Method for producing optically active hydrogen-phosphine borane compound and method for producing optically active 2, 3-bisphosphinopyrazine derivative

Abstract

To provide a method for producing an optically active hydrogen-phosphine borane compound in high optical purity. And to provide a method for obtaining an optically active 2, 3-bis (dialkylphosphino) pyrazine derivative in high optical purity.SOLUTION: The method for producing the optically active hydrogen-phosphine borane compound comprises carrying out the decomposition reaction of the optically active phosphine borane compound by using an aqueous alkali solution and an organic solvent in the presence of a phase transfer catalyst. The method for producing the optically active 2, 3-bis (dialkylphosphino) pyrazine derivative uses the obtained optically active hydrogen-phosphine borane compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an optically active hydrogen-phosphine borane compound and a method for producing an optically active 2,3-bisphosphinopyrazine derivative using the same. [Background technology]

[0002] Optically active phosphine ligands having an asymmetric center on the phosphorus atom play an important role in catalytic asymmetric synthesis reactions using transition metal complexes. Patent Document 1 proposes 1,2-bis(dialkylphosphino)benzene derivatives as optically active phosphine ligands having an asymmetric center on the phosphorus atom. Patent Document 2 proposes a 2,3-bis(dialkylphosphino)pyrazine derivative. This pyrazine derivative is characterized by extremely high electron-withdrawing ability due to the pyrazine skeleton, which in turn reduces the electron density of the phosphorus atom in the phosphine moiety. In the ligands of Patent Documents 1 and 2, the two phosphorus atoms serve as chiral centers.

[0003] Furthermore, Non-Patent Document 1 proposes a 2,3-bis(dialkylphosphino)pyrazine derivative represented by the following chemical formula (A) as a ligand, in which only one of the two phosphorus atoms serves as a chiral center.

[0004] [ka]

[0005] The present applicants also proposed in Patent Document 3 a 2,3-bis(dialkylphosphino)pyrazine derivative as a ligand in which only one of the two phosphorus atoms is a chiral center.

[0006] The ligands of Non-Patent Document 1 and Patent Document 3 are produced using an optically active hydrogen-phosphine borane compound as an intermediate raw material. As a method for producing an optically active hydrogen-phosphine borane compound, for example, Patent Document 4 below proposes that a chiral protecting group in an optically active phosphine borane compound (a) is deprotected with an alkali to produce an optically active hydrogen-phosphine borane compound (b).

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Laid-Open No. 2000-319288 [Patent Document 2] Japanese Patent Application Laid-Open No. 2007-56007 [Patent Document 3] International Publication No. 2019 / 069828 Brochure [Patent Document 4] Japanese Patent Application Laid-Open No. 2010-138136 [Non-patent literature]

[0009] [Non-Patent Document 1] Journal of Organic Chemistry Vol.77,4184-4188(2012) Summary of the Invention [Problem to be solved by the invention]

[0010] Incidentally, transition metal complexes having as a ligand an optically active 2,3-bis(dialkylphosphino)pyrazine derivative in which only one of the two phosphorus atoms in Non-Patent Document 1 and Patent Document 3 serves as a chiral center are known to be useful as catalysts for asymmetric synthesis such as, for example, the hydroboration of olefins, enantioselective substitution of allylic carbonates with diboron, synthesis of optically active piperidine and tetrahydroquinoline derivative compounds by dearomatization / boration of pyridines, enantioselective boration of allyl acetal derivatives and allyl ketal derivatives, asymmetric hydrogenation of dehydroamino acids, asymmetric coupling reactions involving C-C bonds or C-N bonds, asymmetric hydrosilylation reactions, and asymmetric Michael reactions. Therefore, there is a demand for complexes with even improved optical purity in order to improve catalytic activity.

[0011] However, in the method of Patent Document 4, racemization occurs during the production of an optically active hydrogen-phosphine borane compound, which makes it difficult to obtain an optically active 2,3-bis(dialkylphosphino)pyrazine derivative with high optical purity.

[0012] Therefore, a first object of the present invention is to provide a method for obtaining an optically active hydrogen-phosphine borane compound with high optical purity, and a second object of the present invention is to provide a method for obtaining an optically active 2,3-bis(dialkylphosphino)pyrazine derivative with high optical purity. [Means for solving the problem]

[0013] In view of the above circumstances, the present inventors have conducted extensive research and have found that an optically active hydrogen-phosphine-borane compound represented by the following general formula (2) can be obtained with high optical purity by carrying out a reaction of deprotecting a chiral protecting group in an optically active phosphine-borane compound represented by the following general formula (1) with an alkali using a phase-transfer catalyst, thereby completing the present invention.

[0014] That is, the first invention to be provided by the present invention is a method for producing an optically active hydrogen-phosphine-borane compound represented by the following general formula (2), in which a decomposition reaction of an optically active phosphine-borane compound represented by the following general formula (1) is carried out using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst.

[0015] [ka] (In the formula, R 1 and R 2 are a pair of groups whose presence causes asymmetry on the phosphorus atom or makes the phosphorus atom a point on an asymmetric plane, and each represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group; R 3 represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group, and * represents asymmetry.

[0016] [ka] (R in the formula 1 , R 2 and * are the same as in the general formula (1).

[0017] A second invention that the present invention provides is a method for producing an optically active 2,3-bisphosphinopyrazine derivative, which comprises carrying out the following step A and then carrying out the following step B:

[0018] [Process A] A process for obtaining an optically active hydrogen-phosphine-borane compound represented by the following general formula (2) by carrying out a decomposition reaction of an optically active phosphine-borane compound represented by the following general formula (1) using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst.

