Preparation of 2-iodoxybenzoic acid and Dess-Martin periodinane using hypochlorite

Abstract

To provide a method of producing 2-iodine benzoic acid derivative enabling acquisition of the 2-iodine benzoic acid derivative more excellent in safety, environmental harmony and convenience than a conventional production method and enabling acquisition of the 2-iodine benzoic acid derivative in higher yield than the conventional production method, and a production method for synthesizing Dess-Martin periodinane by one pot from 2-iodine-benzoic acid.SOLUTION: A method of producing of 2-iodine benzoic acid of the present invention is provided in which 2-iodobenzoic acid being starting material and hypochlorite or hypochlorite aqueous solution are reacted in the presence of carbon dioxide having a concentration of 4.0% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing 2-iodoxybenzoic acid, a derivative of 2-iodobenzoic acid, which is excellent in safety during production and ease of production, and a method for producing Dess-Martin periodinane. [Background technology]

[0002] 2-Iodoxybenzoic acid (IBX), a derivative of 2-iodobenzoic acid, is less toxic than heavy metal oxidants such as manganese and chromium compounds, and can be used under mild reaction conditions, so it is expected to be an environmentally friendly oxidant. 2-Iodoxybenzoic acid (IBX) can be used in oxidation reactions by itself, and is also known to be convertible into other useful derivatives as shown below.

[0003] Conventional methods for synthesizing IBX include reacting 2-iodobenzoic acid with KBrO3 in sulfuric acid and reacting 2-iodobenzoic acid with potassium peroxymonosulfate (Oxone (trademark)) (Non-Patent Documents 1 and 2).

[0004] As shown below, IBX can also produce Dess-Martin Periodinane (DMP) and 1-tosyloxy-1-oxo-1H-1λ. 5 -Benzo[d][1,2]iodoxol-3-one (1-Tosyloxy-1-oxo-1H-1λ 5 It is known that it is possible to synthesize -benzo[d][1,2]iodoxol-3-one (IBX-OTs) (Non-Patent Documents 1, 3-4).

[0005] [ka] Ac2O: acetic anhydride, AcOH: acetic acid, TsOH: p-toluenesulfonic acid

[0006] However, KBrO3 used in IBX synthesis is designated as a "genotoxic carcinogen" by the Joint FAO / WHO Expert Committee on Food Additives (JECFA), and is classified as "Group 2B: Possibly carcinogenic to humans" by the International Agency for Research on Cancer (IARC). In addition, the reaction requires heating using KBrO3 and sulfuric acid, which generates bromine gas. Oxone (trademark) can also be used as an oxidizing agent (Non-Patent Document 2). However, although Oxone (trademark) is a relatively stable oxidizing agent, it is a peroxide, and in order to synthesize IBX, it is necessary to react it under heating for several hours. In addition, Oxone (trademark) has low solubility in water, so it needs to be reacted at a low concentration. In fact, in Non-Patent Document 2, 0.20 mol of 2-iodobenzoic acid and 0.29 mol of Oxone (trademark) are used, and 650 mL of water is used as a solvent, so the substrate concentration is low at 0.31 mol / L, which is low, and there is a problem with productivity.

[0007] The present applicant has proposed a method of mixing the starting material 2-iodobenzoic acid with hypochlorite or an aqueous hypochlorite solution as a method for producing IBX that is safer and simpler than conventional methods (Patent Document 1). This method is safer and simpler than the method using KBrO3 because it uses hypochlorite or an aqueous hypochlorite solution, but the yield of IBX was only 56% at most. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] JP 2020-138923 A [Non-patent literature]

[0009] [Non-Patent Document 1] DB Dess; JC Martin, J. Am. Chem. Soc. 1991, 113, 7277. [Non-Patent Document 2] M. Frigerio; M. Santagostino; S. Sputore, J. Org. Chem. 1999, 64, 4537. [Non-Patent Document 3] RE Ireland; L. Liu, J. Org. Chem. 1993, 58, 2899. [Non-Patent Document 4] MS Yusubov; DY Svitich; A. Yoshimura; VN Nemykin; VV Zhdankin, Chem. Commun. 2013, 49, 11269. [Non-Patent Document 5] H. Saltzman; JG Sharefkin, Org. Synth. 1963, 43, 60. Summary of the Invention [Problem to be solved by the invention]

[0010] The object of the present invention is to provide a method for producing 2-iodoxybenzoic acid and Dess-Martin periodinane, which are 2-iodobenzoic acid derivatives, in a high yield and which is safer, more environmentally friendly, and simpler than conventional production methods. [Means for solving the problem]

[0011] In order to achieve the above object, the inventors have conducted extensive research and have found a method for producing 2-iodoxybenzoic acid and Dess-Martin periodinane, which are 2-iodobenzoic acid derivatives with excellent safety, environmental friendliness and ease of use, in high yields, and have also discovered a method for synthesizing Dess-Martin periodinane in one pot, which has led to the present invention. Here, one-pot synthesis refers to, for example, synthesizing 2-iodoxybenzoic acid represented by the following structural formula (2), and then starting the synthesis reaction of Dess-Martin periodinane represented by the following structural formula (3) without purifying it. The present invention has the following configurations.

