A method for synthesizing quinoxaline derivative from acid-catalyzed o-phenylenediamine derivative and alpha-keto acid ester

Abstract

This invention discloses an acid-catalyzed method for synthesizing quinoxalinone derivatives from o-phenylenediamine derivatives and α-carbonyl esters. The method uses an acid as a catalyst to catalyze the reaction of o-phenylenediamine derivatives with α-carbonyl esters to prepare quinoxalinone derivatives. The method employs acid catalysis to prepare quinoxalinone derivatives from o-phenylenediamine derivatives and α-carbonyl esters in a mixed alcohol-water solvent. The reaction equation is as follows: This invention is simple to operate, requires low catalyst dosage, is environmentally friendly, and is suitable for large-scale preparation of quinoxalinone derivatives. The product yield can reach over 98%, demonstrating excellent industrial applicability.

Description

Technical Field

[0001] This invention relates to an organic synthesis method, and more particularly to an acid-catalyzed method for synthesizing quinoxalone derivatives from o-phenylenediamine derivatives and α-carbonyl esters. Background Technology

[0002] Quinoxalone derivatives are an important class of nitrogen-containing heterocyclic compounds with wide applications in pharmaceuticals, including as antitumor agents, HIV-1 reverse transcriptase inhibitors, and hypoglycemic agents. In particular, 3-substituted quinoxalone derivatives exhibit excellent chemical properties and pharmacological effects. Their synthesis mainly involves traditional condensation methods, free radical cyclization, and C3 functionalization of quinoxalone. Some relevant literature is as follows:

[0003] In 2013, Christopher Hulme's research group (ShawAY, Denning CR, Hulme, C. Synthesis 2013, 45, 459-462) synthesized quinoxalinone in a one-pot reaction using o-phenylenediamine derivatives and arylethylene glycol as raw materials, as shown in the following formula:

[0004]

[0005] In 2013, Alaimi's research group (Carrer A, Brion J, Messioudi S, et al. Org. Lett. 2013, 15, 5606-5609) used Pd / o-phenanthroline as a catalyst to prepare 3-arylquinoxaline derivatives of arylboronic acid under high temperature and oxygen conditions, as shown in the following formula:

[0006]

[0007] In 2017, Yin et al. reported the reaction of diaryliodonium ion fluoroborate with quinoxalinone under nitrogen conditions to prepare 3-substituted quinoxalinone without transition metal catalysis, as shown in the following formula:

[0008]

[0009] Therefore, it is of great significance to develop green, efficient, high-yield, widely applicable substrate synthesis methods for quinoxaline derivatives with promising industrialization prospects. Summary of the Invention

[0010] The purpose of this invention is to provide a method for synthesizing quinoxalinone derivatives from o-phenylenediamine derivatives and α-carbonyl esters using acid catalysis. This method uses acid as a catalyst to catalyze the reaction of o-phenylenediamine derivatives and α-carbonyl esters to prepare quinoxalinone derivatives. This invention is simple to operate, requires low catalyst dosage, is environmentally friendly, and is suitable for large-scale preparation of quinoxalinone derivatives. It achieves the highest product yield and has good industrial applicability.

[0011] The technical solution of the present invention is as follows:

[0012] The o-phenylenediamine derivative and α-carbonyl ester were dissolved in an alcohol-water mixed solvent. An acid catalyst was added under stirring at room temperature, and stirring was continued for 2-6 hours. A large amount of solid precipitated out. The solid was filtered, washed with water, and dried.

[0013] The alcohol is one or more of methanol, ethanol or isopropanol.

[0014] The acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, acetic acid, and p-toluenesulfonic acid.

[0015]

[0016] The structural formula of the o-phenylenediamine derivative involved in this invention is as follows:

[0017]

[0018] Where R1 is H, a halogen, C1~C 10 Alkyl group, C3-C 12 cycloalkyl, C6-C 30 Aromatic groups, with or without functional groups such as N, S, O, and P.

[0019] The α-carbonyl ester structure involved in this invention is as follows:

[0020]

[0021] Where R2 is H, C1~C 10 Alkyl group, C3-C 12 cycloalkyl, C6-C 30 Aromatic groups, with or without functional groups such as N, S, O, and P.