[0019] [ka] (In the formula, R 1 and R 2are a pair of groups whose presence causes asymmetry on the phosphorus atom or makes the phosphorus atom a point on an asymmetric plane, and each represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group; R 3 represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group, and * represents asymmetry.

[0020] [ka] (R in the formula 1 , R 2 and * are the same as in the general formula (1).

[0021] [Process B] A step of carrying out a nucleophilic substitution reaction between the optically active hydrogen-phosphine borane compound represented by the general formula (2) obtained in step A and a pyrazine derivative represented by the following general formula (3), followed by a deboranization reaction to obtain an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (4).

[0022] [ka] (In the formula, R 4 represents a group selected from a branched alkyl group having 3 or more carbon atoms, an adamantyl group, a cycloalkyl group, and an aryl group; R 5 represents a monovalent substituent, n represents an integer of 0 to 4, and X represents a halogen atom.

[0023] [ka] (R in the formula 1 , R 2 and * are the same as in the general formula (1), and R 4 , R 5 and n have the same meanings as in general formula (3). [Effects of the Invention]

[0024] According to the present invention, an optically active hydrogen-phosphine borane compound can be produced with high optical purity by an industrially advantageous method. Furthermore, by using the obtained optically active hydrogen-phosphine borane compound to introduce an asymmetric source into the structure, the target optically active 2,3-bisphosphinopyrazine derivative can be produced with high optical purity. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention will be described below based on preferred embodiments. The method for producing an optically active hydrogen-phosphine-borane compound represented by the general formula (2) of the present invention (hereinafter referred to as "Step A") is characterized in that a decomposition reaction of an optically active phosphine-borane compound represented by the general formula (1) is carried out using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst.

[0026] The optically active phosphine borane compound used in the step A is a compound represented by the following general formula (1).

[0027] [ka] (In the formula, R 1 and R 2 are a pair of groups whose presence causes asymmetry on the phosphorus atom or makes the phosphorus atom a point on an asymmetric plane, and each represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group; R 3 represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group, and * represents asymmetry.

[0028] R in the general formula (1) 1 and R 2 R represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group. 1 and R 2 may be independent of each other or may be linked by a bridge.

[0029] The hydrocarbon group is not particularly limited, and examples thereof include an alkyl group, an aralkyl group, and an aryl group.

[0030] The alkyl group may be linear, branched, or cyclic. Examples of the linear or branched alkyl group include linear or branched alkyl groups having 1 to 8 carbon atoms, specifically methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, tert-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, tert-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 5-methylpentyl groups. Examples of cyclic alkyl groups include cycloalkyl groups having 3 to 16 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 3-methylcyclopentyl, cycloheptyl, 2-methylcyclohexyl, 3-methylcyclohexyl, and 4-methylcyclohexyl groups. Cyclic alkyl groups also include polycyclic alkyl groups, such as menthyl, bornyl, norbornyl, and adamantyl groups.

[0031] Examples of the aralkyl group include aralkyl groups having 7 to 12 carbon atoms, and specific examples include a benzyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a 2-phenylpropyl group, a 3-phenylpropyl group, a 1-phenylbutyl group, a 2-phenylbutyl group, a 3-phenylbutyl group, a 4-phenylbutyl group, a 1-phenylpentyl group, a 2-phenylpentyl group, a 3-phenylpentyl group, a 4-phenylpentyl group, a 5-phenylpentyl group, a 1-phenylhexyl group, a 2-phenylhexyl group, a 3-phenylhexyl group, a 4-phenylhexyl group, a 5-phenylhexyl group, and a 6-phenylhexyl group.

[0032] The aryl group includes, for example, aryl groups having 6 to 20 carbon atoms, and specific examples thereof include a phenyl group, a naphthyl group, an anthryl group, a biphenyl group, and a binaphthyl group.

[0033] Examples of the substituted hydrocarbon group include hydrocarbon groups in which at least one hydrogen atom is substituted with a substituent such as a hydrocarbon group, an alkoxy group, a halogen atom, an amino group, or an amino group having a protecting group, and groups in which at least one carbon atom is substituted with a heteroatom such as oxygen, nitrogen, sulfur, or phosphorus.

[0034] The substituted hydrocarbon group also includes a heterocyclic group, which may be an aliphatic heterocyclic group or an aromatic heterocyclic group. Examples of the aliphatic heterocyclic group include 5- and 6-membered aliphatic heterocyclic groups, specific examples of which include a pyrrolidyl-2-one group, a piperidino group, a piperazinyl group, a morpholino group, a tetrahydrofuryl group, and a tetrahydropyranyl group. Examples of the aromatic heterocyclic group include 5- and 6-membered aromatic heterocyclic groups, specific examples of which include a pyridyl group, an imidazolyl group, a thiazolyl group, a furfuryl group, a pyranyl group, a furyl group, a benzofuryl group, and a thienyl group.

[0035] In the present invention, when asymmetry is expressed on the phosphorus atom, in order to more effectively exhibit the effect of asymmetry, R 1 and R 2 In the above, a combination of groups with significantly different steric bulkiness is preferred, and specific examples include a combination of a methyl group and a tert-butyl group, and a combination of a methyl group and an adamantyl group.

