Process for the preparation of quinoxaline derivatives

Abstract

This invention discloses a method for preparing quinoxaline derivatives. The method includes the following steps: in a solvent, a compound of formula I and ethyl 3-bromo-2-oxopropionate are reacted as shown below to obtain a compound of formula II. This method has advantages such as high yield, high product purity, low cost, and simple operation.

Description

Technical Field

[0001] This invention relates to a method for preparing quinoxaline derivatives, specifically a method for preparing ethyl 4,5-dihydro-4-oxoimidazo[1,2-A]quinoxaline-2-carboxylate. Background Technology

[0002] Toll-like receptors (TLRs) are an important class of protein molecules involved in nonspecific immunity (innate immunity) and serve as a bridge connecting nonspecific and specific immunity. Ethyl 4,5-dihydro-4-oxoimidazo[1,2-A]quinoxaline-2-carboxylate is a commonly used synthetic building block for many lead compounds of Toll-like receptor modulators. Currently, two synthetic methods for this compound have been reported.

[0003] Reference 1 (Journal of Medicinal Chemistry (1988), 31(6), 1098-1115),

[0004] Using 2-amino-3-chloroquinoxaline as a starting material, a two-step reaction involving substitution cyclization and hydrolysis yields the product ethyl 4,5-dihydro-4-oxoimidazo[1,2-A]quinoxaline-2-carboxylate. However, the inventors were unable to successfully reproduce this reaction under the aforementioned operating conditions. In reproducing the reaction, the inventors primarily generated impurity compounds in the first step. All three nitrogen atoms in 2-amino-3-chloroquinoxaline could be substituted, and the presence of chlorine atoms further increased the influence on the reaction sites, altering the substitution positions and making it difficult to generate the target product.

[0005] In addition, the first step of the synthetic route described in the literature requires repeated recovery of raw materials and reheating to continue the reaction, which takes too long and is cumbersome.

[0006]

[0007] Reference 2 (CN108794485A) uses 3-amino-2-quinoxalinol as a starting material, and through one-step cyclization, yields ethyl 4,5-dihydro-4-oxoimidazo[1,2-A]quinoxalin-2-carboxylate. Although this method is simple to operate, the starting material is expensive and not suitable for industrial application. Moreover, the presence of the carbonyl group in the starting material of Reference 2 increases the activity of the target reaction site, making it more conducive to the formation of the target product. If the starting material 2-amino-3-chloroquinoxalin and ethanol from Reference 1 are used as solvents, those skilled in the art can reasonably expect that the presence of halogen substituents will have a significant impact on protic solvents, making the substitution reaction product more complex and difficult to obtain the target product.

[0008] Therefore, there is a need to develop a preparation method that is low-cost, highly efficient, and easy to operate. Summary of the Invention

[0009] The technical problem this invention aims to solve is to overcome the issues of long reaction times, cumbersome operations, and high costs associated with existing quinoxaline derivative preparation methods, and to provide a method for preparing quinoxaline derivatives. The method provided by this invention offers advantages such as high yield, high product purity, low cost, and simple operation.

[0010] This invention provides a method for preparing quinoxaline derivatives, comprising the following steps: reacting a compound of formula I with ethyl 3-bromo-2-oxopropionate in a solvent to obtain a compound of formula II. .

[0011] Preferably, the solvent is an organic protic solvent, preferably an alcohol solvent, more preferably one or more of methanol, ethanol or isopropanol, and even more preferably ethanol.

[0012] Preferably, the reaction temperature is 30℃-90℃, more preferably 60℃-90℃, more preferably 75℃-85℃, and even more preferably 78℃-79℃.

[0013] Preferably, the molar ratio of the compound as shown in Formula I to ethyl 3-bromo-2-oxopropionate is 1:1-1:2, more preferably 1:1.3-1:1.6, and even more preferably 1:1.4-1:1.5.

[0014] Preferably, the molar volume ratio (mol / L) of the compound as shown in Formula I to the solvent is 1:1-1:6, more preferably 1:2-1:4, and even more preferably 1:2.5-1:3.

[0015] Preferably, the reaction is carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen.

[0016] Preferably, the reaction directly yields the compound shown in Formula II without any intermediate processing steps (e.g., without intermediate separation or purification steps).

[0017] Preferably, the reaction is a one-pot reaction.

[0018] Preferably, the preparation method of the quinoxaline derivative further includes a post-processing step, wherein after the reaction is completed, the crude product of the compound as shown in Formula II is obtained by filtration.

[0019] Preferably, the post-processing step further includes washing the crude product of the compound as shown in Formula II with an alcohol solvent.

[0020] Preferably, the alcohol solvent is one or more of methanol, ethanol, or isopropanol, with ethanol being the most preferred.

