JP5465584B2 - Method for producing pyrazine derivative - Google Patents

Description

  The present invention relates to a method for producing a pyrazine derivative. More specifically, the present invention relates to a ligand of a metal complex used as an asymmetric catalyst in an asymmetric synthesis reaction, a ligand source of a transition metal complex used as an anticancer agent, etc. The present invention relates to a method for producing a bisphosphinopyrazine derivative.

  Organic synthesis reactions catalyzed by metal complexes having optically active phosphine ligands have been known for a long time and are extremely useful, and many research results have been reported. In recent years, ligands in which the phosphorus atom itself is asymmetric have been developed. For example, Patent Document 1 describes an optically active 2,3-bis (dialkylphosphino) pyrazine derivative that can provide a metal complex that exhibits excellent catalytic performance and a method for producing the same.

  The production method described in Patent Document 1 includes a step of obtaining dialkyl-phosphine borane from dialkyl (benzoyloxymethyl) phosphine-borane using potassium persulfate and ruthenium trichloride. Potassium persulfate is a potentially explosive compound. Ruthenium trichloride is an expensive compound and its use is economically disadvantageous.

  In addition, optically active 2,3-bis (dialkylphosphino) pyrazine derivatives have three types of (R, R), (S, S) and (R, S) isomers due to the asymmetry of the phosphorus atom. Is present. In the production of an optically active 2,3-bis (dialkylphosphino) pyrazine derivative, it is required that only a desired one of these isomers can be easily obtained.

JP 2007-56007 A

  Accordingly, an object of the present invention is to provide a method for producing an optically active 2,3-bisphosphinopyrazine derivative which is industrially advantageous and can easily produce any isomer.

  The present invention is a method for producing an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (A), comprising the following steps I, II and III: The object has been achieved by providing a manufacturing method.

（式中、Ｒ¹及びＲ²は、それらが存在することによりリン原子上に不斉を発現させるか又はリン原子が不斉面の一点をなす一対の基であり、それぞれ水素原子、炭化水素基又は置換炭化水素基を示す。）
で表される水素−ホスフィンボラン化合物と、一般式（２）

（式中、Ｒ³は不斉炭化水素基又は置換不斉炭化水素基を示す。）
で表される光学活性イソシアネート化合物とをカップリング反応に付して、一般式（３）

（式中、Ｒ¹、Ｒ²及びＲ³は、前記と同義である。）
で表されるホスフィンボラン化合物を得た後、得られた一般式（３）で表されるホスフィンボラン化合物を光学分割により精製して、一般式（３’）

（式中、Ｒ¹、Ｒ²及びＲ³は、前記と同義であり、＊は不斉を示す。）
で表される光学活性なホスフィンボラン化合物を得る。 [Process I]
General formula (1)

(In the formula, R ¹ and R ² are a pair of groups that cause asymmetry on the phosphorus atom due to their presence, or the phosphorus atom forms one point on the asymmetric surface, respectively, a hydrogen atom, a hydrocarbon, Group or substituted hydrocarbon group.)
And a hydrogen-phosphine borane compound represented by the general formula (2)

(In the formula, R ³ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group.)
And an optically active isocyanate compound represented by general formula (3)

(In the formula, R ¹ , R ² and R ³ are as defined above.)
Then, the phosphine borane compound represented by the general formula (3) is purified by optical resolution to obtain the general formula (3 ′).

(In the formula, R ¹ , R ² and R ³ are as defined above, and * indicates asymmetry.)
An optically active phosphine borane compound represented by the formula:

（式中、Ｒ¹及びＲ²並びに＊は、前記と同義である。）
で表される光学活性な水素−ホスフィンボラン化合物を得る。 [Process II]
The phosphine borane compound represented by the general formula (3 ′) obtained in the step I is subjected to a decomposition reaction, and the general formula (1 ′)

(Wherein R ^1, R ² and * are as defined above.)
An optically active hydrogen-phosphine borane compound represented by the formula:

（式中、Ｒ⁴及びＲ⁵は、水素原子又はアルキル基を示し、同一の基であっても異なる基であってもよく、互いに結合して飽和又は不飽和の環を形成していてもよく、該飽和又は不飽和の環は、置換基を有してもよく、Ｘはハロゲン原子を示す。）
で表される２，３−ジハロゲノピラジンとを反応させて、一般式（５）

