Synthesis method of 3-chloro-6-methylpyridazine

Abstract

The invention discloses a synthesis method of 3-chloro-6-methylpyridazine. The synthesis method comprises the following steps of: adding a catalyst; according to the synthetic method, 3, 6-dichloropyridazine is used as a raw material, 2-(6-chloropyridazine-3-yl) ethyl acetate is obtained through a nucleophilic substitution reaction, and then 2-(6-chloropyridazine-3-yl) ethyl acetate is obtained through a decarboxylation reaction. The synthesis method provided by the invention has the advantages of mild reaction conditions, low potential safety hazard, low cost and better yield, and solves the problems of high potential safety hazard, unsuitability for process amplification and the like in the existing synthesis method.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of 3-chloro-6-methylpyridazine. Background Art

[0002] Halogenated pyridazine compounds are an important class of organic compounds, which are widely used in many fields such as synthesis, pesticides, and medicine. For example, 3-bromo-6-methylpyridazine is used as a key intermediate in the synthesis of C-17 and C-3 modified triterpenes with unique antiviral activity in patent WO2012 / 106190. The triterpenoid compound is used as an HIV maturation inhibitor and is very useful for the treatment of AIDS; in patent WO2010 / 036998, it is used for the synthesis of indole and indoline derivatives, which can be used to prevent or treat diseases such as neurodegeneration or neuropsychiatric disorders; 3-chloro-5-methylpyridazine is also used as a key intermediate in the synthesis of GPR139 receptor modulators in patent WO2020 / 097609; in patent WO2018 / 069863, it is used for the synthesis of inhibitors of hematopoietic prostaglandin D synthase (H-PGDS), which can be used to treat Duchenne muscular dystrophy. Halogenated pyridazine compounds have great application potential in drug development.

[0003] In this class of compounds, 3-chloro-6-methylpyridazine is an important molecular building block. For example, in patent WO2012 / 148775, it is used for the synthesis of bicyclic pyridine compounds, which can be used as PIM inhibitors to prevent and treat PIM kinase-related diseases; in patent WO2013 / 166621, it is used for the synthesis of a new type of 1-(dihydronaphthyl)pyridone as a melanin concentrating hormone receptor 1 (MCHR1) antagonist, which can be used to treat obesity and diabetes; in patent WO2015 / 123089, it is used for the synthesis of a new type of cysteine ​​protease inhibitor, which can be used to treat diseases that require inhibition of bone resorption, such as osteoporosis. Therefore, it is of great significance to develop a new method for synthesizing 3-chloro-6-methylpyridazine.

[0004] In the prior art, the conventional synthetic route of 3-chloro-6-methylpyridazine is to use 6-methyl-3(2H)-pyridazinone as a raw material and obtain the target product through the action of phosphorus oxychloride, which has high safety risks and is not suitable for process scale-up. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 3-chloro-6-methylpyridazine. The synthetic method of the present invention has mild reaction conditions, low safety risks, low cost and good yield.

[0006] The technical solution of the present invention is as follows:

[0007] The first aspect of the present invention protects a method for synthesizing 3-chloro-6-methylpyridazine. The method uses 3,6-dichloropyridazine as a raw material, obtains ethyl 2-(6-chloropyridazine-3-yl)acetate through a nucleophilic substitution reaction, and then obtains it through a decarboxylation reaction.

[0008] Preferably, the synthesis method specifically comprises the following steps:

[0009] S1: Dissolve 3,6-dichloropyridazine in solvent I, then add potassium salt of monoethyl malonate, additives and base in sequence, stir to react, extract, concentrate and purify to obtain intermediate compound 2, i.e. ethyl 2-(6-chloropyridazine-3-yl)acetate.

[0010] S2: Solvent II is added to the intermediate compound 2 to dissolve it, and then water and lithium chloride are added in sequence to obtain a mixed solution. After stirring for reaction, extraction, drying, distillation and purification are performed to obtain 3-chloro-6-methylpyridazine.

[0011] Preferably, in step S1, the solvent I is selected from one or more of acetonitrile, 1,4-dioxane, toluene, and acetone; and the mass volume ratio of the 3,6-dichloropyridazine to the solvent I is 1:5-40 g / mL.

[0012] Preferably, in step S1, the potassium salt of monomalonic acid ester includes one of monoethyl malonate potassium salt and monomethyl malonate potassium salt; and the molar ratio of the 3,6-dichloropyridazine to the potassium salt of monomalonic acid ester is 1:1-3.

