Method for producing organic iodine compound

Abstract

[Problem] To provide a method with which an organic iodine compound, which is useful as a polymerization initiator or the like, can be produced in an efficient and industrially advantageous manner with good purity. [Solution] Provided is a method for producing an organic iodine compound represented by general formula (II) by reacting a tertiary halogeno compound represented by general formula (I) with an iodide salt in the presence of a Lewis acid. (In the formulae, X denotes a chlorine atom or a bromine atom, and R1 and R2 each independently denote an alkyl group having 1-6 carbon atoms or together denote an alkylene group having 2-6 carbon atoms. EWG denotes an electron-withdrawing group.)

Description

Method for producing organic iodine compounds

[0001] The present invention relates to a method for producing an organic iodine compound, and more particularly to an industrially advantageous method for producing an organic iodine compound having a tertiary iodine atom.

[0002] Organic iodine compounds, such as low-molecular-weight alkyl iodine compounds, are useful as synthetic raw materials for various chemical products, such as pharmaceutical intermediates, and as radical reaction initiators and radical polymerization initiators, utilizing the radical species generated by cleavage of their carbon-iodine bonds. Furthermore, with a view to producing functional polymers, such as block copolymers, star polymers, and telechelic polymers, organic iodine compounds capable of generating multiple tertiary radical species have attracted attention from the perspective of controlling the activity of radical species. For example, Non-Patent Document 1 discloses the results of a study into the Ka value, molecular weight distribution, and other aspects of the radical polymerization of methyl methacrylate using various low-molecular-weight alkyl iodine compounds as initiators. Furthermore, Non-Patent Document 2 discloses a method for synthesizing organic iodine compounds by reacting sodium iodide with a sterically bulky secondary or tertiary alkyl halide compound in carbon disulfide in the presence of a Lewis acid. Patent Document 1 discloses a molecular weight control agent for radical polymerization, containing an organic iodine compound of a specific structure as its active ingredient.

[0003] Macromolecules, 2014, 47, pp. 6610-6618J. C. S. Perkin I, 1976, pp. 416-420

[0004] International Publication No. 2018 / 180547

[0005] The method for producing an organic iodine compound disclosed in Non-Patent Document 1 involves, for example, reacting ethylene glycol with bromoisobutyryl bromide in dichloromethane to obtain ethylene glycol bis(2-bromoisobutyrate), which is then reacted with sodium iodide in acetonitrile. However, the yield is low, at 35%. The organic iodine compounds obtained by the method disclosed in Non-Patent Document 2 are limited to those with a structure in which an electron-donating group, such as an alkyl group, benzyl group, or phenacyl group, is bonded to the carbon atom to which the iodine atom is bonded. Furthermore, carbon disulfide, which is highly toxic, easily decomposes, and difficult to handle, must be used. An example in Patent Document 1 discloses the production of an organic iodine compound in which a carboxyl group or ester group is bonded to the carbon atom to which the iodine atom is bonded, but this requires the use of sodium iodide in large excess relative to the starting material and a long reaction time. Therefore, there is a need for an industrially advantageous method for producing sterically bulky organic iodine compounds. An object of the present invention is to provide a method for producing an organic iodine compound, particularly an organic iodine compound having a tertiary iodine atom, in high yield, industrially advantageously, and with high purity. As a result of extensive research, the present inventors have found that the above-mentioned problems can be solved by applying a halogen exchange reaction under specific conditions, and have completed the present invention.

