CN106866529A - A kind of method for synthesizing the carboxylic acid of 6 alkyl, 2 oxo, 1,2 EEDQ 3 - Google Patents

Abstract

The invention discloses a method for synthesizing 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, specifically using 5-alkyl-2-nitrobenzaldehyde as the initial raw material Instead of p-methylaniline, the quinoline ring was constructed by the aminolysis of the ester instead of the Vilsmeier-Haack-Arnold electrophilic cyclization process. The beneficial effect of the present invention is that highly toxic phosphorus oxychloride is not used, and the post-treatment waste water discharge is less; the final product is obtained by hydrolyzing the ester, the process control is simple, the purification is convenient and the yield is high. Using 5-alkyl-2-nitrobenzaldehyde to synthesize 6-alkyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid has the advantages of simple synthesis process and no need of highly toxic phosphorus oxychloride The advantages of participation, and it is not easy to coat raw materials. Compared with the traditional synthesis method, the method disclosed by the invention has high yield and less waste water discharge, and has important practical application value in the field of medicine and chemical industry.

Description

A method for synthesizing 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

technical field

The present invention relates to the technical field of chemical synthesis, in particular to a synthesis method of a class of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, in particular, the use of ester aminolysis to form a ring instead of The Vilsmeier-Haack-Arnold reagent electrophilic cyclization constructs the quinoline ring, and the final product is obtained in high yield by replacing the oxidation process in the existing process by hydrolysis of the ester.

Background technique

6-Alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid is an important chemical and pharmaceutical intermediate, and the emerging 4-quinolinone-3-carboxylic acids, nalidixic acid It has similar properties to pyridopyrimidine compounds and can be widely used in antibacterial drugs, so it has been widely studied. In addition to changing the substituents on the quinolinonic acid benzene nucleus and nitrogen atom to find biologically active drugs, this type of compound can also conduct drug research through the further reaction of the carboxyl group with other substrates, thus making 6-alkyl- 2-oxo-1,2-dihydroquinoline-3-carboxylic acid plays an increasingly important role in the field of drug synthesis.

At present, the synthetic routes of 6-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid are mainly:

.

When p-methylaniline is used as a raw material, a large amount of phosphorus oxychloride is used in the cyclization process, which is troublesome in post-treatment and has a large amount of sewage discharge; potassium permanganate is used as an oxidant in the oxidation process, and the methyl group at the 6-position is easily It is destroyed, the process is difficult to control, and at the same time, due to the poor solubility of the substrate and product, it is easy to cause incomplete oxidation and substrate coating. Literature related to this method includes International Journal of Applied Biology and Pharmaceutical Technology, 2014, 5(2), 85-89, etc.

Srivastava, Ambika et al. used the hydrolysis of cyano group to realize the conversion of acid during the synthesis of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, but the previous reaction still used Vilsmeier -Haack-Arnold reagent is used for cyclization, and a large amount of cerium ammonium nitrate is used in the reaction, and the waste water discharge is large in the post-treatment process.

Therefore, improving the synthesis method or post-treatment method of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid has important practical application value and far-reaching significance in the field of environment and chemical production .

Contents of the invention

The invention discloses a synthesis method of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. The purpose of the invention is to simplify 6-alkyl-2-oxo- The synthesis process and purification method of 1,2-dihydroquinoline-3-carboxylic acid can increase the yield and reduce waste water discharge.

A kind of synthetic method of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid involved in the present invention, technical proposal is, adopt 5-alkyl-2-nitrobenzaldehyde As the initial raw material, the malonate diester group is introduced through the Knaeveninger condensation reaction, and the quinoline ring is constructed by aminolysis of the ester after reduction of the nitro group, hydrolyzed under alkaline conditions, and acidified at low temperature to precipitate a solid. After suction filtration The filter cake is the target product.

The synthesis process of 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid is illustrated in detail in the examples of this specification.

