Method for separating phenothiazine derivative compounds

Abstract

In the general formula (b) (wherein, R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, R 2 A phenothiazine carboxaldehyde derivative compound or a phenothiazine acetyl derivative compound represented by (i) is converted into a compound of the general formula [I] (wherein R 1 and R 2 When the phenothiazine derivative compound is a phenothiazine derivative compound represented by (i) as defined above, ethanol is used to crystallize the phenothiazine derivative compound [I] from the reaction mixture containing the ylide-reacted phenothiazine derivative compound [I] and triphenylphosphine oxide to separate the phenothiazine derivative compound.

Description

Technical Field

[0001] The present invention relates to a method for separating a phenothiazine derivative compound, and more particularly to a method for separating a phenothiazine derivative compound capable of separating the compound with a high yield in industrial production. Background Art

[0002] So far, various synthetic polymer materials, such as synthetic rubber and synthetic resin, have been manufactured and used as raw materials mainly based on fossil resources. Moreover, they have penetrated into every corner of the economy and society, bringing great convenience and benefits to our lives.

[0003] Such synthetic polymer materials are oxidatively degraded by heat, light, oxygen, ozone, etc., and sometimes lose their original physical properties and functions over time. In order to prevent this, antioxidants are added to their manufacturing and molding processes. For example, a certain synthetic polymer material is manufactured through processes such as polymerization of the monomers that constitute it, recovery of unreacted monomers, removal of polymerization medium, coagulation, drying, and granulation. However, in order to prevent the deterioration of the polymer material caused by the thermal history in the drying process and granulation process, antioxidants are added in advance. As antioxidants, phenolic or amine antioxidants can be used. In particular, when appearance is important, low-molecular-weight phenolic antioxidants can be used.

[0004] In addition, when the synthetic polymer material formed into a desired shape component is used under harsh conditions such as high temperature, in order to prevent the function from being reduced due to thermal oxidation degradation, a new antioxidant is added in advance during the forming process. Here, phenolic or amine antioxidants can also be used as antioxidants, and in particular, in order to prevent volatilization or dissolution to the external environment, relatively high molecular weight antioxidants tend to be used. Generally, phenolic antioxidants are used in resinous polymer materials, and amine antioxidants are used in elastomeric polymer materials.

[0005] Problems with adding antioxidants include the cost of adding them, the need to add antioxidants twice in succession, and the need to granulate certain amine antioxidants due to concerns about health hazards to humans due to exposure.

[0006] Furthermore, at the stage of using polymer molded parts, sometimes the appearance is poor due to the surface migration of the antioxidant, the antioxidant volatilizes to the outside due to heat, or the antioxidant is extracted due to water, grease, solvents, etc., which leads to the loss of the original function of the antioxidant. Furthermore, in the case of direct contact between polymer molded parts and food, it is necessary to consider whether the dissolution amount of the antioxidant is allowed in health. In addition, in the case of large molded parts, a large amount of antioxidants may volatilize to the external environment, which is not ideal from the perspective of environmental protection.

[0007] From this viewpoint, attempts have been made to chemically bond antioxidants to polymer materials to suppress the surface migration, volatilization, and dissolution of antioxidants.

[0008] For example, in the case of elastomeric polymer materials, attempts have been made to chemically bond antioxidant components to polymer chains (Patent Documents 1 to 3, Non-Patent Documents 1 to 2). However, these methods further require a modification step, lacking practicality from the perspective of manufacturing cost, and also have the following problems: the copolymerization of conventional antioxidants having polymerizable unsaturated groups and active sites such as NH groups and OH groups, such as N-(4-anilinophenyl)methacrylamide, is difficult.

[0009] In order to solve the above-mentioned problems, the present applicant has proposed using a phenothiazine derivative compound represented by the general formula [I] as a copolymerizable antioxidant (Japanese Patent Application No. 2022-66753).

[0010]

[0011] (Here, R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, R 2 is a hydrogen atom or a methyl group)

[0012] The compound reduces the free radical polymerization inhibition effect peculiar to phenothiazine compounds by replacing the hydrogen atom on the nitrogen atom at position 10 with an aliphatic hydrocarbon group, so that it can be free radical copolymerized with various polymerizable unsaturated monomers. In addition, for the same reason, hydrogen abstraction reaction is substantially avoided for basic compounds such as alkyl lithium compounds, so that it can also be anion copolymerized with various polymerizable unsaturated monomers.

