Method for isolating phenothiazine derivative compounds

Abstract

In the present invention, when converting the phenothiazine carbaldehyde derivative compound or phenothiazine acetyl derivative compound represented by general formula (b) (wherein, R1 is a monovalent aliphatic hydrocarbon group having 1-10 carbon atoms, and R2 is a hydrogen atom or methyl group) into the phenothiazine derivative compound represented by general formula (I) (wherein, R1 and R2 are the same as the above definitions) by a Wittig reaction, the phenothiazine derivative compound (I) is crystallized, by using ethanol, from a reaction mixture containing the phenothiazine derivative compound (I) after the Wittig reaction and triphenylphosphine oxide, thereby isolating the phenothiazine derivative compound.

Description

[Technical field]

[0001] The present invention relates to a method for isolating a phenothiazine derivative compound, and more particularly to a method for isolating a phenothiazine derivative compound, which enables isolation of the compound in high yield in industrial production. [Background technology]

[0002] A wide variety of synthetic polymer materials, such as synthetic rubber and synthetic resins, have been manufactured and used primarily from fossil fuels. These materials have permeated every corner of our economic society, providing great convenience and benefits to our lives.

[0003] Such synthetic polymer materials may be subject to oxidation degradation due to heat, light, oxygen, ozone, etc., and may lose their original physical properties and functions over time. To prevent this, antioxidants are added during the production and molding processes. For example, some synthetic polymer materials are produced through processes such as polymerization of the monomers that constitute them, recovery of unreacted monomers, removal of the polymerization medium, coagulation, drying, and granulation, and an antioxidant is added in advance to prevent deterioration of the polymer material due to heat history in the drying and granulation processes. As the antioxidant, a phenol-based or amine-based antioxidant is used, and when appearance is particularly important, a low molecular weight phenol-based antioxidant is used.

[0004] Furthermore, when synthetic polymer materials that have been molded into desired shapes are used under harsh conditions such as high temperatures, antioxidants are added in advance at the molding stage to prevent loss of functionality due to thermal oxidative degradation. Phenol- or amine-based antioxidants are used here as the antioxidant, but relatively high molecular weight antioxidants tend to be used, particularly to prevent volatilization or elution into the external environment. Generally, phenol-based antioxidants are often used for resinous polymer materials, while amine-based antioxidants are often used for elastomeric polymer materials.

[0005] Problems with adding antioxidants include the cost involved, and the need to add the antioxidant twice, particularly when heat resistance is required for the final product. Also, there are concerns that certain amine-based antioxidants may be harmful to human health if exposed to them, making it necessary to take occupational safety and health measures, such as pelletizing them.

[0006] Furthermore, when using polymeric material molded parts, the antioxidant may migrate to the surface, resulting in poor appearance, or the antioxidant may volatilize to the outside due to heat, or may be extracted by water, oils, solvents, etc., causing the antioxidant to lose its original function. Furthermore, when the polymeric material molded part comes into direct contact with food, etc., care must be taken to ensure that the amount of antioxidant eluted is acceptable from a health standpoint. In addition, in the case of large molded parts, there is a risk that a large amount of antioxidant may volatilize into the external environment, which is undesirable from the standpoint of environmental conservation.

[0007] From this viewpoint, attempts have been made to chemically bind antioxidants to polymeric materials to suppress migration of the antioxidants to the surface, volatilization to the outside, and elution.

[0008] For example, in the case of elastomeric polymer materials, attempts have been made to chemically bond antioxidants to polymer chains (Patent Documents 1-3, Non-Patent Documents 1-2). However, these methods require an additional modification step and are therefore less practical in terms of production costs. In addition, conventional antioxidants such as N-(4-anilinophenyl)methacrylamide that have polymerizable unsaturated groups and active sites such as NH groups and OH groups have problems with their copolymerizability.

[0009] In order to solve the above problems, the present applicant has prepared a compound represented by the general formula TIFF0007642161000001.tif25129 (where R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and R 2is a hydrogen atom or a methyl group) as a copolymerizable antioxidant (Patent Application No. 2022-66753).

[0010] In this compound, the hydrogen atom on the nitrogen atom at the 10th position is replaced with an aliphatic hydrocarbon group, thereby reducing the radical polymerization inhibition effect specific to phenothiazine compounds, and therefore radical copolymerization with various polymerizable unsaturated monomers is possible. For the same reason, hydrogen abstraction reaction with basic compounds such as alkyllithium compounds is substantially avoided, and therefore anionic copolymerization with various polymerizable unsaturated monomers is also possible.

