CN105061338A - 3-methyl-quinoxaline-2-carboxylic acid chemical synthesis method based on ionic liquid system - Google Patents

Abstract

The invention belongs to the technical field of chemical synthesis, and specifically relates to a new high-yield, high-purity, and easy-to-operate chemical synthesis method for 3-methyl-quinoxaline-2-carboxylic acid based on an ionic liquid system: The target product 3-methyl-quinoxaline-2-carboxylic acid was successfully synthesized through two-step reactions of cyclization and hydrolysis using amine and α-halogenated-β-ketoester as raw materials, using ionic liquid as solvent system and catalyst . The core of the present invention is to innovate based on the solvent characteristics and catalyst characteristics of the ionic liquid, so that the cyclization reaction can be carried out at room temperature, the product yield and purity are high, and the reaction time is relatively short, which can reduce energy consumption; at the same time, the ionic The liquid is a non-volatile solvent, which can be activated and reused, which can reduce costs and reduce environmental pollution.

Description

A kind of chemical synthesis method of 3-methyl-quinoxaline-2-carboxylic acid based on ionic liquid system

technical field

The invention belongs to the technical field of chemical synthesis, and in particular relates to a new high-yield, high-purity and easy-to-operate chemical synthesis method for 3-methyl-quinoxaline-2-carboxylic acid based on an ionic liquid system.

Background technique

In recent years, my country's food safety incidents have occurred frequently, especially the occurrence of major food safety incidents such as the "melamine" incident in 2008 and the "clenbuterol" incident in 2011, which have negatively affected the country's image and caused serious economic damage to the food industry. The loss poses a threat to the health and life safety of the broad masses of the people, and has aroused great concern from state leaders and the people. Therefore, in order to ensure food quality and safety, the state has stepped up the detection of food safety hazard factors such as veterinary drug residues, pesticide residues, and illegal additives.

Lalaquindox is a veterinary drug with antibacterial and growth-promoting effects. Because it will remain in the animal body in excess, it has obvious cumulative toxicity and DNA damage and other toxic and side effects. As a growth-promoting additive, my country stipulated that olaquindox was prohibited from being used in poultry, aquatic products and pig breeding with a body weight of more than 35kg in 2001 and 2005 respectively. Lalaquindox itself is unstable, and it will be metabolized in animals and cannot be directly detected. Its metabolite 3-methyl-quinoxaline-2-carboxylic acid is identified by the Joint Expert Committee on Food Additives of the World Health Organization and the Food and Agriculture Organization of the United Nations As for the residue marker of olaquindox, my country has listed 3-methyl-quinoxaline-2-carboxylic acid as a mandatory inspection item since March 1, 2014 (the detection limit is 1ng/mL). Therefore, the research on the synthesis of 3-methyl-quinoxaline-2-carboxylic acid has important practical significance and application value for its hapten synthesis, antibody preparation and rapid detection.

Previously, the applicant of the present invention innovated on the mechanism of promoting the deoxygenation reduction of quinoxaline-1,4-dioxide based on the electron-withdrawing induction effect. Using olaquindox as raw material and ethanol aqueous solution as the solvent medium for the deoxygenation reaction, deoxygenated by sodium sulfite, hydrogen The two-step reaction of sodium oxide hydrolysis successfully synthesized 3-methyl-quinoxaline-2-carboxylic acid, and applied for a national invention patent (an efficient chemical synthesis method for 3-methyl-quinoxaline-2-carboxylic acid , patent application number: 201310660750.7).

The core of the invention is to innovate based on the solvent properties and catalyst properties of the ionic liquid. Ionic liquids are substances composed of specific relatively large organic cations and relatively small inorganic anions that are liquid at room temperature or near room temperature. Compared with traditional organic solvents and electrolytes, ionic liquids have the following properties: Outstanding advantages: (1) Ionic liquids have almost no vapor pressure and non-volatility, and have the potential to be environmentally friendly green solvents; (2) The dissolution of inorganic compounds, organic compounds, and polymers by ionic liquids can be adjusted through the design of anions and cations (3) Due to their high polarity and the ability to dissolve organic and inorganic compounds, some ionic liquids have been used as catalysts for organic synthesis; (4) Since ionic liquids do not form azeotropic systems, they are beneficial to separation Reuse after purification can reduce cost and reduce environmental pollution. Based on the above advantages, the application research of ionic liquids as solvents and catalysts is being carried out rapidly all over the world.

Therefore, the present invention uses o-phenylenediamine and α-halogenated-β-ketoester as raw materials, adopts ionic liquid as solvent system and catalyst, and independently develops a new high-yield , high-purity, easy-to-operate 3-methyl-quinoxaline-2-carboxylic acid chemical synthesis method.