[0013] Furthermore, for the same reason, the deactivation of the catalyst used in the coordination polymerization can be prevented, and thus coordination copolymerization with various polymerizable unsaturated monomers is possible.

[0014] Thus, in order to stabilize the synthetic polymer material produced by addition polymerization of a polymerizable unsaturated monomer against thermal oxidative degradation, a phenothiazine derivative compound [I] is preferred.

[0015] The synthetic polymer material obtained by copolymerizing the phenothiazine derivative compound [I] can effectively stabilize the synthetic polymer material against thermal oxidative degradation because the antioxidant component is chemically bonded. As a result, it is substantially unnecessary to newly add an antioxidant in the manufacturing process and molding process. In addition, the amount of compound [I] used can also be reduced compared to conventional antioxidants.

[0016] In addition, when using polymer material molded parts, it is possible to prevent poor appearance caused by surface migration of antioxidants, volatilization of antioxidants to the outside caused by heat, or extraction of antioxidants caused by water, oils, solvents, etc., resulting in a longer life of polymer molded parts under various degradation environments.

[0017] Furthermore, in the case of direct contact between polymer molded parts and food, etc., it is necessary to consider the amount of antioxidant elution that is permitted from a health perspective, but this is also eliminated. In the case of large molded parts, a large amount of antioxidant may volatilize into the external environment, which is not ideal from the perspective of environmental protection, but this can also be eliminated.

[0018] Specific examples of phenothiazine derivative compounds [I] include 2-vinyl-10-methyl-10H-phenothiazine, 2-(1-methylvinyl)-10-methyl-10H-phenothiazine, 3-vinyl-10-methyl-10H-phenothiazine, 3-(1-methylvinyl)-10-methyl-10H-phenothiazine, etc. The method for producing the phenothiazine derivative compound [I] is not particularly limited, and it can be produced using inexpensive diphenylamine or 10H-phenothiazine as a starting material. For example, in non-patent documents 3 to 4, methods for producing 2-(1-methylvinyl)-10-methyl-10H-phenothiazine and 3-vinyl-10-methyl-10H-phenothiazine are described, respectively.

[0019] The reaction of preparing a phenothiazine derivative compound [I] from 10-alkyl-10H-phenothiazine carboxaldehyde or 10-alkyl-10H-phenothiazine acetyl by a ylide (Wittig) reaction is easy to carry out and can produce compound [I] in high yield. However, it is difficult to separate and remove triphenylphosphine oxide from the reaction mixture, and it is difficult to effectively separate and purify compound [I] on an industrial scale.

[0020] As a laboratory method, column chromatography is used with silica gel as a carrier and a mixed solvent of a good solvent such as chloroform, dichloromethane, ethyl acetate and a poor solvent such as petroleum ether, n-hexane, cyclohexane as an eluent (Non-patent Documents 3-4). However, in this purification method, in order to completely remove triphenylphosphine oxide, not only is it necessary to repeat the separation operation based on column chromatography many times, but also a large amount of organic solvent and carrier are required, so there is a disadvantage that it is not suitable for industrial manufacturing processes.

[0021] In addition to the above-mentioned chromatography-based method, there is a method for separating triphenylphosphine oxide from the ylide reaction mixture, which includes dissolving the reaction mixture in a good solvent and then adding it 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.

[0022] Therefore, in the preparation of phenothiazine derivative compounds based on ylide reactions, a simpler and more efficient method for isolating compound [I] is desired.

[0023] Prior art literature

[0024] Patent Literature

[0025] Patent Document 1: Japanese Patent Application Laid-Open No. 4-264106

[0026] Patent Document 2: Japanese Patent Application Laid-Open No. 5-230132

[0027] Patent Document 3: Japanese Patent Application Publication No. 2009-209268

[0028] Non-patent literature

[0029] Non-patent document 1: Rubber Chem. Technol., Vol. 46, p. 106 (1973)

[0030] Non-patent document 2: Rubber Chem. Technol., Vol. 52, p. 883 (1979)

[0031] Non-patent document 3: Organic Letters, Vol. 23, p. 4564 (2021)

[0032] Non-patent document 4: Energy Environ. Sci., Vol. 10, pp. 2334-2341 (2017) Summary of the invention

[0033] Technical problem to be solved by the invention

[0034] The present invention has been made in view of the above problems and provides a method for isolating a phenothiazine derivative compound [I], which can more simply and efficiently isolate the phenothiazine derivative compound [I] in the production of the phenothiazine derivative compound based on the ylide reaction.

[0035]

[0036] (Here, R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, R 2 is a hydrogen atom or a methyl group).