[0012] [1] The following structural formula (1) [ka] 2-iodobenzoic acid represented by the formula: Concentration of 4.0% by volume or more Carbon Dioxide atmosphere reacting the mixture with hypochlorite or an aqueous hypochlorite solution under The following structural formula (2) [ka] A method for producing 2-iodoxybenzoic acid represented by the formula: [2] The method for producing 2-iodoxybenzoic acid according to [1] above, wherein the hypochlorite or the aqueous solution of hypochlorite is sodium hypochlorite hydrate or an aqueous solution of sodium hypochlorite. [3] The following structural formula (1) [ka] 2-iodobenzoic acid represented by the formula: Concentration of 4.0% by volume or more Carbon Dioxide atmosphere reacting the mixture with hypochlorite or an aqueous hypochlorite solution under The following structural formula (2) [ka] The method is characterized in that 2-iodoxybenzoic acid represented by the formula: is prepared, acetic anhydride is added, and the mixture is heated to further react. The following structural formula (3) [ka] A method for producing Dess-Martin periodinane shown in [4] The method for producing Dess-Martin periodinane according to [3], wherein the hypochlorite or the aqueous hypochlorite solution is sodium hypochlorite hydrate or an aqueous sodium hypochlorite solution. [5] A method for producing the Dess-Martin periodinane according to [3] or [4] above, in which the synthesis is carried out in one pot. Effect of the Invention

[0013] According to the present invention, the desired 2-iodobenzoic acid derivatives, 2-iodoxybenzoic acid and Dess-Martin periodinane, can be efficiently produced without using oxidizing agents that are expensive and dangerous. In addition, Dess-Martin periodinane, which has been synthesized in multiple steps, can be synthesized in one pot. Furthermore, the only by-products derived from the oxidizing agents used are inorganic salts. Furthermore, there is no need to use KBrO3, which is a concern for its carcinogenicity, and the desired 2-iodobenzoic acid derivatives can be produced safely, simply, and highly efficiently. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The method for producing 2-iodoxybenzoic acid of the present invention is characterized by reacting a starting material, 2-iodobenzoic acid, with hypochlorite or an aqueous hypochlorite solution in the presence of carbon dioxide.

[0015] [Embodiment 1] 2-Iodobenzoic acid is used as a starting material, and hypochlorite or an aqueous solution of hypochlorite is used as an oxidizing agent. The mixture is reacted in the presence of carbon dioxide to produce a compound having the following structural formula:

[0016] [ka] The compound represented by the formula: 2-iodoxybenzoic acid (IBX) is synthesized.

[0017] Examples of hypochlorite that can be used as oxidizing agent include sodium hypochlorite, calcium hypochlorite, lithium hypochlorite, potassium hypochlorite, etc. Sodium hypochlorite and calcium hypochlorite are widely used industrially and are inexpensive, so they are desirable. Calcium hypochlorite has low solubility and tends to have low reactivity. Therefore, it is preferable to use sodium hypochlorite in order to improve reactivity and yield.

[0018] The hypochlorite can be used in the form of an aqueous hypochlorite solution. For example, it can be used in the form of an aqueous hypochlorite solution of sodium hypochlorite. The concentration of the aqueous solution is preferably 4% by mass or more, more preferably 12% by mass or more. It can also be used in the form of a hydrate of hypochlorite, which has less water than the aqueous solution. For example, sodium hypochlorite pentahydrate (theoretical concentration: 45%) can be used.

[0019] The amount of hypochlorite or its aqueous solution used in the synthesis of IBX is preferably 2 equivalents or more relative to the starting material 2-iodobenzoic acid, and more preferably in the range of 2 to 2.5 equivalents.

[0020] It has been found that the synthesis reaction of IBX of the present invention proceeds even in an atmosphere with a low carbon dioxide concentration. The carbon dioxide concentration is preferably 4.0% or more. For more efficient synthesis, it is more preferable to carry out the synthesis in an atmosphere with a carbon dioxide concentration of 100%. In the synthesis method of IBX of the present invention carried out in the presence of carbon dioxide, it was possible to synthesize IBX in a yield that exceeded the yield (maximum 56%) obtained by the similar synthesis method described in Patent Document 1.