Contents of the invention

The purpose of the present invention is to provide a new high-yield, high-purity, and easy-to-operate chemical synthesis method for 3-methyl-quinoxaline-2-carboxylic acid based on an ionic liquid system to meet research and application requirements.

Technical scheme of the present invention:

A new high-yield, high-purity, and easy-to-operate chemical synthesis method for 3-methyl-quinoxaline-2-carboxylic acid based on an ionic liquid system (the synthetic route is shown in Figure 1), and the steps are as follows:

(1) Cyclization reaction (the mechanism is shown in Figure 2): o-Phenylenediamine and α-halogenated-β-ketoester are used as raw materials, ionic liquid is used as solvent and catalyst, and the reaction time is appropriate under room temperature and magnetic stirring (Reaction endpoint indicated by TLC). After the reaction was terminated, the reaction solution was extracted with ether, the organic phase was collected, concentrated by rotary evaporation, and then passed through the chromatography column (eluent was ethyl acetate:petroleum ether=1:3~1:10), and the eluent was rotary evaporated to obtain the target mid product. The remaining ionic liquid after extraction is activated by vacuum drying, making it reusable.

Note:

① α-halo-β-ketoesters are methyl 2-fluoroacetoacetate (CAS: 80171-29-5), ethyl 2-fluoroacetoacetate (CAS: 1522-41-4), benzene 2-fluoroacetoacetate Methyl ester (CAS: 139101-19-2), methyl 2-chloroacetoacetate (CAS: 4755-81-1), ethyl 2-chloroacetoacetate (CAS: 609-15-4), 2-chloroacetyl n-Propyl acetate (CAS: 104517-64-8), isopropyl 2-chloroacetoacetate (CAS: 70697-72-2), n-butyl 2-chloroacetoacetate (CAS: 90089-91-1), Isobutyl 2-chloroacetoacetate (CAS: 85153-47-5), Benzyl 2-chloroacetoacetate (CAS: 104517-65-9), Methyl 2-bromoacetoacetate (CAS: 3600-18- 8), ethyl 2-bromoacetoacetate (CAS: 609-13-2), benzyl 2-bromoacetoacetate (CAS: 362610-29-5), methyl 2-iodoacetoacetate (CAS: 1017883- 28-1), ethyl 2-iodoacetoacetate (CAS: 104790-31-5) or benzyl 2-iodoacetoacetate (CAS: 1017883-41-8).

② The ionic liquids are [MIM][PF ₆ ], [EMIM][PF ₆ ], [PMIM][PF ₆ ], [BMIM][PF ₆ ], [MIM][SbF ₆ ], [EMIM][SbF ₆ ], [PMIM][SbF ₆ ], [BMIM][SbF ₆ ], [MIM][BF ₄ ], [EMIM][BF ₄ ], [PMIM][BF ₄ ] or [BMIM][BF ₄ ].

③Target intermediate products are 3-methyl-quinoxaline-2-carboxylic acid methyl ester, 3-methyl-quinoxaline-2-carboxylic acid ethyl ester, 3-methyl-quinoxaline-2-carboxylic acid n-propyl ester , 3-methyl-quinoxaline-2-carboxylic acid isopropyl ester, 3-methyl-quinoxaline-2-carboxylic acid n-butyl ester, 3-methyl-quinoxaline-2-carboxylic acid isobutyl ester or 3 -Methyl-quinoxaline-2-carboxylic acid benzyl ester.

(2) Hydrolysis reaction: use the intermediate product obtained above as raw material, add 5%-20% sodium hydroxide aqueous solution, heat and stir for 1-6 hours, and cool the reaction solution to room temperature after the reaction is completed, adjust with hydrochloric acid solution pH (pH 1-7). Then extract the reaction solution with dichloromethane, collect the organic phase, add anhydrous sodium sulfate for drying, and recrystallize the crude product obtained by rotary evaporation with ethyl acetate (or methanol) to obtain off-white crystals.

(3) The above-mentioned off-white crystals were determined by high-performance liquid chromatography, and the high-performance liquid chromatography conditions were: chromatographic column: C18 reversed-phase column, 250mm×4.6μm (inner diameter), particle size 5μm; mobile phase: 1% formic acid aqueous solution + acetonitrile (75+25); flow rate: 0.5mL/min; detection wavelength: 320nm; injection volume: 20μL; column temperature: 30°C. The chromatogram shows only one main peak and no impurity peaks, proving that it is a pure substance with a very high purity.

