A method for synthesizing a compound 3,5-dibromopyridazine
The synthesis of 3,5-dibromopyridazine via borate esterification and copper bromide conversion solves the problems of violent reaction, difficult purification, and high safety risks in existing technologies, achieving high yield and low cost synthesis.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- KEMEC (SHANGHAI) PHARM TECH CO LTD
- Filing Date
- 2024-07-30
- Publication Date
- 2026-06-12
AI Technical Summary
Existing methods for synthesizing 3,5-dibromopyridazine suffer from problems such as harsh reaction conditions, difficulty in purification, high safety risks, and low yield.
Using 3-bromopyridazine as a raw material, the intermediate 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)pyridazine is generated through a borate esterification reaction. Then, it is converted into the target compound 3,5-dibromopyridazine under the action of copper bromide. The brominated product is constructed by metal-catalyzed CH borate esterification reaction and copper bromide. The post-processing and purification are simple.
It achieves a simple operating procedure, low cost, mild reaction conditions, and high product yield, making it suitable for process scale-up.
Smart Images
Figure CN118955404B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing the compound 3,5-dibromopyridazine. Background Technology
[0002] Dihalopyridazine compounds are an important class of organic compounds with wide applications in synthesis, pesticides, and pharmaceuticals. For example, 3,6-dibromopyridazine, as a key intermediate, was used in patent WO2014 / 131739 for the synthesis of substituted imidazopyrazine compounds, which can be used to treat or prevent diseases, particularly hyperproliferative or angiogenic diseases. In patent WO2007 / 022937, it was used for the synthesis of pyrazine derivatives with anti-inflammatory activity, which can be used to treat diseases directly or indirectly caused by increased or decreased cannabinoid receptor activity, particularly pain. 3,5-Dichloropyridazine is also used as a key intermediate in patent WO2017 / 097728 for the synthesis of piperidine derivatives, which can be used to treat Alzheimer's disease, cerebral amyloid angiopathy, hereditary amyloid cerebral hemorrhage, Dutch type (HCHWA-D), multiple infarct dementia, boxing dementia, or Down syndrome. In patent US2020 / 190091, it is used for the synthesis of a nitrogen-containing heterocyclic compound. This compound exhibits high inhibitory activity against ErbB2 tyrosine kinase, good inhibitory activity against ErbB2-high-expressing human breast cancer cells BT-474 and human gastric cancer cells NCI-N87, and weak inhibitory activity against EGFR kinase. Therefore, this compound is an EGFR / ErbB2 dual-target inhibitor that reduces EGFR kinase inhibitory activity or a small molecule inhibitor selectively targeting ErbB2. Dihalopyridazine compounds have great application potential in drug development.
[0003] In these compounds, 3,5-dibromopyridazine serves as an important molecular building block. For example, it is used in the synthesis of a METTL3 inhibitor compound in patent CN117720533, which exhibits good regulatory and inhibitory effects on METTL3 / METTL14 and AML-related cell lines, and can be used to treat conditions and diseases related to METTL3 / METTL14 methyltransferase activity; in patent US2012 / 088750, it is used in the synthesis of an antibacterial agent; and in patent WO2022 / 173849, it is used in the synthesis of a CCR6 inhibitor. Therefore, developing new synthetic methods for 3,5-dibromopyridazine is of great significance.
[0004] 3,5-Dibromopyridazine is an unstable compound. Due to its unstable chemical properties, it can deteriorate during synthesis, resulting in generally low yields and significant purification difficulties. Current technologies typically synthesize it through halogen exchange, halogenation, or diazotization. However, these methods have drawbacks such as harsh reaction conditions, difficulty in purification, high safety risks, and unsuitability for large-scale production. Summary of the Invention
[0005] To address the shortcomings of existing methods for synthesizing 3,5-dibromopyridazine, the present invention aims to provide a method for synthesizing 3,5-dibromopyridazine that is low in cost, simple and easy to operate, with relatively mild reaction conditions, low safety risks, and ideal yield.