[0006] The present invention has the following aspects: [1] A compound represented by the following general formula (I):

[0007]

[0008] (wherein X represents a chlorine atom or a bromine atom, R １ and R ２ each independently represents an alkyl group having 1 to 6 carbon atoms, or together represent an alkylene group having 2 to 6 carbon atoms. EWG represents a group having electron-withdrawing properties.) A tertiary halogeno compound represented by the following general formula (II) (hereinafter also referred to as "tertiary halogeno compound (I)") is reacted with an iodide salt in the presence of a Lewis acid:

[0009]

[0010] (In the formula, R １ , R ２and EWG are as defined above.) (hereinafter also referred to as "organic iodine compound (II)"). [2] The production method according to [1], wherein the Lewis acid is a metal salt. [3] The production method according to [2], wherein the metal salt is an iron compound. [4] The production method according to any one of [1] to [3], wherein the amount of the iodide salt used is in the range of 1 to 5 times by mole relative to the tertiary halogeno compound. [5] The electron-withdrawing group possessed by the tertiary halogeno compound is a carboxyl group, a cyano group, a hydroxyl group of the formula -COOR ３ an ester group represented by the formula -CONR ３ R ４ an amide group represented by the formula -SO ２ R ３ (wherein, R ３ and R ４ each independently represent an aliphatic hydrocarbon group or an aromatic hydrocarbon group in which one or more carbon atoms may be substituted with an oxygen atom, and the aliphatic hydrocarbon group and the aromatic hydrocarbon group may have a substituent.) is selected from the group consisting of an aldehyde group, and a halogen group.

[0011] According to the present invention, organic iodine compounds, particularly organic iodine compounds having a tertiary iodine atom, can be produced in good yield, industrially advantageously, and with high purity.

[0012] The present invention provides a method for producing an organic iodine compound (II) by reacting a tertiary halogeno compound (I) with an iodide salt in the presence of a Lewis acid and a solvent. According to the present invention, the organic iodine compound (II), i.e., an organic iodine compound having a specific structure containing a tertiary iodine atom and an electron-withdrawing group bonded to the carbon atom to which the iodine atom is bonded, can be produced industrially advantageously and with high purity. Such organic iodine compound (II) is useful as an initiator for precision radical polymerization, a raw material for synthesizing various chemical products, and the like.

[0013] In the above general formula, R １ and R ２Examples of the alkyl group having 1 to 6 carbon atoms that R each independently represent include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, and hexyl. １ and R ２ Examples of the alkylene group having 2 to 6 carbon atoms represented by EWG together include an ethylene group, a propylene group, a butylene group, a pentylene group, etc. In the above general formula, examples of the electron-withdrawing group represented by EWG include a carboxyl group, a cyano group, a group represented by the formula -COOR ３ an ester group represented by the formula -CONR ３ R ４ an amide group represented by the formula -SO ２ R ３ Examples of the group include a sulfonyl group, an aldehyde group, and a halogen group represented by the formula: ３ and R ４ each independently represent a linear, branched, or cyclic aliphatic hydrocarbon group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, or undecyl; or an aromatic hydrocarbon group such as phenyl or naphthyl. Such aliphatic and aromatic hydrocarbon groups may have a substituent such as a hydroxyl group, a halogen atom, an alkoxyl group, an aryl group, an ester group, a tri-substituted silyloxy group, or a nitro group. Furthermore, such aliphatic and aromatic hydrocarbon groups may have one or more carbon atoms substituted with other atoms such as an oxygen atom.

[0014] The Lewis acid used in the production method of the present invention is preferably a metal salt. Examples of metals constituting such metal salts include B, Mg, Al, Sc, Ti, Fe, Zn, Zr, Nb, In, Sn, Cu, Ag, Sb, Hf, and lanthanoids. Of these, transition metal salts containing transition metals are preferred. Examples of transition metal salts that can be used as Lewis acids include halogen salts such as fluorides, chlorides, bromides, and iodides of metals such as Ti, Fe, Zn, Zr, Nb, In, Sn, Cu, Sb, Hf, and lanthanoids; sulfates, nitrates, and trifluoromethanesulfonates. These transition metal salts may be hydrates. Of these, iron compounds such as ferrous chloride, ferric chloride, ferrous sulfate, and ferric sulfate are preferred as transition metal salts. Although there is no strict limitation on the amount of Lewis acid used, it is usually preferably in the range of 0.1 to 10 mol % relative to the tertiary halogeno compound (I), and more preferably in the range of 1 to 8 mol % from the viewpoint of smoothly proceeding the reaction and suppressing undesired side reactions. One Lewis acid may be used alone, or two or more Lewis acids may be used in combination.

