Triazine compound, synthesis method therefor, and applications thereof

Abstract

To provide a novel triazine compound and applications thereof, specifically, a novel triazine compound, a synthesis method for the triazine compound, a substituent-introducing agent comprising the triazine compound, and a protecting agent.SOLUTION: Provided is a triazine compound represented by Chemical Formula (I) (where, Y represents a single bond or a C1-10 alkylene group; and R may be the same or different and represents a hydrogen atom, a linear, branched, or cyclic C1-10 alkyl group, an aryl group, a vinyl group, a halogen atom, a nitrile group, a nitro group, an alkoxy group, or a trichloromethyl group).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel triazine compound, a method for synthesizing the triazine compound, and a substituent-introducing agent and a protecting agent containing the triazine compound. [Background technology]

[0002] In organic synthesis, the reactivity, solubility, absorption wavelength, etc. of a molecule can be manipulated by introducing a substituent into the molecule. Among the substituents, a protecting group is a functional group that induces (protects) a functional group of the molecule to a temporarily inactive structure during a synthetic reaction, and can be removed (deprotected) to return it to its original structure after the reaction. Therefore, substituent-introducing agents and protecting agents are important materials for molecular design.

[0003] For example, acetal-type protecting groups (e.g., methoxymethyl, ethoxymethyl, methoxyethoxymethyl, etc.) are used as protecting groups for nucleophilic functional groups. These protecting groups are stable under various reaction conditions and can be easily deprotected under weakly acidic conditions. Known methods for protecting nucleophilic functional groups with acetal-type protecting groups include (1) a method in which an alkoxymethyl halide is added dropwise in the presence of a small excess of diisopropylethylamine to cause a reaction, and (2) a method in which a large excess of dialkoxymethane is reacted by heating in the presence of a strong acid catalyst (see, for example, Non-Patent Document 1). However, method (1) is based on basic conditions, and therefore cannot be applied to the protection of base-labile alcohols (hydroxyl groups), and has the problem of using highly toxic alkoxymethyl halides. Method (2) is based on strongly acidic conditions, and therefore cannot be applied to acid-labile alcohols (hydroxyl groups), and is uneconomical because it uses a large excess of dialkoxymethane, and furthermore, it is an equilibrium reaction, and therefore the reaction is prone to become complicated. Therefore, a method that can introduce protective groups under mild conditions to functional groups that are unstable to acids and bases has been desired.

[0004] In view of this situation, an acetal-type protecting agent capable of protecting a hydroxyl group under mild reaction conditions has been proposed (see, for example, Patent Document 1). However, this protecting agent has an allyl halogen structure, and since α-haloketones are generated after the introduction of a protecting group, there are concerns about its carcinogenicity, toxicity, etc., similar to alkoxymethyl halides.

[0005] In addition, a protecting agent having a triazine ring structure has been proposed as a protecting agent capable of protecting a hydroxyl group under acidic conditions (see, for example, Patent Document 2). However, the protecting group (e.g., benzyl group, etc.) introduced by this protecting agent is a very strong protecting group, and therefore catalytic reduction or extreme acidic conditions are required for deprotection. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Protective Groups in Organic Synthesis, 3rd ed., Wiley Interscience Publication, John Wiley & Sons, Inc., 1999, pp. 27-49 [Patent documents]

[0007] [Patent Document 1] International Publication No. 2005 / 014508 [Patent Document 2] JP 2013-126976 A Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel triazine compound and uses thereof. Specifically, an object of the present invention is to provide a novel triazine compound, a method for synthesizing the triazine compound, and a substituent-introducing agent and a protecting agent containing the triazine compound. [Means for solving the problem]

[0009] Means for Solving the Problems The present inventors have conducted intensive research to solve the above problems, and as a result have found that a triazine compound obtained by reacting trithiocyanuric acid with a certain type of halogen compound is a novel compound, and that this compound is stable and yet allows the introduction of a substituent or a protecting group into a nucleophilic functional group under acidic conditions, thereby completing the present invention. That is, a first aspect of the present invention is a triazine compound represented by chemical formula (I).

[0010] [ka] (In the formula, Y represents a single bond or an alkylene group having 1 to 10 carbon atoms. R may be the same or different and represents a hydrogen atom, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, an aryl group, a vinyl group, a halogen atom, a nitrile group, a nitro group, an alkoxy group, or a trichloromethyl group.)

[0011] The second invention is a method for synthesizing the triazine compound of the first invention, which comprises reacting trithiocyanuric acid represented by chemical formula (II) with a halogen compound represented by chemical formula (III).