（式中、Ｒ¹、Ｒ²、Ｒ⁴及びＲ⁵並びに＊は、前記と同義である。）
で表される光学活性なビス（ホスフィン−ボラン）ピラジン化合物を得た後、該ビス（ホスフィン−ボラン）ピラジン化合物の脱ボラン化反応を行って、一般式（Ａ）

（式中、Ｒ¹、Ｒ²、Ｒ⁴及びＲ⁵並びに＊は、前記と同義である。）
で表される光学活性な２，３−ビスホスフィノピラジン誘導体を得る。 [Step III]
An optically active hydrogen-phosphine borane compound represented by the general formula (1 ′) obtained in the step II, and the general formula (4)

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or an alkyl group, and may be the same group or different groups, and may be bonded to each other to form a saturated or unsaturated ring. Well, the saturated or unsaturated ring may have a substituent, and X represents a halogen atom.)
Is reacted with 2,3-dihalogenopyrazine represented by the general formula (5)

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ and * are as defined above.)
After obtaining the optically active bis (phosphine-borane) pyrazine compound represented by general formula (A), the bis (phosphine-borane) pyrazine compound is deboraneated.

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ and * are as defined above.)
An optically active 2,3-bisphosphinopyrazine derivative represented by the formula:

  The method for producing an optically active 2,3-bisphosphinopyrazine derivative of the present invention is industrially advantageous in that no explosive compound or expensive compound is used. In addition, according to the production method of the present invention, any isomer of the optically active 2,3-bisphosphinopyrazine derivative can be easily produced.

First, the step I will be described.
In the general formulas (1), (3), and (3 ′), groups represented by R ¹ and R ² will be described below.

R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group or a substituted hydrocarbon group. R ¹ and R ² may be independent from each other or may be linked by crosslinking.

  Although there is no restriction | limiting in particular as said hydrocarbon group, For example, an alkyl group, an aralkyl group, an aryl group etc. are mentioned.

  The alkyl group may be linear, branched or cyclic. Examples of the linear or branched alkyl group include a linear or branched alkyl group having 1 to 8 carbon atoms, and specifically include a methyl group, an ethyl group, an n-propyl group, and a 2-propyl group. N-butyl group, 2-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-pentyl group, tert-pentyl group, 2-methylbutyl group, 3-methylbutyl group, 2,2-dimethylpropyl Group, n-hexyl group, 2-hexyl group, 3-hexyl group, tert-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 5-methylpentyl group and the like. Examples of the cyclic alkyl group include a cycloalkyl group having 3 to 16 carbon atoms, and specifically include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 2-methylcyclopentyl group, and 3-methyl. Examples include a cyclopentyl group, a cycloheptyl group, a 2-methylcyclohexyl group, a 3-methylcyclohexyl group, and a 4-methylcyclohexyl group. The cyclic alkyl group includes a polycyclic alkyl group, and examples of the polycyclic alkyl group include a menthyl group, a bornyl group, a norbornyl group, an adamantyl group, and the like.

  Examples of the aralkyl group include an aralkyl group having 7 to 12 carbon atoms, specifically, a benzyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a 2-phenylpropyl group, a 3-phenylpropyl group, 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group, 1-phenylpentyl group, 2-phenylpentyl group, 3-phenylpentyl group, 4-phenylpentyl group, 5- Examples include phenylpentyl group, 1-phenylhexyl group, 2-phenylhexyl group, 3-phenylhexyl group, 4-phenylhexyl group, 5-phenylhexyl group, 6-phenylhexyl group and the like.

  As said aryl group, a C6-C20 aryl group is mentioned, for example, A phenyl group, a naphthyl group, an anthryl group, a biphenyl group, a binaphthyl group etc. are mentioned specifically ,.

  The substituted hydrocarbon group includes a hydrocarbon group in which at least one hydrogen atom of the hydrocarbon group 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. Or a group in which at least one carbon atom of the hydrocarbon group is substituted with a heteroatom such as oxygen, nitrogen, sulfur, or phosphorus.

