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 obtaining an optically active hydrogen-phosphine borane compound at high optical purity. Also, to provide a method for obtaining an optically active 2,3-bis(dialkylphosphino)pyrazine derivative at high optical purity. Provided is a method for producing an optically active hydrogen-phosphine borane compound comprising carrying out a decomposition reaction of an optically active phosphine borane compound in the presence of a phase-transfer catalyst using an alkaline aqueous solution and an organic solvent. Also provided is a method for producing an optically active 2,3-bis(dialkylphosphino)pyrazine derivative using the optically active hydrogen-phosphine borane compound obtained.

Description

Method for producing optically active hydrogen-phosphine borane compounds and method for producing optically active 2,3-bisphosphinopyrazine derivatives

[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.

[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 a 1,2-bis(dialkylphosphino)benzene derivative as an optically active phosphine ligand 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. The ligands in Patent Documents 1 and 2 have two phosphorus atoms 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, and in this 2,3-bis(dialkylphosphino)pyrazine derivative, only one of the two phosphorus atoms serves as a chiral center.

[0004]

[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 Documents 4 and 5 listed below propose deprotecting a chiral protecting group in an optically active phosphine borane compound (a) with an alkali to produce an optically active hydrogen-phosphine borane compound (b).

[0007]

[0008] Japanese Patent Application Laid-Open No. 2000-319288 Japanese Patent Application Laid-Open No. 2007-56007 International Publication No. 2019 / 069828 Pamphlet Japanese Patent Application Laid-Open No. 2010-138136 Japanese Patent Application Laid-Open No. 2011-219413

[0009] Journal of Organic Chemistry Vol. 77, 4184-4188 (2012)

[0010] Optically active 2,3-bis(dialkylphosphino)pyrazine derivatives exist in three isomers, namely, the (R,R) form, the (S,S) form, and the (R,S) form, due to the asymmetry of the phosphorus atom. In producing optically active 2,3-bis(dialkylphosphino)pyrazine derivatives, it is desired to easily obtain only the desired (R,R) form or the (S,S) form among these isomers.

[0011] Furthermore, 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 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, and there is a demand for complexes with even improved optical purity in order to improve catalytic activity.

[0012] However, in the method of Patent Document 4, racemization proceeds during the production of an optically active hydrogen-phosphine borane compound, which causes a problem in that it is difficult to obtain an optically active 2,3-bis(dialkylphosphino)pyrazine derivative with high optical purity.

[0013] 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.

[0014] 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, and further that an optically active 2,3-bis(dialkylphosphino)pyrazine derivative with high optical purity can be obtained by carrying out a series of steps using the obtained optically active hydrogen-phosphine-borane compound, thereby completing the present invention.

[0015] 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), 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:

[0016] (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.)

[0017] (R in the formula １ , R ２and * are the same as those in formula (1).

[0018] 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:

[0019] [Step 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):

[0020] (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.)

[0021] (R in the formula １ , R ２ and * are the same as those in formula (1).

[0022] [Step 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):

[0023] (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.

[0024] (R in the formula １ , R ２ and * are the same as those in the general formula (1), and R ４ , R５ and n have the same meanings as in the general formula (3).

[0025] A third aspect of the present invention is a method for producing an optically active 2,3-bisphosphinopyrazine derivative, which comprises carrying out the above-mentioned step A and then carrying out the following step B'.

[0026] [Step B'] A step of carrying out a nucleophilic substitution reaction between the optically active hydrogen-phosphine borane compound represented by general formula (2) obtained in step A and a pyrazine derivative represented by general formula (5) below, followed by a deboranization reaction, to obtain an optically active 2,3-bisphosphinopyrazine derivative represented by general formula (6) below.

[0027] (In the formula, R ５ , n and X are the same as those in the general formula (3).

[0028] (R in the formula １ , R ２ and * are the same as those in the general formula (1), and R ５ and n have the same meanings as in the general formula (3).