[0012] [ka]

[0013] [ka] (In the formula, Y and R are the same as above. X represents a halogen atom.)

[0014] The third invention is a substituent-introducing agent characterized by containing the triazine compound of the first invention. The fourth invention is a protecting agent characterized by containing the triazine compound of the first invention. Effect of the Invention

[0015] The triazine compound of the present invention is a stable compound and can introduce a substituent or a protecting group into a nucleophilic functional group under mild acidic conditions, and is therefore expected to be useful as a substituent-introducing agent and a protecting agent. [Brief description of the drawings]

[0016] [Figure 1] 1 is an IR spectrum chart of the pale yellow powder obtained in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention will be described in detail below. <Triazine compounds> The present invention relates to a triazine compound represented by the above chemical formula (I) (hereinafter, sometimes referred to as "the triazine compound of the present invention"). Examples of the triazine compound represented by chemical formula (I) include compounds represented by chemical formulas (I-1) to (I-16).

[0018] [ka]

[0019] [ka]

[0020] [ka]

[0021] Examples of the alkylene group having 1 to 10 carbon atoms represented by Y include linear or branched alkylene groups having 1 to 10 carbon atoms, and specific examples thereof include a methylene group, a methylmethylene group, a dimethylene group, a trimethylene group, an ethylmethylene group, a dimethylmethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a nonamethylene group, and a decamethylene group. In the triazine compound of the present invention, Y is preferably a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms.

[0022] Specific examples of the linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms represented by R include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, a sec-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and a 2-methyl-5-(1-methylethyl)cyclohexyl group.

[0023] Examples of the aryl group represented by R include a phenyl group, a 2-tolyl group, a 3-tolyl group, a 4-tolyl group, a 2,3-xylyl group, a 2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylyl group, a 3,5-xylyl group, a 2,4,6-trimethylphenyl group, a 2,3,5-trimethylphenyl group, a 2,3,6-trimethylphenyl group, a 2,4,5-trimethylphenyl group, a 2,3,5,6-tetramethylphenyl group, a biphenyl group, a 1-naphthyl group, and a 2-naphthyl group.

[0024] Specific examples of the halogen atom represented by R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0025] Examples of the alkoxy group represented by R include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, and an n-pentoxy group.

[0026] In the triazine compound of the present invention, preferred substituents are as follows. R are preferably the same and are a linear or branched alkyl group having 1 to 10 carbon atoms, and more preferably are a linear or branched alkyl group having 1 to 4 carbon atoms. Y are preferably the same and are a single bond or a linear or branched alkylene group having 1 to 10 carbon atoms, and more preferably are a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms.

[0027] <Synthesis method> The triazine compound of the present invention can be synthesized by reacting trithiocyanuric acid represented by chemical formula (II) with a halogen compound represented by chemical formula (III) (see Reaction Scheme (A) described later).

[0028] Trithiocyanuric acid represented by chemical formula (II) can be used as a commercially available reagent.

[0029] Examples of the halogen compound represented by the chemical formula (III) include the halogen compounds represented by the chemical formulas (III-1-1) to (III-16-2).

[0030] [ka]

[0031] [ka]

[0032] These halogen compounds can be used as commercially available reagents, or can be synthesized according to the method described in Org. Synth., 1929, 9, 58, for example.

[0033] In the halogen compound represented by chemical formula (III), specific examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0034] The amount of the halogen compound represented by the chemical formula (III) used is preferably an appropriate ratio within a range of 3 to 6 times the amount of the trithiocyanuric acid compound represented by the chemical formula (II) used.

[0035] For example, the triazine compound of the present invention represented by chemical formula (I-1) is synthesized by reacting trithiocyanuric acid represented by chemical formula (II) with a halogen compound represented by chemical formula (III-1-2) as shown in reaction scheme (A).

[0036] [ka]

[0037] In carrying out this reaction, it is preferable to use a base (i) for removing the acid by-produced as the reaction proceeds, and if necessary, a reaction solvent (ii) may be used appropriately.

[0038] Examples of the base (i) include trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), pyridine, 4-(N,N-dimethylamino)pyridine, picoline, N,N-dimethylaniline, N,N-diethylaniline, imidazole, lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, and sodium carbonate. , potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, trilithium phosphate, trisodium phosphate, tripotassium phosphate, tricesium phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, discesium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, cesium dihydrogen phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, lithium alkoxides (lithium methoxide, etc.), sodium alkoxides (sodium methoxide, sodium ethoxide, etc.), potassium alkoxides (potassium t-butoxide, etc.), etc. These may be used alone or in combination of two or more.

