetate / petroleum ether to obtain N-(cyclopropylmethyl)pyridazin-4-amine, yielding 4.24 g of a yellow solid with a purity of 93% and a yield of 66.1%.

[0145] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

A method for synthesizing 1,4-aminopyridazine derivatives, characterized in that, Includes the following steps: (1) The 3,4,6-trichloropyridazine of formula III reacts with the amine compound R-NH2 of formula IV or its salt to give the compound of formula II; (2) Compound II reacts with hydrogen in the presence of a hydrogenation catalyst to obtain compound I; In the amine compound of formula IV, the R substituent is selected from C1-C3 alkyl, C1-C3 alkyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, and C1-C3 alkyl-NR. e R f C1-C3 alkyl-S-C1-C3 alkyl, and may be substituted by one or more substituents, wherein the substituents are selected from C1-C3 alkyl, hydroxyl, cyano, nitro, and halogen; R e R f The components are independently selected from hydrogen or C1-C4 alkyl groups.

2. The synthesis method according to claim 1, characterized in that, The R substituent in the amine compound of Formula IV is selected from methyl, ethyl, propyl, methoxy, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, and may be substituted by one or more substituents selected from fluorine, chlorine, methyl, hydroxyl, cyano, nitro, methylthio, ethylthio, N'N-dimethylamino, and cyclopropyl.

3. The synthesis method according to claim 1, characterized in that, The R substituent in the amine compound of formula IV is selected from ethyl, 2-mercaptoethyl, N,N-dimethylethylenedimethyl, 3-cyanoethyl, methoxy, cyclopropyl, 1-methyl-cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, and cyclopentyl.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature of step (1) is 10-120℃, preferably 25-60℃, more preferably 30-50℃; and the reaction time of step (1) is 1-24 hours, preferably 1-12 hours.

5. The synthesis method according to claim 1, characterized in that, In step (2), the amount of hydrogenation catalyst used is 0.1-10% by weight, preferably 1-5% by weight, based on the raw material compound of formula II.

6. The synthesis method according to claim 1, characterized in that, The hydrogen pressure applied in step (2) is 0.1-2 MPa, preferably 0.5-2 MPa; the reaction temperature in step (2) is 20-100℃, preferably 20-65℃.

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