Method for producing phenothiazine derivative compound

Abstract

The present invention provides an economical and efficient method for producing a phenothiazine derivative compound.　Provided is a method for producing a phenothiazine derivative compound (I) from a Grignard reagent and a vinyl halide, wherein a transition metal catalyst is used. The Grignard reagent is prepared from a halogen-containing phenothiazine derivative compound represented by general formula (A) (wherein R represents a monovalent aliphatic hydrocarbon group having 1-10 carbon atoms, and X represents a halogen atom). The method makes it possible to produce the phenothiazine derivative compound (I) economically and efficiently on an industrial scale.

Description

Method for producing phenothiazine derivative compound

[0001] The present invention relates to a method for producing a phenothiazine derivative compound. More specifically, the present invention relates to a method for economically and efficiently producing a phenothiazine derivative compound having excellent properties as a copolymerizable antioxidant.

[0002] A wide variety of synthetic polymer materials represented by synthetic rubbers, synthetic resins and the like are produced and used using fossil resources as main raw materials. These have penetrated into every corner of the economic society and have brought great convenience and benefits to our lives.

[0003] Such synthetic polymer materials may undergo oxidative degradation due to oxygen, ozone, heat, light and the like, and their original physical properties and functions may be lost over time. To prevent this, antioxidants are added during the production and molding processing steps. For example, non-staining phenolic antioxidants tend to be used in the production process.

[0004] At the molding processing stage, an antioxidant such as a phenolic or amine-based antioxidant is appropriately selected and added in consideration of the form (rubber or resin) of the final product, the shape, the desired hue and appearance, the environment in which the final product is used, and the like. In general, amine-based antioxidants with excellent antioxidant effects tend to be used for rubber-like members, and phenolic antioxidants tend to be used for resin-like members.

[0005] It should be noted that the following points need to be noted when using conventional addition-type antioxidants. ・For antioxidants that are of concern for effects on the human body, occupational safety and health measures are required during handling ・Occurrence of appearance defect problems due to bleeding out of the antioxidant to the surface of the molded member ・Volatilization of the antioxidant from the molded member due to heat, or loss of the antioxidant due to extraction by water, oils and fats, solvents, etc. ・In the case of molded members for food use or medical use, consideration must be given to ensure that the elution amount of the antioxidant to the outside is health-acceptable ・In the case of large molded members such as automobile tires, a large amount of the antioxidant may volatilize or elute into the external environment

[0006] In particular, in light of the recent problem of tire wear dust (TRWP), there are concerns about the impact of antioxidants released from automobile tires or their wear dust on ecosystems.

[0007] From this perspective, attempts have been made to improve problems associated with the migration of antioxidants within molded materials by chemically bonding antioxidants to the polymer main chain structure (Patent Documents 1-3, Non-Patent Documents 1-2). However, it is difficult to say that any of these methods are versatile or practical.

[0008] In view of these circumstances, the present inventors have proposed that in the manufacturing stage of synthetic polymer materials, a general formula (Here, R １ R is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, 2 A technique has been proposed to stabilize synthetic polymer materials against oxidative degradation by copolymerizing phenothiazine derivative compounds (where is a hydrogen atom or a methyl group) with various polymerizable unsaturated monomers (Patent Document 3).

[0009] Specific examples of phenothiazine derivative compounds include 2-ethenyl-10-methyl-10H-phenothiazine, 2-(1-methylethenyl)-10-methyl-10H-phenothiazine, 3-ethenyl-10-methyl-10H-phenothiazine, and 3-(1-methylethenyl)-10-methyl-10H-phenothiazine. There are no particular restrictions on the method of producing such phenothiazine derivative compounds, and they can be produced using inexpensive diphenylamine or 10H-phenothiazine as starting materials. For example, Non-Patent Documents 3 and 4 describe methods for producing 2-(1-methylethenyl)-10-methyl-10H-phenothiazine and 3-ethenyl-10-methyl-10H-phenothiazine, respectively.

[0010] As a specific example, a method for producing 3-ethenyl-10-methyl-10H-phenothiazine is shown below.

