Preparation method of 4-bromo-3, 6-dichloropyridazine

Abstract

The invention discloses a preparation method of 4-bromo-3, 6-dichloropyridazine, and belongs to the field of organic synthesis. The method comprises the following steps: in the presence of a diazotization reagent, a bromine source and a solvent, taking a compound 1 as a substrate, and reacting to obtain a compound 2; wherein the diazotization reagent is selected from any one or more of nitrous acid, nitrite or nitrite ester, and the bromine source is a mixture of copper bromide and cuprous bromide. According to the method, the 4-bromo-3, 6-dichloropyridazine can be prepared with higher yield and higher purity. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 4-bromo-3,6-dichloropyridazine. Background Art

[0002] The Sandmeyer reaction is a common reaction for preparing halogenated aromatics. It is generally believed that the reaction is 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 copper salts and Sandmeyer reactions catalyzed by cuprous salts.

[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 when copper salts and cuprous salts are used to catalyze the reaction of some aromatic rings, there are significant differences in the products and yields, and cuprous salts have significant Sandmeyer reaction activity, while copper salts generate almost no corresponding products. At present, there is no further research on the catalysts for the Sandmeyer reaction of pyridazine rings in the prior art.

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

[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 agent, and after the reaction is completed, the target compound is separated by column chromatography, with a yield of 50.38%, which is quite unfavorable in industrial production. Summary of the invention

[0006] [Technical issues]

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

[0008] [Technical solution]

[0009] The present invention provides a method for preparing 4-bromo-3,6-dichloropyridazine, and the reaction formula is as follows:

[0010]

[0011] The steps include:

[0012] In the presence of a diazotizing agent, a bromine source and a solvent, compound 1 is used as a substrate to react to obtain compound 2.

[0013] Wherein, 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 cupric bromide is 1:(0.5-15), preferably 1:(0.5-12), specifically 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 diazotization reagent 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 volume ratio of the compound 1 to the 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 comprises the following reaction steps:

[0024] At 20-30°C, add the solvent, compound 1, and bromine source into the reaction vessel, dropwise add the diazotizing agent, and stir to react for 1-8h;

[0025] After the reaction is completed, the pH value of the system is adjusted to 9-10, the filtrate is filtered, the organic phase is washed with water until the pH value is 6-8, the solvent is removed, n-heptane is added for slurrying, filtered, the solid is taken, 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 evaporated under reduced pressure, then toluene is added, and the pH value of the system is adjusted to 9-10, the filtrate is filtered, the organic phase is taken, and the pH value is washed with water to 6-8, the solvent is removed, n-heptane is added for pulping, the solid is filtered, and the solid is taken and dried to obtain 4-bromo-3,6-dichloropyridazine.

[0027] Functions and Effects of the Invention

[0028] According to the preparation method of 4-bromo-3,6-dichloropyridazine involved in the present invention, because the selected bromine source 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the HPLC spectrum of reaction No. 1 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.508 min, and the impurity A is at a retention time of 3.648 min;

[0030] Figure 2 This is the HPLC spectrum of reaction No. 2 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.487 min, and the impurity A is at a retention time of 3.638 min;

[0031] Figure 3 This is the HPLC spectrum of reaction No. 3 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.458 min;

[0032] Figure 4 This is the HPLC spectrum of reaction No. 4 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.460 min;

[0033] Figure 5 This is the HPLC spectrum of reaction No. 5 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.452 min;

[0034] Figure 6 This is the HPLC spectrum of reaction No. 6 in Example 1 of the present invention, wherein: the target compound is at a retention time of 6.449 min;

[0035] Figure 7 This is the HPLC spectrum of reaction No. 7 in Example 1 of the present invention, wherein: the target compound is 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 compound is at a retention time of 6.295 min;

[0037] Fig. 9 It is the HPLC spectrum of the product in Example 3 of the present invention, wherein: the target substance is at the retention time of 6.246 min. DETAILED DESCRIPTION

[0038] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below in conjunction with embodiments and drawings.