  The substituted hydrocarbon group includes a heterocyclic group. In this case, the substituted hydrocarbon group may be an aliphatic heterocyclic group or an aromatic heterocyclic group. Examples of the aliphatic heterocyclic group include 5-membered or 6-membered aliphatic heterocyclic groups, and specific examples thereof include pyrrolidyl-2-one group, piperidino group, piperazinyl group, morpholino group, tetrahydrofuryl group, tetrahydro A pyranyl group etc. are mentioned. Examples of the aromatic heterocyclic group include a 5-membered or 6-membered aromatic heterocyclic group, and specific examples include, for example, a pyridyl group, an imidazolyl group, a thiazolyl group, a furfuryl group, a pyranyl group, a furyl group, and a benzofuryl group. And thienyl group.

In the present invention, when the asymmetry is expressed on the phosphorus atom, a combination in which the steric bulk is greatly different in R ¹ and R ² is preferable in order to exhibit the effect of asymmetry higher. Includes a combination of a methyl group and a tert-butyl group, a combination of a methyl group and an adamantyl group, and the like.

In the present invention, when the phosphorus atom constitutes one point of the axially asymmetric symmetry plane, the portion constituting the asymmetry in R ¹ or R ² is a phosphorus atom in order to exhibit the asymmetry effect higher. As a specific example, R ¹ and R ² are linked by a bridge, and a group including a phosphorus atom is 2,5-dimethylphosphorane or 2,5-diethylphosphorane. Cases.

In the general formulas (2), (3), and (3 ′), the group represented by R ³ will be described.

R ³ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group. The asymmetric hydrocarbon group is not particularly limited, and specific examples include (S) -1-phenylethyl group, (R) -1-phenylethyl group, (S) -1- (p-toluyl) ethyl group. , (R) -1- (p-toluyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (1-naphthyl) ethyl group, (S) -1-cyclohexyl Ethyl group, (R) -1-cyclohexylethyl group, (S) -2- (4-methylphenyl) -1-phenylethyl group, (R) -2- (4-methylphenyl) -1-phenylethyl group Among these, (S) -1-phenylethyl group and (R) -1-phenylethyl group, which can be used industrially at low cost, are preferable.

  The substituted asymmetric hydrocarbon group includes a substituent such as an amino group in which at least one hydrogen atom of the asymmetric hydrocarbon group has a hydrocarbon group, an alkoxy group, a halogen atom, an amino group, a nitro group, or a protective group. Or a group in which at least one carbon atom of the asymmetric hydrocarbon group is substituted with a heteroatom such as oxygen, nitrogen, sulfur, or phosphorus.

  In step I, the hydrogen-phosphine borane compound represented by the general formula (1) and the optically active isocyanate compound represented by the general formula (2) are mixed in a reaction vessel, and the coupling reaction proceeds. In that case, it is preferable to promote the reaction by adding a base to the reaction system. By this coupling reaction, the phosphine borane compound represented by the general formula (3) is generated. As the hydrogen-phosphine borane compound represented by the general formula (1), a mixture of an S form and an R form (for example, a racemic form) can be used. When a mixture of an S form and an R form is used as the hydrogen-phosphine borane compound represented by the general formula (1), the phosphine borane compound represented by the general formula (3) generated by the coupling reaction is represented by Sp. (The Sp form means a compound in which the configuration of the asymmetric phosphorus atom is S, and the Rp form means the compound in which the configuration of the asymmetric phosphorus atom is R). .

  After the coupling reaction, the by-product salt is removed, and purification (optical resolution) is performed to obtain only one side of the enantiomer (Sp body and Rp body) of the phosphine borane compound represented by the general formula (3). And the optically active phosphine borane compound represented by the general formula (3 ′) can be obtained. The phosphine borane compound represented by the general formula (3 ′) has an asymmetric part having an asymmetric surface on the phosphorus atom or the phosphorus atom as an asymmetric surface, and an optically active carbamoyl group, Is a diastereomer having two points.