[0037] Solutions to Solve Problems

[0038] The above-mentioned object of the present invention is achieved by crystallizing a phenothiazine derivative compound [I] from a reaction mixture containing a ylide-reacted phenothiazine derivative compound [I] and triphenylphosphine oxide using ethanol.

[0039] Effects of the Invention

[0040] In the conventional method, the ylide reaction mixture is dissolved in a good solvent for the target product, and then added to a poor solvent for triphenylphosphine oxide to separate the target product. However, in the present invention, on the contrary, the ylide reaction mixture is dissolved in ethanol which is a poor solvent for the phenothiazine derivative compound [I] and a good solvent for triphenylphosphine oxide, and then only the phenothiazine derivative compound [I] is crystallized from the solution, thereby easily separating the phenothiazine derivative compound [I].

[0041] When the method for isolating the phenothiazine derivative compound [I] of the present invention is used, the phenothiazine derivative compound [I] can be produced simply and efficiently on an industrial scale. DETAILED DESCRIPTION

[0042] The phenothiazine derivative compound is represented by the general formula [I].

[0043]

[0044] (Here, R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, R 2 is a hydrogen atom or a methyl group)

[0045] The phenothiazine derivative compound [I] can be easily produced from 10-alkyl-10H-phenothiazine carboxaldehyde (b) or 10-alkyl-10H-phenothiazine acetyl by, for example, ylide reaction.

[0046]

[0047] After the reaction is completed, a conventional post-reaction treatment is performed to obtain a ylide reaction mixture containing the phenothiazine derivative compound [I] and triphenylphosphine oxide as main components. This is dissolved in ethanol and filtered when a small amount of insoluble matter is produced. The filtrate is preferably allowed to stand at 30°C or less, more preferably at -30°C to 10°C for 1 to 24 hours to crystallize the phenothiazine derivative compound [I].

[0048] Here, when the reaction mixture is dissolved in ethanol, the solution is heated to 50°C or higher, preferably to near the boiling point of ethanol. In addition, ethanol is used in an amount that allows the phenothiazine derivative compound [I] and triphenylphosphine oxide to be almost completely dissolved, but the amount can be appropriately adjusted according to the content of triphenylphosphine oxide and the solubility of the phenothiazine derivative compound [I] in ethanol. For example, in the case of 3-vinyl-10-methyl-10H-phenothiazine, about 0.4 liters to 1.5 liters of ethanol are used relative to 100 g of the reaction mixture.

[0049] Furthermore, in the dissolving step, a small amount of a polymerization inhibitor such as p-methoxyphenol may be added. The amount added is 10 ppm to 10,000 ppm, preferably 100 ppm to 1,000 ppm, based on the expected yield of the phenothiazine derivative compound [I].

[0050] In this way, the target phenothiazine derivative compound [I] can be obtained simply, at high purity and in high recovery rate. Therefore, the above separation method is preferred when the phenothiazine derivative compound [I] is industrially produced by ylide reaction.

[0051] Example

[0052] Next, the present invention will be specifically described by way of examples. It should be noted that the present invention, including its effects, is not limited to the examples.

[0053] -Production of Phenothiazine Derivative Compound [IA]-

[0054]

[0055] Reference example

[0056] Preparation of compound (a-1)

[0057] [1st step] [PTZ] → (a-1):

[0058] In a 5L five-necked flask equipped with a stirring device, a thermometer, a dropping funnel, a nitrogen inlet pipe and an outlet pipe, 2.0L of fully dehydrated N,N-dimethylformamide was added, and the temperature in the system was cooled to below 10°C under a nitrogen atmosphere. After adding 103.4g (2.59 mol) of sodium hydride (purity 60%) and stirring for 10 minutes, 401.0g (2.01 mol) of phenothiazine (PTZ) was added in several portions while the temperature in the system was kept below 10°C, and the reaction was allowed to proceed for 30 minutes. While the temperature in the system was kept below 10°C, 312.3g (2.20 mol) of iodomethane was added dropwise, and the reaction was allowed to proceed for another hour. After the reaction was completed, the reaction mixture was added to 4L of a 10% sodium chloride aqueous solution. The precipitated colorless solid was separated by filtration and washed with 4L of distilled water.

[0059] 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 the insoluble matter was filtered. The volatile components were distilled off from the filtrate under reduced pressure to obtain 451.4 g (crude yield 105%) of a crude product. By washing (defatting) it with 0.7 L of isooctane, 421.2 g (yield 98.2%) of 10-methyl-10H-phenothiazine (a-1) was obtained as a slightly gray crystalline solid.