[0011] Furthermore, for the same reason, it is possible to prevent the deactivation of the catalyst used in coordination polymerization, making it possible to carry out coordination copolymerization with various polymerizable unsaturated monomers.

[0012] Thus, the phenothiazine derivative compound [I] is suitable for stabilizing synthetic polymer materials produced by addition polymerization of polymerizable unsaturated monomers against thermo-oxidative deterioration.

[0013] Synthetic polymer materials copolymerized with phenothiazine derivative compound [I] can effectively stabilize the synthetic polymer materials against thermal oxidative degradation because the antioxidant is chemically bonded to the synthetic polymer materials. As a result, it is practically unnecessary to add an additional antioxidant in the manufacturing process and molding process. In addition, the amount of compound [I] used can be reduced compared to conventional antioxidants.

[0014] In addition, when the polymer material molded part is used, it is possible to prevent poor appearance due to migration of the antioxidant to the surface, volatilization of the antioxidant to the outside due to heat, and extraction of the antioxidant by water, oils, solvents, etc., thereby making it possible to extend the life of the polymer molded part even in a variety of deteriorating environments.

[0015] Furthermore, when a polymeric material molded part comes into direct contact with food, etc., it is necessary to take care that the amount of antioxidant eluted is within the acceptable range from a health standpoint, but this problem is also eliminated. In the case of large molded parts, there is a risk that a large amount of antioxidant will volatilize into the external environment, which is undesirable from the standpoint of environmental conservation, but this problem can also be eliminated.

[0016] Specific examples of the phenothiazine derivative compound [I] 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 is no particular limitation on the method for producing such a phenothiazine derivative compound [I], and it can be produced using inexpensive diphenylamine or 10H-phenothiazine as a starting material. 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.

[0017] The Wittig reaction for producing the phenothiazine derivative compound [I] from 10-alkyl-10H-phenothiazinecarbaldehyde or 10-alkyl-10H-phenothiazineacetyl proceeds easily and allows the production of compound [I] in high yield. However, it has been difficult to separate and remove triphenylphosphine oxide from the reaction mixture and to efficiently isolate and purify compound [I] on an industrial scale.

[0018] In laboratory methods, column chromatography is used, using silica gel as a carrier and a mixed solvent of a good solvent such as chloroform, dichloromethane, ethyl acetate, etc. and a poor solvent such as petroleum ether, n-hexane, cyclohexane, etc. as an eluent (Non-Patent Documents 3-4). However, this purification method has the disadvantage that not only does it require multiple repetitions of separation operations by column chromatography to completely remove triphenylphosphine oxide, but it also requires a large amount of organic solvent and carrier, making it unsuitable for industrial production processes.

[0019] Besides the chromatographic method, there is a method for separating triphenylphosphine oxide from a Wittig reaction mixture in which the reaction mixture is dissolved in a good solvent and then added to a poor solvent such as hexane or cyclohexane to precipitate and separate triphenylphosphine oxide. However, the recovery rate and purity of compound [I] are limited.

[0020] Therefore, in the production of phenothiazine derivative compounds by the Wittig reaction, a simpler and more efficient method for isolating compound [I] is desired. [Prior art documents] [Patent documents]

[0021] [Patent Document 1] Japanese Patent Application Publication No. 4-264106 [Patent Document 2] Japanese Patent Application Publication No. 5-230132 [Patent Document 3] JP 2009-209268 A [Non-patent literature]

[0022] [Non-Patent Document 1] Rubber Chem. Technol., vol. 46, p. 106 (1973) [Non-Patent Document 2] Rubber Chem.Technol., vol. 52, p. 883 (1979) [Non-Patent Document 3] Organic Letters, Vol. 23, p. 4564 (2021) [Non-Patent Document 4] Energy Environ.Sci., vol. 10, pp. 2334-2341 (2017) Summary of the Invention [Problem to be solved by the invention]

[0023] The present invention has been made in view of the above problems, and provides a phenothiazine derivative compound by Wittig reaction. TIFF0007642161000002.tif25129 (where R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and R 2 is a hydrogen atom or a methyl group), to provide a simpler and more efficient method for isolating a phenothiazine derivative compound [I]. [Means for solving the problem]

[0024] The object of the present invention can be attained by crystallizing the phenothiazine derivative compound [I] from a reaction mixture containing the phenothiazine derivative compound [I] and triphenylphosphine oxide after the Wittig reaction using ethanol. Effect of the Invention

[0025] In the conventional method, the Wittig reaction mixture is dissolved in a good solvent for the target compound, and then added to a poor solvent for triphenylphosphine oxide to precipitate and separate it. In the present invention, however, the Wittig reaction mixture is dissolved in ethanol, which is a poor solvent for phenothiazine derivative compound [I] but a good solvent for triphenylphosphine oxide, and then only phenothiazine derivative compound [I] is crystallized from the solution, thereby easily isolating phenothiazine derivative compound [I].