[0036] In the present invention, when the phosphorus atom constitutes one point of the axially chiral symmetric plane, in order to more effectively exert the asymmetric effect, R 1 or R 2 It is preferable that the asymmetric moiety in is as close as possible to the phosphorus atom. 1 and R 2 are linked by a bridge, and the group including them and the phosphorus atom is 2,5-dimethylphosphorane or 2,5-diethylphosphorane.

[0037] R in the general formula (1) 3represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group. The asymmetric hydrocarbon group is not particularly limited, and specific examples include a (S)-1-phenylethyl group, a (R)-1-phenylethyl group, a (S)-1-(p-toluyl)ethyl group, a (R)-1-(p-toluyl)ethyl group, a (S)-1-(1-naphthyl)ethyl group, a (R)-1-(1-naphthyl)ethyl group, a (S)-1-cyclohexylethyl group, a (R)-1-cyclohexylethyl group, a (S)-2-(4-methylphenyl)-1-phenylethyl group, and a (R)-2-(4-methylphenyl)-1-phenylethyl group. Among these, the (S)-1-phenylethyl group and the (R)-1-phenylethyl group are preferred because they can be used industrially and inexpensively.

[0038] Examples of the substituted asymmetric hydrocarbon group include hydrocarbon groups in which at least one hydrogen atom of the asymmetric hydrocarbon group is substituted with a substituent such as a hydrocarbon group, an alkoxy group, a halogen atom, an amino group, a nitro group, or an amino group having a protecting group, and groups in which at least one carbon atom of the asymmetric hydrocarbon group is substituted with a heteroatom such as oxygen, nitrogen, sulfur, or phosphorus.

[0039] The optically active phosphine borane compound represented by the general formula (1) includes R 1 and R 2 Examples of optically active phosphine borane compounds in which asymmetry is exhibited on the phosphorus atom due to the presence of: include compounds represented by the following formulae (1A) and (2A).

[0040] [ka]

[0041] Specific examples of the compound represented by the formula (1A) include (S P )-tert-butyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane, (R P )-tert-butyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane. Specific examples of the compound represented by the formula (2A) include (S P )-adamantyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane, (R P )-adamantyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane.

[0042] Also, R 1 and R 2 However, an example of an optically active phosphine borane compound in which the phosphorus atom is a pair of groups that form one point of the asymmetric plane is the compound represented by the following formula (3A): (R,R)-2,5-dimethyl-1-[N-((S)-1-(1-naphthyl)ethyl)carbamoyl]phosphorane borane.

[0043] [ka]

[0044] The optically active phosphine borane compound represented by the general formula (1) is a known compound and can be produced by a known method.

[0045] As a method for producing the optically active phosphine-borane compound represented by the general formula (1), for example, as shown in the following reaction scheme (1), first, a racemic hydrogen-phosphine-borane compound represented by the general formula (5) is subjected to a coupling reaction with an optically active isocyanate compound represented by the general formula (6) to obtain a phosphine-borane compound represented by the general formula (7), which is a mixture of two diastereomers, and then these two diastereomers are separated to obtain an optically active phosphine-borane compound represented by the general formula (1), which is either an Sp or Rp form (see JP 2010-138136 A, etc.).

[0046] [ka] (R in the formula 1 ~R 3and * are the same as in the general formula (1).

[0047] In the step A, the decomposition reaction of the optically active phosphine borane compound represented by the general formula (1) is carried out using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst.

[0048] As the phase transfer catalyst, known catalysts such as phosphonium salts, ammonium salts, crown ethers, porphyrins, azacrowns and thiocrowns can be used, and among these, phosphonium salts and ammonium salts are preferred from the viewpoints of reactivity and purification.

[0049] The phosphonium salt and ammonium salt are preferably those represented by the following general formula (8).

[0050] [ka] (wherein Z represents a nitrogen atom or a phosphorus atom. R 6 ~R 9 represents a hydrocarbon group. Y represents a hydroxyl group, a halogen atom, an organic acid residue, or an inorganic acid residue.

[0051] The hydrocarbon group is R in the general formula (1). 1 and R 2 Examples of the hydrocarbon group include the same groups as those represented by the following formula:

[0052] Examples of the organic acid of the organic acid residue include carboxylic acids such as formic acid, acetic acid, and oxalic acid, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid. Examples of the inorganic acid of the inorganic acid residue include sulfuric acid, bisulfuric acid, nitric acid, phosphoric acid, carbonic acid, and bicarbonate.

[0053] Specific examples of the phosphonium salt include tributylmethylphosphonium bromide, tetrabutylphosphonium bromide, trioctylmethylphosphonium bromide, trioctylethylphosphonium bromide, tributyldodecylphosphonium bromide, tributylhexadecylphosphonium bromide, trioctylethylphosphonium bromide, tributylmethylphosphonium chloride, tetrabutylphosphonium chloride, trioctylmethylphosphonium chloride, trioctylethylphosphonium chloride, tributyldodecylphosphonium chloride, tributylhexadecylphosphonium chloride, and trioctylethylphosphonium chloride.

[0054] Specific examples of the ammonium salt include tributylmethylammonium bromide, tetrabutylammonium bromide, trioctylmethylammonium bromide, trioctylethylammonium bromide, tributyldodecylammonium bromide, tributylhexadecylammonium bromide, trioctylethylammonium bromide, tributylmethylammonium chloride, tetrabutylammonium chloride, trioctylmethylammonium chloride, trioctylethylammonium chloride, tributyldodecylammonium chloride, tributylhexadecylammonium chloride, and trioctylethylammonium chloride.