[0006] To achieve the above objectives, the present invention adopts the following technical solution:
[0007] A method for synthesizing compound 3,5-dibromopyridazine, using 3-bromopyridazine as a starting material, involves a borate esterification reaction to obtain intermediate 2 (3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridazine), which is then converted into the target compound 3 (3,5-dibromopyridazine) under the action of copper bromide. The synthetic route is as follows:
[0008]
[0009] Furthermore, the method for synthesizing the 3,5-dibromopyridazine includes the following steps:
[0010] (1) The catalyst methoxy(cyclooctadiene) iridium dimer and the ligand 4,4'-di-tert-butyl-2,2'-dipyridine were added to organic solvent I, followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxacyclopentaborane). The mixture was stirred for 20-50 minutes, and under inert gas protection, a solution of 3-bromopyridazine in organic solvent I was added. The mixture was heated to reflux and reacted for 10-48 hours. After the reaction was completed, compound 2 was obtained through post-treatment.
[0011] (2) Compound 2 was added to organic solvent II, copper bromide was added, and the mixture was heated to reflux for 10-48 hours. After the reaction was completed, the target compound 3,5-dibromopyridazine was obtained through post-treatment.
[0012] Furthermore, in step (1), the post-processing is as follows: after the reaction is completed, the reaction solution is cooled, filtered, and the filtrate is evaporated to obtain a crude product. The crude product is then purified to obtain compound 2.
[0013] Furthermore, in step (1), the organic solvent I is selected from one or more of methanol, ethanol, tetrahydrofuran, or 2-methyltetrahydrofuran.
[0014] Furthermore, in step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:(5-40) g / mL.
[0015] Furthermore, in step (1), the molar ratio of compound 1 to the catalyst methoxy(cyclooctadiene) iridium dimer is 1:(0.05-0.15), preferably 1:0.10.
[0016] Furthermore, in step (1), the molar ratio of compound 1 to ligand 4,4'-di-tert-butyl-2,2'-dipyridine is 1:(0.1-0.3), preferably 1:0.2.
[0017] Furthermore, in step (1), the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.
[0018] Furthermore, in step (2), the post-processing is as follows: after the reaction is completed, the reaction solution is cooled, filtered, and the filtrate is evaporated to obtain the crude product. The crude product is purified to obtain the target compound 3,5-dibromopyridazine.
[0019] Furthermore, in step (2), the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.
[0020] Furthermore, in step (2), the organic solvent II is selected from 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, or N-methylpyrrolidone.
[0021] Furthermore, in step (2), the mass-to-volume ratio of compound 2 to organic solvent II is 1:(5-40) g / mL.
[0022] Furthermore, in step (2), the molar ratio of compound 1 to copper bromide is 1:(1-3), more preferably (1:2).
[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0024] This invention proposes a method for preparing 3,5-dibromopyridazine. Using 3-bromopyridazine as a starting material, a borate esterification reaction is performed to obtain 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridazine, which is then converted to the target compound 3,5-dibromopyridazine under the action of copper bromide. This synthetic method synthesizes the borate ester through a metal-catalyzed CH borate esterification reaction, followed by the construction of the brominated product using copper bromide. The post-processing and purification are simple, reducing reaction and time costs, and enabling scale-up of the process. Ultimately, the compound 3,5-dibromopyridazine is obtained with a high yield, through a short procedure, simple operation, low cost, and relatively mild reaction conditions. Attached Figure Description
[0025] Figure 1 The image shows the 1H NMR spectrum of 3,5-dibromopyridazine from Example 1. Detailed Implementation
[0026] To make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.
[0027] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0028] The following examples illustrate the synthesis of 3,5-dibromopyridazine. Using 3-bromopyridazine as a starting material, an esterification reaction with borate yielded intermediate 2 (3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridazine), which was then converted to the target compound 3 (3,5-dibromopyridazine) under the action of copper bromide. The synthetic route is as follows:
[0029]
[0030] The technical solution of the present invention will be further explained and illustrated below through embodiments.
[0031] Example 1
[0032] In this embodiment, the compound 3,5-dibromopyridazine was synthesized using the following steps:
[0033] (1) The catalyst methoxy(cyclooctadiene) iridium dimer (20.85 g, 31.45 mmol, 0.05 eq) and the ligand 4,4'-di-tert-butyl-2,2'-dipyridine (16.88 g, 62.90 mmol, 0.10 eq) were added to tetrahydrofuran (1.0 L) at room temperature. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxacyclopentaborane) (159.72 g, 628.99 mmol, 1.00 eq) were added dropwise under nitrogen protection. The mixture was heated to reflux and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled, filtered through diatomaceous earth, the filtrate was evaporated, pulped, filtered, and dried to obtain compound 2 (weight 168.90 g, purity 96%, yield 90%).