[0039] The amount of the base (i) used is preferably an appropriate ratio within a range of 3 to 6 times the amount of trithiocyanuric acid represented by the chemical formula (II) used.

[0040] The reaction solvent (ii) is not particularly limited as long as it does not inhibit the reaction, and examples thereof include solvents such as tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide. These can be combined as necessary and used in appropriate amounts.

[0041] In this reaction, the reaction temperature is preferably set in the range of −10 to 30° C. The reaction time is appropriately set depending on the set reaction temperature, but is preferably set in the range of 1 to 24 hours.

[0042] After completion of the reaction, the target triazine compound of the present invention can be isolated from the resulting reaction solution by, for example, concentrating the reaction solution by distilling off the reaction solvent or by solvent extraction. If necessary, the product can be purified by washing with water or the like, treatment with activated carbon, silica gel chromatography, recrystallization, or the like.

[0043] <Substituent-introducing agents and protecting agents> The triazine compound of the present invention can be used as a substituent-introducing agent for introducing a substituent into a nucleophilic functional group in an organic synthesis reaction. The triazine compound of the present invention can also be used as a protecting agent for introducing a protecting group into a nucleophilic functional group in an organic synthesis reaction. Examples of the nucleophilic functional group include a hydroxyl group, a carboxyl group, an amino group, an amide group, and a mercapto group, with a hydroxyl group being preferred.

[0044] When the triazine compound of the present invention is used as a protecting agent, it can be carried out, for example, by the following steps. Step 1: A step of reacting a compound having a nucleophilic functional group with the triazine compound of the present invention to protect the nucleophilic functional group. Step 2: A step of carrying out a further reaction (such as an oxidation / reduction reaction of an unprotected functional group) on a compound having a protected substituent. Step 3: Deprotecting the protected substituent.

[0045] In step 1, a compound having a nucleophilic functional group is reacted with the triazine compound of the present invention in the presence of an acid catalyst (iii), thereby protecting the nucleophilic functional group. In order to improve reactivity, a reaction promoter (iv) may be used in combination with the acid catalyst (iii). If necessary, a reaction solvent (v) may be used appropriately. In addition, during this reaction, it is preferable to remove water that may be mixed in, for example, in the presence of a dehydrating agent (vi) such as molecular sieves.

[0046] In this reaction, the amount of the triazine compound of the present invention used is preferably an appropriate ratio in the range of 0.2 to 2 times the number of moles of the nucleophilic functional group of the compound having a nucleophilic functional group, and more preferably an appropriate ratio in the range of 0.3 to 1.2 times the number of moles of the nucleophilic functional group.

[0047] Examples of the acid catalyst (iii) include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, benzoic acid, oxalic acid, citric acid, phosphoric acid, hexafluorophosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, boric acid, boron trifluoride, and tetrafluoroboric acid, with camphorsulfonic acid being preferred.

[0048] The amount of the acid catalyst (iii) used is preferably an appropriate ratio within a range of 0.01 to 10 times the amount of the triazine compound of the present invention used, and more preferably an appropriate ratio within a range of 0.1 to 1 times the amount of the triazine compound used.

[0049] Examples of the reaction promoter (iv) include iodine, iodine monochloride, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, and the like, with N-iodosuccinimide being preferred.

[0050] The amount of the reaction accelerator (iv) used is preferably 0.1 to 10 times by mol, more preferably 1 to 5 times by mol, relative to the amount of the triazine compound of the present invention used.

[0051] The reaction solvent (v) may be any solvent that is inactive to the compound having a nucleophilic functional group, the triazine compound of the present invention, and the acid catalyst (iii). Examples of the reaction solvent include toluene, xylene, acetonitrile, 1,2-dimethoxyethane, diethyl ether, tetrahydrofuran, dioxane, chloroform, and dichloromethane, and 1,2-dimethoxyethane is preferred.

[0052] The dehydrating agent (vi) may be any agent capable of removing water mixed in during the reaction, and examples thereof include molecular sieves, magnesium sulfate, and sodium sulfate.

[0053] In this reaction, the reaction temperature is preferably set in the range of −20 to 30° C. The reaction time is appropriately set depending on the set reaction temperature, but is preferably set in the range of 1.5 to 6 hours.

[0054] For example, a reaction scheme (B) shows an example of a reaction in which the hydroxyl group of 3-phenyl-1-propanol is protected with the triazine compound of the present invention represented by the chemical formula (I-1).

[0055] [ka]

[0056] In step 3, the compound having a protected substituent can be deprotected by reacting it under acidic conditions. If necessary, a reaction solvent (vii) may be appropriately used.