[0021] It is not fully understood why IBX can be synthesized in high yields by performing the synthesis in the presence of carbon dioxide, but it is thought that the action of carbon dioxide on hypochlorite results in the appearance of active species in the reaction system that promote oxidation.

[0022] The synthesis reaction of IBX of the present invention does not need to be performed under heating and can be performed at 0 to 30° C. The reaction time is 3 to 24 hours, and the yield does not change significantly even if the reaction time exceeds 12 hours in an atmosphere with a carbon dioxide concentration of 100%.

[0023] [Embodiment 2] The IBX obtained in the above-mentioned embodiment 1 is used to synthesize Dess-Martin periodinane without purification. An inorganic acid such as hydrochloric acid is added to the reaction-terminated solution obtained in embodiment 1 to completely liberate IBX, the supernatant is removed by decantation, the residue is washed several times with a small amount of water, and the water contained therein is distilled off under reduced pressure. Thereafter, acetic anhydride is added and the mixture is heated to obtain the compound represented by the following structural formula:

[0024] [ka] To synthesize the Dess-Martin periodinane represented by the formula:

[0025] The amount of acetic anhydride used in the synthesis of Dess-Martin periodinane is preferably at least 2 equivalents relative to the starting material 2-iodobenzoic acid. It is also possible to add an excess amount to use it as both a reactant and a solvent. Acetic acid is another suitable solvent.

[0026] The reaction solution containing IBX obtained in embodiment 1 can be washed with water to remove the by-product NaCl without any special purification, and then the water is distilled off and acetic anhydride is added to continue the reaction. In other words, Dess-Martin periodinane can be synthesized in one pot from the starting material 2-iodobenzoic acid.

[0027] The reaction temperature after the addition of acetic anhydride is not particularly limited as long as it is not a temperature at which the desired Dess-Martin periodinane decomposes. Specifically, the reaction temperature is preferably 50°C to 100°C, more preferably 70°C to 90°C.

[0028] Since Dess-Martin periodinane is easily hydrolyzed by moisture in the air, it is preferable to carry out the reaction with acetic anhydride under a dry nitrogen or argon atmosphere.

[0029] In both the first and second embodiments of the present invention, an organic solvent can be used as necessary. The organic solvent is not particularly limited as long as it does not react with the hypochlorite used or the desired derivative of 2-iodobenzoic acid. In the first embodiment, water is preferred, and in the second embodiment, acetic acid is preferred. EXAMPLES

[0030] Hereinafter, preferred embodiments of the method for producing 2-iodobenzoic acid derivatives according to the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[0031] [Example 1] 724 mg (4.4 mmol) of sodium hypochlorite pentahydrate was weighed into a glass reaction vessel, 1.3 mL of water and 496 mg (2.0 mmol) of 2-iodobenzoic acid were added, and a balloon filled with carbon dioxide was attached and reacted at room temperature for 12 hours. 1.0 M hydrochloric acid was added to the resulting reaction mixture to adjust the final pH to about 1 to 2, and the resulting white precipitate was filtered with a glass filter. It was washed four times with about 5 mL of water, and then washed three times with about 5 mL of acetone. The white solid was dried under reduced pressure (0.3 mmHg) for 2 hours, and 493 mg (88% yield) of 2-iodoxybenzoic acid (IBX) crystals was obtained. 1 H-NMR (DMSO-d6,500MHz)δ8.13(d,J=7.5Hz,1H),8.03(dd,J=7.5,1.0Hz,1H),8.00(t,J=7.5Hz,1H),7.84(td,J=7.5,1.0Hz,1H)

[0032] [Examples 2 to 8] The reaction was carried out in the same manner as in Example 1, except that the reaction conditions were changed as shown in Table 1. As a result, the target IBX was obtained in a yield of 65% to 93%.

[0033] [Table 1]

[0034] [Comparative Examples 1 to 2] The reaction was carried out in the same manner as in Example 1, except that the reaction conditions were changed as shown in Table 2. As a result, the target IBX was obtained in a yield of 12% to 46%.

[0035] [Table 2]

[0036] [Comparative Example 3] The synthesis was carried out according to Example 5 described in Patent Document 1. 316 mg (1.9 mmol) of sodium hypochlorite pentahydrate was weighed into a glass reaction vessel, 3.2 mL of water and 238 mg (0.96 mmol) of 2-iodobenzoic acid were added, and the mixture was allowed to react at room temperature for 12 hours. After the reaction, about 10 mL of water was added, and the resulting precipitate was filtered and washed several times with about 3 mL of water and twice with about 3 mL of acetone. After drying under reduced pressure, 151 mg (yield 56%) of 2-iodoxybenzoic acid (IBX) crystals were obtained.

