CN-121974795-A - Alpha-bromo-carboxylic acid compound and preparation method thereof

Abstract

The invention relates to a preparation method of alpha-bromo carboxylic acid. The method comprises the steps of dissolving a malonic acid substrate, N-bromosuccinimide (NBS) and pyridine in a reaction solvent under the protection of nitrogen, and reacting for 1 hour under the condition of blue light irradiation and 50 ℃. Separating the crude reaction product by column chromatography or preparative plate chromatography to obtain the target delta-bromocarboxylic acid compound. The method has the advantages of mild reaction conditions, simple and convenient operation, easily available raw materials, low cost, good functional group compatibility and substrate universality. In the obtained product, due to the higher reactivity of bromine atoms, the product can be further derived into various alpha-heteroatom substituted carboxylic acids, and has application potential in the fields of synthetic chemistry, drug research and development and the like.

Inventors

• CHEN JIANPING
• WANG LIJIE
• WANG CHENG

Assignees

• 南京工业大学

Dates

Publication Date

20260505

Application Date

20260210

Claims (4)

1. 1. The preparation method of the alpha-bromo-carboxylic acid is characterized in that the alpha-bromo-carboxylic acid compound has a structure shown in a formula (I): In formula (I), R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, containing ester groups, ether linkages, carbonyl C2-C10 alkyl, molecular fragments derived from isoxadif-C acid, R 1 、R 2 can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and N-benzoyl piperidine ring; the preparation method comprises the following steps: (1) In the atmosphere of nitrogen, dissolving a malonic acid derivative shown in a formula (II), a bromine source and alkali in an organic solvent to form a reaction mixture, wherein the feeding mole ratio of the malonic acid derivative shown in the formula (II), the bromine source and the alkali is (1.0): (1.0-3.0): (0.5-2.0); (2) The reaction mixture obtained in the step (1) is placed under the irradiation of blue light with the wavelength of 395-480nm and the power of 5-30W, and stirred and reacted for 0.5-3 hours at the temperature of 30-60 ℃ to carry out decarboxylation and bromination; (3) After the reaction is finished, quenching, extracting, drying and concentrating the reaction system to obtain the alpha-bromo-carboxylic acid compound shown in the formula (I). Wherein formula (II) is: wherein R 1 and R 2 are as defined for formula (I).
2. 2. The method for producing an α -bromocarboxylic acid compound according to claim 1, wherein the reaction solvent is at least one of N-N dimethylformamide, N-N dimethylacetamide, dimethylsulfoxide, acetonitrile, N-methyl-2-pyrrolidone, and tetrahydrofuran.
3. 3. The method for producing an α -bromocarboxylic acid compound according to claim 1, wherein in the step (1), the base is at least one of pyridine, 2,4, 6-trimethylpyridine, 2, 6-diethylpyridine, triethylamine, 1, 8-diazabicyclo [5.4.0] undecene, potassium fluoride, potassium phosphate, and potassium bicarbonate.
4. 4. The bromine source of claim 1 being at least one of N-bromosuccinimide, 1-3-dibromo-5, 5-dimethylhydantoin, 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione, and 1,3, 5-tribromo-1, 3, 5-thiazinan-2, 4, 6-trione.

Description

Alpha-bromo-carboxylic acid compound and preparation method thereof Technical Field The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of an alpha-bromo-carboxylic acid compound. According to the method, N-bromosuccinimide is taken as a bromine source, and an alpha-bromocarboxylic acid compound is synthesized in a green and efficient way through a free radical mono-decarboxylation bromination reaction of a malonic acid derivative under the drive of a visible light. Background The alpha-bromo carboxylic acid is an important synthetic building block, and because of the excellent leaving capability of bromine atoms, nucleophilic substitution reactions such as ammoniation, etherification, thioetherification and the like can be effectively carried out on carbon atoms connected with bromine, so the alpha-bromo carboxylic acid is one of important intermediates in the fields of organic synthesis and pharmaceutical industry. For example, alpha-bromosuccinic acid is an important precursor for synthesizing helicobacter pylori resistant drug spirotetrazine methyl ether and cancer vaccine TLR2 agonist, while 2-bromo-3-cyclopropylpropionic acid is an important intermediate for synthesizing benzoxazinone-isoxazoles for treating prostate cancer. Although the alpha-bromocarboxylic acid has wide application value, the synthesis method still has a plurality of defects. At present, the synthesis method of the alpha-bromocarboxylic acid compound mainly comprises the following steps of (1) reacting monocarboxylic acid with bromine water under the catalysis of phosphorus trihalide at high temperature, namely, helv-Wu Erha-Zelinstro reaction, (2) reacting monocarboxylic acid with bromine water or N-bromosuccinimide (NBS) at high temperature under the participation of strong acid (J.Org.Chem.1978, 43,3684;J.Org.Chem.1975,40,3420), and (3) subjecting alpha-amino acid to diazotization reaction under a nitrous acid and potassium bromide system to synthesize the alpha-bromocarboxylic acid (Helv.Chim. Acta 1983,66,1028). The prior literature shows that although the synthesis method of the alpha-bromo-carboxylic acid has been developed, the traditional method generally depends on bromine or a strong acid medium to participate in the reaction, and has the problems of severe reaction conditions, high reagent toxicity, difficult three-waste treatment and the like. Although the synthesis path taking alpha-amino acid as the precursor achieves remarkable effect, the synthesis path has strong dependence on amino acid substrates with high added value and has the risks of explosion and the like of diazonium intermediates. In view of the outstanding role of alpha-bromocarboxylic acid in organic chemistry and industry, it would be valuable to develop a method for synthesizing alpha-bromocarboxylic acid with green and mild reaction conditions and a wide range of substrates. In view of this, the present invention has been proposed. Disclosure of Invention The invention aims at overcoming the limitations of the existing synthesis method of the alpha-bromo carboxylic acid compound, and provides a novel method for green and efficient synthesis of the alpha-bromo carboxylic acid compound by using N-bromo-succinimide as a bromine source through free radical monocarboxylic decarboxylation bromination reaction of malonic acid derivative under the drive of visible light. It is another object of the present invention to provide the use of the alpha-bromo carboxylic acid compounds prepared by the above process in further derivatization syntheses, which compounds are useful as key intermediates for the preparation of a variety of high value fine chemicals. The invention is realized in such a way that under the action of illumination and alkali, a malonic acid substrate reacts with a bromine source to obtain an alpha-bromocarboxylic acid compound; the alpha-bromo carboxylic acid compound has a structure shown in a formula (I): In formula (I), R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, containing ester groups, ether linkages, carbonyl C2-C10 alkyl, molecular fragments derived from isoxadif-C acid, R 1、R2 can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and N-benzoyl piperidine ring; the preparation method comprises the following steps: (1) In the atmosphere of nitrogen, dissolving a malonic acid derivative shown in a formula (II), a bromine source and alkali in an organic solvent to form a reaction mixture, wherein the feeding mole ratio of the malonic acid derivative shown in the formula (II), the bromine source and the alkali is (1.0): (1.0-3.0): (0.5-2.0), preferably 1.0:2.0:1.0; (2) The reaction mixture obtained in the step (1) is placed under the irradiation of blue light with the wavelength of 395-480nm and the power of 5-30W, and stirred and reacted for 0