CN100432061C - Method of synthesizing 2-fluorobromomethylbenzothiazole - Google Patents

Abstract

The present invention relates to a kind of synthetic method of novel 2-difluorobromomethylbenzothiazole, the synthetic method of this compound has following steps: take carbon tetrachloride as solvent, reactant 2-difluoromethylbenzothiazole and The molar ratio of N-bromosuccinimide is: 1:3, reflux reaction under light for 72 hours; N-bromosuccinimide needs to be added in batches, adding N-bromosuccinimide once every 24 hours Succinimide; after the reaction is completed, suction filtration while hot; remove the solvent in the filtrate, and the residue is separated by neutral alumina column chromatography to obtain a light yellow solid that is 2-difluorobromomethylbenzothiazole; The method of the present invention successfully brominates this type of difluoromethyl group for the first time, which has innovative significance.

Description

The synthetic method of 2-difluorobromomethylbenzothiazole

Technical field:

The invention relates to a synthesis method of 2-difluorobromomethylbenzothiazole.

Background technique:

At present, a large number of biologically active compounds contain heteroatoms such as O, N, and S, and heterocyclic compounds are the largest category in organic compounds. Many substances that play an important role in physiological processes, such as nucleic acid bases Groups, amino acids, vitamins and alkaloids all contain heterocyclic structures. Some functional heterocyclic compounds with special functions and uses designed by people according to needs can be used as drugs, dyes, biosimilar materials, organic conductors, engineering polymer materials, etc.

In the field of medicinal chemistry, the introduction of a fluorine atom or a perfluoroalkyl group into the host molecule is considered to be one of the most effective methods for modifying the host compound. Due to the small radius of the fluorine atom and its high electronegativity, the bond energy of the C-F bond formed by it is much larger than that of the C-H bond, which significantly increases the stability and physiological activity of organic fluorine compounds. Fluoroorganic compounds also have high fat solubility and hydrophobicity, which can promote their absorption and delivery speed in vivo and change their physiological effects. Therefore, many fluorine-containing medicines and pesticides have the characteristics of less dosage, low toxicity, high efficacy, and strong metabolism in terms of performance, which makes them account for an increasing proportion of new medicines and pesticides. The bromine on the difluorobromomethyl group is a reactive site, and many pharmacophore groups can be connected through the reaction to synthesize homomolecular or heteromolecular twin drugs.

There is only one kind of synthetic method of this compound reported at present, and the concrete reaction is as follows:

This shows, need to explore more, the method for the synthesis of 2-difluorobromomethylbenzothiazole with mild reaction conditions.

Invention content:

The object of the present invention is to provide a kind of synthetic method of 2-difluorobromomethylbenzothiazole.

In order to achieve the above object, the reaction mechanism that the inventive method adopts is:

According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:

A kind of synthetic method of 2-difluorobromomethylbenzothiazole is characterized in that the method has the following steps: taking carbon tetrachloride as solvent, reactant 2-difluoromethylbenzothiazole and N-bromo The molar ratio of succinimide is: 1:3, reflux reaction under light for 72 hours; N-bromosuccinimide needs to be added in batches, and N-bromosuccinimide should be added every 24 hours Amine; after the reaction is completed, filter while hot; remove the solvent in the filtrate, and the residue is separated by neutral alumina column chromatography to obtain a light yellow solid that is 2-difluorobromomethylbenzothiazole.

Compared with the prior art, the method of the present invention has the following obvious outstanding features and significant advantages: effectively reduce the cost of raw materials, and the general synthesis methods of this type of compound all need to use bromodifluoroacetic acid, which is only produced by individual foreign reagent companies , and the price is very expensive, generally only about 10 grams of packaging can be provided, and kilogram-level products cannot be provided, which cannot satisfy the synthesis of the 2-difluorobromomethylbenzothiazole compound involved in the patent of the present invention. The raw material of difluoroacetic acid used in the patent of the present invention has been completely localized and produced on a large scale, and the price is cheap. Therefore, from the perspective of raw material cost, the patent of the present invention has obvious advantages. In addition, if bromotetrafluorobutanol is used as a raw material, in addition to the high price of raw materials, the reaction temperature is relatively high and the reaction conditions are not mild enough. In addition, the light bromination of 2-difluoromethyl benzodiazole compounds has not been successfully reported so far. The bromination method involved in the patent of the present invention is innovative and can be used for other benzene containing 2-difluoromethyl The bromination of oxadiazole compounds is instructive.

Detailed ways:

Embodiment 1: 1. add 0.93 grams of 2-difluoromethylbenzothiazole, 1.0 grams of N-bromosuccinimide in a 50 milliliter two-necked bottle, and heat reflux of 20 milliliters of carbon tetrachloride under light, every 24 Add 0.5 grams of N-bromosuccinimide in 1 hour; ②React for 72 hours, filter off the solid in the reaction system while hot, wash twice with carbon tetrachloride, spin the filtrate to remove the solvent, and neutralize the alumina column Chromatography gave 0.39 g of the product with a yield of 30%.

Embodiment two: 1. add 1.85 grams of 2-difluoromethylbenzothiazole, 2.0 grams of N-bromosuccinimide in a 100 milliliter two-necked bottle, and 40 milliliters of carbon tetrachloride are heated to reflux under light, every 24 Add 0.8 grams of N-bromosuccinimide in 1 hour; ②React for 72 hours, filter off the solid in the reaction system while hot, wash twice with carbon tetrachloride, spin the filtrate to remove the solvent, neutral alumina column Chromatography gave 0.74 g of the product with a yield of 28%.

Embodiment 3: The following steps are adopted for the preparation of 2-difluorobromomethylbenzothiazole: 1. 3.7 grams of 2-difluoromethylbenzothiazole and 4.0 grams of N-bromosuccinimide are added to a 250 ml two-necked bottle gram, 100 milliliters of carbon tetrachloride was heated to reflux under light, and 1.0 grams of N-bromosuccinimide was added every 24 hours; Carbonization was washed twice, the filtrate was spun to remove the solvent, and the neutral alumina column chromatography gave 1.3 g of the product with a yield of 25%.

Claims (1)

1. the synthetic method of a 2-difluoro brooethyl benzothiazole, it is characterized in that this synthetic method has following steps: be solvent with the tetracol phenixin, the mol ratio of reactant 2-difluoromethyl benzo thiazole and N-bromo-succinimide is: 1: 3, back flow reaction was 72 hours under illumination; The N-bromo-succinimide needs to add in batches, adds one time the N-bromo-succinimide in per 24 hours; After reaction finishes, suction filtration while hot; Remove the solvent in the filtrate, residuum neutral alumina column chromatography for separation gets faint yellow solid and is 2-difluoro brooethyl benzothiazole.