[0015] Examples of iodide salts used in the production method of the present invention include alkali metal iodide salts such as lithium iodide, sodium iodide, and potassium iodide; and alkaline earth metal iodide salts such as magnesium iodide, calcium iodide, and barium iodide. From the viewpoints of availability and smooth reaction progress, alkali metal iodide salts such as lithium iodide, sodium iodide, and potassium iodide are preferred, and sodium iodide is more preferred. The amount of iodide salt used is not particularly limited, but from the viewpoints of smooth reaction progress and easy production of high-purity organic iodine compound (II) with good productivity, it is usually preferably 1 molar or more, more preferably 1.2 molar or more, relative to the tertiary halogeno compound (I). Furthermore, from the viewpoints of ease of operation and economic efficiency, the amount of iodide salt used is preferably 5 molar or less, more preferably 2.5 molar or less, and even more preferably 1.8 molar or less, relative to the tertiary halogeno compound (I).

[0016] The production method of the present invention can be carried out in the absence or presence of a solvent. When the production method is carried out in the presence of a solvent, examples of the solvent that can be used include hydrocarbons, ethers, ketones, nitriles, amides, and esters. Among these, at least one selected from ketones, nitriles, and esters is preferred. Examples of ketones include acetone, 2-butanone, methyl isopropyl ketone, and methyl isobutyl ketone. Examples of esters include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and methyl propionate. Examples of nitriles include acetonitrile and propionitrile. When a solvent is used, these solvents may be used alone or in combination of two or more. Among these, ketones such as acetone and 2-butanone are preferred, and acetone is more preferred, from the viewpoints of facilitating smooth reaction and enabling industrially advantageous production of organic iodine compound (II) having a specific structure. When a solvent is used, the amount used is not particularly limited, but is usually preferably in the range of 0.1 to 50 times by mass, more preferably 0.1 to 10 times by mass, relative to the tertiary halogeno compound (I). When two or more solvents are used in combination, it is preferable that the total amount of the solvents used falls within the above range.

[0017] The production method of the present invention can be carried out by mixing a tertiary halogeno compound (I), a Lewis acid, and an iodide salt, optionally in the presence of a solvent. The order of addition is not particularly limited; for example, the tertiary halogeno compound (I) may be sequentially mixed with a Lewis acid and an iodide salt and stirred. The production method of the present invention may be carried out under air or an inert gas atmosphere such as nitrogen, helium, or argon. The production method of the present invention can be carried out under atmospheric pressure, elevated pressure, or reduced pressure. From the viewpoint of ease of operation, atmospheric pressure is preferred. The reaction temperature varies depending on the types and amounts of the tertiary halogeno compound (I), solvent, Lewis acid, and iodide salt. However, from the viewpoint of industrially advantageous reaction proceeding, a temperature of 0°C or higher is preferred, 20°C or higher is more preferred, and 30°C or higher is even more preferred. The reaction temperature is preferably 100°C or lower, more preferably 90°C or lower, and even more preferably 80°C or lower. The reaction time varies depending on the type and amount of the tertiary halogeno compound (I), Lewis acid, iodide salt, and optionally the solvent, as well as the reaction temperature, but is usually in the range of 10 minutes to 24 hours.

[0018] The organic iodine compound (II) thus obtained can be isolated and purified by a method commonly used for isolating and purifying organic compounds. For example, the reaction mixture is washed with water, an aqueous sodium hydrogen sulfite solution, an acidic aqueous solution, or the like to separate the organic layer, which is then dried over anhydrous sodium sulfate or the like as needed, and concentrated to obtain a crude product containing the organic iodine compound (II). The crude product can also be further purified by a conventional purification method such as distillation, column chromatography, or recrystallization to increase its purity.

