Preparation method of 2, 5-dimethoxypyridine

Abstract

The invention provides a preparation method of 2, 5-dimethoxypyridine, which comprises the following step: carrying out C-O coupling reaction on a compound with a structure as shown in a formula II, a coupling agent, a catalyst and a ligand to obtain the 2, 5-dimethoxypyridine with a structure as shown in a formula III. According to the method, the cuprous halide which is low in price is adopted as the catalyst, the methoxylation reaction of 5-chlorine in 2, 5-dichloropyridine is successfully realized through ligand regulation and control, and compared with a traditional method for synthesizing 2, 5-dimethoxypyridine by taking 2, 5-dibromopyridine as a raw material, the raw material cost is greatly reduced, and the atom economy is improved.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing 2,5-dimethoxypyridine. Background Art

[0002] As an important organic synthesis intermediate, 2,5-dimethyloxypyridine has great potential in the construction of many complex compounds. In addition, this compound can also play the role of an organic ligand for metal ions to form metal complexes with unique properties. In the pharmaceutical field, 2,5-dimethyloxypyridine plays a key role because many drugs and related intermediates contain this structural unit, such as anti-inflammatory and anticancer drugs.

[0003] The current mainstream method for preparing 2,5-dimethoxypyridine is to use 2,5-dibromopyridine as a raw material, first replace the bromine atoms on the 2-carbon or 5-carbon, and then replace the remaining bromine atoms. CN114478367A discloses a method for preparing a 2,5-dioxopyridine derivative, which is to react 2,5-dibromopyridine with excess sodium methoxide in a one-pot process with the aid of a copper catalyst, thereby improving the reaction efficiency to a certain extent. However, the system still relies on 2,5-dibromopyridine as a raw material. The cheaper 2,5-dichloropyridine is difficult to participate in the second-stage CO coupling reaction due to the inertness of the 5-chlorine.

[0004] Ma Dawei's team discovered and systematically studied a series of oxalyl diamide ligands that showed excellent activity in promoting Cu-catalyzed coupling reactions of other nucleophiles, and found that with the help of two simple oxalyl diamide ligands, Cu-catalyzed alkoxylation of unactivated aryl chlorides and bromides can be carried out at 60-100 ° C. Only 2-3 equivalents of alcohol are needed to obtain a variety of alkyl aromatic ethers from primary and secondary alcohols with high yields (J.Am.Chem.Soc.2019,141,8,3541–3549). However, substrates with chlorine substitution on the meta-carbon of pyridine have not been studied. CN113666826A discloses a method for methoxylation of aromatic or heteroaromatic groups, which uses a similar reaction system to further improve the methoxylation of aromatic or heteroaromatic groups, using MeO-9-BBN as a methoxy source, avoiding a strong base reaction system, and can be applied to the methoxylation of some substrates containing base-sensitive groups. However, MeO-9-BBN is expensive, and the applicable substrates of this system still do not include pyridines, especially compounds with halogen substitution at the meta-position of pyridine.

[0005] However, none of the above existing technologies can achieve the preparation of 2,5-dimethoxypyridine by using 2,5-dichloropyridine instead of 2,5-dibromopyridine as a raw material. It is necessary to develop a new cheap metal catalytic system that can effectively achieve the methoxylation reaction of the 5-position C-Cl bond in 2,5-dichloropyridine. Summary of the invention

[0006] In view of this, the present invention aims to overcome the following defects in the prior art:

[0007] 1) The existing methods for preparing 2,5-dimethoxypyridine all use 2,5-bromopyridine as the starting material, which is more expensive and less atom-economical than 2,5-dichloropyridine, which is an obvious disadvantage in the field of large-scale industrial production. However, the low reactivity of the 5-chlorine limits the application of 2,5-dichloropyridine in this reaction.

[0008] 2) The 5-position chlorine of 2,5-dichloropyridine or, extended to a wider range, the methoxy or other functionalization of the meta-position chlorine of pyridine. Currently, the mainstream technology still relies on the catalytic system of precious metals such as palladium, and there are relatively few cases of successful application of cheap transition metals.

[0009] 3) In recent years, the rapid development of new copper catalytic systems has made great progress in the alkoxylation or other functionalization of aromatic or heteroaryl chlorides, but the research on the methoxylation of pyridine meta-chloride is still blank.

[0010] A preparation method of 2,5-dimethoxypyridine is proposed. The method utilizes a novel catalytic system of inexpensive metallic copper and attempts to develop a more inexpensive and efficient synthesis method of 2,5-dimethoxypyridine using 2,5-dichloropyridine as a raw material.

