A method for synthesizing imidazopyridazine compounds

Abstract

The application discloses a synthesis method of imidazopyridazine compounds, and a synthesis route is as follows: a compound shown in a general formula (1) and a compound shown in a general formula (2) are subjected to ring formation reaction under the action of a catalyst zinc halide, so as to prepare a compound shown in a general formula (3), namely, the imidazopyridazine compound; the synthesis method uses inexpensive zinc halide as the catalyst, so that the reaction can be completed in a very short time, the conversion is very thorough, meanwhile, no side reaction occurs, the product can be obtained in an ideal yield through simple post-treatment, the reaction time and the cost of treatment and purification are greatly reduced, and the method is very suitable for industrial scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing imidazopyridazine compounds. Background Technology

[0002] Imidazolidine compounds are an important class of intermediates with wide applications in synthesis, pesticides, and pharmaceuticals. For example, as important molecular building blocks, imidazopyridazine compounds are used in the synthesis of drugs that can treat or improve Huntington's disease, as described in patents WO2020 / 005877A1, WO2020 / 231977A1, and US2022 / 151938A1; in patent WO2022 / 166860A1, they are used in the synthesis of compounds with good PIM kinase inhibitory effects. This compound is a novel, highly active, and low-toxicity ideal PIM inhibitor that can be used to treat or prevent diseases such as acute myeloid leukemia, myelofibrosis, chronic lymphocytic leukemia, and other hematologic malignancies, as well as solid tumors such as gastric cancer and prostate cancer; and in patent US2014 / 256733, they are used in the synthesis of compounds that inhibit mixed lineage kinases (MLK). Imidazolidine compounds have great potential for application in drug development, so it is of great significance to study the synthetic methods of imidazopyridazine compounds.

[0003] In existing technologies, the imidazole ring formation reaction of 3-aminopyridazine compounds with haloketone compounds is a common method for synthesizing imidazole-pyridazine compounds. However, the synthesis process often encounters problems such as slow conversion, incomplete conversion, and difficulty in purification. Current solutions can only be achieved by changing the base or reaction solvent, but these methods are not universal and often result in side reactions. Summary of the Invention

[0004] To address the aforementioned problems in existing technologies, this invention provides a method for synthesizing imidazopyridazine compounds. This method uses inexpensive zinc halide as a catalyst, enabling the conversion to be completed quickly and completely without side reactions. The product is obtained through simple alkalization, significantly reducing reaction time and purification costs, making it highly suitable for industrial-scale production.

[0005] The technical solution of the present invention is as follows:

[0006] The first objective of this invention is to provide a method for synthesizing imidazopyridazine compounds, the synthetic route of which is as follows:

[0007]

[0008] The compound shown in general formula (1) and the compound shown in general formula (2) undergo a cyclization reaction under the action of zinc halide catalyst to obtain the compound shown in general formula (3), namely imidazopyridazine compounds.

[0009] In general formulas (1) and (3), R 1 R 2 R 3 Each can be independently represented as one of the following: hydrogen group, C1-C6 alkyl group, halogen, C1-C6 alkoxy group, halo-C1-C6 alkyl group, halo-C1-C6 alkoxy group, C1-C6 alkylthio group, C1-C6 alkoxycarbonyl group, and C1-C3 cyano group.

[0010] In general formula (2), X represents Cl, Br or I;

[0011] In general formulas (2) and (3), Y represents one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 alkoxycarbonyl.

[0012] In one embodiment of the present invention, in general formulas (1) and (3), R 1 R 2 R 3 Each can be independently represented as one of the following: hydrogen group, methyl group, tert-butyl group, fluorine group, chlorine group, bromine group, methoxy group, trifluoromethyl group, trifluoromethoxy group, methyl ester group, and cyano group.

[0013] In one embodiment of the present invention, in general formulas (2) and (3), Y represents one of hydrogen group, methyl group, tert-butyl group, cyclopropyl group, cyclohexyl group, methoxy group, methyl ester group, and ethyl ester group.