(4) Perform mass spectrometry and nuclear magnetic resonance identification on the above-mentioned off-white crystals, mass spectrometry conditions: electrospray ionization, negative ionization mode; drying gas temperature: 350°C; drying gas flow rate: 8.00L/min; capillary outlet voltage: -88.5V; Capillary entrance voltage: -20.3V; scanning range: m/z is 50-500. NMR conditions: ¹ HNMR: solvent: DMSO; resonance frequency: 300.13MH _Z . Through high-performance liquid chromatography-mass spectrometry identification and nuclear magnetic resonance identification, it was determined that the above-mentioned off-white crystals were the target product 3-methyl-quinoxaline-2-carboxylic acid.

The present invention has the following advantages:

1. High product yield and purity: the present invention uses ionic liquid as a solvent system and catalyst to fully ensure the occurrence of cyclization reaction and the uniqueness of the product, thereby obtaining high yield and high purity 3-methyl-quinoxaline -2-Carboxylic acid.

2. Simple operation and short reaction time: the present invention only needs two-step reactions of cyclization and hydrolysis, and uses common laboratory equipment such as magnetic stirrer and rotary evaporator, and the operation method is very simple. At the same time, the cyclization reaction only needs 40-90 minutes, which shortens the reaction time compared with the several hours required by other synthetic methods of 3-methyl-quinoxaline-2-carboxylic acid.

3. Low cost and low pollution: Since the ionic liquid does not form an azeotropic system, it is conducive to repeated use after activation, which can reduce costs and reduce environmental pollution. At the same time, ionic liquids have almost no vapor pressure and are non-volatile, so they have the potential to be environmentally friendly green solvents with little pollution to the environment.

4. Low energy consumption: the cyclization reaction of the present invention is carried out at room temperature, which can reduce energy consumption compared with other synthesis methods of 3-methyl-quinoxaline-2-carboxylic acid that require heating.

Description of drawings

Fig. 1 is the synthetic route of 3-methyl-quinoxaline-2-carboxylic acid of the present invention;

Fig. 2 is the cyclization reaction mechanism of the present invention;

Fig. 3 is the high performance liquid phase chromatogram of the synthetic product of embodiment 1 (3a) and embodiment 3 (3b) of the present invention;

Fig. 4 is the 3-methyl-quinoxaline-2-carboxylic acid mass spectrum that the present invention synthesizes;

Fig. 5 is the ¹ H NMR spectrum of 3-methyl-quinoxaline-2-carboxylic acid synthesized in the present invention.

Detailed ways

Example 1

(1) Add 0.216g (2mmol) o-phenylenediamine, 0.361g (2.2mmol) ethyl 2-chloroacetoacetate and 4mL [EMIM][BF4] to the reaction test tube, and stir the reaction with magnetic force for 60min at room temperature (monitored by TLC The end point of the reaction is determined). The reaction solution was extracted with 3×15mL ether, the organic phase was collected, concentrated by rotary evaporation, and then subjected to column chromatography (eluent: ethyl acetate:petroleum ether=1:9), and the eluent was rotary evaporated to obtain the target intermediate product 3- Methyl-quinoxaline-2-carboxylic acid ethyl ester weighs 0.389g, and the yield reaches 90%. The remaining ionic liquid after extraction is activated by vacuum drying, making it reusable.

(2) Add 0.216g of ethyl 3-methyl-quinoxaline-2-carboxylate prepared above and 15mL of 10% sodium hydroxide solution into a 50mL three-neck round bottom flask, react at 90°C for 2h, stop the reaction and then cool to room temperature, and adjust the pH value of the reaction solution to 5 with dilute hydrochloric acid. The reaction solution was extracted with 3×15 mL of dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and then rotary evaporated to obtain a solid, which was then recrystallized with methanol to obtain 0.152 g of off-white crystals.

(3) The above-mentioned off-white crystals were determined by high performance liquid chromatography. The high performance liquid chromatography conditions were as follows: chromatographic column: C18 reversed-phase column, 250mm×4.6μm (inner diameter), particle size 5μm; mobile phase: 1% formic acid aqueous solution + acetonitrile (75+25); flow rate: 0.5mL/min; detection wavelength: 320nm; injection volume: 20μL; column temperature: 30°C. As shown in Figure 3a, the off-white crystal chromatogram has only one main peak and no other impurity peaks, proving that it is a pure substance with very high purity.

Example 2

Use [EMIM][BF4] after activation in Example 1, implement completely according to the operating scheme of Example 1, the first step reaction obtains target intermediate product 3-methyl-quinoxaline-2-carboxylic acid ethyl ester, weighs The weight is 0.379g, and the yield is 88%. Example 2 fully proves that the ionic liquid can be completely reused after the activation operation of the present invention.