[0013] Preferably, in step S1, the additive is selected from one or more of magnesium chloride and zinc chloride; and the molar ratio of the 3,6-dichloropyridazine to the additive is 1:1-3.

[0014] Preferably, in step S1, the base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, and the molar ratio of the 3,6-dichloropyridazine to the base is 1:1-3.

[0015] Preferably, in step S1, the stirring reaction is carried out at a temperature of 60-200°C and for a time of 12-48 hours.

[0016] Preferably, in step S2, the solvent II is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone; and the mass volume ratio of the intermediate compound 2 to the solvent II is 1:5-40 g / mL.

[0017] Preferably, in step S2, the mass volume ratio of the intermediate compound 2 to the water is 1:1-2 g / mL; the mass volume ratio of the intermediate compound 2 to the lithium chloride is 1:3-6 g / mL.

[0018] Preferably, in step S2, the stirring reaction is carried out at a temperature of 60-200° C. and for a time of 36-60 h.

[0019] The beneficial technical effects of the present invention are:

[0020] The invention provides a novel method for synthesizing 3-chloro-6-methylpyridazine. The method uses 3,6-dichloropyridazine as a raw material, obtains ethyl 2-(6-chloropyridazine-3-yl)acetate through a nucleophilic substitution reaction, and then converts the ethyl 2-(6-chloropyridazine-3-yl)acetate into a target compound 3-chloro-6-methylpyridazine through a decarboxylation reaction.

[0021] The synthesis method of the present invention avoids the use of hazardous reagents such as phosphorus oxychloride, and has the advantages of mild reaction conditions, low safety hazards, low cost and ideal yield, etc. It not only provides a potential route for the process synthesis of 3-chloro-6-methylpyridazine, but also contributes to the development and utilization of halogenated pyridazine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the H NMR spectrum of compound 2 in Example 1 of the present invention.

[0023] Figure 2 This is the H NMR spectrum of 3-chloro-6-methylpyridazine in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs.

[0025] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0026] The invention firstly provides a method for synthesizing 3-chloro-6-methylpyridazine. The method comprises the following steps: using 3,6-dichloropyridazine as a raw material, performing a nucleophilic substitution reaction to obtain ethyl 2-(6-chloropyridazine-3-yl)acetate, and then performing a decarboxylation reaction to obtain ethyl 2-(6-chloropyridazine-3-yl)acetate.

[0027] In some embodiments, the synthesis method specifically comprises the following steps:

[0028] S1: Dissolve 3,6-dichloropyridazine in solvent I, then add potassium salt of monoethyl malonate, additives and base in sequence, stir to react, extract, concentrate and purify to obtain intermediate compound 2, i.e. ethyl 2-(6-chloropyridazine-3-yl)acetate.

[0029] S2: Solvent II is added to the intermediate compound 2 to dissolve it, and then water and lithium chloride are added in sequence to obtain a mixed solution. After stirring for reaction, extraction, drying, distillation and purification are performed to obtain 3-chloro-6-methylpyridazine.

[0030] In some embodiments, in step S1, the solvent I is selected from one or more of acetonitrile, 1,4-dioxane, toluene, and acetone; the mass volume ratio of the 3,6-dichloropyridazine to the solvent I is g / mL 1:5-40, including but not limited to 1:5, 1:10, 1:20, 1:30, and 1:40.

[0031] In some embodiments, in step S1, the potassium salt of monomalonate includes one of monoethyl malonate and monomethyl malonate; the molar ratio of the 3,6-dichloropyridazine to the potassium salt of monomalonate is 1:1-3, including but not limited to 1:1, 1:1.5, 1:2, 1:2.5, 1:3; preferably 1:1.2.

[0032] In some embodiments, in step S1, the additive is selected from one or more of magnesium chloride and zinc chloride, preferably magnesium chloride. The molar ratio of 3,6-dichloropyridazine to the additive is 1:1-3, including but not limited to 1:1, 1:1.5, 1:2, 1:2.5, 1:3, preferably 1:1.5.

[0033] In some embodiments, in step S1, the base is selected from one or more of triethylamine, diethylamine, and N,N-diisopropylethylamine, and the molar ratio of 3,6-dichloropyridazine to the base is 1:1-3, including but not limited to 1:1, 1:1.5, 1:2, 1:2.5, 1:3, preferably 1:1.5.

