A process for the preparation of 2-chloro-7-nitroquinoxaline

Abstract

The application discloses a preparation method of 2-chloro-7-nitroquinoxaline and belongs to the technical field of synthetic chemistry. The preparation method is as follows: taking 2-hydroxyquinoxaline as a starting material, first, 2-chloroquinoxaline is prepared by chlorination of 2-hydroxyquinoxaline under the action of a catalyst, and then 2-chloro-7-nitroquinoxaline is prepared by nitration of the 2-chloroquinoxaline. The synthetic method has the advantages of cheap and easily available raw materials, simple operation, relatively mild reaction conditions and high yield.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing 2-chloro-7-nitroquinoxaline. Background Technology

[0002] Quinoxaline compounds are an important class of lead compounds with broad biological activities. Their derivatives can be used to synthesize many important drugs, such as anticancer drugs, antiviral drugs, and antibacterial drugs, as well as many important dyes, fragrances, and pesticides. Due to their wide range of applications and biological activities, the synthesis of quinoxaline compounds has attracted widespread attention. 2-Chloro-7-nitroquinoxaline can be used to prepare RhoA inhibitors, which are widely used to treat mental illnesses.

[0003] The literature [Journal of Medicinal Chemistry, 2011, vol. 54, 4508-4522] describes the synthesis of 7-nitro-2(1H)-quinoxalone from 2-hydroxyquinoxaline via nitration, followed by chlorination with phosphorus oxychloride and phosphorus pentachloride to yield 2-chloro-7-nitroquinoxaline, with an overall yield of 38.6%. The second chlorination step uses phosphorus pentachloride, a chemical reagent unsuitable for industrial production, and the chlorination yield is relatively low. The specific reaction route is shown below:

[0004]

[0005] The literature [Bulletin des Societes Chimiques Belges, 1986, vol. 95, 663-670] reports a reaction using 7-nitroquinoxaline as a starting material, generating N-nitrooxides via m-chloroperoxybenzoic acid, followed by a Katada reaction via phosphorus oxychloride to yield 2-chloro-7-nitroquinoxaline, with an overall yield of 4.1%. The first step, the formation of N-oxides, produces isomers, resulting in a low yield. The specific reaction route is shown below:

[0006]

[0007] Given the aforementioned problems, it is essential to design a high-yield and easy-to-operate route for the synthesis of 2-chloro-7-nitroquinoxaline. Summary of the Invention

[0008] To solve the above-mentioned technical problems, the technical solution adopted in this invention can be summarized as follows: using 2-hydroxyquinoxaline as a starting material, it is first chlorinated with phosphorus oxychloride under the action of a catalyst to prepare 2-chloroquinoxaline, and then nitrated with nitric acid to prepare 2-chloro-7-nitroquinoxaline. The synthesis method of this invention has the advantages of inexpensive and readily available raw materials, simple operation, relatively mild reaction conditions, and high yield.

[0009] To achieve the above objectives, the present invention provides a method for preparing 2-chloro-7-nitroquinoxaline, comprising the following steps:

[0010] 1) 2-hydroxyquinoxaline and a catalyst were added to an organic solvent, and phosphorus oxychloride was added dropwise under heating to give 2-chloroquinoxaline;

[0011] 2) 2-Chloroquinoxaline was mixed with acetic acid, and nitric acid and an initiator were added at room temperature to nitrate 2-chloro-7-nitroquinoxaline.

[0012] The reaction route is shown below:

[0013]

[0014] Furthermore, in step 1) of the technical solution, the catalyst is selected from triphenylborane.

[0015] Furthermore, in step 1) of the technical solution, the organic solvent is selected from toluene or a mixture of acetonitrile and toluene.

[0016] Furthermore, in the process of optimizing the implementation scheme of the present invention, it was found that: in step 1), the organic solvent is preferably a mixture of acetonitrile and toluene, the amount of phosphorus oxychloride used is relatively small, and the reaction temperature is relatively low.

[0017] Further, in step 1) of the technical solution, the molar ratio of 2-hydroxyquinoxaline, catalyst and phosphorus oxychloride is 1:0.01-0.02:1.2-2.2.

[0018] Furthermore, in step 2) of the technical solution, the nitric acid is selected from fuming nitric acid of 90% or higher or 65-70% nitric acid.

[0019] Furthermore, in step 2) of the technical solution, when using 68-70% nitric acid, acetic anhydride needs to be added, but when using fuming nitric acid, acetic anhydride does not need to be added.

[0020] Furthermore, in step 2) of the technical solution, the initiator is selected from sodium nitrite.

[0021] Furthermore, in step 2) of the technical solution, the molar ratio of 2-chloroquinoxaline, nitric acid, or initiating reagent is 1:1.2-1.3:0.01-0.05.

[0022] Beneficial effects of the invention

[0023] 1. This invention uses readily available and stable triphenylborane as a catalyst, which accelerates the reaction rate, reduces the amount of POCl3 required, and allows for a more moderate reaction temperature. The raw materials used in this invention are inexpensive and readily available, the operation is simple, the reaction conditions are relatively mild, no obvious isomer formation was observed during nitration, and the yield remained stable over time and with temperature control below 40°C. The product is an off-white solid.