[0060]

[0061] 1 H NMR (400 MHz, 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)

[0062] Preparation of compound (b-1)

[0063] [Second step] (a-1) → (b-1):

[0064] In a 3L five-necked flask equipped with a stirring device, a dropping funnel, a thermometer, a gas inlet, a gas outlet and a reflux cooling tube, 0.7L of fully dehydrated N,N-dimethylformamide was placed. Under a nitrogen atmosphere, while the internal temperature in the system was maintained at 10°C or less, 509g (3.32 mol) of phosphorus oxychloride was added dropwise, and the reaction was carried out for another 30 minutes. Next, 291.2g (1.37 mol) of 10-methyl-10H-phenothiazine (a-1) obtained in the first step was added, and the reaction was carried out at 60°C for 17 hours. After the reaction was completed, the contents were poured into 2.3kg of a 50% sodium acetate aqueous solution cooled in an ice water bath, and 194g of sodium hydroxide was added to adjust the pH to 6 or more.

[0065] The resulting solution was allowed to stand for 2 hours while cooling in an ice-water bath. After filtering the precipitated solid, wash it with 3L of distilled water to dissolve the inorganic electrolyte. The remaining dark brown solid was dissolved in 1.5L of warm ethyl acetate at about 50°C, and after separating the lower layer (water tank), the organic layer was dried over anhydrous magnesium sulfate. After filtering the insoluble matter, the volatile components were distilled off from the filtrate under reduced pressure to obtain 329.0g (crude yield 99.9%) of a crude product as a reddish brown oily substance. The crude product was dissolved in about 1L of ethyl acetate, and low Rf components were removed by passing through a silica gel (Wakogel C300) column. By distilling off the volatile components from the eluent under reduced pressure, 321.6g of a yellow solid (yield 97.6%) was obtained. Furthermore, recrystallization was carried out using 320 ml of ethyl acetate to obtain 308.2 g (yield 93.6%) of 10-methyl-10H-phenothiazine-3-carbaldehyde (b-1) as yellow crystals.

[0066]

[0067] 1 H NMR (400 MHz, 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)

[0068] Example

[0069] Preparation of compound 〔IA〕

[0070] [Third step] (b-1) → [IA]:

[0071] 2.3 L of tetrahydrofuran was placed in a 5 L five-necked flask equipped with a stirring device, a thermometer, a gas introduction pipe and a gas discharge pipe, and the internal temperature of the reaction container was cooled to below 10°C while replacing the inside of the reaction container with nitrogen. 206.6 g (1.84 mol) of potassium tert-butoxide and then 648.6 g (1.82 mol) of methyltriphenylphosphonium bromide were added and reacted for 30 minutes. 363.6 g (1.51 mol) of compound (b-1) was added thereto and reacted at -10 to 40°C for 1 hour to obtain a reaction mixture.

[0072] The reaction mixture was added to 2L of 10% sodium chloride aqueous solution and stirred. The organic layer was recovered, and the aqueous layer was extracted with ethyl acetate and mixed with the previous organic layer. 0.4g of p-methoxyphenol was added to the mixture, and the insoluble matter was filtered after drying with anhydrous magnesium sulfate. The volatile components were distilled off from the filtrate under reduced pressure to obtain 853.2g of light yellow solid. It was crushed in a mortar to make a powder. 1 H-NMR showed that its weight fraction composition was [IA] 41.6 wt%, triphenylphosphine oxide (TPPO) 58.4 wt%.

[0073] Isolation of compound 〔IA〕

[0074] 753 g of the powdery light yellow solid was dissolved in 2 L of ethanol and left overnight at 5°C or below to allow [IA] to crystallize. The amount of the crystallized yellow crystals was 283 g (yield 89%). The weight fractions were [IA] 97.6 wt%, TPPO 2.4 wt%. It should be noted that the yield was calculated by the following formula.

[0075] 100×283 / 〔(753 / 853.2)×1.51×239.34〕=89%

[0076] Furthermore, the same operation was performed on 283 g of the precipitated yellow crystals using 2.8 L of ethanol to obtain 257 g (yield 81%) of light yellow crystals [IA]. 1 The obtained light yellow crystals were analyzed by H-NMR, and no signal derived from TPPO was observed. The yield was calculated by the following formula.