[0055] In the present invention, it is particularly preferable to use tetrabutylammonium bromide or tetrabutylphosphonium bromide as the phase transfer catalyst.

[0056] The amount of the phase transfer catalyst added is preferably 0.1 to 1.0 mol, more preferably 0.6 to 1.0 mol, per 1.0 mol of the optically active phosphine borane compound represented by the general formula (1).

[0057] The alkaline aqueous solution used in step A is an aqueous solution prepared by dissolving a base such as an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, or an alkaline earth metal carbonate in water. Examples of the base include sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, and potassium carbonate.

[0058] The alkaline aqueous solution is usually used as a 20 to 80 mass % aqueous solution, preferably a 20 to 50 mass % aqueous solution.

[0059] The amount of the alkaline aqueous solution used is preferably 1.0 to 10.0 mol, more preferably 2.0 to 6.0 mol of the base in the alkaline aqueous solution per 1.0 mol of the optically active phosphine borane compound represented by the general formula (1).

[0060] Examples of organic solvents used in step A include aromatics such as benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, anisole, nitrobenzene, and nitrotoluene; aliphatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, ligroin, and cyclohexane; ether solvents such as diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzyl ether, dioxane, and tetrahydrofuran; secondary and tertiary alcohols such as 2-propanol, 2-butanol, and 2-methyl-2-propanol; and organic polar solvents such as N,N-dimethylacetamide, hexamethylphosphoramide, and sulfolane. Among these organic solvents, tetrahydrofuran is particularly preferred.

[0061] In the step A, an alcohol can be added as needed to further promote the reaction. Examples of the alcohol to be added include methanol, ethanol, iso-propanol, n-propanol, etc. Two or more of these can be mixed and used.

[0062] The amount of the alcohol added is preferably 10 to 50 parts by mass, particularly preferably 20 to 40 parts by mass, relative to 100 parts by mass of the organic solvent.

[0063] The reaction temperature for the decomposition reaction of the optically active phosphine-borane compound in step A is preferably 25° C. or lower, more preferably 20° C. or lower, and particularly preferably 12 to 18° C. from the viewpoints of reactivity and maintaining optical purity. The reaction time is usually 20 to 50 hours, preferably 20 to 30 hours.

[0064] After the decomposition reaction is completed, the optically active phosphine-borane compound represented by the general formula (2) can be isolated by conventional purification procedures such as separation and washing, crystallization, distillation, sublimation, column chromatography, etc. Alternatively, after removing by-product salts from the reaction solution after the completion of the reaction, the step B described below can be carried out directly.

[0065] The optically active hydrogen-phosphine borane compound represented by the general formula (2) obtained in the step A is useful as a compound for introducing an asymmetric source into the structure of a ligand in which the phosphorus atom is the chiral center.

[0066] The optically active hydrogen-phosphine borane compound represented by the general formula (2) obtained in the step A has an improved optical purity compared to conventional products. Therefore, by using the compound as a compound for introducing an asymmetric source into the structure of an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (4), a compound with a higher optical purity can be obtained.

[0067] [ka] (R in the formula 1 , R 2 and * are the same as in the general formula (1), and R 4 represents a group selected from a branched alkyl group having 3 or more carbon atoms, an adamantyl group, a cycloalkyl group, and an aryl group; R 5 represents a monovalent substituent, and n represents an integer of 0 to 4.

[0068] R 4 Examples of branched alkyl groups having 3 or more carbon atoms represented by the formula (I) include those having 3 to 8 carbon atoms, such as an isopropyl group, a tert-butyl group, and a 1,1,3,3-tetramethylbutyl group (sometimes commonly referred to as a "tert-octyl group"). Of these, those having 4 to 8 carbon atoms are preferred, with a tert-butyl group and a 1,1,3,3-tetramethylbutyl group being particularly preferred.

[0069] R 4 Examples of the cycloalkyl group represented by the formula (I) include cycloalkyl groups having 3 to 7 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 2-methylcyclopentyl group, a 3-methylcyclopentyl group, a cycloheptyl group, a 2-methylcyclohexyl group, a 3-methylcyclohexyl group, and a 4-methylcyclohexyl group.

[0070] R 4 Examples of the aryl group represented by the formula (I) include aryl groups having 6 to 18 carbon atoms. Specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a dimethylphenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.

[0071] R 5 The monovalent substituent represented by the formula (I) is not particularly limited, and examples thereof include a linear or branched alkyl group having 1 to 5 carbon atoms, a nitro group, an amino group, a hydroxyl group, a fluoro group, a chloro group, a bromo group, an iodo group, and a trialkylsilyl group having 1 to 5 carbon atoms.

[0072] The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) can be produced by a nucleophilic substitution reaction between the optically active hydrogen-phosphineborane compound represented by the general formula (2) obtained in the step A and a pyrazine derivative represented by the following general formula (3), followed by a deboronation reaction (hereinafter referred to as "step B").

[0073] [ka] (R in the formula 4 , R 5 and n are as defined in the general formula (4). X represents a halogen atom.

[0074] The phosphinopyrazine derivative represented by the general formula (3) can be produced, for example, according to the following reaction scheme (2), by performing an aromatic nucleophilic substitution reaction in which a deprotonated phosphine-borane (3b) is reacted with a 2,3-dihalogenopyrazine derivative (3a), followed by a deboronation reaction (see WO2019 / 069828 pamphlet, etc.).

[0075] [ka] (R in the formula 4 , R 5 and n are as defined in the general formula (4). X represents a halogen atom.