[0034] In some embodiments, in step S1, the stirring reaction temperature is 60-200°C, including but not limited to 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 140°C, 160°C, 180°C, 200°C, and the time is 12-48h, including but not limited to 12h, 18h, 24h, 30h, 36h, 42h, 48h.

[0035] In some embodiments, in step S1, the specific process of extraction, concentration and purification is: adjusting the solution after the reaction to pH = 7 with an acidic aqueous solution, extracting with an organic solvent III, combining the organic phases, washing and concentrating to obtain a crude product, and purifying the crude product to obtain the intermediate compound 2 (ethyl 2-(6-chloropyridazine-3-yl)acetate).

[0036] In some embodiments, the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0037] In some embodiments, the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0038] In some embodiments, the purification method is selected from one or more of column chromatography, recrystallization, and distillation.

[0039] In some embodiments, in step S2, the solvent II is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone; the mass volume ratio of the intermediate compound 2 to the solvent II g / mL is 1:5-40, including but not limited to 1:5, 1:10, 1:20, 1:30, and 1:40.

[0040] In some embodiments, in step S2, the mass volume ratio of the intermediate compound 2 to the water is g / mL 1:1-2; the mass volume ratio of the intermediate compound 2 to the lithium chloride is g / mL 1:3-6, including but not limited to 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, preferably 1:5.

[0041] In some embodiments, in step S2, the stirring reaction temperature is 60-200°C, including but not limited to 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 140°C, 160°C, 180°C, 200°C, and the time is 36-60h, including but not limited to 36h, 40h, 45h, 50h, 55h, 60h.

[0042] In some embodiments, in step S2, the specific process of extraction, drying, distillation and purification is: cooling the reaction solution obtained after the stirring reaction to room temperature, washing with water, extracting with organic solvent IV, drying and concentrating the organic phase to obtain a crude product, and purifying the crude product to obtain the target product 3-chloro-6-methylpyridazine.

[0043] In some embodiments, the organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane. The purification method is selected from one or more of column chromatography, recrystallization, and distillation.

[0044] In some embodiments of the present invention, a method for synthesizing 3-chloro-6-methylpyridazine is provided: 3,6-dichloropyridazine (compound 1) is used as a raw material, and a nucleophilic substitution reaction is performed to obtain an intermediate 2 (ethyl 2-(6-chloropyridazine-3-yl)acetate), which is then converted into a target compound 3 (3-chloro-6-methylpyridazine) by a decarboxylation reaction. The synthetic route is as follows:

[0045]

[0046] The technical solution of the present invention is further explained below by way of embodiments.

[0047] Example 1

[0048] The compound 3-chloro-6-methylpyridazine has the following synthesis steps:

[0049] (1) 3,6-Dichloropyridazine (50.00 g, 335.63 mmol, 1.00 eq) was dissolved in acetonitrile (1.0 L), and then potassium monoethyl malonate (68.55 g, 402.75 mmol, 1.20 eq), magnesium chloride (47.93 g, 503.44 mmol, 1.50 eq) and triethylamine (67.93 g, 671.26 mmol, 2.00 eq) were added, and stirred at 70°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 7 with 1M hydrochloric acid aqueous solution, extracted twice with dichloromethane (800 mL × 2), and the organic phases were combined and washed with water (1.0 L) and saturated brine (1.0 L) in turn, and the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the intermediate ethyl 2-(6-chloropyridazin-3-yl)acetate (weight 62.40 g, purity 98%, yield 91%), namely compound 2.

[0050] The H NMR spectrum of the obtained compound 2 is as follows Figure 1 The characterization data are as follows:

[0051] 1 H NMR (400MHz, cdcl3) δ7.52 (dd, J=23.8, 8.8Hz, 2H), 4.18 (q, J=7.1Hz, 2H), 4.03 (s, 2H), 1.25 (t, J=7.1Hz, 3H).

[0052] (2) Water (50 mL) and lithium chloride (52.82 g, 1.25 mol, 5.00 eq) were added to a solution of ethyl 2-(6-chloropyridazin-3-yl)acetate (50.00 g, 249.22 mmol, 1.00 eq) in dimethyl sulfoxide (500 mL), and the mixture was stirred at 100° C. for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 3, i.e., the target product 3-chloro-6-methylpyridazine (weight 29.60 g, purity 98%, yield 91%).