[0014] In one embodiment of the present invention, zinc halide is one or more of zinc chloride, zinc bromide, and zinc iodide.

[0015] In one embodiment of the present invention, the compound represented by general formula (1) has any of the following structures:

[0016]

[0017] In one embodiment of the present invention, the compound represented by general formula (2) is any one of the following structures:

[0018]

[0019]

[0020] In one embodiment of the present invention, the compound represented by general formula (3) has any of the following structures:

[0021]

[0022] In one embodiment of the present invention, the specific steps of the synthesis method are as follows:

[0023] The compound shown in general formula (1) is dissolved in an organic solvent, and then zinc halide and the compound shown in general formula (2) are added. The reaction is stirred until complete to obtain a reaction solution. After post-treatment, the compound shown in general formula (3) is obtained, which is the imidazopyridazine compound.

[0024] In one embodiment of the present invention, the organic solvent is one or more of acetonitrile, ethanol, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone.

[0025] Preferably, the organic solvent is acetonitrile.

[0026] In one embodiment of the present invention, the molar ratio of the compound shown in general formula (1) to the compound shown in general formula (2) is 1:1-4.

[0027] Preferably, the molar ratio of the compound shown in general formula (1) to the compound shown in general formula (2) is 1:1.

[0028] In one embodiment of the present invention, the molar ratio of the compound represented by general formula (1) to zinc halide is 1:0.02-1.

[0029] Preferably, the molar ratio of the compound represented by general formula (1) to zinc halide is 1:0.1.

[0030] In one embodiment of the present invention, the mass-to-volume ratio of the compound of general formula (1) to the organic solvent is 1:5-40 g / mL; the reaction temperature is 30-130℃; and the reaction time is 2-40 h.

[0031] Preferably, the reaction temperature is 70°C and the reaction time is 6 hours.

[0032] In one embodiment of the present invention, the post-processing method is as follows: the reaction solution is cooled to room temperature, the solvent is directly evaporated, then added to water, the pH is adjusted to 7-8 with an alkaline aqueous solution, the mixture is stirred thoroughly, filtered, and the filter cake is collected; the collected solid is added to ethyl acetate, heated to reflux, filtered while hot, and the filtrate is evaporated to dryness to obtain the target compound.

[0033] In one embodiment of the present invention, the alkaline aqueous solution is one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, and potassium hydroxide solution.

[0034] The beneficial technical effects of this invention are as follows:

[0035] This invention uses inexpensive zinc halide as a catalyst and 3-aminopyridazine compounds as raw materials to carry out a cyclization reaction in the presence of haloketone compounds to prepare imidazopyridazine compounds in high yield.

[0036] The synthesis method of this invention uses inexpensive zinc halide as a catalyst, which enables the reaction to be completed in a very short time and the conversion to be very thorough, while no side reactions occur. The product can be obtained in ideal yield through simple post-processing, which greatly reduces the reaction time and the cost of processing and purification, making it very suitable for industrial scale-up production. Attached Figure Description

[0037] Figure 1 This is a schematic diagram of the synthesis route of the present invention.

[0038] Figure 2 This is the 1H NMR spectrum of the target compound (3aa) in Example 1 of this invention.

[0039] Figure 3 This is the 1H NMR spectrum of the target compound (3ba) in Example 10 of the present invention.

[0040] Figure 4 This is the 1H NMR spectrum of the target compound (3ca) in Example 11 of this invention.

[0041] Figure 5 This is the 1H NMR spectrum of the target compound (3dB) in Example 12 of the present invention. Detailed Implementation

[0042] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0043] Example 1

[0044] The synthetic route for compound 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (3aa) is as follows:

[0045]

[0046] (1) At room temperature, compound 1a (3.00 kg, 20.90 mol, 1.0 eq) was dissolved in acetonitrile (7.00 L) solution, and then zinc bromide (0.47 kg, 2.09 mol, 0.1 eq) and compound 2a (1.93 kg, 20.90 mol, 1.0 eq) were added. The mixture was stirred at 70 °C for 6 hours.