[0029] 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, it is possible to produce the desired optically active 2,3-bisphosphinopyrazine derivative with high optical purity.

[0030] 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 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.

[0031] The optically active phosphine borane compound used in the step A is a compound represented by the following general formula (1).

[0032] (In the formula, R１ 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.)

[0033] 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.

[0034] The hydrocarbon group is not particularly limited, and examples thereof include an alkyl group, an aralkyl group, and an aryl group.

[0035] 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, such as a methyl group, an ethyl group, an n-propyl group, a 2-propyl group, an n-butyl group, a 2-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, a 2-pentyl group, a tert-pentyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 2,2-dimethylpropyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a tert-hexyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, and a 5-methylpentyl group. 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.

[0036] Examples of the aralkyl group include aralkyl groups having 7 to 12 carbon atoms, and specific examples thereof 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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 ２In the above, combinations with large differences in steric bulkiness are 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.

[0041] In the present invention, when the phosphorus atom constitutes one point of the axially asymmetric 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, and specific examples include R 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.

[0042] R in the general formula (1) ３ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group. The asymmetric hydrocarbon group is not particularly limited, and specific examples include an (S)-1-phenylethyl group, an (R)-1-phenylethyl group, an (S)-1-(p-toluyl)ethyl group, an (R)-1-(p-toluyl)ethyl group, an (S)-1-(1-naphthyl)ethyl group, an (R)-1-(1-naphthyl)ethyl group, an (S)-1-cyclohexylethyl group, an (R)-1-cyclohexylethyl group, an (S)-2-(4-methylphenyl)-1-phenylethyl group, and an (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.

[0043] 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.

[0044] The optically active phosphine borane compound represented by the general formula (1) includes R １ and R ２Examples of optically active phosphine borane compounds in which asymmetry is exhibited on the phosphorus atom due to the presence of the following formulae (1A) and (2A) include compounds represented by the following formulae (1A) and (2A).

[0045]

[0046] Specific examples of the compound represented by the formula (1A) include (S Ｐ )-tert-butyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane, (R Ｐ Specific examples of the compound represented by formula (2A) include (S Ｐ )-adamantyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane, (R Ｐ )-adamantyl(methyl)[N-((S)-1-phenylethyl)carbamoyl]phosphineborane.

[0047] 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 a compound represented by the following formula (2B): (R,R)-2,5-dimethyl-1-[N-((S)-1-(1-naphthyl)ethyl)carbamoyl]phosphorane borane.

[0048]

[0049] The optically active phosphine borane compound represented by the general formula (1) is a known compound and can be produced by a known method.

[0050] 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), a racemic hydrogen-phosphine borane compound represented by the general formula (7) is first subjected to a coupling reaction with an optically active isocyanate compound represented by the general formula (8) to obtain a phosphine borane compound represented by the general formula (9), which is a mixture of two diastereomers, and then these two diastereomers are separated to obtain the Sｐ Body or R ｐ It is possible to obtain an optically active phosphine borane compound represented by the general formula (1), which is one of the two (see JP 2010-138136 A, etc.).

[0051] (R in the formula １ ~R ３ and * are the same as those in formula (1).

[0052] 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.

[0053] 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.

[0054] The phosphonium salt and ammonium salt are preferably those represented by the following general formula (10).

[0055] (wherein Z represents a nitrogen atom or a phosphorus atom. R ６ ~R ９ represents a hydrocarbon group; and Y represents a hydroxyl group, a halogen atom, an organic acid residue, or an inorganic acid residue.

[0056] 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:

[0057] 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.

[0058] 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.

[0059] 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.

[0060] In the present invention, it is particularly preferable to use tetrabutylammonium bromide or tetrabutylphosphonium bromide as the phase transfer catalyst.

[0061] 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).

[0062] 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.