[0011] However, the above method has drawbacks, such as requiring large quantities of raw materials and auxiliary materials during manufacturing, and producing large amounts of by-products, and is not necessarily satisfactory as an industrial manufacturing method.

[0012] To enhance the practicality and versatility of phenothiazine derivative compounds, which possess excellent properties as copolymerizable antioxidants, there is a need for economical and efficient methods for producing these compounds.

[0013] JP-A-4-264106 JP-A-5-230132 WO2024 / 247785 JP-A-2000-239192 JP-A-1-106835

[0014] Rubber Chem. Technol., Vol. 46, p. 106 (1973) Rubber Chem. Technol., Vol. 52, p. 883 (1979) Organic Letters, Vol. 21, p. 4564 (2021) Energy Environ. Sci., Vol. 10, pp. 2334-2341 (2017)

[0015] The object of the present invention is to provide an economical and efficient method for producing phenothiazine derivative compounds.

[0016] The objective of the present invention is to provide a general formula A Grignard reagent prepared from a halogen-containing phenothiazine derivative compound represented by (where R is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and X is a halogen atom), and a phenothiazine derivative compound from vinyl halide. This is achieved by using a transition metal catalyst as the catalyst in the reaction that produces [the substance].

[0017] While the reaction of producing styrene derivative compounds from vinyl halides using a Grignard reagent prepared from an aryl halide compound with a transition metal catalyst is known (Patent Documents 4 and 5), examples of its application to the production of phenothiazine derivative compounds [I] are not described in these documents.

[0018] The manufacturing method of the present invention makes it possible to produce phenothiazine derivative compound [I] economically and efficiently on an industrial scale. Specifically, it is possible to reduce the amount of raw materials and by-products generated by the reaction when producing phenothiazine derivative compound [I].

[0019] The present invention provides a method for producing a phenothiazine derivative compound [I] by reacting a Grignard reagent prepared from a halogen-containing phenothiazine derivative compound [A] with a vinyl halide in the presence of a transition metal catalyst, characterized in that the transition metal catalyst used is an iron-based catalyst, a cobalt-based catalyst, a manganese-based catalyst, a nickel-based catalyst, a rhodium-based catalyst, or a palladium catalyst.

[0020] The Grignard reagent used in the present invention can be easily prepared from a halogen-containing phenothiazine derivative compound [A].

[0021] The halogen-containing phenothiazine derivative compound [A] can be produced by reacting halogen-containing diphenylamine with sulfur / iodine and then N-alkylating it. Alternatively, 10H-phenothiazine may be N-alkylated and then halogenated, or 10H-phenothiazine may be halogenated and then N-alkylated.

[0022] The Grignard reagent can be prepared by reacting compound [A] with metallic magnesium in an aprotic solvent such as tetrahydrofuran. Specifically, the desired Grignard reagent can be prepared by adding a tetrahydrofuran solution of halogen-containing phenothiazine derivative compound [A] dropwise to a mixed solution of metallic magnesium and tetrahydrofuran at room temperature to reflux temperature, and refluxing for several hours. The reaction is carried out in an inert gas atmosphere such as nitrogen or argon to avoid the influence of oxygen and moisture.

[0023] In preparing Grignard reagents, it is common practice to activate metallic magnesium in the reaction vessel to ensure the reaction proceeds smoothly. Activation methods include thermal activation or chemical activation using iodine, methyl iodide, or ethyl bromide. The metallic magnesium is commercially available in tape or shaving form, and is used in 1 to 3 molar amounts relative to compound [A].

[0024] The reaction to produce phenothiazine derivative compound [I] by reacting a Grignard reagent prepared from halogen-containing phenothiazine derivative compound [A] with vinyl halide is carried out in the presence of a transition metal catalyst. Approximately 1.0 to 2.0 molar amounts of vinyl halide are used relative to halogen-containing phenothiazine derivative compound [A].

[0025] Examples of halogenated vinyl include vinyl fluoride, vinyl chloride, vinyl bromide, or vinyl iodide, with vinyl chloride or vinyl bromide being used because they are inexpensive and readily available.