[0047] (2) After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to evaporate the solvent. Then, it was added to water (10.0 L), and the pH was adjusted to 7-8 with 5M sodium hydroxide aqueous solution. After stirring thoroughly, the mixture was filtered and the filter cake was collected. The collected solid was added to ethyl acetate (10.0 L), heated to reflux, filtered while hot, and the filtrate was evaporated to dryness to obtain 3.65 kg of yellow solid compound 3aa with a purity of 98% and a yield of 94%.

[0048] The 1H NMR spectrum of the obtained compound 3aa is as follows: Figure 2 As shown, the obtained characterization data are as follows:

[0049] 1 H NMR (600MHz, CDCl3) δ7.66(s,1H),6.84(s,1H),2.63(s,3H),2.49(s,3H).

[0050] Examples 2-9

[0051] Examples 2-9 are the same as Example 1, except that the catalyst, solvent, reaction temperature, and reaction time used in the reaction were adjusted, and compound 3aa was obtained respectively. See Table 1 for details.

[0052] Comparative Example 1

[0053] Comparative Example 1 is the same as Example 1, except that the catalysts used in the reaction are adjusted, as shown in Table 1.

[0054] Comparative Example 2

[0055] The synthetic route for compound 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (3aa) is as follows:

[0056]

[0057] (1) At room temperature, compound 1a (50.00 g, 348.25 mmol, 1.0 eq) was dissolved in acetonitrile (125.00 mL) solution, and then triethylamine (91.63 g, 905.46 mmol, 2.60 eq) and compound 2a (32.22 g, 348.25 mmol, 1.0 eq) were added. The mixture was stirred at 70 °C for 6 hours.

[0058] (2) After the reaction was complete, the reaction solution was cooled to room temperature. Water (150 mL) was added to the reaction solution, and the mixture was extracted three times (100 mL * 3) with ethyl acetate. The organic phases were combined, washed three times (100 mL * 3) with water, and once with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 30.50 g of yellow solid compound 3aa with a purity of 98% and a yield of 48%.

[0059] The effects of various reaction conditions on the reaction yield in the synthesis of compound 3aa were investigated through Examples 1-9 and Comparative Examples 1 and 2. The results obtained are shown in Table 1.

[0060] Table 1 Synthesis conditions and results of the examples and comparative examples

[0061]

[0062]

[0063] As can be seen from the above charts, compared with Examples 1-3 and Comparative Example 1, the reaction yield was significantly improved under the action of catalysts ZnBr2, ZnCl2 and ZnI2, among which ZnBr2 was the most effective catalyst.

[0064] Comparing Examples 1 and 4-5, halving the amount of catalyst to 0.05 equivalents resulted in a worse conversion rate and a lower reaction yield; while increasing the amount of catalyst by half to 0.15 equivalents resulted in a stable reaction yield.

[0065] Comparing Examples 1 and 6-7, the reaction was slightly less effective in ethyl acetate and ethanol, while acetonitrile was a better solvent and more conducive to the reaction.

[0066] Comparing Examples 1 and 8, the reaction temperature was lowered, which slowed down the reaction rate and reduced the reaction yield. The reaction at 70°C was more suitable.

[0067] Comparing Examples 1 and 9, the reaction time was prolonged, but the yield of the target compound remained unchanged. Comparing Example 9 and Comparative Example 2 further highlights the advantage of the high reaction yield of the method described in this invention.

[0068] Example 10

[0069] The synthetic route for compound 6-chloro-2-methylimidazo[1,2-b]pyridazine (3ba) is as follows:

[0070]

[0071] Referring to Example 1, using compound 1b (3-amino-6-chloropyridazine) (3.00 kg, 23.16 mol, 1.0 eq) as the starting material, and maintaining the molar ratio of compounds 1b, 2a, and zinc bromide at 1:1:0.1, and with the other conditions the same as in Example 1, 3.62 kg of pale yellow solid compound 3ba with a purity of 97% and a yield of 90% was obtained.