[0063] The alkaline aqueous solution is usually used as an aqueous solution of 20 to 80% by mass, preferably 20 to 50% by mass.

[0064] The amount of the alkaline aqueous solution used is preferably an amount such that the amount of base in the alkaline aqueous solution is 1.0 to 10.0 mol, more preferably 2.0 to 6.0 mol, per 1.0 mol of the optically active phosphine-borane compound represented by the general formula (1).

[0065] 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. Of these organic solvents, tetrahydrofuran is particularly preferred.

[0066] In the step A, an alcohol may be added as needed to further promote the reaction. Examples of the alcohol to be added include methanol, ethanol, iso-propanol, and n-propanol. Two or more of these may be mixed and used.

[0067] The amount of the alcohol added is preferably 10 to 50 parts by mass, and particularly preferably 20 to 40 parts by mass, per 100 parts by mass of the organic solvent.

[0068] 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.

[0069] After completion of the decomposition reaction, the optically active phosphine-borane compound represented by the general formula (2) can be isolated by a conventional purification procedure such as separation and washing, crystallization, distillation, sublimation, column chromatography, etc. Alternatively, after removing by-product salts from the reaction solution after completion of the reaction, the reaction solution can be directly subjected to the step B or step B' described below.

[0070] 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 a phosphorus atom is a chiral center.

[0071] 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 optically active 2,3-bisphosphinopyrazine derivatives represented by the following general formulas (4) and (6), in particular, it is possible to obtain derivatives with higher optical purity.

[0072] (R in the formula １ , R ２ and * are the same as those 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.

[0073]

[0074] (R in the formula １ , R ２ , R ５ and * are the same as those in formula (4).

[0075] A method for producing the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) will be described below.

[0076] The 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.

[0077] The 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.

[0078] The 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.

[0079] The 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.

[0080] The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) can be produced by subjecting the optically active hydrogen-phosphineborane compound represented by the general formula (2) obtained in the step A to a nucleophilic substitution reaction with a pyrazine derivative represented by the following general formula (3), followed by a deboronation reaction (hereinafter referred to as "step B").

[0081] (R in the formula ４ , R ５ and n are the same as those in the general formula (4). X represents a halogen atom.

[0082] The phosphinopyrazine derivative represented by the general formula (3) can be produced, for example, according to the following reaction scheme (2), by reacting a 2,3-dihalogenopyrazine derivative (5) with a deprotonated phosphine-borane (3a) to perform an aromatic nucleophilic substitution reaction, followed by a deboronation reaction (see WO2019 / 069828 pamphlet, etc.).

[0083] (R in the formula ４ , R ５ and n are the same as those in the general formula (4). X represents a halogen atom.

[0084] 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) (hereinafter referred to as "Method B1"), and an optically active phosphinopyrazine-borane derivative represented by the following general formula (11) can be obtained.

[0085] (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 general formula (4).

[0086] The solution A may be in the form of a solution or a slurry. Examples of solvents that can be used in the solution 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 as a mixed solvent. Furthermore, it is not necessary to completely dissolve the phosphinopyrazine derivative represented by the general formula (3), and the reaction can be initiated even in a slurry state.

[0087] 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.

[0088] 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).

[0089] 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).

[0090] 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, without any particular limitation. Examples of such solvents include tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, hexane, toluene, etc. These solvents can be used alone or as a mixed solvent.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] By adding a base to a solution containing the optically active phosphine-borane represented by the general formula (2), the deprotonation of the optically active phosphine-borane represented by the general formula (2) is rapidly carried out, and if necessary, after the addition of the base is completed, a ripening reaction can be carried out subsequently in order to complete the deprotonation reaction.

[0096] 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.

[0097] 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.

[0098] 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 ripening reaction can be subsequently carried out to complete the nucleophilic substitution reaction.

[0099] 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 (11) can be obtained, similarly to Method B1.

[0100] The solvent to be used may be the same as that 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] The temperature at which the base is added is preferably −80 to 20° C., particularly −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.