[0077] 100×257 / 〔(753 / 853.2)×1.51×239.34〕=81%

[0078]

[0079] Melting point 102℃

[0080] 1 H NMR (400MHz, CDCl3, δppm): 3.37 (s, 3H, NC H 3)5.14(d, J=10.8Hz, 1H, C H 2=CH-PTZ (trans relative to phenothiazinyl)) 5.61 (d, J=17.6 Hz, 1H, C H 2=CH-PTZ (cis relative to phenothiazinyl)) 6.59 (dd, J=10.8 Hz, 17.6 Hz, 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)

[0081] Comparative Example 1

[0082] 20 g of the powdered reaction mixture obtained in Example was dissolved in about 100 mL of dichloromethane. Column chromatography (carrier: Wakogel C300) was performed using dichloromethane as an eluent. Height 60mm). Dichloromethane was distilled off from the fraction of [I] (eluent volume about 300ml) to obtain 12.7g of light yellow solid (yield 150%). Its weight fraction composition was [I] 68.7wt%, TPPO 31.3wt%. It should be noted that the yield was calculated by the following formula.

[0083] 100×12.7 / 〔(20 / 853.2)×1.51×239.34〕=150%

[0084] The same operation was performed on 12.7 g of a light yellow solid to obtain 8.5 g of a light yellow solid (yield 100%). 1 The obtained light yellow solid was analyzed by H-NMR, and no signal derived from TPPO was observed. The yield was calculated by the following formula.

[0085] 100×8.5 / 〔(20 / 853.2)×1.51×239.34〕=100%

[0086] 8.5 g of the light yellow solid was dissolved in 100 ml of ethanol and the mixture was left to stand at 5°C or below overnight to allow crystallization of [IA]. The amount of light yellow crystals precipitated was 6.9 g (yield 81%).

[0087] 100×6.9 / 〔(20 / 853.2)×1.51×239.34〕=81%

[0088] Comparative Example 2

[0089] 10 g of the light yellow powder obtained in Example 1 was dissolved in 150 ml of methanol and allowed to stand overnight at 5°C or below to allow [IA] to crystallize. The amount of the crystallized yellow crystals was 3.2 g (yield 76%). The weight fractions were [IA] 99.0 wt%, TPPO 1.0 wt%.

[0090] 100×3.2 / 〔(10 / 853.2)×1.51×239.34〕=76%

[0091] Furthermore, the same operation was carried out on 3.2 g of the precipitated yellow crystals using 200 ml of methanol to obtain 2.1 g (yield 50%) of light yellow crystals [IA]. 1 The obtained light yellow crystals were analyzed by H-NMR, and no signal derived from TPPO was observed.

[0092] 100×2.1 / 〔(10 / 853.2)×1.51×239.34〕=50%

[0093] Comparative Example 3

[0094] 10 g of the light yellow solid powder obtained in Example 1 was dissolved in 20 ml of isopropanol and allowed to stand overnight at 5°C or below to allow [IA] to crystallize. The amount of the crystallized yellow crystals was 3.8 g (yield 90%). The weight fractions were [IA] 93.3 wt%, TPPO 6.7 wt%.

[0095] 100×3.8 / 〔(10 / 853.2)×1.51×239.34〕=90%

[0096] Furthermore, the same operation was carried out on 3.8 g of the precipitated yellow crystals using 30 ml of isopropyl alcohol to obtain 2.6 g (yield 61%) of pale yellow crystals [IA]. 1 The obtained light yellow crystals were analyzed by H-NMR, and no signal derived from TPPO was observed.

[0097] 100×2.6 / 〔(10 / 853.2)×1.51×239.34〕=61%.

Claims

1. A method for separating a phenothiazine derivative compound, characterized in that: When a phenothiazine carboxaldehyde derivative compound or a phenothiazine acetyl derivative compound represented by the general formula (b) is converted into a phenothiazine derivative compound represented by the general formula [I] by a ylide reaction, ethanol is used to crystallize the phenothiazine derivative compound [I] from a reaction mixture containing the phenothiazine derivative compound [I] after the ylide reaction and triphenylphosphine oxide, In the general formula (b), R 1 is a monovalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, R 2 is a hydrogen atom or a methyl group, In the general formula [I], R 1 and R 2 Same as the above definition.

2. The method for separating a phenothiazine derivative compound according to claim 1, wherein: Crystallization using ethanol is performed at -30°C to 30°C.

3. The method for separating a phenothiazine derivative compound according to claim 1, wherein: The phenothiazine derivative compound [I] is 3-vinyl-10-methyl-10H-phenothiazine.

Images