[0072] The obtained 3ba 1H NMR spectrum is as follows Figure 3 As shown, the obtained characterization data are as follows:

[0073] 1 H NMR (400MHz, cdcl3) δ7.78(d,J=9.4Hz,1H),7.70(d,J=3.2Hz,1H),6.99(d,J=9.4Hz,1H),2.51–2.46(m,3H).

[0074] Example 11

[0075] The synthetic route for compound 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (3ca) is as follows:

[0076]

[0077] Referring to Example 1, using compound 1c (3-amino-4-bromo-6-chloropyridazine) 1c (3.00 kg, 14.39 mol, 1.0 eq) as the starting material, and maintaining the molar ratio of compounds 1c, 2a, and zinc bromide at 1:1:0.1, and with the other conditions the same as in Example 1, 3.41 kg of pale yellow solid compound 3ca was obtained with a purity of 97% and a yield of 93%.

[0078] The obtained 3ca 1H NMR spectrum is as follows Figure 4 As shown, the obtained characterization data are as follows:

[0079] 1 H NMR (600MHz, CDCl3) δ7.77(s,1H),7.32(s,1H),2.52(s,3H).

[0080] Example 12

[0081] The synthetic route for compound 6-chloroimidazolo[1,2-b]pyridazine (3db) is as follows:

[0082]

[0083] Referring to Example 1, using compound 1d (3-amino-6-chloropyridazine) (3.00 kg, 23.16 mol, 1.0 eq) as the starting material, and maintaining the molar ratio of compounds 1d, 2b, and zinc bromide at 1:1:0.1, and with the other conditions the same as in Example 1, 3.31 kg of light brown solid compound 3db with a purity of 98% and a yield of 91% was obtained.

[0084] The obtained 3dB 1H NMR spectrum is as follows Figure 5 As shown, the obtained characterization data are as follows:

[0085] 1 H NMR (600MHz, DMSO) δ8.33 (s, 1H), 8.21 (d, J = 9.5 Hz, 1H), 7.84 (s, 1H), 7.34 (d, J = 9.5 Hz, 1H).

Claims

1. A method for synthesizing imidazopyridazine compounds, characterized in that, The synthetic route of the synthetic method is as follows: The compound shown in general formula (1) and the compound shown in general formula (2) undergo a cyclization reaction under the action of zinc halide catalyst to obtain the compound shown in general formula (3), namely imidazopyridazine compounds; In general formulas (1) and (3), R 1 It can be represented as one of hydrogen, methyl, or halogen; R 2 Represented as hydrogen-based; R 3 Represented as halogen; In general formula (2), X represents Cl, Br or I; In general formulas (2) and (3), Y represents either hydrogen or methyl.

2. The synthesis method according to claim 1, characterized in that, Zinc halides are one or more of zinc chloride, zinc bromide, and zinc iodide.

3. The synthesis method according to claim 1, characterized in that, The specific steps of the synthesis method are as follows: The compound shown in general formula (1) is dissolved in an organic solvent, and then zinc halide and the compound shown in general formula (2) are added. The reaction is stirred until complete to obtain a reaction solution. After post-treatment, the compound shown in general formula (3) is obtained, which is the imidazopyridazine compound.

4. The synthesis method according to claim 3, characterized in that, The organic solvent is one or more of acetonitrile, ethanol, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone.

5. The synthesis method according to claim 3, characterized in that, The molar ratio of the compound shown in general formula (1) to the compound shown in general formula (2) is 1:1-4.

6. The synthesis method according to claim 3, characterized in that, The molar ratio of the compound shown in general formula (1) to zinc halide is 1:0.02-1.

7. The synthesis method according to claim 3, characterized in that, The mass-to-volume ratio of the compound shown in general formula (1) to the organic solvent is 1:5-40 g / mL.

8. The synthesis method according to claim 3, characterized in that, The reaction temperature is 30-130℃, and the reaction time is 2-40h.

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