Example 3

(1) Add 0.216g (2mmol) o-phenylenediamine, 0.542g (2.2mmol) benzyl 2-bromoacetoacetate and 4mL [BMIM][PF ₆ ] into the reaction test tube, and stir the reaction with magnetic stirring for 50min at room temperature ( The end point of the reaction was monitored by TLC). The reaction solution was extracted with 3×15mL ether, the organic phase was collected, concentrated by rotary evaporation, and then subjected to column chromatography (eluent: ethyl acetate:petroleum ether=1:9), and the eluent was rotary evaporated to obtain the target intermediate product 3- Benzyl methyl-quinoxaline-2-carboxylate, weighing 0.493 g, yielded 87%.

(2) Add 0.278 g of the above-prepared 3-methyl-quinoxaline-2-benzoic acid benzyl ester and 15 mL of 5% sodium hydroxide solution into a 50 mL three-neck round bottom flask, reflux for 1 hour, stop the reaction and cool to room temperature , Benzyl alcohol was extracted with 3×10 mL ether. The pH of the aqueous phase was adjusted to 5 with dilute hydrochloric acid, extracted with 3×15 mL of dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and rotary evaporated to obtain a solid, which was then recrystallized with ethyl acetate to obtain 0.147 g of off-white crystals.

(3) The above-mentioned off-white crystals are measured by high performance liquid chromatography, and the conditions of high performance liquid chromatography are the same as those in Example 1. As shown in Figure 3b, the off-white crystal chromatogram has only one main peak and no other impurity peaks, proving that it is a pure substance with very high purity.

Example 4

The final products of Example 1 and Example 3 were identified.

Mass spectrometry conditions: electrospray ionization, negative ionization mode; drying gas temperature: 350°C; drying gas flow rate: 8.00L/min; capillary outlet voltage: -88.5V; capillary inlet voltage: -20.3V; scan range: m/z 50-500.

NMR conditions: ¹ HNMR: solvent: DMSO; resonance frequency: 300.13MH _Z .

Through high-performance liquid chromatography-mass spectrometry identification (as shown in Figure 4) and NMR identification ( ^1H NMR spectrum as shown in Figure 5), it is determined that the off-white crystals finally obtained in Example 1 and Example 3 are all 3- Methyl-quinoxaline-2-carboxylic acid.

Claims (3)

1. the new high yield pulp1 based on ionic liquid system, high purity, easy-operating 3-methyl-Oxoquinoxaline-2-carboxylic acid chemical synthesis process, it is characterized in that: with O-Phenylene Diamine and alpha-halogen-'beta '-ketoester for raw material, adopt ionic liquid as solvent system and catalyzer, through cyclisation and hydrolysis two-step reaction, obtain target product 3-methyl-Oxoquinoxaline-2-carboxylic acid.

2. expressing alpha-halogen-'beta '-ketoester as claimed in claim 1 is 2-acetyl fluoride methyl acetate (CAS:80171-29-5), 2-acetyl fluoride ethyl acetate (CAS:1522-41-4), 2-acetyl fluoride phenylmethyl acetate (CAS:139101-19-2), 2-chloro methyl acetoacetate (CAS:4755-81-1), 2-chloroacetyl acetacetic ester (CAS:609-15-4), 2-chloracetyl n-propyl acetate (CAS:104517-64-8), 2-chloracetyl isopropyl acetate (CAS:70697-72-2), 2-chloracetyl n-butyl acetate (CAS:90089-91-1), 2-chloracetyl isobutyl acetate (CAS:85153-47-5), 2-chloracetyl phenylmethyl acetate (CAS:104517-65-9), 2-acetobrom methyl acetate (CAS:3600-18-8), 2-ethyl bromoacetoacetate (CAS:609-13-2), 2-acetobrom phenylmethyl acetate (CAS:362610-29-5), 2-iodacetyl methyl acetate (CAS:1017883-28-1), 2-iodacetyl ethyl acetate (CAS:104790-31-5) or 2-iodacetyl phenylmethyl acetate (CAS:1017883-41-8).

3. expressing ionic liquid as claimed in claim 1 is [MIM] [PF ₆], [EMIM] [PF ₆], [PMIM] [PF ₆], [BMIM] [PF ₆], [MIM] [SbF ₆], [EMIM] [SbF ₆], [PMIM] [SbF ₆], [BMIM] [SbF ₆], [MIM] [BF ₄], [EMIM] [BF ₄], [PMIM] [BF ₄] or [BMIM] [BF ₄].