[0105] 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, and after the addition of the base, a maturation reaction can be carried out subsequently, if necessary, to complete the nucleophilic substitution reaction.

[0106] After completion of the nucleophilic substitution reaction in the methods B1 and B2, the optically active phosphinopyrazine-borane derivative represented by the general formula (11) can be obtained by carrying out purification by a conventional method 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 a deboranization reaction of the optically active phosphinopyrazine-borane derivative represented by the general formula (11).

[0107] Examples of the deboranizing agent include N,N,N',N'-tetramethylethylenediamine (TMEDA), triethylenediamine (DABCO), triethylamine, and HBF ４ , 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 (11).

[0108] The reaction temperature of the deboranation reaction is preferably −20 to 80° C., and 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.

[0109] After the completion of the deboranation 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).

[0110] 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 and subsequently carrying out a deboranation reaction. Therefore, it is preferable that the step B is carried out by the above-mentioned Method B2.

[0111] Next, a method for producing the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (6) will be described.

[0112] The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (6) can be produced by subjecting the optically active hydrogen-phosphineborane compound represented by the general formula (2) obtained in the step A to a nucleophilic substitution reaction with a pyrazine derivative represented by the following general formula (5), followed by a deboronation reaction (hereinafter referred to as "step B'").

[0113]

[0114] (In the formula, R ５ , n and X are the same as those in the general formula (3).

[0115] X in the general formula (5) represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, and is preferably a chlorine atom.

[0116] 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 (5) can be carried out by mixing a solution or slurry (Liquid A') containing the phosphinopyrazine derivative represented by the general formula (5) with a solution (Liquid B') containing a deprotonated product of the optically active hydrogen-phosphine borane compound represented by the general formula (2) (hereinafter referred to as "Method B1'"). An optically active phosphinopyrazine-borane derivative represented by the following general formula (12) can be obtained.

[0117] (R in the formula １ , R ２ and * are the same as those in the general formula (1), and R ５ and n have the same meanings as in the general formula (3).

[0118] The solution A' may be in the form of a solution or a slurry. Examples of solvents that can be used in the solution A' include those that can dissolve the phosphinopyrazine derivative represented by the general formula (5) and are inert to the phosphinopyrazine derivative represented by the general formula (5). 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 as a mixed solvent. Furthermore, it is not necessary to completely dissolve the phosphinopyrazine derivative represented by the general formula (5), and the reaction can be initiated even in a slurry state.

[0119] The concentration of the phosphinopyrazine derivative represented by the general formula (5) 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.

[0120] 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).

[0121] The solution B' is 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).

[0122] 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, without any particular limitation. Examples of such solvents include tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, hexane, toluene, etc. These solvents can be used alone or as a mixed solvent.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] By adding a base to a solution containing the optically active phosphine-borane represented by the general formula (2), the deprotonation of the optically active phosphine-borane represented by the general formula (2) is rapidly carried out. If necessary, a maturation reaction can be carried out after the addition of the base is completed in order to complete the deprotonation reaction.

[0128] The solutions 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 (5) in the solution A' is 2.0 to 4.0, particularly 2.0 to 3.0, from the viewpoints of reactivity and economy.

[0129] 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' or the solution A' to the solution B' at a constant rate. 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.

[0130] By mixing the solutions A' and B', a nucleophilic substitution reaction between the phosphinopyrazine derivative represented by the general formula (5) and the deprotonated optically active phosphine-borane represented by the general formula (2) is rapidly carried out, and if necessary, a ripening reaction can be subsequently carried out to complete the nucleophilic substitution reaction.

[0131] 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 (5) 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 (12) can be obtained, similarly to Method B1'.

[0132] The solvent to be used may be the same as that used in Method B1'. The concentration of the phosphinopyrazine derivative represented by the general formula (5) 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.

