A process for the preparation of 4-bromo-3,6-dichloropyridazine

Abstract

This invention discloses a method for preparing 4-bromo-3,6-dichloropyridazine, belonging to the field of organic synthesis. The method involves reacting compound 1 as a substrate in the presence of a diazotizing reagent, a bromine source, and a solvent to obtain compound 2. The diazotizing reagent is selected from any one or more of nitrous acid, nitrites, or nitrite esters, and the bromine source is a mixture of copper bromide and cuprous bromide. This method can produce 4-bromo-3,6-dichloropyridazine with higher yield and higher purity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 4-bromo-3,6-dichloropyridazine. Background Technology

[0002] The Sandmeyer reaction is a common reaction used to prepare haloaromatics, and it is generally believed to be a free radical reaction catalyzed by cuprous salts. However, some literature reports that copper salts can also catalyze the Sandmeyer reaction on the benzene ring, and there is no significant difference in yield between the two reactions and the cuprous salt-catalyzed Sandmeyer reaction.

[0003] However, the article "Efficient and Regioselective Halogenations of 2-Amino-1,3-thiazoles with Copper Salts" (J. Org. Chem. 2009, 74, 2578–2580) points out that some aromatic rings show significant differences in products and yields when catalyzed by copper and cuprous salts, respectively. Furthermore, cuprous salts exhibit significant Sandmeyer reactivity, while copper salts produce virtually no corresponding products. Currently, there is no further research on catalysts for the Sandmeyer reaction of pyridazine rings in existing technologies.

[0004] Chinese patent CN 1146348118 A discloses a compound with cancer therapeutic activity, of which 4-bromo-3,6-dichloropyridazine is an important intermediate.

[0005] CN 116348118 A also discloses a method for preparing 4-bromo-3,6-dichloropyridazine, which uses cuprous bromide as a bromine source and tert-butyl nitrite as a diazotizing reagent. After the reaction, the target compound is separated by column chromatography with a yield of 50.38%. This yield is quite unfavorable for industrial production. Summary of the Invention

[0006] [Technical Issues]

[0007] A method for preparing 4-bromo-3,6-dichloropyridazine with higher yield and lower impurity content is provided.

[0008] [Technical Solution]

[0009] This invention provides a method for preparing 4-bromo-3,6-dichloropyridazine, the reaction formula of which is as follows:

[0010]

[0011] Includes the following steps:

[0012] In the presence of a diazotizing agent, a bromine source, and a solvent, compound 1 was reacted to yield compound 2.

[0013] The diazotizing agent is selected from any one or more of nitrous acid, nitrite, or nitrite ester.

[0014] The bromine source is a mixture of copper bromide and cuprous bromide.

[0015] In one embodiment of the present invention, the molar ratio of cuprous bromide to copper bromide is 1:(0.5-15), preferably 1:(0.5-12), and specifically can be 1:0.5, 1:1, 1:2, 1:9 or 1:12.

[0016] In one embodiment of the present invention, the molar ratio of the diazotizing agent to the compound 1 is (1-2):1, specifically 1.5:1.

[0017] In one embodiment of the present invention, the diazotizing agent is tert-butyl nitrite.

[0018] In one embodiment of the present invention, the molar ratio of the bromine source to the compound 1 is (1.0-1.8):1, specifically 1.0:1, 1.3:1 or 1.5:1.

[0019] In one embodiment of the present invention, the solvent is selected from any one or more of acetonitrile, ethyl acetate, methyl acetate, formic acid, acetic acid, water, hydrochloric acid, and DMSO.

[0020] In one embodiment of the present invention, the mass-to-volume ratio of compound 1 to solvent is 1 g:(5-20) mL, specifically 1:10.

[0021] In one embodiment of the present invention, the reaction time is 1-8 hours.

[0022] In one embodiment of the present invention, the reaction temperature is 20-30°C.

[0023] In one embodiment of the present invention, the preparation method of 4-bromo-3,6-dichloropyridazine specifically includes the following reaction steps:

[0024] At 20-30℃, add solvent, compound 1, and bromine source to the reaction vessel, add diazotizing reagent dropwise, and stir the reaction for 1-8 hours;

[0025] After the reaction was completed, the pH of the system was adjusted to 9-10, filtered, the filtrate was collected, the organic phase was collected, washed with water until the pH was 6-8, the solvent was removed, n-heptane was added and slurry was stirred, filtered, the solid was collected and dried to obtain 4-bromo-3,6-dichloropyridazine.

[0026] In one embodiment of the present invention, after the reaction is completed, the solvent is removed by vacuum distillation, then toluene is added and the pH of the system is adjusted to 9-10. The mixture is filtered, the filtrate is collected, the organic phase is taken, washed with water until the pH is 6-8, the solvent is removed, n-heptane is added and slurry is stirred, filtered, the solid is collected, and dried to obtain 4-bromo-3,6-dichloropyridazine.