[0076] The nucleophilic substitution reaction between the optically active hydrogen-phosphine borane compound represented by the general formula (2) and the pyrazine derivative represented by the general formula (3) can be carried out by mixing a solution or slurry containing the phosphinopyrazine derivative represented by the general formula (3) (liquid A) with a solution containing a deprotonated product of the optically active hydrogen-phosphine borane compound represented by the general formula (2) (liquid B) (hereinafter referred to as "Method B1"). This gives an optically active phosphinopyrazine-borane derivative represented by the following general formula (9).

[0077] [ka] (R in the formula 1 , R 2 and * are the same as in the general formula (1), and R 4 , R 5 and n have the same meaning as in general formula (4).

[0078] The liquid A may be in the form of a solution or a slurry. Examples of solvents that can be used in the liquid A include those that can dissolve the phosphinopyrazine derivative represented by the general formula (3) and are inert to the phosphinopyrazine derivative represented by the general formula (3). Examples of such solvents include tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, hexane, and toluene. These solvents can be used alone or in combination. Furthermore, the phosphinopyrazine derivative represented by the general formula (3) does not necessarily need to be completely dissolved, and the reaction can be initiated even in a slurry state.

[0079] The concentration of the phosphinopyrazine derivative represented by the general formula (3) in the solution A is preferably 0.1 to 80% by mass, and particularly preferably 1 to 50% by mass from the viewpoints of productivity and control of side reactions.

[0080] The solution B is a solution containing an optically active phosphine-borane compound obtained by deprotonating the optically active phosphine-borane represented by the general formula (2).

[0081] The solution B can be prepared, for example, by dissolving the optically active phosphine-borane represented by the general formula (2) in a solvent and then adding a base, thereby deprotonating the optically active phosphine-borane represented by the general formula (2).

[0082] The solvent for dissolving the optically active phosphine-borane represented by the general formula (2) can be any solvent that is inert to the optically active phosphine-borane represented by the general formula (2) and the optically active phosphine compound produced from the optically active phosphine-borane by deprotonation. Examples of such solvents include tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, hexane, and toluene. These solvents can be used alone or in combination.

[0083] The concentration of the optically active phosphine-borane represented by the general formula (2) in the solution B is preferably 1 to 80 mass%, and particularly preferably 5 to 30 mass%, from the viewpoints of reactivity and productivity. The solution B may be prepared using the reaction solution obtained by removing by-product salts from the reaction solution after completion of the reaction in the step A.

[0084] Examples of the base used in the deprotonation of the optically active phosphine-borane represented by the general formula (2) include n-butyllithium, sec-butyllithium, lithium diisopropylamide, methylmagnesium bromide, t-butoxypotassium, Hunig's base, potassium hydroxide, sodium hydroxide, etc. Among these, n-butyllithium is preferred.

[0085] The amount of the base added is preferably 1.0 to 2.0, particularly 1.0 to 1.5, in terms of molar ratio of the base to the optically active phosphine-borane represented by the general formula (2), from the viewpoints of economy and reactivity.

[0086] The temperature at which the deprotonation is carried out by adding the base is preferably −20 to 20° C., and particularly preferably −20 to 0° C., from the viewpoint of being able to deprotonate the optically active phosphine-borane represented by the general formula (2) while maintaining its optical purity.

[0087] By adding a base to a solution containing the optically active phosphine-borane represented by the general formula (2), the optically active phosphine-borane represented by the general formula (2) is rapidly deprotonated. If necessary, a maturation reaction can be carried out after the addition of the base is completed in order to complete the deprotonation reaction.

[0088] The liquids A and B are preferably mixed so that the molar ratio of the optically active phosphine compound deprotonated from the optically active phosphine-borane represented by the general formula (2) to the phosphinopyrazine derivative represented by the general formula (3) in the liquid A is 1.0 to 2.0, particularly 1.0 to 1.5, from the viewpoints of reactivity and economy.

[0089] From the viewpoint of obtaining a product of stable quality, it is preferable to mix the solutions A and B by adding the solution B to the solution A at a constant rate, or the solution A to the solution B. The mixing temperature is preferably −80 to 50° C., and particularly preferably −20 to 0° C., from the viewpoint of obtaining a product of high optical purity in high yield.

[0090] By mixing the solutions A and B, a nucleophilic substitution reaction between the phosphinopyrazine derivative represented by the general formula (3) and the deprotonated optically active phosphine-borane represented by the general formula (2) is rapidly carried out, and if necessary, a subsequent aging reaction can be carried out to complete the nucleophilic substitution reaction.

[0091] Furthermore, the nucleophilic substitution reaction between the optically active hydrogen-phosphine borane compound represented by the general formula (2) and the pyrazine derivative represented by the general formula (3) can also be carried out by adding a base to a solution or slurry containing them (hereinafter referred to as "Method B2"). In this manner, the optically active phosphinopyrazine-borane derivative represented by the general formula (9) can be obtained, similarly to Method B1.

[0092] Examples of the solvent to be used include the same as those used in Method B1. The concentration of the phosphinopyrazine derivative represented by the general formula (3) in the solution or slurry is preferably 0.1 to 80 mass %, and particularly preferably 1 to 50 mass %, from the viewpoints of productivity and control of side reactions.

[0093] In the method B2, the molar ratio of the optically active phosphine-borane represented by the general formula (2) to the phosphinopyrazine derivative represented by the general formula (3) is preferably 1.0 to 2.0, particularly 1.0 to 1.5, from the viewpoints of reactivity and economy.