[0019] The obtained organic iodine compound (II) can be effectively used as a raw material for synthesizing various chemical products such as pharmaceutical intermediates. In addition, the compound (II) can be suitably used as a polymerization initiator for living radical polymerization, for example, as a precision radical polymerization initiator for RCMP (reversible coordination mediated polymerization), RTCP (reversible chain transfer catalyzed polymerization), RAFT (reversible addition fragmentation chain transfer polymerization), ATRP (atom transfer radical polymerization), etc., for producing functional polymers with narrow molecular weight distributions, such as block copolymers and star polymers.

[0020] Although the method for producing an organic iodide compound of the present invention has been described above, the present invention is not limited to the configurations of the above-described embodiments. For example, the method for producing an organic iodide compound of the present invention may additionally include any other configuration in the configurations of the above-described embodiments, or may be substituted with any other configuration that produces a similar effect.

[0021] The present invention will be specifically described below with reference to examples, but is not limited to these examples. In each example, the purity of the product was determined by quantitative NMR (qNMR). The change in conversion rate during the reaction was tracked by sampling the reaction mixture at appropriate times. １ H NMR was used.

[0022] Example 1 Synthesis of ethyl 2-iodo-2-methylpropanoate

[0023] 1.95 g (10 mmol) of ethyl 2-bromo-2-methylpropanoate was dissolved in 7.8 g of acetone at room temperature (25°C), and then 2.25 g (15 mmol) of sodium iodide and 81 mg (0.5 mmol) of ferric chloride were added thereto. The mixture was heated to 55°C and stirred for 1 hour. １After confirming that the conversion rate was over 99% using HNMR, 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 35% sodium hydrogen sulfite, dilute hydrochloric acid, and water to separate the organic layer. The resulting organic layer was dried over sodium sulfate, concentrated under reduced pressure, and dried under vacuum to give 2.2 g of ethyl 2-iodo-2-methylpropanoate (isolated yield 91%, purity 98%).

[0024] Comparative Example 1 Synthesis of ethyl 2-iodo-2-methylpropanoate 1.95 g (10 mmol) of ethyl 2-bromo-2-methylpropanoate was dissolved in 7.8 g of acetone at room temperature (25°C), and then 3.00 g (20 mmol) of sodium iodide was added thereto, and the mixture was heated to 55°C and stirred. １ The conversion rate was monitored using HNMR and was found to be 47% after 6 hours.

[0025] Example 2 Synthesis of ethyl 2-iodo-2-methylpropanoate The same reaction procedures as in Example 1 were carried out, except that 139 mg (0.5 mmol) of ferrous sulfate heptahydrate was added instead of 81 mg (0.5 mmol) of ferric chloride, to obtain 2.17 g of ethyl 2-iodo-2-methylpropanoate (isolated yield: 90%, purity: 98%).

[0026] Example 3 Synthesis of 2-iodo-2-methylpropionic acid

[0027] 1.67 g (10 mmol) of 2-bromo-2-methylpropionic acid was dissolved in 7.8 g of acetone at room temperature (25°C), and then 2.25 g (15 mmol) of sodium iodide and 81 mg (0.5 mmol) of ferric chloride were added. The mixture was heated to 55°C and stirred for 1 hour. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 35% sodium hydrogen sulfite, dilute hydrochloric acid, and water to separate the organic layer. The resulting organic layer was dried over sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 1.90 g of 2-iodo-2-methylpropionic acid (isolated yield 89%, purity 98%).