[0011] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0012] A method for preparing 2,5-dimethoxypyridine, comprising: performing a CO coupling reaction with a compound having a structure as shown in formula II, a coupling agent, a catalyst, and a ligand to obtain 2,5-dimethoxypyridine having a structure as shown in formula III, and the reaction route is as follows:

[0013]

[0014] 2,5-dichloropyridine and sodium methoxide undergo a nucleophilic substitution reaction to obtain a compound as shown in Formula II.

[0015] In some embodiments of the present invention, the ligand in the CO coupling reaction system is More preferably, the ligand in the CO coupling reaction system is

[0016]

[0017] In some embodiments of the present invention, the coupling agent is one or more of a sodium methoxide-methanol solution and / or sodium methoxide solid with a mass percentage of 25-30%. More preferably, the coupling agent is a sodium methoxide-methanol solution with a mass percentage of 30%.

[0018] In some embodiments of the present invention, the catalyst is one or more of cuprous halide, cupric halide, cuprous oxide, cupric acetate, and cupric acetylacetonate. More preferably, the catalyst is cuprous chloride, cuprous bromide, or cuprous iodide.

[0019] In some embodiments of the present invention, the CO coupling reaction system further contains a first organic solvent. More preferably, the first organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. More preferably, the first organic solvent is N,N-dimethylformamide.

[0020] In some embodiments of the present invention, the nucleophilic substitution reaction further contains a second organic solvent selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. More preferably, the first organic solvent is N,N-dimethylformamide.

[0021] In some embodiments of the present invention, the molar ratio of the compound represented by formula II, the coupling agent, the ligand, and the catalyst in the CO coupling reaction is 1.0:(1.0-6.0):(0.05-0.5):(0.02-0.25). More preferably, the molar ratio of the compound represented by formula II, the coupling agent, the ligand, and the catalyst in the CO coupling reaction is 1.0:2.0:0.1:0.05.

[0022] In some embodiments of the present invention, the reaction temperature of the CO coupling reaction is 60-120° C., and the reaction time is 4-24 hours. More preferably, the reaction temperature of the CO coupling reaction is 85° C., and the reaction time is 15 hours.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] The present invention adopts low-cost cuprous halide as a catalyst and successfully realizes the methoxylation reaction of 5-chlorine in 2,5-dichloropyridine through ligand regulation. Compared with the traditional method of synthesizing 2,5-dimethoxypyridine using 2,5-dibromopyridine as a raw material, the raw material cost is greatly reduced and the atom economy is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The HNMR spectrum of the product obtained in Example 1;

[0026] Figure 2 This is the GC chart of the product obtained in Example 1. DETAILED DESCRIPTION

[0027] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0028] Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0029] Where values ​​are described herein as a range, it should be understood that such disclosure includes disclosure of all possible sub-ranges within that range, as well as specific values ​​falling within that range, regardless of whether a specific value or a specific sub-range is explicitly stated.

[0030] In this document, "multiple" and the like, unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0031] In this document, the terms “preferred” and “more preferred” are only used to describe implementation methods or examples with better effects, and it should be understood that they do not constitute limitations on the scope of protection of the present invention.

[0032] In this document, the words "further" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present invention.

[0033] In this article, the term "and / or" is a description of the association relationship of objects, indicating that three relationships may exist. For example, A and / or B means: A or B, or A and B.

[0034] As used herein, the term "about" means + / - 10%, preferably + / - 5%, more preferably + / - 1% of the specified value.

[0035] The terms “include,” “including,” “have,” “contain,” etc. used in this article are open-ended terms, meaning including but not limited to.

[0036] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention.

[0037] The ligands used in the following examples and comparative examples are named L1, L2, L3, L4, and L5, respectively, and their structural formulas are as follows:

[0038]

[0039] The present invention is described in detail below with reference to Examples and Comparative Examples.

[0040] Example 1, Preparation of 2,5-dimethoxypyridine (CuCl+L3)

[0041]

[0042] DMF (200mL), 5-chloro-2-methoxypyridine (20.0g), cuprous chloride (0.69g) and L3 (4.9g) were mixed evenly, replaced with nitrogen 3 times, 30% sodium methoxide-methanol solution (50.0g) was added dropwise, and the temperature was raised to 85°C for reaction for 15h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 96.3%. After the reaction solution was cooled to room temperature, solid impurities were filtered out, and the filtrate was added with water and ethyl acetate for extraction. The organic phase was collected and washed with saturated brine, and then concentrated under reduced pressure to remove the solvent. The product 2,5-dimethoxypyridine 16.5g was obtained by continued reduced pressure distillation, GC purity 98.5%, and reaction yield 85.1%. The HNMR spectrum of the product is shown as follows Figure 1 As shown, the GC spectrum is Figure 2 As shown, it was confirmed that the HNMR spectrum of the product was consistent with the HNMR spectrum structure of 2,5-dimethoxypyridine.