[0133] 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 (5) is preferably 2.0 to 4.0, particularly 2.0 to 3.0, from the viewpoints of reactivity and economy.

[0134] The base to be used may be the same as that used in Method B1', but among them, potassium t-butoxide is preferred. The base may be added as is or dissolved in a solvent.

[0135] 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.

[0136] The temperature at which the base is added is preferably −80 to 20° C., particularly −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.

[0137] By adding a base to a solution or slurry containing the phosphine pyrazine derivative represented by the general formula (5) 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, and after the addition of the base, a ripening reaction can be carried out subsequently, if necessary, to complete the nucleophilic substitution reaction.

[0138] After completion of the nucleophilic substitution reaction in the methods B1' and B2', the optically active phosphinopyrazine-borane derivative represented by the general formula (12) can be obtained by carrying out purification by a conventional method 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 a deboranization reaction of the optically active phosphinopyrazine-borane derivative represented by the general formula (12).

[0139] Examples of the deboranizing agent include N,N,N',N'-tetramethylethylenediamine (TMEDA), triethylenediamine (DABCO), triethylamine, and HBF ４ , 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 (12).

[0140] The reaction temperature of the deboranation reaction is preferably −20 to 80° C., and more preferably −20 to 50° C., from the viewpoint of obtaining a 2,3-bisphosphinopyrazine derivative represented by general formula (6) with high optical purity. The reaction time of the deboranation reaction is preferably 30 minutes or more, particularly preferably 1 to 10 hours.

[0141] After the 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 (6).

[0142] In the present invention, the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (6) can be produced in one pot from the phosphinepyrazine derivative represented by the general formula (5) and the optically active hydrogen-phosphineborane compound represented by the general formula (2) by carrying out a nucleophilic substitution reaction by the method B2' and subsequently carrying out a deboranation reaction. Therefore, it is preferable that the step B' is carried out by the method B2'.

[0143] The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (4) and the optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (6) obtained by the production method of the present invention form complexes together with transition metals as ligands, and these transition metal complexes are useful as asymmetric synthesis catalysts.

[0144] Examples of transition metals that can form complexes include rhodium, ruthenium, iridium, palladium, nickel, iron, and copper.

[0145] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0146] [Production Example 1] <(R Ｐ )-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R Ｐ ,R)-PB-MBI)> In a manner similar to that described in Example 2 (paragraph 0074) of JP-A-2011-219413, (R)-PB-MBI) with a diastereomeric excess of 99.6% was obtained. Ｐ )-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R Ｐ ,R)-PB-MBI) was synthesized.

[0147]

[0148] (R Ｐ , R)-PB-MBI identification data １ H NMR (500MHz, CDCl ３ ) 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). １３ C NMR (126MHz, CDCl ３ ) δ167.7 (d, J = 56.6 Hz), 142.39, 128.92, 127.77, 126.12, 49.81, 28.80 (d, J = 30.0 Hz), 25.49, 21.85, 3.63 (d, J = 36.0 Hz). ３１ P NMR (202 MHz, CDCl ３ ) δ33.91-33.43(m).

[0149] [Example 1] <(S Ｐ )-tert-butylmethylphosphine-borane ((S Ｐ )-PB)> Place (R) in a four-neck flask equipped with a mechanical stirrer, thermometer, three-way cock, and dropping funnel. Ｐ)-tert-butyl(methyl)[N-((R)-1-phenylethyl)carbamoyl]phosphineborane ((R Ｐ ,R)-PB-MBI)) (39.9 g, 150 mmol), and tetrabutylammonium bromide (n-Bu ４ NBr) (49.0 g, 152 mmol, 1.0 eq.) was 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 stirring was carried out for 26 hours. After stirring was completed, the flask was again immersed in a 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. Thereafter, 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.%.