[0027] The role and effect of invention

[0028] According to the preparation method of 4-bromo-3,6-dichloropyridazine of the present invention, since the bromine source selected is a mixed bromine source of copper bromide and cuprous bromide, 4-bromo-3,6-dichloropyridazine can be prepared with higher yield and higher purity. Attached Figure Description

[0029] Figure 1 This is the HPLC chromatogram of reaction number 1 in Example 1 of the present invention, wherein: the target analyte is located at a retention time of 6.508 min, and impurity A is located at a retention time of 3.648 min;

[0030] Figure 2 This is the HPLC chromatogram of reaction number 2 in Example 1 of the present invention, wherein: the target analyte is at a retention time of 6.487 min, and impurity A is at a retention time of 3.638 min;

[0031] Figure 3 This is the HPLC chromatogram of reaction number 3 in Example 1 of the present invention, wherein the target analyte is located at a retention time of 6.458 min.

[0032] Figure 4 This is the HPLC chromatogram of reaction number 4 in Example 1 of the present invention, wherein the target analyte is located at a retention time of 6.460 min.

[0033] Figure 5 This is the HPLC chromatogram of reaction number 5 in Example 1 of the present invention, wherein the target analyte is located at a retention time of 6.452 min.

[0034] Figure 6 This is the HPLC chromatogram of reaction number 6 in Example 1 of the present invention, wherein the target analyte is located at a retention time of 6.449 min.

[0035] Figure 7 This is the HPLC chromatogram of reaction number 7 in Example 1 of the present invention, wherein the target analyte is located at a retention time of 6.264 min.

[0036] Figure 8 This is the HPLC spectrum of the product in Example 2 of the present invention, wherein the target analyte is located at a retention time of 6.295 min.

[0037] Figure 9 This is the HPLC chromatogram of the product in Example 3 of the present invention, wherein the target analyte is located at a retention time of 6.246 min. Detailed Implementation

[0038] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.

[0039] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.

[0040] In the following examples, the commercially available ammonia solution is a commercially available aqueous solution containing 25% to 28% ammonia, which has not been titrated before use.

[0041] <Example 1>

[0042] Preparation method of 4-bromo-3,6-dichloropyridazine

[0043] In this embodiment, the bromine source was screened, and the screening method is as follows:

[0044] Add 20 mL of acetonitrile to the reaction vessel, then add 2 g of 4-amino-3,6-dichloropyridazine (12.2 mmol, 1.0 eq) and a bromine source (specific conditions are shown in Table 1). Control the temperature at 20 °C, and then add 1.89 g of tert-butyl nitrite (18.3 mmol, 1.5 eq) dropwise. After the addition is complete, maintain the reaction at 20 °C and stir for 3 h. Take a sample and send it for HPLC analysis.

[0045] The screening results are shown in the table below.

[0046] Table 1 Screening of bromine sources

[0047] Serial Number Copper bromide / eq Cuprous bromide / eq reaction temperature Target product liquid phase yield 1 1.5 0 20℃ 71.2％ 2 0 1.5 20℃ 45.4％ 3 0.5 1.0 20℃ 89.5％ 4 0.75 0.75 20℃ 90.3％ 5 1.0 0.5 20℃ 92.6％ 6 0.9 0.1 20℃ 94.8％ 7 1.2 0.1 20℃ 92.5％

[0048] As shown in the table above and Figure 1-2 As shown, when copper bromide is used alone as the bromine source ( Figure 1 There will be a significant impurity A (RT≈3.64 min), while when cuprous bromide is used alone as the bromine source ( Figure 2 In addition to impurity A (RT≈3.64 min), a more noticeable impurity B (RT=5.11 min) will also be generated.

[0049] For example, as shown in the table above and Figure 3-7 As shown, when using a mixed bromine source of copper bromide and cuprous bromide, impurities A and B can be effectively suppressed, and no new impurities with a content greater than 10% are generated.

[0050] <Example 2>

[0051] Preparation method of 4-bromo-3,6-dichloropyridazine

[0052] This embodiment provides a method for preparing 4-bromo-3,6-dichloropyridazine, comprising the following steps:

[0053] Add 100 mL of acetonitrile to the reaction vessel, then add 10 g of 4-amino-3,6-dichloropyridazine (61.0 mmol, 1.0 eq), 12.3 g of copper bromide (54.9 mmol, 0.9 eq), and 0.88 g of cuprous bromide (6.1 mmol, 0.1 eq) in sequence. Control the temperature at 20 °C, and then add 9.44 g of tert-butyl nitrite (91.5 mmol, 1.5 eq) dropwise. After the addition is complete, maintain the reaction at 20 °C and stir for 4 h.