[0053] The H NMR spectrum of the obtained target compound 3 (3-chloro-6-methylpyridazine) is as follows: Figure 2 The characterization data are as follows:

[0054] 1 H NMR (400MHz, cdcl3) δ7.39 (d, J = 8.8Hz, 1H), 7.31 (d, J = 8.8Hz, 1H), 2.66 (d, J = 10.6Hz, 3H).

[0055] Embodiment 2-8

[0056] Examples 2-8 are substantially the same as Example 1, except that the amount of potassium salt of ethyl malonate, the amount of lithium chloride, additives, organic solvent I, organic solvent II, etc. used in the reaction are adjusted, as shown in Table 1.

[0057] Through Examples 1-8, the effects of various reaction conditions on the reaction yield in the synthesis of intermediate 2 (ethyl 2-(6-chloropyridazine-3-yl)acetate) and target compound 3 (3-chloro-6-methylpyridazine) were verified, and the results are shown in Table 1.

[0058] Table 1: Synthesis conditions and results of the examples

[0059]

[0060] As shown in Table 1 above, when the molar ratio of compound 1 to potassium ethyl malonate and additives is changed, the reaction effect is better. When the molar ratio of compound 2 to lithium chloride is 1:5.0-6.0, the reaction effect is better. When the solvents acetonitrile and 1,4-dioxane are used, the reaction in step (1) can be carried out, and acetonitrile is more effective as a solvent. When the solvent is dimethyl sulfoxide or N,N-dimethylformamide, the reaction in step (2) can be carried out, and dimethyl sulfoxide is more effective as a solvent. When the additive is magnesium chloride or zinc chloride, the reaction in step (1) can be carried out, and magnesium chloride is more effective as an additive.

[0061] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3-chloro-6-methylpyridazine, characterized in that: The synthesis method uses 3,6-dichloropyridazine as a raw material, obtains ethyl 2-(6-chloropyridazine-3-yl)acetate through a nucleophilic substitution reaction, and then obtains the ethyl 2-(6-chloropyridazine-3-yl)acetate through a decarboxylation reaction.

2. The synthesis method according to claim 1, characterized in that The synthesis method specifically comprises the following steps: S1: dissolving 3,6-dichloropyridazine in solvent I, then sequentially adding ethyl malonate potassium salt, additives and a base, stirring for reaction, extracting, concentrating and purifying to obtain an intermediate compound 2, namely ethyl 2-(6-chloropyridazine-3-yl)acetate; S2: Solvent II is added to the intermediate compound 2 to dissolve it, and then water and lithium chloride are added in sequence to obtain a mixed solution. After stirring for reaction, extraction, drying, distillation and purification are performed to obtain 3-chloro-6-methylpyridazine.

3. The synthesis method according to claim 2, characterized in that In step S1, the solvent I is selected from one or more of acetonitrile, 1,4-dioxane, toluene, and acetone; and the mass volume ratio of the 3,6-dichloropyridazine to the solvent I is 1:5-40 g / mL.

4. The synthesis method according to claim 2, characterized in that In step S1, the potassium salt of malonic acid monoester includes one of ethyl malonate potassium salt and methyl malonate potassium salt; and the molar ratio of the 3,6-dichloropyridazine to the potassium salt of malonic acid monoester is 1:1-3.

5. The synthesis method according to claim 2, characterized in that In step S1, the additive is selected from one or more of magnesium chloride and zinc chloride; the molar ratio of the 3,6-dichloropyridazine to the additive is 1:1-3.

6. The synthesis method according to claim 2, characterized in that In step S1, the base is selected from one or more of triethylamine, diethylamine, and N,N-diisopropylethylamine, and the molar ratio of the 3,6-dichloropyridazine to the base is 1:1-3.

7. The synthesis method according to claim 2, characterized in that In step S1, the stirring reaction is carried out at a temperature of 60-200°C and for a time of 12-48 hours.

8. The synthesis method according to claim 2, characterized in that In step S2, the solvent II is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone; the mass volume ratio of the intermediate compound 2 to the solvent II is 1:5-40 g / mL.

9. The synthesis method according to claim 2, characterized in that: In step S2, the mass volume ratio of the intermediate compound 2 to the water is 1:1-2 g / mL; the mass volume ratio of the intermediate compound 2 to the lithium chloride is 1:3-6 g / mL.

10. The synthesis method according to claim 2, characterized in that: In step S2, the stirring reaction is carried out at a temperature of 60-200°C and for a time of 36-60 hours.

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