Preparation method of fluoro indole carboxylic acid compound

Abstract

The invention discloses a preparation method of a fluoro indole carboxylic acid compound, and relates to the field of organic synthesis. Aiming at the current situations that in the prior art, the ring closing yield of a 7-position fluoro indole carboxylic acid compound is low and the use amount of a catalyst is large, a fluoro iodoaniline compound with a general formula (1) is used as a raw material and reacts with pyruvic acid in the presence of mixed alkali, anhydrous sulfate and a catalyst, and the fluoro indole carboxylic acid compound is prepared with high yield and high purity; the method is simple and convenient to operate and treat, mild in reaction condition, high in comprehensive yield and higher in safety, and is a process synthesis route which is high in cost performance and suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of fluoroindole carboxylic acid compounds. Background technique [0002] Fluoroindole carboxylic acid compounds are an important class of benzoheterocyclic compounds, which are often used as drug intermediates and are widely used in the medical field, such as the preparation of protein arginine deiminase (PAD) inhibitors It is a key intermediate for the treatment of cancer and autoimmune diseases (WO2019152883A1); it is also the main raw material for the preparation of indoleamine-2.3-dioxygenase (IDO) inhibitors for the treatment of cancer, inflammation, infectious diseases, Central nervous system diseases, etc. (WO2017048612A1). In view of its great application value in the medical field, it is very necessary to study its preparation method. [0003] Regarding the preparation of fluoroindole carboxylic acid compounds, there are many reports in the prior a...

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Problems solved by technology

[0003] Regarding the preparation of fluoroindole carboxylic acid compounds, there are many reports in the prior art. Starting from the structure, the preparation method mainly uses phenyl derivatives as raw materials to construct indole rings, including the following three types: 1.5,7- Preparation of difluoroindole-2-carboxylic acid: use 2,4-difluorophenylhydrazine hydrochloride and ethyl pyruvate as raw materials, react in hydrochloric acid to obtain hydrazone intermediates, and then reflux in polyphosphoric acid to construct indole The indole ring is then hydrolyzed to obtain the target object. This method not only needs strong acid reflux, but also has certain potential safety hazards, and the yield is relatively low. The total yield of the two-step ring closure is 29%, which is not suitable for industrial scale production (WO9907351 A2; Journal of Medicinal Chemistry, 2007,50(20):5034-5038.); (2) Preparation of 7-fluoroindole-2-carboxylic acid: adopt 2-fluoroaniline and ethyl pyruvate as raw materials, in Schlenk reaction tube , in the presence of oxygen, palladium acetate catalyzes ring closure, and then hydrolyzes to obtain the target compound. The yield of this method is low, and the amount of catalyst is 20% of the quality of raw material 2-fluoroaniline. The production cost is high and the reaction time is long, so it is only suitable for experiments. The preparation of a small amount of products indoors is difficult to scale up production (CN109748840A; The Journal of organic chemistry, 2018,83(23):14472-14488); (3) 6,7-difluoro-5-iodo-1H-indole- Preparation of 2-carboxylic acid and 5,6,7-trifluoro-1H-indole-2-carboxylic acid: using 2,3-difluoroaniline and 2,3,4-trifluoroaniline as raw materials respectively, through N -Iodosuccinimide is iodized with a low yield, and in the presence of alkali with pyruvic acid, palladium acetate is ring-closed to obtain the target object, the former yield is 6%, and the latter yield is 62%. This method also has a catalyst Large dosage, low reaction yield, low cost performance of process preparation, etc. At the same time, through the verification of this method, it is found that hydrolysis by-products and raw material coupling by-products are easy to be produced in the reaction, product purification is difficult, and it is difficult to obtain high-purity products used in In the preparation of the original drug, to a certain extent, the popularization and application of this type of compound is limited.

[0004] In general, in the prior art, the preparation of such compounds mainly has the following problems: 1. High-temperature reaction of strong acid, which has potential safety hazards; 2. Large amount of catalyst used, high production cost; 3. Low reaction yield and difficult purification of products, etc. ; Lack of a synthetic route suitable for industrial scale production to carry out industrial scale-up production

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