A preparation method of 5-chloropyridazine-3-carboxylic acid

Abstract

The present invention belongs to the field of medicine and chemical technology, and is particularly related to a method for preparing 5-chloropyridazine-3-carboxylic acids. The present invention provides a method for preparing 5-chloropyridazine-3-carboxylic acids, characterized in that the method comprises the following steps: (1) in a catalytic system, reacting a compound of formula III with methanol and carbon monoxide to prepare a compound of formula II; (2) hydrolyzing the compound of formula II to prepare a compound of formula I; wherein the catalytic system in the step (1) comprises a catalyst and a ligand, the catalyst being palladium acetate, and the ligand being 1,1-bis(diphenylphosphino)ferrocene; the alkali in the step (1) being sodium acetate; the pressure being 5-20 psi; the reaction temperature being 45-70° C.; and the reaction time being 6-16 h. The main advantage of the present invention is that the use of chlorine can be avoided, the raw material has low toxicity, no autoclave is required, the operation is simple and safe, the post-processing is simple, and the conversion rate of the raw material, the yield of the target product, the absence of by-products, and the purity are high are improved at the same time.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and chemistry, and specifically relates to a preparation method of 5-chloropyridazine-3-carboxylic acid. Background Art

[0002] 5-Chloropyridazine-3-carboxylic acid is an important raw material and intermediate with wide applications in industry. For example, it is used to develop and prepare METTL3 inhibitor compounds. METTL3 is a protein involved in RNA methylation, and its abnormality is related to a variety of diseases such as leukemia, lung cancer and glioma. In addition, it plays an important role in the compounds that regulate the function of GPR35, and further has potential value in proliferative diseases, immune diseases and inflammatory diseases.

[0003] Among the prior art, only WO2023033142A1 discloses the preparation of 5-chloropyridazine-3-carboxylic acid. The method provided uses 3-carboxypyridazine as a substrate and chlorine as a chlorine source. There is a problem of poor selective chlorination. In addition, chlorine is a toxic gas and has strict requirements on the use environment. In addition, the atomic utilization rate is not high.

[0004] Therefore, it is necessary to develop a new method for preparing 5-chloropyridazine-3-carboxylic acid, which can avoid the use of chlorine gas, while improving the conversion rate of raw materials, and further has a good yield of the target product, no by-products, and high purity. Summary of the invention

[0005] The present invention provides a method for preparing 5-chloropyridazine-3-carboxylic acid, characterized in that it comprises the following steps:

[0006] (1) reacting a compound of formula III with methanol and carbon monoxide in a catalytic system to prepare a compound of formula II;

[0007] (2) hydrolyzing the compound of formula II to obtain the compound of formula I;

[0008] The reaction formula is as follows:

[0009]

[0010] The catalytic system in step (1) comprises a catalyst and a ligand, the catalyst is palladium acetate, and the ligand is 1,1-bis(diphenylphosphino)ferrocene;

[0011] The base used in step (1) is sodium acetate; the pressure is 5-20 psi, preferably 10-15 psi; the reaction temperature is 45-70° C., preferably 50-65° C.; and the reaction time is 6-16 h, preferably 10-12 h.

[0012] Furthermore, in the step (1), the molar ratio of the compound of formula III to the base is 1: (1-5), preferably 1: (2-3).

[0013] Furthermore, in the step (1), the mass volume ratio of the compound of formula III to methanol is 1: (5-20), preferably 1: (10-15).

[0014] Furthermore, in step (1), the molar ratio of the compound of formula III to the catalyst is 1: (0.001-0.01), preferably 1: (0.003-0.005).

[0015] Furthermore, the step (1) also includes a post-processing purification step, such as cooling, silica gel filtration, concentration, column chromatography, etc.

[0016] Furthermore, the hydrolysis reaction in step (2) comprises: reacting the compound of formula II with a base in a solvent to obtain the compound of formula I.

[0017] Furthermore, in step (2), the solvent is selected from one or more of ether solvents, alcohol solvents and water, the ether solvents are such as tetrahydrofuran, 1,4-dioxane, etc., and the alcohol solvents are such as methanol, ethanol, etc.

[0018] Furthermore, the step (2) may optionally further include a post-treatment step, for example, adjusting the pH to 3-4, precipitating solids, filtering and evaporating to dryness, etc.

[0019] The advantages of the method of the present invention mainly lie in:

[0020] The present application provides a new method for preparing a specific substrate 5-chloropyridazine-3-carboxylic acid, which can avoid the use of chlorine, has low toxicity of raw materials, does not require an autoclave, is easy and safe to operate, has simple post-processing, and improves the conversion rate of raw materials. Further, the yield of the target product is good, there are no by-products, and the purity is high, which provides a source of raw materials / intermediates for the development of potential drugs and improves accessibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the 5-chloro-3-pyridazinecarboxylic acid methyl ester in Example 1 1 H NMR spectrum. DETAILED DESCRIPTION

[0022] To facilitate those skilled in the art to understand the content of the present invention, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under normal conditions.

[0023] Unless otherwise specified, the raw materials or reagents used in the examples are all commercially available. The room temperature described in the examples refers to 20-35°C. Unless otherwise specified, the reagents are used directly without purification. All solvents are purchased from commercial suppliers, such as Aldrich, and are used without treatment.