[0150]

[0151] Example 2 n-Bu ４ The amount of NBr used is (R Ｐ , R)-PB-MBI to the molar ratio (n-Bu ４ NBr / (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. ３１The chemical purity determined by P NMR and GC was 78.2% and 61.2%, respectively, and the optical purity was 98.2 ee %.

[0152] Example 3 n-Bu ４ The amount of NBr used is (R Ｐ , R)-PB-MBI to the molar ratio (n-Bu ４ NBr / (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.

[0153] Example 4 n-Bu ４ The amount of NBr used is (R Ｐ , R)-PB-MBI to the molar ratio (n-Bu ４ NBr / (R Ｐ The reaction was carried out in the same manner as in Example 1, except that the amount of (S)-PB-MBI) was 0.6. Ｐ )-PB was obtained. 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.

[0154] Example 5 n-Bu ４ Instead of NBr, tetrabutylphosphonium bromide (n-Bu ４ The reaction was carried out in the same manner as in Example 1, except that (S PBr) (15.3 g, 150 mmol, 0.3 eq.) was used, and 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.%.

[0155]

[0156]

[0157] [Production Example 2] <Phosphinepyrazine Derivative (3A)> A stirrer was placed in a four-necked flask equipped with a septum, a thermometer, a three-way cock, and a dropping funnel. After replacing the atmosphere in the vessel 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. Thereafter, the mixture was stirred in the refrigerant bath for 30 minutes to obtain t-Bu ２ P (BH ３ A THF solution of 2,3-dichloroquinoxaline (15.0 g, 75.4 mmol) was prepared 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 refrigerant bath at 0°C, and Solution B (83.1 mmol, 1.1 eq.) was slowly added dropwise so that the temperature of the reaction solution 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 warmed to room temperature and stirred overnight. After stirring, the reaction mixture was washed four times with pure water (50 mL) and then with saturated saline (50 mL). The solvent was removed from the separated organic layer by vacuum distillation in a water bath at 30°C. 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. The phosphinepyrazine derivative (3A) was obtained as a yellow solid by washing with a small amount of chilled MeOH. ３１ The chemical purity determined by P NMR was 99.9%.

[0158]

[0159] Identification data of phosphine pyrazine derivative (3A) １ H NMR (500MHz, CDCl ３ ) 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, CDCl ３) 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 (202 MHz, CDCl ３ ) δ 26.54.

[0160] [Example 6] <(R)-3H-QuinoxP ＊ A four-neck flask equipped with a mechanical stirrer, thermometer, three-way stopcock, and dropping funnel was charged with the phosphine pyrazine derivative (3A) (3.11 g, 10.1 mmol) and the (SP)-tert-butylmethylphosphine-borane obtained in Example 1 (>99.5 e.e.%, 1.41 g, 12.0 mmol, 1.2 eq.). The system was then purged with nitrogen, and dehydrated 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 reaction temperature did not exceed -10°C. After stirring for approximately 6 hours in the refrigerant bath, tetramethylethylenediamine (TMEDA) (1.80 g, 15.5 mmol, 1.5 eq.) was added dropwise. The reaction mixture was warmed to room temperature and then stirred for approximately 5 hours. After stirring was completed, the reaction mixture was immersed in a 0°C refrigerant bath, n-hexane (2.1 g) was added, and 2M 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 saline (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 insoluble solids were removed by filtration. The solvent was then removed by distillation under reduced pressure in a 30°C water bath. The residue obtained at room temperature was dissolved in THF (15 mL), and the flask was then immersed in a 0°C refrigerant bath, and MeOH (30 mL) was added dropwise. After the dropwise addition, the mixture was stirred in a refrigerant bath for about 30 minutes, and the solid was filtered off using a glass filter. The filtered cake 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%) ３１The chemical purity determined by P NMR was 99.9% and the optical purity was 99.8 ee.

[0161]

[0162] (R)-3H-QuinoxP ＊ Identification data of １ H NMR (500MHz, CDCl ３ ) 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, CDCl ３ ) 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 (202 MHz, CDCl ３ ) δ 21.6 (d, J = 109.0 Hz), -14.4 (d, J = 103.5 Hz).