[0026] By using the method for isolating the phenothiazine derivative compound [I] according to the present invention, it becomes possible to easily and efficiently produce the phenothiazine derivative compound [I] on an industrial scale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The phenothiazine derivative compound has the general formula TIFF0007642161000003.tif25129 (where R 1is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and R 2 is a hydrogen atom or a methyl group).

[0028] The phenothiazine derivative compound [I] can be easily produced, for example, from 10-alkyl-10H-phenothiazinecarbaldehyde (b) or 10-alkyl-10H-phenothiazineacetyl by the Wittig reaction. TIFF0007642161000004.tif25111

[0029] After the reaction is completed, a general post-reaction treatment is carried out to obtain a Wittig reaction mixture mainly composed of phenothiazine derivative compound [I] and triphenylphosphine oxide. After dissolving this in ethanol, if a trace amount of insoluble matter is produced, it is filtered off, and the filtrate is allowed to stand at preferably 30°C or lower, more preferably -30°C to 10°C, for 1 to 24 hours to crystallize the phenothiazine derivative compound [I].

[0030] Here, when dissolving the reaction mixture in ethanol, the solution is heated to 50°C or higher, preferably to the boiling point of ethanol. The amount of ethanol used is such that the phenothiazine derivative compound [I] and triphenylphosphine oxide are almost completely dissolved, and the amount is appropriately adjusted depending on the content of triphenylphosphine oxide and the solubility of the phenothiazine derivative compound [I] in ethanol. For example, in the case of 3-ethenyl-10-methyl-10H-phenothiazine, about 0.4 to 1.5 liters of ethanol are used per 100 g of the reaction mixture.

[0031] Furthermore, the dissolving step may be carried out by adding a small amount of a polymerization inhibitor such as paramethoxyphenol, etc. The amount of the polymerization inhibitor added is 10 to 10,000 ppm, preferably 100 to 1,000 ppm, based on the expected yield of the phenothiazine derivative compound [I].

[0032] Since the target substance, phenothiazine derivative compound [I], can be obtained simply and with high purity and high recovery, this isolation method is suitable for industrial production of phenothiazine derivative compound [I] by Wittig reaction. EXAMPLES

[0033] The present invention will now be described in detail with reference to examples. However, the present invention, including its effects, is not limited to these examples.

[0034] -Production of phenothiazine derivative compound [IA]- TIFF0007642161000005.tif26159

[0035] Reference example Preparation of compound (a-1) [1st process] [PTZ] → (a-1): 2.0L of thoroughly dehydrated N,N-dimethylformamide was placed in a 5L five-neck flask equipped with a stirrer, a thermometer, a dropping funnel, a nitrogen gas inlet tube, and an outlet tube, and the temperature in the system was cooled to 10°C or less under a nitrogen atmosphere. 103.4g (2.59 mol) of sodium hydride (purity 60%) was added and stirred for 10 minutes, and then 401.0g (2.01 mol) of phenothiazine (PTZ) was added in several portions and reacted for 30 minutes while maintaining the temperature in the system at 10°C or less. 312.3g (2.20 mol) of iodomethane was added dropwise while maintaining the temperature in the system at 10°C or less, and the reaction was continued for another hour. After the reaction was completed, the reaction mixture was added to 4L of 10% sodium chloride aqueous solution. The precipitated colorless solid was filtered and washed with 4L of distilled water.

[0036] The obtained solid was dissolved in 2.5 L of warm ethyl acetate at about 50°C, and the lower layer (aqueous layer) was separated. The upper layer (organic layer) was dried over anhydrous magnesium sulfate, and then insoluble matter was filtered off. Volatile components were removed from the filtrate under reduced pressure to obtain 451.4 g of a crude product (crude yield 105%). This was washed (defatted) with 0.7 L of isooctane to obtain 421.2 g of 10-methyl-10H-phenothiazine (a-1) as a slightly grayish crystalline solid (yield 98.2%). TIFF0007642161000006.tif25129 1 H NMR (400MHz, Acetone-d6, δ ppm): 3.39 (s, 3H, NC H 3) 6.91-6.98 (m, 4H, Ar) 7.14 (dd, J=7.6Hz, J=1.6Hz, 2H, Ar) 7.21 (td, J=7.6Hz, J=1.6Hz, 2H, Ar)

