CN109081826B - Preparation method of oxidant IBX - Google Patents

Abstract

The invention discloses a preparation method of 2-iodoxybenzoic acid. 2-iodobenzoic acid, potassium hydrogen persulfate and the like are taken as raw materials, and the target product 2-iodoxybenzoic acid is obtained through one-step reaction. The invention has simple and stable process operation, easy product separation, high yield and product purity of more than 99.5 percent. And the raw materials are cheap and easy to obtain, so that the production cost of the existing biological, medical and chemical intermediates is greatly reduced, and the industrial scale production is facilitated.

Description

Preparation method of oxidant IBX

Technical Field

The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of an oxidant IBX.

Background

IBX is o-iodoxybenzoic acid (2-Iodoxybenzoi)C acid) of formula C₇H₅IO₄. IBX is white crystals, melting point: 232 ℃ and 233 ℃ are readily soluble in DMSO, but are almost insoluble in a-general organic solvent. IBX is convenient to prepare, non-toxic and stable to water and air. The reaction performance is unique. High selectivity, mild reaction conditions and high yield, and is an ideal oxidant.

IBX is generally prepared by using o-iodobenzoic acid as a raw material and oxidizing the raw material by using various oxidants, wherein the reaction is as follows:

depending on the oxidizing agent used, there are several methods: oxidizing potassium permanganate, potassium bromate, chlorine and potassium hydrogen persulfate.

In the four methods, potassium permanganate can cause heavy metal pollution; potassium bromate is a carcinogenic substance and can emit bromine vapor in the reaction process, so that the operation is greatly inconvenient and the risk of environmental pollution is caused; chlorine is toxic, and the leakage of chlorine is easy to cause personal injury and death and regional pollution; the oxidation purity of the potassium hydrogen persulfate is not high. Therefore, it is necessary to optimize the synthesis process and improve the product purity.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the preparation method of IBX, which is simple, convenient and stable to operate, easy to separate products, high in yield, high in purity, environment-friendly, low in production cost and suitable for industrial mass production.

The invention provides a preparation method of IBX, which starts from o-iodobenzoic acid and obtains IBX through oxidation reaction, wherein the reaction equation is as follows:

the preparation method of 2-iodoxybenzoic acid is characterized by comprising the following steps: mixing 2-iodobenzoic acid and a high-boiling-point solvent, adding the solution with the concentration of not more than 90% into a potassium hydrogen persulfate aqueous solution with the temperature of 50-70 ℃ for heat preservation reaction, subsequently heating to 90-105 ℃, adding the rest solution into the mixture for continuous reaction, and processing to obtain IBX.

Further, in the above technical solution, not more than 90% is preferably added to 80-90% of the solution.

Further, in the technical scheme, after the 2-iodobenzoic acid and the high-boiling-point solvent are mixed, the solution is heated to 50-60 ℃ and then added into the potassium persulfate aqueous solution.

Further, in the above technical scheme, the adding operation may be one-time adding, or slow dropping, and the preferable mode is slow dropping.

Further, in the technical scheme, the molar feeding proportion of the 2-iodobenzoic acid to the potassium hydrogen persulfate is 1: 1.2-1.8.

Further, in the above technical solution, the high boiling point solvent is selected from dimethyl sulfoxide, DMF, DMA or sulfolane. Preferably, the reaction solvent is sulfolane.

Further, in the technical scheme, after the heat preservation reaction is finished, the reaction product is cooled to the temperature of between 10 ℃ below zero and 20 ℃, and then is crystallized and filtered, so that a qualified product can be obtained.

Further, in the technical scheme, the sulfolane with the high boiling point solvent can be recycled for 5-8 times, the yield is reduced by no more than 3%, and the purity of the obtained product can be kept above 99.0%.

Furthermore, in the technical scheme, when the temperature is raised by adopting a segmented program, the conversion rate of the raw materials is high, the yield reaches over 90 percent, and the one-time purity of the product can reach over 99.5 percent.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.

The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally carried out under conventional conditions.

The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.

The average room temperature described in the following examples of the present invention is 20-35 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment.

Example 1

2-Iodobenzoic acid (50.0g,0.20mol) was added to sulfolane (250mL) and the solution was heated to 50 ℃. 90% of the above solution was slowly added dropwise to an aqueous solution (300mL) of potassium hydrogen persulfate (147.4g,0.24mol,1.2equiv) at 50 ℃ and the reaction was allowed to proceed for 3 hours with incubation. The reaction solution was then heated to 95 ℃ and the remaining 10% 2-iodobenzoic acid solution was slowly added dropwise to the reaction solution and the reaction was continued for 3 hours. After the reaction was complete, it was cooled to 5 ℃ and stirring was continued at this temperature for 1.5 hours. 1L of water was added with stirring, filtered (the filtrate was used repeatedly), the filter cake was rinsed with water and acetone in sequence, and dried at room temperature for 16 hours to give 53.2g (95.04% yield) of a white solid with an IBX purity of 99.7% (confirmed by nuclear magnetic and HPLC). The solid was identified as IBX by HNMR detection. H NMR (400MHz, DMSO-d6):8.136(d, J ═ 7.6Hz,1H),8.026(dd, J ═ 1.0,7.5Hz,1H),8.007(td, J ═ 1.5,8.5Hz,1H),7.825(t, J ═ 7.6Hz,1H).

And (3) performing a recycling experiment, namely replacing the 250mL of sulfolane with the filtrate obtained after the filtration by adding water, directly cooling after the reaction is finished, stirring and filtering (the operation of adding 1L of water is cancelled), and keeping other conditions unchanged to obtain the product IBX, wherein the yield is 93.12%, and the purity is 99.5% (confirmed by nuclear magnetism and HPLC).