[0021] Preferably, the washing is performed twice.

[0022] The reaction can be monitored using conventional monitoring methods in the art (e.g., HPLC, TLC or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reactants, or the cessation of the addition of compounds as shown in Formula II.

[0023] In one embodiment, the raw materials for the preparation method are the compound represented by Formula I, ethyl 3-bromo-2-oxopropionate, and the solvent.

[0024] In one embodiment, the preparation method further includes the following post-processing steps: after the reaction is completed, the crude product of the compound as shown in Formula II is obtained by filtration; or, it is further washed (e.g., twice) with an alcohol solvent (e.g., ethanol).

[0025] The "one-pot reaction" described in this invention refers to a reaction in which multiple steps that require separate reactions to synthesize the target molecule are completed in the same reaction vessel without the need for separation or purification of intermediate products.

[0026] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0027] The reagents and raw materials used in this invention are all commercially available.

[0028] The positive and progressive effects of this invention are as follows: the preparation method of quinoxaline derivatives provided by this invention has the advantages of high yield, high product purity, low cost, and simple operation. Detailed Implementation

[0029] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0030] Example 1:

[0031] 1 g of 2-amino-3-chloroquinoxaline and 1.6 g of ethyl 3-bromo-2-oxopropionate were added to 15 mL of ethanol. The system was purged with nitrogen and then refluxed under a nitrogen atmosphere for 24 hours. After the reaction was completed, the solid was filtered and washed twice with 15 mL of ethanol to obtain 687 mg of white solid with a purity of 98.5% and a yield of 47%.

[0032] LCMS: Column: Phenomenex Kinetex EVO (30 4.6mm 2.6 μm); Flow Rate: 3 mL / min; Solvent system: A) water + 10 mM NH4HCO3, B) acetonitrile; Gradient: From 95:5 to 5:95 in 1.00 min, 5:95 for 0.35 min, from 5:95 to 95:5 in 0.10 min, 95:5 for 0.05 min.), 98.5%. Rt = 0.543 min; MS Calcd.: 257.1; MS Found: 258.3 [M+H] + .

[0033] HNMR: 1H NMR (400MHz, DMSO-d6) δ: 1.33 (t, J = 2.0 Hz, 3H), 3.41 (br,1H), 4.31 (q, J = 2.0 Hz, 2H), 7.01-7.44 (m, 3H), 7.99-8.05 (m, 1H), 9.05(s,1H).

Claims

1. A method for preparing a quinoxaline derivative of Formula II, characterized in that, The reaction includes the following steps: in a solvent, a compound of formula I and ethyl 3-bromo-2-oxopropionate are reacted as shown below to give a compound of formula II. ； The solvent is ethanol; The reaction temperature is 60℃-90℃; The reaction directly yields the compound shown in Formula II without any intermediate processing steps; The reaction is a one-pot reaction.

2. The preparation method according to claim 1, characterized in that, It meets one of the following conditions, (1) The molar ratio of the compound shown in Formula I to ethyl 3-bromo-2-oxopropionate is 1:1 to 1:2; (2) The molar volume ratio of the compound as shown in Formula I to the solvent is 1:1 to 1:6 mol / L; (3) The reaction is carried out under a protective gas atmosphere.

3. The preparation method according to claim 2, characterized in that, It meets one of the following conditions, (1) The molar ratio of the compound as shown in Formula I to ethyl 3-bromo-2-oxopropionate is 1:1.3-1:1.6; (2) The molar volume ratio of the compound as shown in Formula I to the solvent is 1:2-1:4 mol / L; (3) The reaction is carried out under a nitrogen atmosphere.

4. The preparation method according to claim 3, characterized in that, It meets one of the following conditions, (1) The reaction temperature is 75℃-85℃; (2) The molar ratio of the compound shown in Formula I to ethyl 3-bromo-2-oxopropionate is 1:1.4-1:1.5; (3) The molar volume ratio of the compound shown in Formula I to the solvent is 1:2.5-1:3 mol / L.

5. The preparation method according to claim 4, characterized in that, The reaction temperature is 78℃-79℃.

6. The preparation method according to any one of claims 1-5, characterized in that, It also includes the following post-processing steps: after the reaction is completed, the crude product of the compound as shown in Formula II is obtained by filtration.

7. The preparation method according to claim 6, characterized in that, The post-processing step further includes washing the crude product of the compound shown in Formula II with an alcohol solvent.

8. The preparation method according to claim 7, characterized in that, The post-processing step satisfies one of the following conditions. (1) The washing is performed twice; (2) The alcohol solvent is one or more of methanol, ethanol or isopropanol.

9. The preparation method according to claim 8, characterized in that, The post-processing step satisfies the following condition: the alcohol solvent is ethanol.

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