[0026] The transition metal catalyst is selected from a group of compounds consisting of nickel-based catalysts, iron-based catalysts, cobalt-based catalysts, manganese-based catalysts, rhodium-based catalysts, and palladium-based catalysts, with nickel-based or iron-based catalysts being preferred.

[0027] Examples of iron-based catalysts include iron(II) fluoride, iron(III) fluoride, iron(II) chloride, iron(III) chloride, iron(II) bromide, iron(III) bromide, iron(II) iodide, iron(III) iodide, iron(II) acetate, iron(III) acetate, iron(II) oxalate, iron(III) oxalate, iron(II) sulfate, iron(III) sulfate, iron(III) nitrate, and iron(III) acetylacetonethate. These may be either anhydrous or hydrated salts. Furthermore, iron coordination complexes containing phosphorus-containing organic compounds or nitrogen-containing organic compounds as ligands may also be used.

[0028] Examples of cobalt-based catalysts include cobalt(II) fluoride, cobalt(II) chloride, cobalt(II) bromide, cobalt(II) iodide, cobalt(II) acetate, cobalt(III) acetate, cobalt(II) acetylacetodium, cobalt(II) nitrate, and cobalt(II) sulfate. These may be either anhydrous or hydrated salts. Furthermore, cobalt coordination complexes containing phosphorus-containing organic compounds or nitrogen-containing organic compounds as ligands may also be used.

[0029] Examples of manganese-based catalysts include manganese(II) fluoride, manganese(II) chloride, manganese(II) bromide, manganese(II) iodide, manganese(III) acetate, manganese(II) acetyl acetonethate, manganese(II) nitrate, and manganese(II) sulfate. These may be either anhydrous or hydrated salts. Furthermore, manganese coordination complexes containing phosphorus-containing organic compounds or nitrogen-containing organic compounds as ligands may also be used.

[0030] Examples of nickel-based catalysts include [1,3-bis(diphenylphosphino)propane]dichloronickel(II), [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), bis(triphenylphosphine)dichloronickel(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloronickel(II), nickel(II) acetate, bis(acetylacetethonato)nickel(II), and nickel(II) nitrate.

[0031] Examples of rhodium-based catalysts include rhodium(II) fluoride, rhodium(II) chloride, rhodium(II) bromide, rhodium iodide, rhodium(II) acetate, rhodium(II) acetylacetodium, and rhodium(III) acetylacetodium. Alternatively, rhodium-coordinate complexes containing phosphorus-containing organic compounds or nitrogen-containing organic compounds as ligands may also be used.

[0032] Palladium-based catalysts include palladium(O) / carbon, palladium(II) chloride, palladium(II) acetate, palladium(II) sulfate, palladium(II) nitrate, tetrakistriphenylphosphine palladium(O), 1,1′-bis(diphenylphosphine)ferrocenedichloropalladium(II), bis(acetylacetonate)palladium(II), bis(benzylideneacetone)palladium(O), bis(tri-3-butylphosphine)palladium(O), and tris(ben Examples include zylideneacetone)dipalladium(0), bis(tricyclohexylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), di-μ-chlorobis[(η-allyl)palladium(II)], 1,1′-bis(di-3-butylphosphine)ferrocenepalladium dichloride, [1,2-bis(diphenylphosphine)ethane]dichloropalladium, [1,3-bis(diphenylphosphine)propane]dichloropalladium, etc.

[0033] The transition metal catalyst is used in a ratio of 0.01 to 1 mol% relative to the Grignard reagent.

[0034] The reaction is carried out in an inert gas atmosphere, such as nitrogen or argon, to avoid the influence of oxygen and moisture.

[0035] While there are no particular restrictions on the reaction solvent as long as it is an aprotic solvent, ether-based solvents, nitrogen-containing solvents, aliphatic hydrocarbon solvents, and aromatic hydrocarbon solvents are preferably used individually or in combination of two or more. Ether-based solvents such as tetrahydrofuran and 1,4-dioxane are particularly preferred.

[0036] The reaction is carried out at a temperature of 0 to 100°C, preferably between 0°C and the solvent reflux temperature.

[0037] Next, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples, including its effects.