The beneficial effects of the present invention are: (1) the hydrolysis process is simple and easy to control, the purification is simple and easy, and the substrate is not easy to coat; (2) compared with the Vilsmeier-Haack-Arnold electrophilic cyclization, the wastewater discharge in the post-synthesis treatment is less; (3) The synthesis method does not cause damage to the alkyl chain, has few side reactions, high purity and high yield.

detailed description

Embodiment 1: Preparation of 2-(5-methyl-2-nitrostyryl) diethyl malonate

Add 1.65 g (10 mmol) of 5-methyl-2-nitrobenzaldehyde, diethyl malonate (1.60 g, 10 mmol) and 10 mL of acetic anhydride into a 50 mL single-necked round bottom flask equipped with magnetic stirring, and mix The solution was reacted at 110 ^o C for 6 hours until the raw materials disappeared. After cooling to room temperature, 20 mL of water was added to dilute, and extracted with dichloromethane. The organic phase was dried and purified by column chromatography to obtain a light yellow oily product (2.79 g, yield 90.9%).

Example 2: Preparation of 2-(5-methyl-2-nitrostyryl) dimethyl malonate

Dimethyl malonate was used as the raw material, the feeding method and post-treatment were the same as in Example 1, and the yield was 86%.

Embodiment 3: Preparation of 2-(5-ethyl-2-nitrostyryl) diethyl malonate

Using 5-ethyl-2-nitrobenzaldehyde as a raw material, the feeding method and post-treatment are the same as in Example 1, and the yield is 90%.

Example 4: Preparation of 2-(5-propyl-2-nitrostyryl)diethyl malonate

Using 5-propyl-2-nitrobenzaldehyde as a raw material, the feeding method and post-treatment are the same as in Example 1, and the yield is 67.9%.

Example 5: Preparation of 2-(5-isopropyl-2-nitrostyryl)diethyl malonate

5-isopropyl-2-nitrobenzaldehyde was used as the raw material, the feeding method and post-treatment were the same as in Example 1, and the yield was 82.3%.

Example 6: Preparation of ethyl 6-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylate

Put 2-(5-alkyl-2-nitrostyryl)diethyl malonate (2.0g) and reduced iron powder (3-5 equivalents) in a 50mL single-necked round bottom flask with a stirring and reflux device Add 15mL of glacial acetic acid, stir at 80°C for about 2 hours, use a strong magnet to remove iron powder, and filter the filter cake to dry to obtain a solid product. The yield of ethyl 6-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate was 99.4%, 6-ethyl-2-oxo-1,2-dihydroquinoline-3 -The yield of ethyl carboxylate is 96%, the yield of ethyl 6-propyl-2-oxo-1,2-dihydroquinoline-3-carboxylate is 99.2%, and the yield of 6-isopropyl-2-oxo The yield of ethyl -1,2-dihydroquinoline-3-carboxylate was 97.4%.

Example 7: Preparation of 6-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Dissolve ethyl 6-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (1.5 g, 6.5 mmol) in a mixture of 40 mL methanol and water (volume ratio 1:1) Add sodium hydroxide or potassium hydroxide (2-8 equivalents) to the solvent, and react at 80°C for 2 hours. After cooling down to room temperature, dilute hydrochloric acid was used to acidify the reaction solution to pH ≈ 4, and the yellow filter cake obtained by suction filtration was the product, with a mass of 1.25 pieces and a yield of 94.8%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 14.87 (s, 1H), 13.16 (s, 1H), 8.89(s, 1H), 7.82 (s, 1H), 7.62 (dd, J = 8.5, 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H).

Example 8: Preparation of 6-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

The method is the same as in Example 7, and the product is a yellow solid with a yield of 98.9%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ14.89(s, 1H), 13.18 (s, 1H), 8.92 (s, 1H), 7.87 (s, 1H), 7.67 (dd, J = 8.5 , 2.0Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6Hz, 3H).

Claims (3)

1. the present invention relates to one kind synthesis 6- alkyl -2- oxo -1, the method for 2- EEDQ -3- carboxylic acids, it is characterised in that adopt Use following experimental program：

。

2. the ester used in 6- alkyl -2- oxos -1,2- EEDQ -3- carboxylic acid building-up processes as claimed in claim 1 It is dimethyl malenate or diethyl malonate, the alkali used in condensation reaction is sodium acid carbonate or saleratus, and alkyl chain is Methyl, ethyl, propyl group or isopropyl.

3. 6- alkyl -2- oxo -1 as claimed in claim 1, the synthesis of 2- EEDQ -3- carboxylic acids, the rear place of iron powder reducing Reason is in the following ways：Strong magnets go iron power removing, suction filtration to obtain product.