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

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

[0041] <Example 1>

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

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

[0044] Add 20 mL of acetonitrile to the reactor, 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) in sequence, control the temperature at 20°C, add 1.89 g of tert-butyl nitrite (18.3 mmol, 1.5 eq) dropwise, keep stirring the reaction at 20°C for 3 h, and take samples for HPLC detection.

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

[0046] Table 1 Screening of bromine sources

[0047] Serial number Copper bromide / eq Cuprous bromide / eq Reaction temperature Liquid phase yield of target product 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 ≈ 3.64min), while when cuprous bromide is used alone as the bromine source ( Figure 2 ), in addition to impurity A (RT≈3.64min), a more obvious impurity B (RT=5.11min) will also be generated.

[0049] As shown in the above table and Figure 3-7 As shown, when a mixed bromine source of copper bromide and cuprous bromide is used, both impurity A and impurity B can be effectively contained, and no new impurities with a content greater than 10% will be 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 reactor, and 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). Control the temperature at 20 °C, and add 9.44 g of tert-butyl nitrite (91.5 mmol, 1.5 eq). After the addition is completed, keep stirring the reaction at 20 °C for 4 hours.

[0054] The reaction solution was collected, the solvent was evaporated under reduced pressure, 50 mL of toluene was added, the pH was adjusted to 9-10 with commercially available ammonia water at room temperature, filtered, the filtrate was taken, the organic phase was washed with water until the pH was 7, concentrated under reduced pressure, 10 mL of n-heptane was added for 30 min, filtered, the solid was taken, and dried to obtain 9.87 g of 4-bromo-3,6-dichloropyridazine, with a yield of 71.0%. Figure 8 As shown, the purity of 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 10L of acetonitrile to the reactor, and then add 1kg of 4-amino-3,6-dichloropyridazine (6.10mol, 1.0eq), 1.63kg of copper bromide (7.32mol, 1.2eq), and 87.5g of cuprous bromide (0.61mol, 0.1eq). Control the temperature at 20°C, add 943.5g of tert-butyl nitrite (9.15mol, 1.5eq) dropwise, and keep stirring the reaction at 20°C for 2h.

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

[0060] Functions and Effects of the Embodiments

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

[0062] Furthermore, since the molar ratio of the selected bromine source is 1:(1-15) between cuprous bromide and cupric bromide, the liquid phase yield can reach more than 90%, up to 94.8%, and the separation yield can reach 76.7%.

[0063] Furthermore, the above embodiment also develops a post-treatment method, which can not only avoid the column chromatography method which is difficult to apply in industry, but also effectively remove impurities to obtain the target product with a purity of more than 98%.

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

Claims

1. A method for preparing 4-bromo-3,6-dichloropyridazine, characterized in that: The reaction formula is as follows: The steps include: In the presence of a diazotizing agent, a bromine source and a solvent, compound 1 is used as a substrate to react to obtain compound 2. Wherein, the diazotizing agent is selected from any one or more of nitrous acid, nitrite or nitrite ester, The bromine source is a mixture of copper bromide and cuprous bromide.

2. The method for preparing 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that: The molar ratio of cuprous bromide to cupric bromide is 1:(0.5-15).

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

12.

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

1.

5. The method for preparing 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that: The diazotizing agent is tert-butyl nitrite.

6. The method for preparing 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that: The molar ratio of the bromine source to the compound 1 is (1.0-1.8):

1.

7. 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.

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

9. The method for preparing 4-bromo-3,6-dichloropyridazine according to claim 1, characterized in that: The reaction time is 1-8h and the temperature is 20-30℃.

10. The method for preparing 4-bromo-3,6-dichloropyridazine according to any one of claims 1 to 9, characterized in that: The process comprises the following reaction steps: At 20-30°C, add the solvent, compound 1, and bromine source into the reaction vessel, dropwise add the diazotizing agent, and stir to react for 1-8h; After the reaction is completed, the pH value of the system is adjusted to 9-10, the filtrate is filtered, the organic phase is washed with water until the pH value is 6-8, the solvent is removed, n-heptane is added for slurrying, filtered, the solid is taken, and dried to obtain 4-bromo-3,6-dichloropyridazine.

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