[0038] Reference Example - Preparation of (A-1) - 32.0 g (0.15 mol) of 10-methyl-10H-phenothiazine and 300 mL of acetonitrile were charged into a 500 mL three-necked flask equipped with a stirrer, thermometer, gas inlet, and gas outlet. 26.7 g (0.15 mol) of N-bromosuccinimide was added at a rate of 3.0 g / 10 min at 0°C under a nitrogen atmosphere. After the reaction was complete, the precipitated solid was filtered off, yielding 45.5 g of crude product (crude yield 89%) as a slightly greenish solid. 1 From the signal integral values ​​of the chemical shifts shown in parentheses in the 1H-NMR (400 MHz, CDCl3) analysis, the crude product was a mixture of 3-bromo-10-methyl-10H-phenothiazine (3.34 ppm), 3,7-dibromo-10-methyl-10H-phenothiazine (3.30 ppm), and 10-methyl-10H-phenothiazine (3.38 ppm), in amounts of 78 mol%, 10 mol%, and 12 mol%, respectively. After removing the low-RF components using a silica gel column (Wako Gel C300) with dichloromethane as the eluent, the eluent was evaporated to dryness under reduced pressure to obtain 41.2 g of a yellow solid. Subsequently, recrystallization was performed three times using acetone to obtain 22.0 g (yield 50%) of a slightly greenish solid (A-1). 1 ¹H-NMR analysis revealed that the obtained solid was a mixture consisting of 94 mol%, 3 mol%, and 3 mol% of 3-bromo-10-methyl-10H-phenothiazine, 3,7-dibromo-10-methyl-10H-phenothiazine, and 10-methyl-10H-phenothiazine, respectively.

[0039] Example 1 - Preparation of phenothiazine derivative compound (I-A) from (A-1) - In a 1 L five-necked flask equipped with a stirrer, thermometer, reflux tubing, dropping funnel, gas inlet tube, and gas outlet tube, 100 mL of tetrahydrofuran, 2.9 g (0.12 mol) of shaved metallic magnesium, and 1.1 g (0.01 mol) of ethyl bromide were charged while purging the reaction vessel with nitrogen, and the mixture was stirred for 1 hour under reflux conditions. Next, a solution of 29.2 g (0.1 mol) of 3-bromo-10-methyl-10H-phenothiazine (A-1) in tetrahydrofuran was added dropwise over 10 minutes, and the reaction was carried out for a further 2 hours under reflux conditions. After the contents were cooled to room temperature, the supernatant was transferred to another reaction vessel. To this, 0.27 g (0.0005 mol) of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) was added, and 16.0 g (0.15 mol) of vinyl bromide was introduced into the reaction vessel over 30 minutes while maintaining the reaction temperature at 40-50°C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. After the reaction was complete, aqueous ammonium chloride solution was added to the reaction solution to separate the organic layer. The organic layer was recovered, and the aqueous layer was extracted with ethyl acetate and mixed with the organic layer. The organic layer was washed with saturated brine, then dried with anhydrous magnesium sulfate, and insoluble matter was filtered off. The solvent was removed under reduced pressure to obtain 24.0 g of a yellow solid. Next, reaction catalyst residue and low RF components were removed using a silica gel column (Wako Gel C300) with dichloromethane as the eluent, and the eluent was evaporated to dryness under reduced pressure to obtain 26.5 g of a yellow solid. Furthermore, 16.8 g (70% yield) of 3-ethenyl-10-methyl-10H-phenothiazine (I-A) was obtained by recrystallization using ethyl acetate. The amount of magnesium bromide, a byproduct, is estimated to be approximately 13 g stoichiometrically. Melting point: 102°C 11H NMR (400 MHz, CDCl₃, δ ppm): 3.37 (s, 3H, N-CH₃) 5.14 (d, J=10.8 Hz, 1H, CH₂=CH-PTZ (trans to the phenothiazine group)) 5.61 (d, J=17.6 Hz, 1H, CH₂=CH-PTZ (cis to the phenothiazine group)) 6.59 (dd, J=10.8 Hz, 17.6 Hz, 1H, CH₂=CH-PTZ) 6.75 (d, J=8.4 Hz, 1H, Ar) 6.81 (d, J=9.2 Hz, 1H, Ar) 6.92 (td, J=7.6 Hz, 1.2 Hz, 1H, Ar) 7.11-7.23 (m, 4H, Ar)

[0040] Example 2 The same procedure as in Example 1 was carried out except that 9.4 g (0.15 mol) of vinyl chloride was used in place of 16.0 g (0.15 mol) of vinyl bromide, to obtain 18.6 g (yield 78%) of the phenothiazine derivative compound (I-A). The amount of by-produced magnesium halide is estimated to be about 11 g stoichiometrically.