When the optically active isocyanate compound represented by the general formula (2) is added to the hydrogen-phosphine borane compound represented by the general formula (1), an S-form is used as the group R ³ in the isocyanate compound, Whether to use the R isomer or not may be appropriately determined according to the ease of optical resolution of the diastereomers of the phosphine borane compound represented by the general formula (3 ′). For example, when R ¹ and R ² are a combination of a methyl group and a tert-butyl group, the following can be said.
When an optically active isocyanate compound represented by the general formula (2) is one in which R ³ is an (S) -asymmetric hydrocarbon group or an (S) -substituted asymmetric hydrocarbon group, it is optical by crystallization. When splitting, the phosphine borane compound represented by the general formula (3 ′) of the Sp isomer is easily crystallized. On the other hand, as the optically active isocyanate compound represented by the general formula (2), when R ³ is an (R) -asymmetric hydrocarbon group or an (R) -substituted asymmetric hydrocarbon group, crystallization is performed. When the optical resolution is performed, the phosphine borane compound represented by the general formula (3 ′) of the Rp body is easily crystallized.

  As the hydrogen-phosphine borane compound represented by the general formula (1), a commercially available product can be used, and for example, it can be obtained from Nippon Chemical Industry Co., Ltd. Commercially available products can also be used for the optically active isocyanate compound represented by the general formula (3), for example, available from Tokyo Chemical Industry Co., Ltd.

  In the coupling reaction, a solvent is appropriately used. As the solvent, a solvent that does not decompose the reaction substrate is used. Specific examples include toluene, hexane, tetrahydrofuran (THF), diethyl ether, dioxane, acetone, ethyl acetate, chlorobenzene, dimethylformamide (DMF), acetonitrile, methanol. , Ethanol, water and the like, preferably toluene or THF.

  The amount of the solvent added during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.

  The amount of raw materials charged during the reaction is preferably a hydrogen-phosphine borane compound represented by the general formula (1) based on the optically active isocyanate compound represented by the general formula (2). 1.5 equivalents and the optimum value is 1 equivalent.

  Addition of a base during the reaction promotes the reaction. The base used here is not particularly limited, and for example, pyridine, triethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,5-diazabicyclo [4.3. 0] Organic bases such as nonene-5 (DBN) and 4- (N, N-dimethylamino) pyridine (DMAP), inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, n-butyllithium , Sec-butyllithium, tert-butyllithium, lithium diisopropylamide, isopropylmagnesium chloride, methylmagnesium bromide and the like. N-Butyllithium is preferred.

  The amount of the base charged can be appropriately set according to the required degree of acceleration of the reaction, but is usually 0.1 mol with respect to the optically active isocyanate compound represented by the general formula (2). % To 150 mol%, preferably 1 mol% to 10 mol%. The order of preparation is not particularly important and can be arbitrarily determined according to workability and the like.

  The reaction temperature is usually −80 to 50 ° C., preferably 0 to 30 ° C., where the reaction is promoted and side reactions and racemization are suppressed.

  The reaction time is usually 1 minute to 24 hours, preferably 30 minutes to 4 hours, which is sufficient time for the reaction to be completed.

  After the coupling reaction, by-products such as by-product salts are removed, and then optical resolution is performed by purification, only one side of the enantiomer, that is, a phosphine borane compound represented by the general formula (3 ′) can be obtained. it can. The purification method performed at this time is not particularly limited as long as optical resolution is possible, and examples include separation washing, crystallization, distillation, sublimation, column chromatography, and the like, but preferably industrially. This is an advantageous crystallization.

  Specific examples of the phosphine borane compound represented by the general formula (3 ′) include the following compounds. However, the phosphine borane compounds are merely examples, and the scope of the present invention is not limited thereto.

（ａ）（Ｓ_P）−ｔｅｒｔ−ブチル（メチル）［Ｎ−（（Ｓ）−１−フェニルエチル）カルバモイル］ホスフィンボラン、又は（Ｒ_P）−ｔｅｒｔ−ブチル（メチル）［Ｎ−（（Ｓ）−１−フェニルエチル）カルバモイル］ホスフィンボラン
（ｂ）（Ｓ_P）−アダマンチル（メチル）［Ｎ−（（Ｓ）−１−フェニルエチル）カルバモイル］ホスフィンボラン、又は（Ｒ_P）−アダマンチル（メチル）［Ｎ−（（Ｓ）−１−フェニルエチル）カルバモイル］ホスフィンボラン The structural formula in the case of introducing asymmetry on the phosphorus atom is exemplified.