[0022] The volume ratio of alcohol to water in the solvent is 100 to 0.01:1.

[0023] The mass ratio of the solvent to the o-phenylenediamine derivative substrate is 100 to 1:1.

[0024] The molar ratio of the o-phenylenediamine derivative substrate to the α-carbonyl ester substrate is 0.5–2:1, and the molar ratio of the o-phenylenediamine derivative substrate to the acid catalyst is 10. 4 ~10:1.

[0025] The beneficial effects of this invention are:

[0026] Compared with other methods for synthesizing quinoxalone derivatives, this invention is simple, inexpensive, green, and efficient. It is easy to operate, requires low catalyst dosage, is environmentally friendly, and is suitable for large-scale preparation of quinoxalone derivatives. The product yield can reach over 98%, demonstrating good industrial applicability. Attached Figure Description

[0027] Figure 1 The diagram for 1:3-phenylquinoxaline-2(1H)-one of this invention is shown.

[0028] Figure 2 The diagram shows the 3-(4-methoxyphenyl)quinoxaline-2(1H)-one of this invention;

[0029] Figure 3 The diagram shows the 3-(4-trifluoromethylphenyl)quinoxaline-2(1H)-one of this invention;

[0030] Figure 4 The diagram shows the 3-methylquinoxaline-2(1H)-one of this invention;

[0031] Figure 5 The diagram shows the 3-(3-chlorophenyl)quinoxaline-2(1H)-one of this invention. Detailed Implementation

[0032] The embodiments shown in the accompanying drawings will further illustrate the invention, but are not intended to limit the invention. Nuclear magnetic resonance (NMR) measurements were performed using a Bruker NMR spectrometer.

[0033] Example 1

[0034]

[0035] 108.1 g (1 mol) of o-phenylenediamine and 164.2 g of methyl 2-oxo-2-phenylacetate were added to a 500 mL single-necked flask, followed by 200 mL of isopropanol and 200 mL of water. While stirring at room temperature, 10 mL of boric acid aqueous solution (0.01 mol / L) was added, and stirring was continued for 4 hours. The solid was filtered, the filter cake was washed with water, and dried to obtain 217.8 g of yellow solid, with a yield of 98%.

[0036] The product was analyzed, and the HNMR data are shown below:

[0037] 1 HNMR (500MHz, CDCl3) δ11.31 (s, 1H), 8.40 (dd, J=6.5, 2.9Hz, 2H), 7.95 (d, J=7 .9Hz,1H),7.57-7.48(m,4H),7.37(t,J=7.4Hz,1H),7.31(d,J=8.1Hz,1H), see attachment Figure 1 .

[0038] The product was identified as 3-phenylquinoxaline-2(1H)-one.

[0039] Example 2

[0040] The reaction conditions in Example 1 were changed from isopropanol to ethanol, and the rest were the same as in Example 1. The product yield was 92%.

[0041] Example 3

[0042] The reaction conditions in Example 1 were changed from isopropanol to methanol, and the rest were the same as in Example 1. The product yield was 90%.

[0043] Example 4

[0044] In Example 1, boric acid was replaced with hydrochloric acid, and the rest of the reaction conditions were the same as in Example 1. The product yield was 81%.

[0045] Example 5

[0046] In Example 1, boric acid was replaced with sulfuric acid, and the rest of the reaction conditions were the same as in Example 1. The product yield was 85%.

[0047] Example 6

[0048] In Example 1, boric acid was replaced with p-toluenesulfonic acid, and the rest of the reaction conditions were the same as in Example 1. The product yield was 75%.

[0049] Example 7

[0050] The volume of the boric acid aqueous solution in Example 1 was changed to 1 ml, and the rest were the same as in Example 1. The product yield was 80%.

[0051] Example 8

[0052] The volume of the boric acid aqueous solution in Example 1 was changed to 20 ml, and the rest were the same as in Example 1. The product yield was 95%.

[0053] Example 9

[0054] The volume of isopropanol in the reaction conditions of Example 1 was changed to 100 mL, and the rest were the same as in Example 1. The product yield was 90%.