[0037] Preparation of compound (b-1) [Second process] (a-1) → (b-1): 0.7 L of thoroughly dehydrated N,N-dimethylformamide was placed in a 3 L five-neck flask equipped with a stirrer, dropping funnel, thermometer, gas inlet, gas outlet and reflux condenser. Under a nitrogen atmosphere, 509 g (3.32 mol) of phosphoryl chloride was added dropwise while maintaining the internal temperature of the system at 10°C or less, and the reaction was continued for another 30 minutes. Next, 291.2 g (1.37 mol) of 10-methyl-10H-phenothiazine (a-1) obtained in the first step above was added, and the reaction was continued at 60°C for 17 hours. After the reaction was completed, the contents were poured into 2.3 kg of 50% aqueous sodium acetate solution cooled in an ice-water bath, and 194 g of sodium hydroxide was added to adjust the pH to 6 or higher.

[0038] The obtained solution was left to stand for 2 hours while cooling in an ice water bath. The precipitated solid was filtered off, washed with 3 L of distilled water to dissolve the inorganic electrolytes. The remaining brown solid was dissolved in 1.5 L of warm ethyl acetate at about 50 ° C., the lower layer (water bath) was separated, and the organic layer was dried with anhydrous magnesium sulfate. After filtering off the insoluble matter, the volatile components were distilled off from the filtrate under reduced pressure to obtain 329.0 g of crude product (crude yield 99.9%) as a reddish brown oily substance. The crude product was dissolved in about 1 L of ethyl acetate, and passed through a silica gel (Wako Gel C300) column to remove low Rf components. The volatile components were distilled off from the eluate under reduced pressure to obtain 321.6 g of yellow solid (yield 97.6%). Further, by recrystallization using 320 ml of ethyl acetate, 308.2 g of 10-methyl-10H-phenothiazine-3-carbaldehyde (b-1) was obtained as yellow crystals (yield 93.6%). TIFF0007642161000007.tif29129 1 H NMR (400MHz, Acetone d6, δ ppm): 3.49 (s, 3H, NC H 3) 7.00-7.06 (m, 2H, Ar) 7.10 (d, J=8.4Hz, 1H, Ar) 7.15-7.19 (m, 1H, Ar) 7.22-7.28 (m, 1H, Ar) 7.61 (d, J=1.6Hz, 1H, Ar) 7.75 (dd, J=8.4Hz, J=1.6Hz, 1H, Ar) 9.85 (s, 1H, -C H O)

[0039] Working Example Preparation of compound [IA] [3rd process] (b-1) → [IA]: 2.3L of tetrahydrofuran was placed in a 5L five-neck flask equipped with a stirrer, a thermometer, a gas inlet tube, and a gas outlet tube, and the inside temperature was cooled to 10°C or less while replacing the inside of the reaction vessel with nitrogen. 206.6g (1.84 mol) of potassium tert-butoxide was added, followed by 648.6g (1.82 mol) of methyltriphenylphosphonium bromide, and the reaction was carried out for 30 minutes. 363.6g (1.51 mol) of compound (b-1) was added thereto, and the reaction was carried out at -10 to 40°C for 1 hour to obtain a reaction mixture.

[0040] The reaction mixture was added to 2 L of 10% sodium chloride aqueous solution and stirred. The organic layer was collected, while the aqueous layer was extracted with ethyl acetate and mixed with the previous organic layer. 0.4 g of p-methoxyphenol was added to this mixture, which was then dried over anhydrous magnesium sulfate, after which insoluble matter was filtered off, and volatile components were distilled off from the filtrate under reduced pressure to obtain 853.2 g of a pale yellow solid. This was pulverized in a mortar to obtain a powder. 1 H-NMR revealed that the weight fraction composition was 41.6 wt% [IA] and 58.4 wt% triphenylphosphine oxide (TPPO).