(A) (S _P ) -tert-butyl (methyl) [N-((S) -1-phenylethyl) carbamoyl] phosphine borane or (R _P ) -tert-butyl (methyl) [N-((S ) -1-phenylethyl) carbamoyl] phosphine borane (b) (S _P ) -adamantyl (methyl) [N-((S) -1-phenylethyl) carbamoyl] phosphine borane, or (R _P ) -adamantyl (methyl) ) [N-((S) -1-phenylethyl) carbamoyl] phosphine borane

（ｃ）（Ｒ，Ｒ）−２，５−ジメチル−１−［Ｎ−（（Ｓ）−１−（１−ナフチル）エチル）カルバモイル］ホスホランボラン A structural formula in the case where a phosphorus atom constitutes one point of an axially asymmetric plane is illustrated.

(C) (R, R) -2,5-dimethyl-1- [N-((S) -1- (1-naphthyl) ethyl) carbamoyl] phospholamborane

Next, the step II will be described.
In a reaction vessel, the phosphine borane compound represented by the general formula (3 ′) obtained in Step I and a base are mixed to decompose the phosphine borane compound. It is preferable to add alcohol to promote the decomposition reaction. After the reaction, by-products are removed to obtain an optically active hydrogen-phosphine borane compound represented by the general formula (1 ′).

  A solvent is appropriately used during the reaction. As the solvent, a solvent that does not decompose the reaction substrate is used. Specific examples include toluene, hexane, tetrahydrofuran (THF), diethyl ether, dioxane, acetone, ethyl acetate, chlorobenzene, dimethylformamide (DMF), acetonitrile, methanol. , Ethanol, water and the like, preferably DMF or acetonitrile.

  The amount of the solvent added during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.

  The base is not particularly limited. For example, pyridine, triethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,5-diazabicyclo [4.3.0] Examples thereof include organic bases such as nonene-5 (DBN) and 4- (N, N-dimethylamino) pyridine (DMAP), and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. These bases are preferably supplied as a solution in order to react in a homogeneous system or a liquid-liquid two-phase system. For example, when potassium hydroxide is used as the base, it is preferably used as a 1 to 70% potassium hydroxide aqueous solution or a methanol solution, and more specifically, a 50% potassium hydroxide aqueous solution is suitably used.

  The amount of the base charged can be appropriately set according to the required degree of acceleration of the reaction, but is usually 0.01 equivalent to the phosphine borane compound represented by the general formula (3 ′). 10 equivalents, preferably 0.1 equivalents to 5 equivalents. The order of preparation is not particularly important and can be arbitrarily determined according to workability and the like.

  Alcohol is added to promote the reaction. The alcohol used here is not particularly limited, but examples thereof include methanol and ethanol, and methanol is preferred.

  The reaction temperature is usually −80 to 50 ° C., preferably 0 to 30 ° C., where the reaction is promoted and side reactions and racemization are suppressed.

  The reaction time is usually 1 minute to 24 hours, and preferably 3 hours to 20 hours, which is sufficient time for the reaction to be completed.

  After the reaction, the resulting product can be subjected to Step III after simple purification work such as removal of by-product salts, or by purification work such as liquid separation washing, crystallization, distillation, sublimation and column chromatography. After isolating only the optically active hydrogen-phosphine borane compound represented by the general formula (1 ′), it can be subjected to Step III.

Next, the step III will be described.
In the general formula (4), examples of the halogen atom represented by X include fluorine, chlorine, bromine, and iodine.

In the general formula (4), R ⁴ and R ⁵ represent a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be the same or different. The alkyl group represented by R ⁴ and R ⁵ may be linear, branched or cyclic. Examples of the linear or branched alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, an ethyl group, isopropyl group, n-propyl group, isobutyl group, n -Butyl group, sec-butyl group, tert-butyl group, isoheptyl group, n-heptyl group, isohexyl group, n-hexyl group and the like can be mentioned. Examples of the cyclic alkyl group include a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopentyl group and a cyclohexyl group. These groups may be appropriately substituted with at least one monovalent substituent.