[0094] The base to be used may be the same as that used in Method B1, but potassium t-butoxide is preferred. The base may be added as is or dissolved in a solvent.

[0095] The amount of the base added is preferably 0.8 to 1.5, particularly 0.9 to 1.2, in terms of molar ratio of the base to the optically active phosphine-borane represented by the general formula (2), from the viewpoints of economy and reactivity.

[0096] The temperature at which the base is added is preferably −80 to 20° C., and particularly preferably −20 to 0° C., from the viewpoint of being able to deprotonate the optically active phosphine-borane represented by the general formula (2) while maintaining its optical purity.

[0097] By adding a base to a solution or slurry containing the phosphine pyrazine derivative represented by the general formula (3) and the optically active hydrogen-phosphine borane compound represented by the general formula (2), deprotonation and nucleophilic substitution reaction of the optically active phosphine-borane represented by the general formula (2) are rapidly carried out. After the addition of the base, a maturation reaction can be carried out subsequently, if necessary, to complete the nucleophilic substitution reaction.

[0098] After completion of the nucleophilic substitution reaction in the methods B1 and B2, the optically active phosphinopyrazine-borane derivative represented by the general formula (9) can be obtained by conventional purification such as separation and washing, extraction, distillation, and desolvation, if necessary. However, a deboranizing agent can be added to the reaction solution after completion of the nucleophilic substitution reaction to carry out the deboranization reaction of the optically active phosphinopyrazine-borane derivative represented by the general formula (9).

[0099] Examples of the deboranizing agent include N,N,N',N'-tetramethylethylenediamine (TMEDA), triethylenediamine (DABCO), triethylamine, HBF4, trifluoromethanesulfonic acid, etc., with TMEDA being preferred. The amount of the deboranizing agent added is preferably 2 to 20 equivalents, more preferably 3 to 10 equivalents, relative to the optically active phosphinopyrazine-borane derivative represented by general formula (9).

[0100] The reaction temperature of the deboranation reaction is preferably −20 to 80° C., more preferably −20 to 50° C., from the viewpoint of obtaining a 2,3-bisphosphinopyrazine derivative represented by general formula (4) with high optical purity. The reaction time of the deboranation reaction is preferably 30 minutes or more, particularly preferably 1 to 10 hours.

[0101] After completion of the deboranization reaction, if necessary, purification can be carried out by conventional methods such as separation and washing, extraction, crystallization, distillation, sublimation, and column chromatography to obtain the desired optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4).

[0102] In the present invention, the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) can be produced in one pot from the phosphinepyrazine derivative represented by the general formula (3) and the optically active hydrogen-phosphineborane compound represented by the general formula (2) by carrying out a nucleophilic substitution reaction by the above-mentioned Method B2, followed by a deboranation reaction. Therefore, it is preferable that the step B is carried out by the above-mentioned Method B2.

[0103] The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) obtained by the production method of the present invention forms a complex together with a transition metal as a ligand, and this transition metal complex is useful as an asymmetric synthesis catalyst.

[0104] Examples of transition metals that can form complexes include rhodium, ruthenium, iridium, palladium, nickel, iron, and copper. [Example]

[0105] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0106] [Manufacturing Example 1] <(R P )-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R P ,R)-PB-MBI)> A diastereomeric excess of 99.6% (R P )-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R P ,R)-PB-MBI) was synthesized.

[0107] [ka]

[0108] (R P ,R)-PB-MBI identification data 1 H NMR(500MHz, CDCl3) δ7.36-7.22(m,6H),5.18-5.12(m,1H),1.52(d,J=6.9Hz,3H),1.44(d,J=9.7Hz,3H),1.14(d,J=14.3Hz,9H),0.87-0.30(m,3H). 13C NMR(126MHz, CDCl3) δ167.7(d,J=56.6Hz),142.39,128.92,127.77,126.12,49.81,28.80(d,J=30.0Hz),25.49,21.85,3.63(d,J=36.0Hz). 31 P NMR(202MHz,CDCl3) δ33.91-33.43(m).

[0109] [Example 1] <(S P )-tert-butylmethylphosphine-borane ((S P )-PB)> A four-neck flask equipped with a mechanical stirrer, a thermometer, a three-way stopcock, and a dropping funnel was filled with (R P )-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R P ,R)-PB-MBI)) (39.9 g, 150 mmol) and tetrabutylammonium bromide (n-Bu4NBr) (49.0 g, 152 mmol, 1.0 eq.) were added, and the system was purged with nitrogen. After adding dehydrated THF (110 g), the flask was immersed in a refrigerant bath at 5°C to 10°C, and 25 wt% aqueous potassium hydroxide solution (206 g, 919 mmol, 6.1 eq.) was slowly added dropwise so that the temperature of the reaction solution did not exceed 15°C. After the dropwise addition, the flask was immersed in a refrigerant bath at 15°C to 17°C, and the solution temperature was adjusted to 15°C to 18°C, and the mixture was stirred for 26 hours. After stirring, the flask was again immersed in the refrigerant bath at 5°C to 10°C, and n-hexane (101 g) was added and stirred. After removing the aqueous layer, pure water (151 g) was added dropwise to the organic layer and stirred, and the aqueous layer was then removed. After that, 3M hydrochloric acid (90.0 mL, 270 mmol, 1.8 eq.) was added dropwise and stirred, and then the organic layer was separated and washed three times with pure water (60 mL). Insoluble matter in the organic layer was removed by filtration through Celite, and the filter cake was washed with n-hexane (201 g). The solvent was removed from the obtained filtrate by distillation under reduced pressure in a water bath at 30 °C, and then vacuum dried at 0 °C to obtain a white solid (S P )-tert-butylmethylphosphine-borane ((S P )-PB) was obtained in a crude yield of 15.6 g.31 The chemical purity determined by P NMR and GC was 98.6% and 96.6%, respectively, and the optical purity was 99.7 ee%.