[0041] Isolation of compound [IA] 753 g of the powdery pale yellow solid was dissolved in 2 L of ethanol and left overnight at 5°C or less to crystallize [IA]. The amount of the precipitated yellow crystals was 283 g (yield 89%). The weight fraction composition was 97.6 wt% [IA] and 2.4 wt% TPPO. The yield was calculated using the following formula. 100×283 / [(753 / 853.2)×1.51×239.34] = 89%

[0042] Furthermore, the same procedure was carried out using 2.8 L of ethanol with 283 g of the precipitated yellow crystals, yielding 257 g (81% yield) of [IA] as pale yellow crystals. 1 As a result of H-NMR analysis, no signal derived from TPPO was observed. The yield was calculated according to the following formula. 100×257 / [(753 / 853.2)×1.51×239.34] = 81% TIFF0007642161000008.tif25129 Melting point 102℃ 1 H NMR (400MHz, CDCl3, δ ppm): 3.37 (s, 3H, NC H 3) 5.14 (d, J=10.8Hz, 1H, C H 2=CH-PTZ (Phenotia) Trans to the dimethyl group 5.61 (d, J=17.6Hz, 1H, C H 2=CH-PTZ (Phenotia) Cis to the dimethyl group 6.59 (dd, J=10.8Hz, 17.6Hz, 1H, CH2=C H -PTZ) 6.75 (d, J=8.4Hz, 1H, Ar) 6.81 (d, J=9.2Hz, 1H, Ar) 6.92 (td, J=7.6Hz, 1.2Hz, 1H, Ar) 7.11-7.23 (m, 4H, Ar)

[0043] Comparative Example 1 20 g of the powdery reaction mixture obtained in the examples was dissolved in about 100 mL of dichloromethane. Column chromatography (carrier: Wakogel C300, φ60 mm, height 60 mm) was performed using dichloromethane as the eluent. Dichloromethane was distilled off from the fraction of [I] (eluent volume about 300 ml) to obtain 12.7 g of a pale yellow solid (yield 150%). The weight fraction composition was [I] 68.7 wt% and TPPO 31.3 wt%. The yield was calculated from the following formula. 100×12.7 / 〔(20 / 853.2)×1.51×239.34〕=150%

[0044] The same procedure was carried out on 12.7 g of the pale yellow solid to obtain 8.5 g of a pale yellow solid (yield 100%). 1 As a result of H-NMR analysis, no signal derived from TPPO was observed. The yield was calculated according to the following formula. 100×8.5 / 〔(20 / 853.2)×1.51×239.34〕=100%

[0045] 8.5 g of the pale yellow solid was dissolved in 100 ml of ethanol and left overnight at 5° C. or lower to crystallize [IA]. The amount of the precipitated pale yellow crystals was 6.9 g (yield 81%). 100×6.9 / 〔(20 / 853.2)×1.51×239.34〕=81%

[0046] Comparative Example 2 10 g of the powdery pale yellow solid obtained in the example was dissolved in 150 ml of methanol and then left overnight at 5°C or lower to crystallize [IA]. The amount of the precipitated yellow crystals was 3.2 g (yield 76%). The weight fraction composition of the crystals was 99.0 wt% [IA] and 1.0 wt% TPPO. 100×3.2 / 〔(10 / 853.2)×1.51×239.34〕=76%

[0047] The same procedure was carried out on 3.2 g of the precipitated yellow crystals using 200 ml of methanol, yielding 2.1 g (50% yield) of [IA] as pale yellow crystals. 1 As a result of H-NMR analysis, no signal derived from TPPO was observed. 100×2.1 / 〔(10 / 853.2)×1.51×239.34〕=50%

[0048] Comparative Example 3 10 g of the powdery pale yellow solid obtained in the example was dissolved in 20 ml of isopropanol and then left overnight at 5°C or lower to crystallize [IA]. The amount of the precipitated yellow crystals was 3.8 g (yield 90%). The weight fraction composition of the crystals was 93.3 wt% [IA] and 6.7 wt% TPPO. 100×3.8 / 〔(10 / 853.2)×1.51×239.34〕=90%

[0049] The same procedure was carried out on 3.8 g of the precipitated yellow crystals using 30 ml of isopropanol to obtain 2.6 g (61% yield) of [IA] as pale yellow crystals. 1 As a result of H-NMR analysis, no signal derived from TPPO was observed. 100×2.6 / 〔(10 / 853.2)×1.51×239.34〕=61%

Claims

1. general formula (where R １ is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and R 2 is a hydrogen atom or a methyl group), to obtain a phenothiazine carbaldehyde derivative compound or a phenothiazine acetyl derivative compound represented by the general formula (where R １ and R 2 wherein x is as defined above), the phenothiazine derivative compound [I] is crystallized from a reaction mixture containing the phenothiazine derivative compound [I] after the Wittig reaction and triphenylphosphine oxide using ethanol.

2. 2. The method for isolating a phenothiazine derivative compound according to claim 1, wherein the crystallization using ethanol is carried out at -30°C to 30°C.

3. 2. The method for isolating a phenothiazine derivative compound according to claim 1, wherein the phenothiazine derivative compound [I] is 3-ethenyl-10-methyl-10H-phenothiazine.

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