[0163] [Example 7] <(S Ｐ )-tert-butylmethylphosphine-borane ((S Ｐ )-PB)> In the same manner as in Example 1, 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.

[0164]

[0165] <(R,R)-QuinoxP ＊In a four-neck flask equipped with a mechanical stirrer, a thermometer, a three-way stopcock, and a dropping funnel, 2,3-dichloroquinoxaline (12.0 g, 60.2 mmol) and (S Ｐ )-PB (15.7 g, 133 mmol, 2.2 eq.) was added, and the system was purged with nitrogen. After adding dehydrated THF (108 g), the flask was immersed in a refrigerant bath at -10°C to 0°C, and a THF solution of approximately 20 wt% tert-butoxypotassium (85.1 g, 152 mmol, 2.5 eq.) was slowly added dropwise so that the liquid temperature did not exceed 10°C. The reaction solution was heated to 15°C to 20°C and stirred for approximately 1 hour. Thereafter, N,N,N',N'-tetramethylethylenediamine (TMEDA) (17.4 g, 150 mmol, 2.5 eq.) was added, and the mixture was stirred overnight at 15°C to 20°C. The reaction mixture was immersed in a refrigerant bath at -5°C to 0°C, and n-hexane (26.0 g, 302 mmol) was added. Thereafter, 2M hydrochloric acid (146 mL, 292 mmol) was slowly added dropwise so that the liquid temperature did not exceed 5°C. The reaction mixture was heated to 15-20°C, and after removing the aqueous layer, the organic layer was washed three times with pure water (100 g). The solvent was then removed from the separated organic layer in a 30°C water bath by distillation under reduced pressure. The obtained crude product was dissolved in methanol (80 g) in a 70°C water bath, allowed to cool to room temperature, and then cooled in a 0°C refrigerant bath for 30 minutes. The insoluble matter in the solution was filtered off, and the resulting residue was washed with a small amount of cooled methanol and then vacuum dried to obtain (R,R)-QuinoxP. ＊ (12.6 g, 62%). ３１ The chemical purity determined by P NMR was 99.8% and the optical purity was 99.9 ee%.

[0166]

[0167] (R,R)-QuinoxP ＊ Identification data of １ H NMR (500MHz, CDCl ３ ) δ 8.12-8.08 (m, 2H), 7.74-7.70 (m, 2H), 1.44-1.43 (m, 6H), 1.03-1.00 (m, 18H). １３ C NMR (126MHz, CDCl ３) δ 165.29-165.25(m),141.78,129.78-129.66(m),32.12-32.01(m),27.81-27.69(m),4.95-4.89(m). ３１ P NMR(202MHz,CDCl ３ ) δ -16.69.

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 hydrogen-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. (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.) (R in the formula １ , R ２ and * are the same as those in formula (1).

2. The above 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 above 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. 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 the following step B. [Step 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): (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.) (R in the formula １ , R ２ and * are defined as in the general formula (1). [Step 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): (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. (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. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 7, wherein the deboranizing agent is tetramethylethylenediamine.

10. A method for producing an optically active 2,3-bisphosphinopyrazine derivative, comprising carrying out the following step A and then the following step B': [Step 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): (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.) (R in the formula １ , R ２ and * are defined as in the general formula (1). [Step 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 (5), followed by a deboranization reaction to obtain an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (6): (R ５ represents a monovalent substituent, n represents an integer of 0 to 4, and X represents a halogen atom. (R in the formula １ , R ２ and * are the same as those in the general formula (1), and R ５ and n have the same meanings as in the general formula (3).

11. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 10, 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 (5) 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 (6) in one pot.

12. The method for producing an optically active 2,3-bisphosphinopyrazine derivative according to claim 11, wherein the base is potassium t-butoxide.

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