[0057] Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid, with hydrochloric acid being preferred.

[0058] The amount of the acid used is preferably an appropriate ratio within a range of 1 to 40 times the amount of the compound having a protected substituent used.

[0059] The reaction solvent (vii) may be any solvent capable of dissolving a compound having a protected substituent and an acid. Examples of the reaction solvent include toluene, xylene, acetonitrile, 1,2-dimethoxyethane, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, and the like. Of these, 1,2-dimethoxyethane is preferred.

[0060] In this reaction, the reaction temperature is preferably set in the range of 0 to 80° C. The reaction time is appropriately set depending on the set reaction temperature, but is preferably set in the range of 0.5 to 24 hours. EXAMPLES

[0061] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. The main raw materials used in the examples are as follows:

[0062] Trithiocyanuric acid (see chemical formula (II), manufactured by Tokyo Chemical Industry Co., Ltd.) Methoxymethyl chloride (see chemical formula (III-1-2), manufactured by Tokyo Chemical Industry Co., Ltd.) N,N-Diisopropylethylamine (Tokyo Chemical Industry Co., Ltd.) Dichloromethane (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) 3-Phenyl-1-propanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Camphorsulfonic acid (Tokyo Chemical Industry Co., Ltd.) N-Iodosuccinimide (Fujifilm Wako Pure Chemical Industries, Ltd.) 1,2-Dimethoxyethane (Fujifilm Wako Pure Chemical Industries, Ltd.) Molecular sieve 5A (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)

[0063] Example 1 <Synthesis of 2,4,6-tris(methoxymethylthio)-1,3,5-triazine> A 100 mL flask was charged with 1.77 g (10 mmol) of trithiocyanuric acid, 4.65 g (36 mmol) of N,N-diisopropylethylamine, and 26.5 g of dichloromethane, and after replacing with nitrogen, 2.90 g (36 mmol) of methoxymethyl chloride was added dropwise with stirring at -10°C. The mixture was then stirred at room temperature for 7 hours. The obtained organic layer was washed with 26.5 g of saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure. The obtained concentrate was separated and purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 5 (volume ratio)) to obtain 2.57 g of pale yellow powder (yield: 83%).

[0064] The resulting pale yellow powder 1 The H-NMR spectrum data was as follows: · 1 H-NMR (CDCl3) δ: 5.34 (s, 6H), 3.41(s, 9H). The IR spectrum data of this pale yellow powder was as shown in the chart of FIG. From these spectral data, the obtained pale yellow powder was identified as the title triazine compound represented by chemical formula (I-1).

[0065] Example 2 <Protection reaction of 3-phenyl-1-propanol (reaction scheme (B) above)> In a 100 mL flask, 272 mg (2 mmol) of 3-phenyl-1-propanol, 618 mg (2 mmol) of 2,4,6-tris(methoxymethylthio)-1,3,5-triazine, and 250 mg of molecular sieves 5A were charged, and after replacing with nitrogen, 10 mL of 1,2-dimethoxyethane and 46.5 mg (0.2 mmol) of camphorsulfonic acid were added. Next, 2.25 g (10 mmol) of N-iodosuccinimide was added at 0°C, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution obtained was 1H-NMR analysis confirmed that the target product ([3-(methoxymethoxy)propyl]benzene) was obtained in an amount of 84%. [Industrial Applicability]

[0066] The triazine compound of the present invention is a stable compound, and yet allows the introduction of a substituent or a protecting group into a nucleophilic functional group under mild acidic conditions. Therefore, the triazine compound of the present invention is expected to be useful as a substituent-introducing agent and / or a protecting agent in organic synthesis reactions such as pharmaceutical synthesis.

Claims

1. A triazine compound represented by chemical formula (I): 【Chemistry 1】 (In the formula, Y represents a single bond or an alkylene group having 1 to 10 carbon atoms. R may be the same or different and represents a hydrogen atom, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, an aryl group, a vinyl group, a halogen atom, a nitrile group, a nitro group, an alkoxy group, or a trichloromethyl group.)

2. 2. The method for synthesizing a triazine compound according to claim 1, which comprises reacting trithiocyanuric acid represented by the chemical formula (II) with a halogen compound represented by the chemical formula (III). 【Chemistry 2】 【Chemistry 3】 (In the formula, Y and R are the same as defined above. X represents a halogen atom.)

3. A substituent-introducing agent comprising the triazine compound according to claim 1.

4. A protecting agent comprising the triazine compound according to claim 1.

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