R ⁴ and R ⁵ may be bonded to each other to form a saturated or unsaturated ring. Examples of the ring formed by combining R ⁴ and R ⁵ include a saturated or unsaturated 5-membered ring or 6-membered ring. For example, a benzene ring, a cyclohexane ring, a cyclopentane ring, etc. are mentioned. These rings may be appropriately substituted with at least one monovalent substituent.

Examples of the substituent of R ⁴ and R an alkyl group represented by ^5, or may monovalent be substituted ring R ⁴ and R ⁵ are formed by bonding is not particularly limited. Examples of the substituent include a halogen atom.

Particularly preferred as R ⁴ and R ⁵ is a case where both are bonded to each other to form a benzene ring which may be substituted with at least one monovalent substituent.

  As the 2,3-dihalogenopyrazine derivative represented by the general formula (4), a commercially available product can be used. For example, 2,3-dichloroquinoxaline is available from Tokyo Chemical Industry Co., Ltd.

  In the step III, the optically active hydrogen-phosphine borane compound represented by the general formula (1 ′) obtained in the step II and the 2,3-dihalogenopyrazine derivative represented by the general formula (4) Is carried out, for example, by reacting in an inert solvent at -78 to 30 ° C for 1 to 24 hours in the presence of a base. By this reaction, a bis (phosphine-borane) pyrazine compound represented by the general formula (5) is obtained.

  The amount of raw material charged during the reaction is based on the 2,3-dihalogenopyrazine derivative represented by the general formula (4) as an optically active hydrogen-phosphine borane represented by the general formula (1 ′). The compound is preferably 2 to 10 equivalents, more preferably 2 to 3 equivalents.

  Examples of the inert solvent include tetrahydrofuran, N, N-dimethylformamide, diethyl ether, dibutyl ether, dioxane, hexane, toluene, and the like, preferably tetrahydrofuran. The amount of the inert solvent added during the reaction can be appropriately set in consideration of the fluidity of the reaction mixture during the reaction and the effect of the solvent on the reaction.

  Examples of the base include n-butyllithium, methylmagnesium bromide, t-butoxypotassium, potassium hydroxide, sodium hydroxide and the like, preferably n-butyllithium. The amount of the base charged can be appropriately set according to the required degree of acceleration of the reaction, but with respect to the 2,3-dihalogenopyrazine derivative represented by the general formula (4), Usually 2 to 10 equivalents, preferably 2 to 3 equivalents. The order of preparation is not particularly important and can be arbitrarily determined according to workability and the like.

  In the deboration reaction of the bis (phosphine-borane) pyrazine compound represented by the general formula (5), for example, the reaction system containing the bis (phosphine-borane) pyrazine compound obtained by the reaction is desorbed. It is carried out by adding a borane agent and reacting at 0 to 100 ° C. for 10 minutes to 3 hours. By this deboraneation reaction, an optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (A), which is an object of the present invention, is obtained.

  Examples of the deboronating agent include N, N, N ′, N ′,-tetramethylethylenediamine (TMEDA), triethylenediamine (DABCO), triethylamine, etc., preferably TMEDA. The amount of the deboronating agent charged is 2,3-dibenzene represented by the general formula (4) used in obtaining the bis (phosphine-borane) pyrazine compound represented by the general formula (5). It is 2-20 equivalent normally with respect to a halogenopyrazine derivative, Preferably it is 2-10 equivalent.

  The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (A) produced by the deboraneation reaction may be subjected to liquid separation washing, crystallization, distillation, sublimation, column chromatography, etc. as necessary. It may be subjected to purification work.

  Specific examples of the 2,3-bis (dialkylphosphino) pyrazine derivative represented by the general formula (A) include (R, R) -2,3-bis (tert-butylmethylphosphino). Quinoxaline, (S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline, (R, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline; (R, R)- 2,3-bis (adamantylmethylphosphino) quinoxaline, (S, S) -2,3-bis (adamantylmethylphosphino) quinoxaline, (R, S) -2,3-bis (adamantylmethylphosphino) quinoxaline (R, R) -2,3-bis (tert-butylmethylphosphino) pyrazine, (S, S) -2,3-bis (tert-butylmethylphosphino) Pyrazine, (R, S) -2,3-bis (tert-butylmethylphosphino) pyrazine; (R, R) -2,3-bis (adamantylmethylphosphino) pyrazine, (S, S) -2, Examples include 3-bis (adamantylmethylphosphino) pyrazine, (R, S) -2,3-bis (adamantylmethylphosphino) pyrazine, and the like.