[0034] (2) Compound 2 (100.00 g, 350.94 mmol, 1.00 eq) was added to acetonitrile (1.0 L), and copper bromide (156.77 g, 701.88 mmol, 2.00 eq) was slowly added at room temperature. The mixture was heated to reflux and reacted for 12 hours. After the reaction was complete, the reaction solution was cooled, filtered, the filtrate was evaporated to dryness, pulped, filtered, and dried to obtain the target compound 3,5-dibromopyridazine (80.10 g, purity 98%, yield 94%).
[0035] The 1H NMR spectrum of the obtained compound 3 (3,5-dibromopyridazine) is as follows: Figure 1 As shown, the characterization data is as follows:
[0036] 1 H NMR (400MHz, cdcl3) δ9.24 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H).
[0037] Examples 2-9
[0038] Examples 2-9 are the same as Example 1, except that the amounts of catalyst, ligand, copper bromide, organic solvent I, and organic solvent II used in the reaction are adjusted, as shown in Table 1.
[0039] Examples 1-9 were used to verify the effect of various reaction conditions on the reaction yield in the synthesis of intermediate 2 (3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridazine) and target product 3 (3,5-dibromopyridazine). The results are shown in Table 1.
[0040] Table 1: Synthesis conditions and results of the examples and comparative examples
[0041]
[0042]
[0043] As shown in Table 1:
[0044] Comparing Examples 1-5, the reaction effect was already better when the molar ratio of raw material 1 to catalyst and ligand was 1:0.05:0.10.
[0045] Comparing Examples 1 and 6-7, the reaction effect was better when the molar ratio of compound 2 to copper bromide was 1:0.10.
[0046] The reaction in step (1) can be carried out in both methanol and tetrahydrofuran solvents, with tetrahydrofuran being a better solvent.
[0047] The reaction in step (2) can be carried out in both solvents acetonitrile and N,N-dimethylformamide, with acetonitrile being a better solvent.
[0048] The above description represents a preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, any equivalent or modified versions made without departing from the spirit of the present invention fall within the scope of protection of the present invention.
Claims
1. A method for synthesizing the compound 3,5-dibromopyridazine, characterized in that, Using 3-bromopyridazine as a starting material, 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)pyridazine was obtained via borate esterification, and then converted to the target compound 3,5-dibromopyridazine under the action of copper bromide. The synthetic route is as follows: ； The synthesis method includes the following steps: (1) The catalyst methoxy(cyclooctadiene) iridium dimer and the ligand 4,4''-di-tert-butyl-2,2''-dipyridine were added to organic solvent I, and 4,4,4'',4'',5,5,5'',5''-octamethyl-2,2''-bi(1,3,2-dioxacyclopentaborane) were added. The mixture was stirred for 20-50 minutes to obtain mixture I. Under inert gas protection, the organic solvent I solution of 3-bromopyridazine was added dropwise to mixture I. The mixture was heated to reflux and reacted for 10-48 hours. After the reaction was completed, compound 2 was obtained after post-treatment. (2) Compound 2 was added to organic solvent II, copper bromide was added, and the mixture was heated to reflux for 10-48 hours. After the reaction was completed, the target compound 3,5-dibromopyridazine was obtained after post-treatment.
2. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (1), the post-processing is as follows: after the reaction is completed, the reaction solution is cooled, filtered, and the filtrate is evaporated to obtain the crude product. The crude product is purified to obtain compound 2.
3. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (2), the post-processing is as follows: after the reaction is completed, the reaction solution is cooled, filtered, and the filtrate is evaporated to obtain the crude product. The crude product is purified to obtain the target compound 3,5-dibromopyridazine.
4. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (1), the inert gas is one or more of nitrogen or argon.
5. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (1), the organic solvent I is one or more of methanol, ethanol, tetrahydrofuran, or 2-methyltetrahydrofuran.
6. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:(5-40) g / mL; The molar ratio of compound 1 to the catalyst is 1:(0.05-0.15); The molar ratio of compound 1 to the ligand is 1:(0.1-0.3).
7. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (2), the organic solvent II 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, or N-methylpyrrolidone.
8. The method for synthesizing compound 3,5-dibromopyridazine according to claim 1, characterized in that, In step (2), the mass-to-volume ratio of compound 2 to organic solvent II is 1:(5-40) g / mL; the molar ratio of compound 1 to copper bromide is 1:(1-3).