[0024] Abbreviations or glossaries

[0025] Palladium acetate, Pd(CH3COO)2;

[0026] [bis(diphenylphosphino)ferrocene]palladium dichloride, Pd(dppf)Cl2;

[0027] Tris(dibenzylideneacetone)dipalladium, Pd2(dba)3;

[0028] Dichlorobis(triphenylphosphine)palladium, PdCl2(PPh3)2;

[0029] 1,1-Bis(diphenylphosphino)ferrocene, DPPF;

[0030] 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos;

[0031] 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, BINAP.

[0032] Example 1

[0033]

[0034] 3,5-Dichloropyridazine (120 g, 0.806 mol), DPPF (13.47 g, 0.02418 mol), palladium acetate (0.9 g, 0.004 mol), sodium acetate (198 g, 2.418 mol) were dissolved in methanol (1700 mL), and the mixture was reacted at 65°C for 12 h under a CO bag environment at a pressure of 15 psi. The reaction was monitored by TLC to determine that the raw material was completely reacted. The mixture was cooled, filtered through diatomaceous earth, and the crude product was concentrated to 147 g. The column chromatography system was PE / EA=20 / 1-10 / 1-5 / 1 to obtain an off-white solid 5-chloro-3-pyridazinecarboxylic acid methyl ester (NMR spectrum as shown in FIG. 1 ). Figure 1 The yield was 44.6%.

[0035] The NMR data are as follows:

[0036] 1 H NMR (400 MHz, CDCl3) δ 9.34 (d, J=2.4Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 4.10 (s, 3H).

[0037] 5-Chloro-3-pyridazinecarboxylic acid methyl ester (52 g, 0.301 mol) was dissolved in THF (700 mL) and 1N NaOH solution (390 mL) at room temperature for 2 h. TLC showed that the raw material was completely reacted. 1N HCl was added to adjust the pH to 3-4, and a solid was precipitated. It was filtered and evaporated to dryness to obtain an off-white solid 5-chloropyridazine-3-carboxylic acid (38 g, yield 80%).

[0038] Embodiments 2 to 23

[0039] The catalyst, ligand, base, temperature and time parameters were changed according to the method of Example 1, and the preparation of the target product was monitored, as shown in Table 1 below:

[0040] Table 1

[0041]

[0042] In combination with Examples 1 to 4, for the same catalyst, ligand and base, the reaction temperature and time have a great influence on the reaction process. For example, when the temperature is 40°C, there is no reaction, and even if the reaction time is longer, there is no reaction. When the reaction is 65°C, the reaction time is not enough and only a small amount of new points are generated. After a certain reaction time, such as 12 h, the raw material conversion is complete, the product yield is high, and the purity is high; in combination with Examples 5 to 8, under the action of the catalyst, ligand, and base, no matter how the reaction time and temperature are changed, the reaction efficiency is very low; similarly, Examples 9 to 23 have low reaction efficiency; for the specific substrate of the present invention, especially the meta-selective substitution such as 3,5-dichloropyridazine, the reaction can be made more efficient under specific conditions, such as the comprehensive consideration of various parameters such as catalyst, ligand, base, temperature, and time, the raw material reaction is completely converted, and the purity and yield are further good.

Claims

1. A method for preparing 5-chloropyridazine-3-carboxylic acid, characterized in that: The steps include: (1) reacting the compound of formula III with methanol and carbon monoxide in a catalytic system to prepare the compound of formula II; (2) hydrolyzing the compound of formula II to obtain the compound of formula I; The reaction formula is as follows: ； The catalytic system in step (1) comprises a catalyst and a ligand, the catalyst is palladium acetate, and the ligand is 1,1-bis(diphenylphosphino)ferrocene; The base used in step (1) is sodium acetate, the pressure is 10-15 psi, the reaction temperature is 50-65° C., and the reaction time is 6-16 h.

2. The preparation method according to claim 1, characterized in that: The reaction time in step (1) is 10 to 12 h.

3. The preparation method according to claim 1, characterized in that: In the step (1), the molar ratio of the compound of formula III to the base is 1: (1-5).

4. The preparation method according to claim 3, characterized in that: In the step (1), the molar ratio of the compound of formula III to the base is 1: (2-3).

5. The preparation method according to claim 1, characterized in that: In the step (1), the molar ratio of the compound of formula III to the catalyst is 1: (0.001-0.01).

6. The preparation method according to claim 5, characterized in that: In the step (1), the molar ratio of the compound of formula III to the catalyst is 1: (0.003-0.005).

7. The preparation method according to claim 1, characterized in that: In the step (1), the mass volume ratio of the compound of formula III to methanol is 1: (5-20).

8. The preparation method according to claim 1, characterized in that: The step (1) also includes post-processing purification steps: cooling, diatomaceous earth filtration, concentration, and column purification.

9. The preparation method according to claim 1, characterized in that: The hydrolysis reaction in step (2) comprises: reacting the compound of formula II with a base in a solvent to obtain the compound of formula I.

10. The preparation method according to claim 9, characterized in that: In the step (2), the solvent is selected from one or more of an ether solvent, an alcohol solvent and water, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the alcohol solvent is selected from methanol or ethanol.

Images