[0110] [ka]

[0111] [Example 2] The amount of n-Bu4NBr used is (R P ,R)-PB-MBI to the molar ratio (n-Bu4NBr / (R P The reaction was carried out in the same manner as in Example 1, except that the amount of (S)-PB-MBI was 0.1. P )-PB was obtained. 31 The chemical purity determined by P NMR and GC was 78.2% and 61.2%, respectively, and the optical purity was 98.2 ee%.

[0112] [Example 3] The amount of n-Bu4NBr used is (R P ,R)-PB-MBI to the molar ratio (n-Bu4NBr / (R P The reaction was carried out in the same manner as in Example 1, except that the (SP)-PB-MBI) was changed to 0.3, to obtain a white solid (SP)-PB. 31 The chemical purity determined by P NMR and GC was 84.6% and 74.6%, respectively, and the optical purity was 98.9 ee%.

[0113] [Example 4] The amount of n-Bu4NBr used is (R P ,R)-PB-MBI to the molar ratio (n-Bu4NBr / (R P The reaction was carried out in the same manner as in Example 1, except that the (SP)-PB-MBI) was changed to 0.6, to obtain a white solid (SP)-PB. 31 The chemical purity determined by P NMR and GC was 95.0% and 92.2%, respectively, and the optical purity was 99.7 ee%.

[0114] [Example 4] The reaction was carried out in the same manner as in Example 1, except that tetrabutylphosphonium bromide (n-Bu4PBr) (15.3 g, 150 mmol, 0.3 eq.) was used instead of n-Bu4NBr, to obtain a white solid (S P )-PB was obtained. 31 The chemical purity determined by P NMR and GC was 82.4% and 76.5%, respectively, and the optical purity was 99.2 ee%.

[0115] [ka]

[0116] [Table 1]

[0117] [Manufacturing Example 2] <Phosphine pyrazine derivative (3A)> A stirrer was placed in a four-neck flask equipped with a septum, thermometer, three-way stopcock, and dropping funnel. After replacing the atmosphere with nitrogen, di-tert-butylphosphine-borane and dehydrated THF (81.1 g) were added. The flask was immersed in a refrigerant bath at 0 °C, and a hexane solution of n-butyllithium (37.9 g, 89.3 mmol) was added dropwise so that the liquid temperature did not exceed 15 °C. The mixture was then stirred in the refrigerant bath for 30 minutes to prepare a THF solution of t-Bu2P(BH3)Li (Solution B). 2,3-Dichloroquinoxaline (15.0 g, 75.4 mmol) was placed in a four-neck flask equipped with a mechanical stirrer, thermometer, three-way stopcock, and dropping funnel. The system was purged with nitrogen and then dehydrated THF (65.8 g) was added. The flask was immersed in a 0 °C refrigerant bath, and Solution B (83.1 mmol, 1.1 eq.) was slowly added dropwise, ensuring the reaction temperature did not exceed 15 °C. After stirring in the refrigerant bath for 1 hour, N,N,N',N'-tetramethylethylenediamine (TMEDA) (22.0 g, 190 mmol, 2.5 eq.) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. After stirring, the reaction mixture was washed four times with purified water (50 mL), followed by washing with saturated brine (50 mL). The solvent was removed from the separated organic layer by distillation under reduced pressure in a 30 °C water bath. The residue obtained in a refrigerant bath at 0°C was washed with MeOH (15 mL), and the solid was filtered off using a glass filter. Washing with a small amount of chilled MeOH gave the phosphinepyrazine derivative (3A) as a yellow solid. 31 The chemical purity determined by P NMR was 99.9%.

[0118] [ka]

[0119] Identification data of phosphine pyrazine derivative (3A) 1 H NMR(500MHz,CDCl3) δ 8.16-8.13(m,1H),8.02-7.98(m,1H),7.80-7.75(m,2H),1.28(d,J=12.0Hz,18H). 13 C NMR(126MHz,CDCl3) δ 160.96(d, J=34.9Hz),153.43(d,J=37.3Hz),141.32,140.63,131.48,130.05,129.59,128.45,34.49(d,J=21.5Hz),30.24(d,J=14.4Hz). 31 P NMR(202MHz, CDCl3) δ 26.54.