[0037] [Comparative Example 4] With reference to the Oxone method described in Non-Patent Document 2, synthesis was carried out at a substrate concentration of 2.5 mol / L. 374 mg (1.2 mmol) of Oxone™ was weighed into a glass reaction vessel, 0.4 mL of water and 250 mg (1.0 mmol) of 2-iodobenzoic acid were added, and the mixture was reacted at 70°C for 3 hours. After returning the mixture to room temperature, about 10 mL of water was added, and the resulting precipitate was filtered and washed four times with about 5 mL of water and three times with 5 mL of acetone. After drying under reduced pressure, 106 mg (yield 38%) of 2-iodoxybenzoic acid (IBX) crystals were obtained.

[0038] [Example 9] 724mg (4.4mmol) of sodium hypochlorite pentahydrate was weighed into a glass reaction vessel, 1.3mL of water and 496mg (2.0mmol) of 2-iodobenzoic acid were added, and a balloon filled with carbon dioxide was attached and reacted at room temperature for 12 hours. 3M hydrochloric acid was added to the reaction solution to adjust the final pH to about 1-2, and the supernatant was removed by decantation. The residue was washed several times with a small amount of water, and then dried under reduced pressure at 0.3mmHg for 2 hours to distill off the water. Then, 1.5mL of acetic acid and 1.7mL (18mmol) of acetic anhydride were added, and the reaction was carried out at 85°C for 1.5 hours (until the solution became completely homogeneous) under an argon atmosphere. After that, it was allowed to cool to room temperature and left as it was for 12 hours. The supernatant of the precipitated solid was removed by decantation, and then washed several times with anhydrous ether to obtain 710-760mg of Dess-Martin periodinane crystals (yield 84-90%). 1 H-NMR (CDCl3,500MHz)δ8.31(d,J=8.5Hz,1H),8.29(d,J=8.5Hz,1H),7.93(m,1H),8.07(m,1H),7.80(m,1H),2.33(s,3H),2.01(s,6H).

[0039] [Comparative Example 5] With reference to the Oxone method described in Non-Patent Document 2, a one-pot synthesis was carried out with a substrate concentration of 1.5 mol / L. 1.37 g (4.4 mmol) of Oxone (trademark) was weighed into a glass reaction vessel, and 1.3 mL of water and 496 mg (2.0 mmol) of 2-iodobenzoic acid were added and reacted at 70°C for 3 hours. 3 M hydrochloric acid was added to the reaction solution to adjust the final pH to about 1 to 2, and the supernatant was removed by decantation. The residue was washed several times with a small amount of water and then dried under reduced pressure at 0.3 mmHg for 2 hours to distill off the water. Then, 1.5 mL of acetic acid and 1.7 mL (18 mmol) of acetic anhydride were added and reacted at 85°C for 1.5 hours under an argon atmosphere. After cooling to room temperature, the extracted solution was 1 When the reaction solution was examined by 1 H NMR, it was found that almost no target product was produced.

Claims

1. The following structural formula (1) 【Chemistry 1】 The method is characterized in that 2-iodobenzoic acid represented by the formula: is reacted with hypochlorite or a hypochlorite aqueous solution in an atmosphere of carbon dioxide having a concentration of 4.0% by volume or more. The following structural formula (2) 【Chemistry 2】 A method for producing 2-iodoxybenzoic acid represented by the formula:

2. 2. The method for producing 2-iodoxybenzoic acid according to claim 1, wherein the hypochlorite or the aqueous hypochlorite solution is sodium hypochlorite hydrate or an aqueous sodium hypochlorite solution.

3. The following structural formula (1) 【Chemistry 3】 2-iodobenzoic acid represented by the formula: is reacted with hypochlorite or an aqueous hypochlorite solution in an atmosphere of carbon dioxide having a concentration of 4.0% by volume or more; The following structural formula (2) 【Chemistry 4】 The method is characterized in that 2-iodoxybenzoic acid represented by the formula: is prepared, and acetic anhydride is added thereto, followed by heating and further reaction. The following structural formula (3) 【Chemistry 5】 A method for producing Dess-Martin periodinane represented by the formula:

4. The method for producing Dess-Martin periodinane according to claim 3, wherein the hypochlorite or the aqueous hypochlorite solution is sodium hypochlorite hydrate or an aqueous sodium hypochlorite solution.

5. The method for producing Dess-Martin periodinane according to claim 3 or 4, wherein the synthesis is carried out in one pot.

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