A kind of synthetic method of 3-chloro-6-methylpyridazine

Abstract

The present invention discloses a method for synthesizing 3-chloro-6-methylpyridazine. The synthesis method of the present invention 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 product through a decarboxylation reaction. The synthesis method of the present invention has mild reaction conditions, low safety risks, low cost, and excellent yield, thus solving the problems of high safety risks and unsuitability for process amplification in existing syntheses.

Description

Technical Field

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

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

[0003] 3-Chloro-6-methylpyridazine serves as an important molecular building block in this class of compounds. For example, in WO2012 / 148775, it was used to synthesize bicyclic pyridine compounds, which are used as PIM inhibitors to prevent and treat PIM kinase-related conditions. In WO2013 / 166621, it was used to synthesize novel 1-(dihydronaphthyl)pyridones, melanin-concentrating hormone receptor 1 (MCHR1) antagonists useful for the treatment of obesity and diabetes. In WO2015 / 123089, it was used to synthesize a new class of cysteine ​​protease inhibitors useful for treating diseases requiring the inhibition of bone resorption, such as osteoporosis. Therefore, developing new methods for synthesizing 3-chloro-6-methylpyridazine is of great significance.

[0004] In the prior art, the conventional synthesis route for 3-chloro-6-methylpyridazine uses 6-methyl-3(2H)-pyridazinone as a raw material and reacts with phosphorus oxychloride to obtain the target product. This 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 method has mild reaction conditions, low safety risks, low cost and high yield.

[0006] The technical solutions of the present invention are as follows:

[0007] The first aspect of the present invention protects a method for synthesizing 3-chloro-6-methylpyridazine. The method comprises using 3,6-dichloropyridazine as a raw material, obtaining ethyl 2-(6-chloropyridazin-3-yl)acetate through a nucleophilic substitution reaction, and then obtaining the ethyl 2-(6-chloropyridazin-3-yl)acetate 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 monoethyl malonate potassium salt, additives and base in sequence, stir to react, extract, concentrate and purify to obtain intermediate compound 2, i.e., ethyl 2-(6-chloropyridazin-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, the solution is extracted, dried, distilled, and purified 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 malonate monoester potassium salt includes one of malonate monoethyl ester potassium salt and malonate monomethyl ester potassium salt; and the molar ratio of the 3,6-dichloropyridazine to the malonate monoester potassium salt 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, and 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 g / mL 1:5-40.

[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 present invention provides a novel method for synthesizing 3-chloro-6-methylpyridazine. The method uses 3,6-dichloropyridazine as a raw material, undergoes a nucleophilic substitution reaction to obtain ethyl 2-(6-chloropyridazin-3-yl)acetate, and then undergoes a decarboxylation reaction to convert the ethyl 2-(6-chloropyridazin-3-yl)acetate into the target compound 3-chloro-6-methylpyridazine.

[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 risks, low cost and ideal yield. It not only provides a potential route for the process synthesis of 3-chloro-6-methylpyridazine, but also further contributes to the development and utilization of halogenated pyridazine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This 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 with reference to the accompanying drawings and embodiments. It should be understood that the described embodiments are only a subset of the embodiments of the present invention, and not all of them. Based on the described embodiments of the present invention, all other embodiments derived by persons of ordinary skill in the art without inventive effort fall within the scope of protection of the present invention. Unless otherwise defined, technical or scientific terms used herein shall have the ordinary meanings understood by persons of ordinary skill in the art to which the present invention pertains.

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

[0026] The present invention first 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-chloropyridazin-3-yl)acetate, and then performing a decarboxylation reaction to obtain the ethyl 2-(6-chloropyridazin-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 monoethyl malonate potassium salt, additives and base in sequence, stir to react, extract, concentrate and purify to obtain intermediate compound 2, i.e., ethyl 2-(6-chloropyridazin-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, the solution is extracted, dried, distilled, and purified 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 malonate monoester includes one of the potassium salt of ethyl malonate monoester and the potassium salt of methyl malonate monoester; the molar ratio of the 3,6-dichloropyridazine to the potassium salt of malonate monoester is 1:1-3, including but not limited to 1:1, 1:1.5, 1:2, 1:2.5, and 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, and 200°C, and the time is 12-48h, including but not limited to 12h, 18h, 24h, 30h, 36h, 42h, and 48h.

[0035] In some embodiments, in step S1, the specific process of extraction, concentration, and purification is: adjusting the reaction solution 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-chloropyridazin-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, and 200°C, and the time is 36-60h, including but not limited to 36h, 40h, 45h, 50h, 55h, and 60h.

[0042] In some embodiments, in step S2, the specific process of extraction, drying, distillation, and purification is as follows: 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, wherein 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-chloropyridazin-3-yl)acetate), which is then converted into the target compound 3 (3-chloro-6-methylpyridazine) through a decarboxylation reaction. The synthetic route is as follows:

[0045]

[0046] The technical solution of the present invention is further explained below through examples.

[0047] Example 1

[0048] The compound 3-chloro-6-methylpyridazine is synthesized as follows:

[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 1 M aqueous hydrochloric acid solution and extracted twice with dichloromethane (800 mL × 2). The organic phases were combined and washed with water (1.0 L) and saturated brine (1.0 L) in sequence. 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) 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) were added water (50 mL) and lithium chloride (52.82 g, 1.25 mol, 5.00 eq), 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] Examples 2-8

[0056] Examples 2-8 are basically the same as Example 1, except that the amount of potassium salt of monoethyl 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-chloropyridazin-3-yl)acetate) and target compound 3 (3-chloro-6-methylpyridazine) were verified. 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 the additive 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 description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiment. It is understood that other improvements and variations directly derived or imagined 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 scope of protection of the present invention.

Claims

1. A method for synthesizing 3-chloro-6-methylpyridazine, 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, an additive, and a base, stirring for reaction, extracting, concentrating, and purifying to obtain intermediate compound 2, i.e., ethyl 2-(6-chloropyridazin-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, the solution is extracted, dried, distilled, and purified to obtain 3-chloro-6-methylpyridazine; In step S1, the additive is selected from one or more of magnesium chloride and zinc chloride.

2. The synthesis method according to claim 1, wherein 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.

3. The synthesis method according to claim 1, wherein In step S1, the potassium salt of malonate monoester is selected from one of the potassium salt of ethyl malonate monoester and the potassium salt of methyl malonate monoester; and the molar ratio of the 3,6-dichloropyridazine to the potassium salt of malonate monoester is 1:1-3.

4. The synthesis method according to claim 1, characterized in that In step S1, the molar ratio of the 3,6-dichloropyridazine to the additive is 1:1-3.

5. The synthesis method according to claim 1, 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.

6. The synthesis method according to claim 1, characterized in that In step S1, the stirring reaction temperature is 60-200° C. and the time is 12-48 hours.

7. The synthesis method according to claim 1, 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.

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

9. The synthesis method according to claim 1, characterized in that In step S2, the stirring reaction temperature is 60-200° C. and the time is 36-60 h.

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