[0120] [Example 6] <(R)-3H-QuinoxP * > In a four-neck flask equipped with a mechanical stirrer, a thermometer, a three-way stopcock, and a dropping funnel, the phosphine pyrazine derivative (3A) (3.11 g, 10.1 mmol), the phosphine pyrazine derivative (S P )-tert-Butylmethylphosphine-borane (>99.5 ee%, 1.41 g, 12.0 mmol, 1.2 eq.) was added, and the system was purged with nitrogen. Then, anhydrous THF (9.12 g) was added. The flask was immersed in a -20 °C refrigerant bath, and a 1M THF solution of potassium tert-butoxide (12.9 g, 11.5 mmol, 1.1 eq.) was slowly added dropwise, ensuring that the temperature of the reaction mixture did not exceed -10 °C. After stirring in the refrigerant bath for approximately 6 hours, tetramethylethylenediamine (TMEDA) (1.80 g, 15.5 mmol, 1.5 eq.) was added dropwise. The reaction mixture was warmed to room temperature and stirred for approximately 5 hours. After stirring, the reaction mixture was immersed in a 0°C cooling bath, n-hexane (2.1 g) was added, and 2 M hydrochloric acid (16.1 g, 33.4 mmol, 3.3 eq.) was slowly added dropwise so that the liquid temperature did not exceed 15°C. The organic layer was washed three times with pure water (50 mL) and then with saturated brine (60 mL). The solvent was removed from the separated organic layer by distillation under reduced pressure in a 30°C water bath. THF was added to the resulting residue, and the insoluble solids were removed by filtration. The solvent was then removed by distillation under reduced pressure in a 30°C water bath. The resulting residue was dissolved in THF (15 mL) at room temperature, and the flask was then immersed in a 0°C cooling bath, and MeOH (30 mL) was added dropwise. After the dropwise addition, the mixture was stirred in a refrigerant bath for approximately 30 minutes, and the solid was filtered off using a glass filter. The filtered material was washed with a small amount of cooled MeOH-THF (v / v=2:1) ​​mixed solvent to obtain orange solid (R)-3H-QuinoxP * (2.49 g, 65%) 31 The chemical purity determined by P NMR was 99.9% and the optical purity was 99.8 ee%.

[0121] [ka]

[0122] of (R)-3H-QuinoxP* 1 H NMR (500MHz,CDCl3) δ 8.03–7.98(m,2H),7.67–7.62(m,2H),1.35(d,J=5.5Hz、3H),1.28(d,J=11.5Hz,9H),1.14–1.07(m,18H). 13 C NMR (126MHz, CDCl3) δ 167.78-167.29(m),166.65-166.15(m),141.24,141.10,129.85,129.70,129.66,129.58,35.43-3 5.26(m),34.69-34.46(m),31.43-31.29(m),30.78-30.53(m,2C),27.81-27.69(m),6.78-6.57(m). 31 P NMR(202MHz,CDCl3) δ 21.6(d,J=109.0Hz)、-14.4(d,J=103.5Hz).

Claims

1. A method for producing an optically active hydrogen-phosphine-borane compound represented by the following general formula (2), which comprises carrying out a decomposition reaction of an optically active phosphine-borane compound represented by the following general formula (1) using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst: 【Chemistry 1】 (In the formula, R １ and R ２ are a pair of groups whose presence causes asymmetry on the phosphorus atom or makes the phosphorus atom a point on an asymmetric plane, and each represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group; R ３ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group, and * represents asymmetry.) 【Chemistry 2】 (R in the formula １ , R ２ and * are the same as those in formula (1).

2. The R ３ The method for producing an optically active hydrogen-phosphine borane compound according to claim 1, wherein is an (S)-1-phenylethyl group or an (R)-1-phenylethyl group.

3. The R １ and R ２ 2. The method for producing an optically active hydrogen-phosphine borane compound according to claim 1, wherein the combination of is a combination of a methyl group and a tert-butyl group, or a combination of a methyl group and an adamantyl group.

4. The method for producing an optically active hydrogen-phosphine borane compound according to claim 1, wherein the decomposition reaction is carried out at 25° C. or lower.

5. 2. The method for producing an optically active hydrogen-phosphine borane compound according to claim 1, wherein the phase transfer catalyst is a tetrabutylammonium salt.

6. A method for producing an optically active 2,3-bisphosphinopyrazine derivative, comprising carrying out the following step A and then carrying out the following step B: [Process A] A step of carrying out a decomposition reaction of an optically active phosphine-borane compound represented by the following general formula (1) using an alkaline aqueous solution and an organic solvent in the presence of a phase transfer catalyst to obtain an optically active hydrogen-phosphine-borane compound represented by the following general formula (2): 【Transformation 3】 (In the formula, R １ and R ２ are a pair of groups whose presence causes asymmetry on the phosphorus atom or makes the phosphorus atom a point on an asymmetric plane, and each represents a hydrogen atom, a hydrocarbon group, or a substituted hydrocarbon group; R ３ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group, and * represents asymmetry.) 【Chemistry 4】 (R in the formula １ , R ２ and * are the same as those in formula (1). [Process B] A step of carrying out a nucleophilic substitution reaction between the optically active hydrogen-phosphine borane compound represented by the general formula (2) obtained in step A and a pyrazine derivative represented by the following general formula (3), followed by a deboranization reaction to obtain an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (4): 【Transformation 5】 (In the formula, R ４ represents a group selected from a branched alkyl group having 3 or more carbon atoms, an adamantyl group, a cycloalkyl group, and an aryl group; R ５ represents a monovalent substituent, n represents an integer of 0 to 4, and X represents a halogen atom. 【Transformation 6】 (R in the formula １ , R ２ and * are the same as those in the general formula (1), and R ４ , R ５ and n have the same meanings as in the general formula (3).

7. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 6, wherein the step B is a step of adding a base to a solution or slurry containing the phosphinopyrazine derivative represented by the general formula (3) and the optically active hydrogen-phosphineborane compound represented by the general formula (2) to carry out a nucleophilic substitution reaction, and then adding a deboranizing agent to carry out a deboranization reaction, thereby obtaining the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) in one pot.

8. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 7, wherein the base is potassium t-butoxide.

9. 8. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 7, wherein the deboranizing agent is tetramethylethylenediamine.

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