[0054] The reaction solution was collected, the solvent was removed by vacuum distillation, 50 mL of toluene was added, and the pH was adjusted to 9-10 with commercially available ammonia at room temperature. The mixture was filtered, and the filtrate was collected. The organic phase was washed with water until the pH reached 7. The solution was concentrated under reduced pressure, and 10 mL of n-heptane was added and stirred for 30 min. The mixture was filtered, and the solid was collected and dried to give 9.87 g of 4-bromo-3,6-dichloropyridazine, with a yield of 71.0%. Figure 8 As shown, the purity of the 4-bromo-3,6-dichloropyridazine prepared in this example is 98.7%.

[0055] <Example 3>

[0056] Preparation method of 4-bromo-3,6-dichloropyridazine

[0057] This embodiment provides a method for preparing 4-bromo-3,6-dichloropyridazine, comprising the following steps:

[0058] Add 10 L of acetonitrile to the reactor, then add 1 kg of 4-amino-3,6-dichloropyridazine (6.10 mol, 1.0 eq), 1.63 kg of copper bromide (7.32 mol, 1.2 eq), and 87.5 g of cuprous bromide (0.61 mol, 0.1 eq) in sequence. Control the temperature at 20 °C, and then add 943.5 g of tert-butyl nitrite (9.15 mol, 1.5 eq) dropwise. After the addition is complete, maintain the reaction at 20 °C and stir for 2 h.

[0059] The reaction solution was collected, and the pH was adjusted to 9-10 using commercially available ammonia at room temperature. The mixture was filtered, and the filtrate was collected. The organic phase was washed with water until the pH reached 7. The solution was concentrated under reduced pressure, and 5 L of n-heptane was added and stirred for 30 min. The mixture was filtered, and the solid was collected and dried to give 1.07 kg of 4-bromo-3,6-dichloropyridazine, with a yield of 76.7%. Figure 9 As shown, the purity of the 4-bromo-3,6-dichloropyridazine prepared in this example is 98.0%.

[0060] The role and effect of the embodiments

[0061] According to the preparation method of 4-bromo-3,6-dichloropyridazine involved in the above embodiments, since the bromine source selected is a mixed bromine source of copper bromide and cuprous bromide, the present invention can obtain 4-bromo-3,6-dichloropyridazine in higher yield under milder reaction conditions.

[0062] Furthermore, since the selected bromine source is cuprous bromide with a molar ratio of 1:(1-15), the liquid phase yield can reach over 90%, with a maximum of 94.8%, and the separation yield can reach 76.7%.

[0063] Furthermore, the above embodiments also developed a post-processing method that not only avoids column chromatography methods that are difficult to apply in industry, but also effectively removes impurities to obtain the target product with a purity of over 98%.

[0064] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. A process for the preparation of 4-bromo-3,6-dichloropyridazine, characterized in that, The reaction formula is as follows: Includes the following steps: In the presence of a diazotizing agent, a bromine source, and a solvent, compound 1 was reacted to yield compound 2. The diazotizing agent is selected from tert-butyl nitrite. The bromine source is a mixture of copper bromide and cuprous bromide; the molar ratio of cuprous bromide to copper bromide is 1:(0.5-15). The molar ratio of the bromine source to compound 1 is (1.0-1.8):

1.

2. The process for the preparation of 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that, The molar ratio of cuprous bromide to copper bromide is 1:0.5, 1:1, 1:2, 1:9 or 1:

12.

3. The process for the preparation of 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that, The molar ratio of the diazotizing agent to compound 1 is (1-2):

1.

4. The method for preparing 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that, The solvent is selected from any one or more of acetonitrile, ethyl acetate, methyl acetate, formic acid, acetic acid, water, hydrochloric acid, and DMSO.

5. The process for the preparation of 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that, The mass-to-volume ratio of compound 1 to the solvent is 1 g: (5-20) mL.

6. The process for the preparation of 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that, The reaction time is 1-8 hours, and the temperature is 20-30℃.

7. Process for the preparation of 4-bromo-3,6-dichloropyridazine according to any one of claims 1 to 6, characterized in that, The reaction steps include the following: At 20-30℃, add solvent, compound 1, and bromine source to the reaction vessel, add diazotizing reagent dropwise, and stir the reaction for 1-8 hours; After the reaction was completed, the pH of the system was adjusted to 9-10, filtered, the filtrate was collected, the organic phase was collected, washed with water until the pH was 6-8, the solvent was removed, n-heptane was added and slurry was stirred, filtered, the solid was collected and dried to obtain 4-bromo-3,6-dichloropyridazine.

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