  The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (A) obtained by the production method of the present invention is, for example, a coordination of a metal complex used as an asymmetric catalyst in an asymmetric synthesis reaction. Useful as a child. As a metal atom which comprises this metal complex, transition metals, such as rhodium, ruthenium, iridium, palladium, nickel, iron, are mentioned, for example.

  The optically active 2,3-bisphosphinopyrazine derivative represented by the general formula (A) obtained by the production method of the present invention is also useful as a ligand source for a transition metal complex used as an anticancer agent. (For example, refer to JP 2007-320909 A). Gold, copper, or silver is mentioned as a metal atom which comprises this transition metal complex.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is merely illustrative, and the scope of application of the present invention is not limited thereto.

  All synthesis operations were performed using well-dried glass containers. The reaction was performed under a nitrogen atmosphere. General reagents were used as the raw material reagent and the solvent. A racemic tert-butylmethylphosphine borane manufactured by Nippon Chemical Industry Co., Ltd. was used.

NMR spectrum measurement was performed with a JEOL ( ¹ H; 300 MHz, ¹³ C; 75.4 MHz, ³¹ P; 121.4 MHz) NMR apparatus. Tetramethylsilane ( ¹ H) was used as an internal standard. The specific rotation measurement was performed with a specific rotation polarimeter SEPA-300 manufactured by Horiba.

[Example 1]
<Step I> (S _P) -tert- butyl (methyl) [N - ((S)-1-phenylethyl) carbamoyl] phosphine - the production 3L four-necked flask borane, mechanical stirring seal, a thermometer, etc. A pressure dropping funnel and an exhaust part were provided. Thereto, 141.8 g (1202 mmol) of racemic-tert-butylmethylphosphine borane and 600 cc of THF were added, and the racemic-tert-butylmethylphosphine borane was dissolved, and 1.59 mol / L n-butyl was maintained at 10 ° C. or lower. 75 cc (119 mmol) of a lithium-hexane solution was added dropwise. Subsequently, 176.8 g (1201 mmol) of (S)-(−)-α-methylbenzyl isocyanate was added dropwise at the same temperature. Thereafter, the temperature was returned to room temperature and aged with stirring overnight. The reaction was stopped by adding 90 g of 5% by weight hydrochloric acid, and then 240 cc of hexane and 240 cc of water were added to separate into two layers. The aqueous layer was removed, and the organic layer was washed with 240 g of 2.5% by weight aqueous sodium bicarbonate followed by 240 cc of water and concentrated to give a crude product (white flaky solid) as a phosphine borane represented by the general formula (3). Compound was obtained (348.3 g). The crude product was crystallized with 240 cc of ethyl acetate and 1800 cc of hexane, filtered and dried to obtain a colorless powder. The colorless powder obtained was identified as the title compound by NMR analysis. The NMR analysis results are shown below. The obtained colorless powder had a yield of 118.6 g (447 mmol), a yield of 37% (from isocyanate), and a diastereomeric excess> 97% de. The diastereomeric excess was determined from the area ratio of SP and RP specific portion protons in ¹ H-NMR.

(NMR analysis result)
¹ H-NMR (CDCl ₃ );
(S _P ) -body (object); -0.5-1 (3H, m), 1.14 (9H, d, 14.7 Hz), 1.45 (3H, d, 10.5 Hz), 1 .53 (3H, d, 6.9 Hz), 5.15 (1 H, pent, 6.9 Hz), 7.2-7.4 (6H, m).
(R _P ) -body; -0.5-1 (3H, m), 1.25 (9H, d, 14.7 Hz), 1.42 (3H, d, 10.5 Hz), 1.53 (3H , D, 6.9 Hz), 5.15 (1H, pent, 6.9 Hz), 7.2-7.4 (6H, m).