[0055] Example 10

[0056] In Example 1, the methyl 2-oxo-2-phenylacetate was replaced with 200g, and the rest of the reaction conditions were the same as in Example 1. The product yield was 95%.

[0057] Example 11

[0058] The substrate of methyl 2-oxo-2-phenylacetate in Example 1 was changed to methyl 2-(4-methoxyphenyl)-2-oxoacetate, and the rest was the same as in Example 1. The reaction yielded a yellow solid with a yield of 92%.

[0059] The product was analyzed, and the HNMR data are shown below:

[0060] 1 HNMR (500MHz, CDCl3) δ10.05(s,1H),8.47(d,J=8.8Hz,2H),7.91(d,J=7.9Hz,1H),7.47(d,J=8 .4Hz,1H),7.35(d,J=7.3Hz,1H),7.19(d,J=8.0Hz,1H),7.01(d,J=8.8Hz,2H),3.89(s,3H), see attached Figure 2 .

[0061] The product was identified as 3-(4-methoxyphenyl)quinoxaline-2(1H)-one.

[0062] Example 12

[0063] The substrate of methyl 2-oxo-2-phenylacetate in Example 1 was changed to methyl 2-(4-trifluoromethylphenyl)-2-oxoacetate, and the rest was the same as in Example 1. The reaction yielded a yellow solid with a yield of 94%.

[0064] The product was analyzed, and the HNMR data are shown below:

[0065] 1 H NMR (500MHz, CDCl3) δ 10.39 (s, 1H), 8.54 (d, J = 8.1Hz, 2H), 7.96 (d, J = 7.9Hz, 1H), 7.76 (d, J = 8.2Hz, 3H), 7.56 (t, J = 7.6Hz, 1H), 7.40 (t, J = 7.8Hz, 1H), see appendix. Figure 3 .

[0066] The product was identified as 3-(4-trifluoromethylphenyl)quinoxaline-2(1H)-one.

[0067] Example 13

[0068] The substrate of methyl 2-oxo-2-phenylacetate in Example 1 was replaced with methyl 2-oxopropionate, and the rest was the same as in Example 1. The reaction yielded a white solid with a yield of 95%.

[0069] The product was analyzed, and the HNMR data are shown below:

[0070] 1H NMR (500MHz, CDCl3) δ 11.61 (s, 1H), 7.81 (d, J = 8.1Hz, 1H), 7.54–7.44 (m, 1H), 7.37–7.27 (m, 2H), 2.63 (s, 3H). (See appendix) Figure 4 .

[0071] The product was identified as 3-methylquinoxaline-2(1H)-one.

[0072] Example 14

[0073] The substrate of methyl 2-oxo-2-phenylacetate in Example 1 was changed to methyl 2-(3-chlorophenyl)-2-oxoacetate, and the rest was the same as in Example 1. The reaction yielded a white solid with a yield of 95%.

[0074] The product was analyzed, and the HNMR data are shown below:

[0075] 1 HNMR (500MHz, CDCl3) δ10.87(s,1H),8.45(s,1H),8.37(d,J=7.6Hz,1H),7.95(d,J=8.0Hz,1H),7. 55(t,J=7.8Hz,1H),7.46(dt,J=15.4,7.9Hz,2H),7.39(t,J=7.6Hz,1H),7.28(d,J=8.0Hz,1H), see attachment Figure 5 .

[0076] The test revealed 3-(3-chlorophenyl)quinoxaline-2(1H)-one.

Claims

1. A method for synthesizing quinoxalinone derivatives from o-phenylenediamine derivatives and α-carbonyl esters using acid catalysis, characterized in that: The method is as follows: 108.1 g of 1 mol o-phenylenediamine and 164.2 g of methyl 2-oxo-2-phenylacetate were added to a 500 mL single-necked flask, followed by 200 mL of isopropanol and 200 mL of water. While stirring at room temperature, 10 mL of 0.01 mol / L boric acid aqueous solution was added, and stirring continued for 4 hours. The solid was filtered, the filter cake was washed with water, and dried to obtain 217.8 g of a yellow solid, with a yield of 98%. The product was 3-phenylquinoxaline-2(1H)-one. The reaction formula is: 。

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