[0041] Example 3 The same procedure was carried out in Example 1 except that 1.1 g (0.0068 mol) of iron(III) chloride was used in place of [1,3-bis(diphenylphosphino)propane]dichloronickel(II), to obtain 7.2 g (yield 30%) of the phenothiazine derivative compound (IA). The amount of by-produced magnesium bromide is estimated to be about 5 g stoichiometrically.

[0042] Comparative Example - Production of phenothiazine derivative compound (I-A) from (B)- Into a 5 L five-necked flask equipped with a stirring device, a magnetic stirrer bar, a thermometer, a gas inlet tube and a gas outlet tube, 2.3 L of tetrahydrofuran was charged, and the internal temperature was cooled to 10°C or lower while the inside of the reaction vessel was purged with nitrogen. 175.0 g (1.56 mol) of potassium tert-butoxide, followed by 557.3 g (1.56 mol) of methyltriphenylphosphonium bromide were added, and the reaction was carried out for 30 minutes. To this was added 313.7 g (1.30 mol) of 10-methyl-10H-phenothiazine-3-carbaldehyde (B), and the mixture was reacted at -10 to 40°C for 1 hour. The resulting reaction mixture was added to 1.7 L of a 10% aqueous sodium chloride solution to terminate the reaction. While the organic layer was collected, the aqueous layer was extracted with ethyl acetate, which was then combined with the previous organic layer. 0.35 g of p-methoxyphenol was added to this mixed solution, and after drying over anhydrous magnesium sulfate, insoluble matter was filtered off, and volatile components were distilled off from the filtrate under reduced pressure to obtain 718.4 g of a pale yellow solid. This was pulverized in a mortar to form a powder. After the powdery pale yellow solid was dissolved in 2.1 L of ethanol, a small amount of insoluble matter was filtered off, and the filtrate was allowed to stand overnight at 5°C or lower to crystallize the phenothiazine derivative compound (I-A). The crystallized yellow crystals weighed 286.3 g (yield 92.0%). Further, the same operation was performed on 286.3 g of the crystallized yellow crystals using 3.3 L of ethanol, to obtain 259.2 g (yield 83.3%) of (I-A) as pale yellow crystals. The amount of triphenylphosphine oxide, which is a by-product, is stoichiometrically estimated to be about 360 g.

[0043] From the above results, the following can be said: (1) In the comparative example, 1.78 times the amount of methyltriphenylphosphonium bromide by weight of compound (B), and generally about 1.5 to 1.8 times, is required, and there is a problem that about 1.0 to 1.4 times the amount of triphenylphosphine oxide by weight of compound (I-A) is produced as a by-product. (2) On the other hand, in the examples, compared to the comparative example, the amount of vinyl halide required to produce the phenothiazine derivative compound (I-A) is 0.55 times (Examples 1 and 3), 0.32 times (Example 2) by weight of compound (A-1), and generally about 0.3 to 0.8 times, and the by-products (magnesium halide, etc.) produced at that time are easy to dispose of, and the amount is about 0.4 to 0.8 times that of compound (I-A).

Claims

1. General formula A Grignard reagent prepared from a halogen-containing phenothiazine derivative compound represented by (where R is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and X is a halogen atom), and a phenothiazine derivative compound from vinyl halide. A method for producing a phenothiazine derivative compound using a transition metal catalyst.

2. A method for producing a phenothiazine derivative compound according to claim 1, wherein the transition metal catalyst is a nickel-based catalyst.

3. A method for producing a phenothiazine derivative compound according to claim 1, wherein the transition metal catalyst is an iron-based catalyst.

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