[0024] 2. Replicating the background technology in J. Med. Chem., it was found that during the first step of the nitration reaction, as the reaction time increased or the temperature rose, the product would continue to nitrate or form isomers, thus decreasing the yield. During the second step of the chlorination reaction, since the raw materials are insoluble in toluene or acetonitrile, a large excess of POCl3 is required as the reaction solvent, generating a large amount of phosphoric acid-containing wastewater, and the resulting product is yellowish-brown. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions made based on the teachings of the present invention shall fall within the scope of protection of the present invention.

[0026] Example 1

[0027]

[0028] 2-Hydroxyquinoxaline (20 g, 0.137 mol) and triphenylborane (0.5 g, 0.002 mol) were mixed with 40 mL of dry acetonitrile and 120 mL of toluene. Phosphorus oxychloride (25.2 g, 0.164 mol) was added dropwise. After the addition was complete, the mixture was heated to 80 °C and reacted for 1.5 hours. The temperature was then lowered to 40-50 °C, and volatile substances were removed by rotary evaporation under reduced pressure. The residue was added to 200 mL of ice water, slurried, and filtered. The filter cake was washed with 5% sodium bicarbonate aqueous solution and water, and dried under vacuum at 40 °C to obtain 20.6 g of 2-chloroquinoxaline, with a yield of 91.5% and an HPLC yield of 99.2%. 1 HNMR (400MHz, CDCl3, ppm) δ: 8.77 (s, 1H), 8.11-8.09 (m, 1H), 8.02-7.99 (m, 1H), 7.81-7.74 (m, 2H).

[0029] Example 2

[0030]

[0031] 2-Hydroxyquinoxaline (20 g, 0.137 mol), triphenylborane (0.66 g, 0.0027 mol), and 200 mL of toluene were mixed. The mixture was heated to 35-40 °C and phosphorus oxychloride (31.4 g, 0.205 mol) was added dropwise. After the addition was complete, the mixture was heated to 110 °C and reacted for 1 hour. The mixture was then cooled to 40-50 °C, and volatile substances were removed by rotary evaporation under reduced pressure. The residue was added to 200 mL of ice water, slurried, and filtered. The filter cake was washed with 5% sodium bicarbonate aqueous solution and water, and dried under vacuum at 40 °C to obtain 19.0 g of 2-chloroquinoxaline, with a yield of 84.3% and an HPLC resolution of 98.4%.

[0032] Example 3

[0033]

[0034] 2-Chloroquinoxaline (16.5 g, 0.100 mol) was mixed with 95 mL of acetic acid, cooled to 15 °C, and 90% fuming nitric acid (8.4 g, 0.120 mol) was added dropwise. While controlling the temperature, 70 mg of sodium nitrite was added to initiate the reaction, which then turned red. The temperature was raised to 34 °C and reacted at 30-34 °C for 1 hour. The mixture was then cooled to 10 °C, filtered, and slurried with methanol. The filter cake was washed with sodium bicarbonate and water, and dried under vacuum at 35-40 °C to obtain 18.0 g of 2-chloro-7-nitroquinoxaline, with a yield of 85.7% and an HPLC accuracy of 99.3%. 1 HNMR (400MHz, CDCl3, ppm) δ: 8.93 (s, 1H), 8.91 (d, 1H), 8.55 (dd, 1H), 8.29 (d, 1H).

[0035] Example 4

[0036]

[0037] 2-Chloroquinoxaline (20 g, 0.1220 mol), 80 mL of acetic acid, and 15 mL of acetic anhydride were mixed and cooled to 15 °C. 68% nitric acid (15.8 g, 0.17 mol) was added dropwise while controlling the temperature. 70 mg of sodium nitrite was added to initiate the reaction, which turned red. The temperature was then raised to 36 °C and reacted at 30-35 °C for 2 hours. After removing volatile substances by rotary evaporation under reduced pressure, the residue was added to 200 mL of ice water, slurried with methanol, and filtered. The filter cake was washed with 5% sodium bicarbonate aqueous solution and water, and dried under vacuum at 35-40 °C to obtain 22.7 g of off-white solid 2-chloro-7-nitroquinoxaline, with a yield of 89.3% and an HPLC accuracy of 98.9%.

[0038] The above embodiments are only for illustrating the technical concept and features of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention are covered within the protection scope of the present invention.

Claims

1. A method for preparing 2-chloro-7-nitroquinoxaline, characterized in that, The reaction route is shown below: ； Includes the following steps: 1) 2-Hydroxyquinoxaline and a catalyst are added to an organic solvent, and phosphorus oxychloride is added dropwise under heating to obtain 2-chloroquinoxaline; the catalyst is selected from triphenylborane; the organic solvent is selected from toluene or a mixture of acetonitrile and toluene. 2) 2-Chloroquinoxaline is mixed with acetic acid, and nitric acid and an initiator are added at room temperature to nitrate 2-chloro-7-nitroquinoxaline; the initiator is selected from sodium nitrite.

2. The method for preparing 2-chloro-7-nitroquinoxaline according to claim 1, characterized in that: In step 1), the molar ratio of 2-hydroxyquinoxaline, catalyst and phosphorus oxychloride is 1:0.01-0.02:1.2-2.

2.

3. The method for preparing 2-chloro-7-nitroquinoxaline according to claim 1, characterized in that: In step 2), the nitric acid is selected from fuming nitric acid of 90% or higher or 65-70% nitric acid.

4. The method for preparing 2-chloro-7-nitroquinoxaline according to claim 1, characterized in that: In step 2), the molar ratio of 2-chloroquinoxaline, nitric acid, or initiating reagent is 1:1.2-1.3:0.01-0.05.

Images