[0028] Example 4 Synthesis of 2-hydroxyethyl 2-iodo-2-methylpropanoate

[0029] (1) To a mixture of 120 g (0.719 mol) of 2-bromo-2-methylpropionic acid, 178.4 g (2.87 mol) of ethylene glycol, and 480 mL of toluene, 14.1 g (0.144 mol) of sulfuric acid was slowly added dropwise at 25°C. After the addition was completed, the mixture was heated to 70-75°C and stirred for 4 hours. The reaction mixture was cooled to 25°C and washed successively with 400 mL of water, 120 mL of a 9% aqueous solution of sodium bicarbonate, and 120 mL of water to separate the organic layer. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain 120 g of 2-hydroxyethyl 2-bromo-2-methylpropanoate (isolated yield: 79.1%). (2) 50 g (0.237 mol) of the 2-hydroxyethyl 2-bromo-2-methylpropanoate obtained above and 240 mL of acetone were mixed, and 56.8 g (0.38 mol) of sodium iodide and 1.54 g (9.48 mmol) of ferric chloride were added sequentially to this mixture, followed by stirring under reflux for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. 300 mL of dichloromethane was added to the residue, which was then washed sequentially with a 2% aqueous solution of sodium hydrogen sulfite, a 1N aqueous solution of hydrochloric acid, and saturated brine to separate the organic layer. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and further dried under vacuum to obtain 55.8 g of 2-hydroxyethyl 2-iodo-2-methylpropanoate (isolated yield 87.4%, purity 98%).

[0030] Example 5 Synthesis of ethylene glycol bis(2-iodo-2-methylpropanoate)

[0031] (1) 100 g (0.60 mol) of 2-bromoisobutyric acid, 16.9 g (0.27 mol) of ethylene glycol, and 5.4 g (0.05 mol) of 98% sulfuric acid were mixed and heated, and the mixture was maintained at 80 to 90°C while stirring and reacting under reduced pressure for 1 hour. The reaction mixture was cooled to room temperature (25°C), and 35.1 g of toluene was added. The solution was washed successively with 45 g of water, 156 g of a 3% by mass aqueous sodium hydroxide solution, and 35.5 g of water, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain 83.0 g of ethylene glycol bis(2-bromo-2-methylpropanoate) (hereinafter referred to as "ester compound 1") (yield: 85%). (2) 83.0 g of ester compound 1 obtained in (1) above was mixed with 42.7 g of acetone, and then 87 g (0.58 mol) of sodium iodide and 2.3 g (0.01 mol) of ferric chloride were added and heated to 55°C, and the mixture was allowed to react for 1 hour with stirring. The reaction mixture was cooled to room temperature (25°C), and 85.4 g of ethyl acetate was added. This solution was washed with 83 g of water and 21 g of a 35% by mass aqueous solution of sodium hydrogen sulfite. The organic layer was separated and further washed again with 42 g of 1.3% by mass hydrochloric acid, and the organic layer was separated. This organic layer was concentrated under reduced pressure, and water was added to the resulting residue, followed by filtration. 71 g of methanol was added to the obtained crystals, and the mixture was heated to 40°C to dissolve them, and then cooled to 5°C. The precipitated crystals were collected by filtration and dried, yielding 89 g of ethylene glycol bis(2-iodo-2-methylpropanoate) (yield 85%, purity 99%).

[0032] The organic iodide compounds obtained by the production method of the present invention are useful as raw materials for synthesizing various chemical products such as pharmaceutical intermediates, and as polymerization initiators.

Claims

1. A compound represented by the following general formula (I): (wherein X represents a chlorine atom or a bromine atom, R １ and R ２ each independently represents an alkyl group having 1 to 6 carbon atoms, or together represent an alkylene group having 2 to 6 carbon atoms. EWG represents a group having electron-withdrawing properties.) A tertiary halogeno compound represented by the following general formula (II): (In the formula, R １ , R ２ and EWG are as defined above.

2. The method of claim 1, wherein the Lewis acid is a metal salt.

3. The method of claim 2, wherein the metal salt is an iron compound.

4. The method according to claim 1, wherein the amount of the iodide salt used is in the range of 1 to 5 times by mole relative to the amount of the tertiary halogeno compound.

5. The electron-withdrawing group of the tertiary halogeno compound is a carboxyl group, a cyano group, a group represented by the formula -COOR ３ an ester group represented by the formula -CONR ３ R ４ an amide group represented by the formula -SO ２ R ３ (wherein, R ３ and R ４ each independently represent an aliphatic hydrocarbon group or an aromatic hydrocarbon group in which one or more carbon atoms may be substituted with an oxygen atom, and the aliphatic hydrocarbon group and the aromatic hydrocarbon group may have a substituent.) aldehyde group, and halogen group.

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