[0043] Example 2, Preparation of 2,5-dimethoxypyridine (CuBr+L3)

[0044]

[0045] DMF (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous bromide (0.10 g) and L3 (0.49 g) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (5.0 g) was added dropwise, and the temperature was raised to 85° C. for reaction for 15 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 82.9%.

[0046] Example 3, Preparation of 2,5-dimethoxypyridine (CuBr+L4)

[0047]

[0048] DMF (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous bromide (0.10 g) and L4 (0.41 g) were mixed evenly, replaced with nitrogen three times, 30% sodium methoxide-methanol solution (5.0 g) was added dropwise, and the temperature was raised to 85° C. for reaction for 15 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 85.4%.

[0049] Example 4, Preparation of 2,5-dimethoxypyridine (CuI+L1)

[0050]

[0051] DMSO (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous iodide (0.26 g) and L1 (1.0 g) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (7.5 g) was added dropwise, and the temperature was raised to 95° C. for reaction for 24 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 77.8%.

[0052] Example 5. Preparation of 2,5-dimethoxypyridine (CuI+L5)

[0053]

[0054] DMSO (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous iodide (0.13 g) and L1 (0.29 g) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (7.5 g) was added dropwise, and the temperature was raised to 120° C. for reaction for 24 h. Sample IPC analysis (HPLC) showed that the reaction conversion rate was 80.5%.

[0055] Example 6, Preparation of 2,5-dimethoxypyridine

[0056]

[0057] DMF (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous chloride (0.027 g) and L3 (0.25 g) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (2.5 g) was added dropwise, and the temperature was raised to 95° C. for reaction for 24 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 65.5%.

[0058] Example 7, Preparation of 2,5-dimethoxypyridine

[0059]

[0060] DMF (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous chloride (0.34 g) and L3 (2.46 g) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (15.1 g) was added dropwise, and the temperature was raised to 85° C. for reaction for 15 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 75.6%.

[0061] Comparative Example 1: Preparation of 2,5-dimethoxypyridine (CuI+ without ligand)

[0062]

[0063] DMSO (15 mL), 5-chloro-2-methoxypyridine (3.0 g) and sodium methoxide-methanol solution (30%, 10.0 g) were mixed evenly, replaced with nitrogen three times, and CuI (3.0 g) was added. The reaction solution was stirred and heated to about 110°C and continued to stir for 24 hours. Samples were taken for IPC analysis (HPLC) and the product was <1%.

[0064] Comparative Example 2: Preparation of 2,5-dimethoxypyridine

[0065]

[0066] DMSO (20 mL), 5-chloro-2-methoxypyridine (2.0 g), cuprous iodide (13.3 mg) and L1 (51.3 mg) were mixed evenly, replaced with nitrogen three times, and 30% sodium methoxide-methanol solution (7.5 g) was added dropwise, and the temperature was raised to 95° C. for reaction for 24 h. Sampling IPC analysis (HPLC) showed that the reaction conversion rate was 3.1%.

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 2,5-dimethoxypyridine, characterized in that: The compound shown in formula II is subjected to CO coupling reaction with a coupling agent, a catalyst and a ligand to obtain 2,5-dimethoxypyridine shown in formula III. The reaction route is as follows: 2,5-dichloropyridine and sodium methoxide undergo a nucleophilic substitution reaction to obtain a compound as shown in Formula II.

2. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The ligand in the CO coupling reaction system is One or a combination of the following.

3. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The ligand in the CO coupling reaction system is 4. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The coupling agent is a sodium methoxide-methanol solution and / or sodium methoxide solid with a mass percentage of 5-30%; more preferably, the coupling agent is a sodium methoxide-methanol solution with a mass percentage of 30%.

5. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The catalyst is one or more of cuprous halide, cupric halide, cuprous oxide, cupric acetate, and cupric acetylacetonate; more preferably, the catalyst is cuprous chloride, cuprous bromide, or cuprous iodide.

6. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The CO coupling reaction system further contains a first organic solvent. More preferably, the first organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran; more preferably, the first organic solvent is N,N-dimethylformamide.

7. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The nucleophilic substitution reaction also contains a second organic solvent selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran; more preferably, the first organic solvent is N,N-dimethylformamide.

8. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: In the CO coupling reaction, the molar ratio of the compound represented by formula II, the coupling agent, the ligand and the catalyst is 1.0:(1.0-6.0):(0.05-0.5):(0.02-0.25).

9. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: In the CO coupling reaction, the molar ratio of the compound represented by formula II, the coupling agent, the ligand and the catalyst is 1.0:2.0:0.1:0.

05.

10. The method for preparing 2,5-dimethoxypyridine according to claim 1, characterized in that: The reaction temperature of the CO coupling reaction is 60-120° C., and the reaction time is 4-24 h; more preferably, the reaction temperature of the CO coupling reaction is 85° C., and the reaction time is 15 h.

Images