2-Iodobenzoic acid (50.0g,0.20mol) was added to sulfolane (250mL) and the solution was heated to 50 ℃. 90% of the above solution was added at a time to an aqueous solution (300mL) of potassium hydrogen persulfate (147.4g,0.24mol,1.2equiv) at 50 ℃ and the reaction was allowed to proceed for 3 hours with incubation. The reaction solution was then heated to 95 ℃ and the remaining 10% 2-iodobenzoic acid solution was added once to the reaction solution and the reaction was continued for 3 hours. After the reaction was complete, it was cooled to 5 ℃ and stirring was continued at this temperature for 1.5 hours. 1L of water was added with stirring, filtered, and the filter cake was rinsed with water and acetone in sequence and dried at room temperature for 16 hours to give 51.7g of a white solid (92.33% yield) with IBX purity of 99.8% (confirmed by nuclear magnetic and HPLC).

Example 2

2-iodobenzoic acid (5kg,20mol) was added to DMF (25L) and the solution was heated to 60 ℃. 85% of the solution was slowly added dropwise to an aqueous solution (40L) of potassium hydrogen persulfate (22.1kg,36mol,1.8equiv) at 60 ℃ and the reaction was carried out for 3 hours while maintaining the temperature. The reaction was heated to 95 ℃ and the remaining 15% 2-iodobenzoic acid solution was slowly added dropwise to the reaction solution and the reaction was continued for 2 hours. After completion of the reaction, it was cooled to 0 ℃ and stirred at this temperature for a further 1 hour. Adding 100L of water while stirring, filtering, washing the filter cake with water and acetone sequentially, and drying at room temperature for 16 hours to obtain 4.51kg of white solid (yield 80.53%), wherein the IBX purity is 99.8% (confirmed by nuclear magnetism and HPLC), and the nuclear magnetism data is consistent with the standard spectrogram.

Example 3

2-iodobenzoic acid (50kg,200mol) was added to dimethyl sulfoxide (250L) and the solution was heated to 55 ℃. 90% of the above solution was slowly added dropwise to an aqueous solution (300L) of potassium hydrogen persulfate (159.6kg,260mol,1.3equiv) at 70 ℃. The reaction was carried out at 70 ℃ for 3 hours. The reaction was heated to 90 ℃ and the remaining 10% 2-iodobenzoic acid solution was slowly added dropwise to the reaction solution and the reaction was continued for 3 hours. After completion of the reaction, it was cooled to 0 ℃ and stirred at this temperature for 2 hours. 1000L of water is added under stirring, the filter cake after filtration is sequentially leached by water and acetone and dried for 16 hours at room temperature to obtain 45.4kg of white solid (yield 81.07 percent), the IBX purity is 99.8 percent (confirmed by nuclear magnetism and HPLC), and the nuclear magnetism is consistent with a standard spectrogram.

Comparative example 1 (literature example)

The synthetic routes reported in the document J.org.chem.1999,64,4537-4538 are as follows:

2-Iodobenzoic acid (50.0g,0.20mol) was added in one portion to an aqueous solution (650mL, 0.45M) of oxone (181.0g,0.29mol,1.3 equiv). The reaction was heated to 70-73 ℃ and reacted for 3 hours. After completion of the reaction, it was cooled to 5 ℃ and stirring was continued at this temperature for 1.5 hours. After filtration, the filter cake is washed by water and acetone in turn and dried for 16 hours at room temperature to obtain 44.8-45.7g (79-81%) of the product.

IBX was 95% pure (confirmed by nuclear magnetic and elemental analysis) and the impurities were 2-iodoxybenzoic acid (4%) and 2-iodobenzoic acid (0.5%).

Comparative example 2 (literature example)

The synthetic routes reported in the Organic Syntheses, col. vol.77, p.141(2000) are as follows:

80g (0.48mol) of KBrO3 were added to 2M sulfuric acid (750mL), and the reaction solution was heated to 60 ℃ with an oil bath. 2-iodobenzoic acid (80g, 0.323mol) was added to the reaction solution in portions over 40 minutes. The solution turned orange-red, bromine vapor evolved, and a white solid formed. After the addition was completed, the reaction was maintained at 65 ℃ for 2 hours. The reaction mixture was cooled to 2-3 ℃ with an ice bath, filtered, and the filter cake was washed sequentially with 500mL of deionized water, 2X 80mL of ethanol, and 500mL of cold deionized water to give 88.2g (yield: 98%) of wet IBX.

Claims (5)

1. The preparation method of 2-iodoxybenzoic acid is characterized by comprising the following steps: mixing 2-iodobenzoic acid and a high-boiling-point solvent, adding 80-90% of the solution into a potassium hydrogen persulfate aqueous solution at 50-70 ℃ for heat preservation reaction, then heating to 90-105 ℃, adding the rest solution for continuous reaction, and treating to obtain IBX, wherein the high-boiling-point solvent is selected from dimethyl sulfoxide, DMF or sulfolane.

2. The method of claim 1, wherein: after the 2-iodobenzoic acid is mixed with the high boiling point solvent, the solution is heated to 50-60 ℃ and then added into the potassium hydrogen persulfate aqueous solution.

3. The method of claim 1, wherein: the addition was carried out slowly dropwise.

4. The method of claim 1, wherein: the molar feeding proportion of the 2-iodobenzoic acid to the potassium hydrogen persulfate is 1: 1.2-1.8.

5. The method of claim 1, wherein: the sulfolane with high boiling point solvent can be recycled for 5-8 times.