<Step II> Production of optically active hydrogen-phosphine borane compound [(R) -tert-butylmethylphosphine-borane] A 200 cc four-necked flask is equipped with a mechanical stirring seal, a thermometer, and an exhaust part, and step I (S _P ) -tert-butyl (methyl) [N-((S) -1-phenylethyl) carbamoyl] phosphine-borane obtained in 1) and 100 cc of DMF were added, and phosphine-borane was added. After dissolution, the temperature was adjusted to 10 ° C. or lower in an ice water bath. Thereto were added 21.26 g (189 mmol) of a 50 wt% aqueous potassium hydroxide solution and 25 cc of methanol. Next, the ice-water bath was removed and the mixture was aged with stirring for 18 hours. Next, 100 cc of cold water and 100 cc of petroleum ether were placed in a 500 cc Erlenmeyer flask, and the reaction was stopped by dispersing the reaction solution therein. The aqueous layer and the organic layer were separated, the aqueous layer was re-extracted with 100 cc of petroleum ether, combined with the previously separated organic layer, washed twice with 50 cc of water, and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (Wakogel C200) gave a colorless powder. The colorless powder obtained was identified as the title compound by NMR analysis. The NMR analysis results are shown below. The obtained colorless powder had a yield of 3.01 g (25.5 mmol) and a yield of 67%.

(NMR analysis result)
¹ H-NMR (CDCl ₃ );
-0.5-1 (3H, m), 1.22 (9H, d, 14.7Hz), 1.32 (3H, dd, 10.5Hz, 6.0Hz), 4.4 (1H, dm, 355 Hz).

<Step III> Optically active 2,3-bisphosphinopyrazine derivative [(S, S) -2,3-bis (tert-butylmethylphosphino) quinoxaline (abbreviation: (S, S) -QuinoxP ^* )] at the production flask, obtained in step II (R) -tert- butyl methyl phosphine - borane 3.01g of (25.5 mmol) was dissolved in dehydrated THF25cc, cooled to -78 ° C.. To this was added dropwise 15.5 cc (25.6 mmol) of a 1.65 mol / L n-butyllithium-hexane solution, and the mixture was aged and stirred at the same temperature for 15 minutes. Subsequently, 1,703 mg (8.56 mmol) of 2,3-dichloroquinoxaline was added all at once with good stirring. After the addition, the mixture was returned to room temperature over 1 hour and stirred for 3 hours. Subsequently, 10.07 g (87 mmol) of tetramethylethylenediamine was added, followed by stirring and aging at room temperature (25 ° C.) for 2 hours. The reaction was stopped by adding 1M hydrochloric acid, and hexane was added to extract organic components. The organic layer was washed with 1M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1) to obtain the title compound as an orange powder. Further, the crystals were recrystallized and purified from hot methanol to obtain orange cubic crystals. The yield was 2,149 mg (6.427 mmol), and the yield was 75%. The analysis results of the obtained title compound are shown below.

(result of analysis)
¹ H-NMR (CDCl ₃ );
1.02 (18 H, t, 6.0 Hz), 1.4 (6 H, t, 3.2 Hz), 7.68-7.75 (2 H, m), 8.07-8.14 (2 H, m ).
¹³ C-NMR (CDCl ₃ );
4.8 (d), 27.6 (t), 31.9 (t), 129.6 (d), 141.6, 165.1 (d), 165.2 (d).
³¹ P-NMR (CDCl ₃ );
-16.6.
Specific rotation: + 53.5 ° ([α] ^D ₂₂ (c = 1, CHCl ₃ ); where (R, R) -QuinoxP ^* is known to have a specific rotation of −54.3 °)
Melting point: 102-103 ° C

[Example 2]
<Step I> Production of (R _P ) -tert-butyl (methyl) [N-((R) -1-phenylethyl) carbamoyl] phosphine-borane (S)-(−)-α-methylbenzyl isocyanate 176. A colorless powder was obtained in the same procedure as in Step I of Example 1, except that 8 g was replaced with 17.7 g of (R)-(+)-α-methylbenzyl isocyanate and the reaction scale was adjusted accordingly. It was.
The obtained colorless powder was identified as the title compound because NMR analysis showed the same result as the (R _P ) _-form shown in Step I of Example 1. The obtained colorless powder had a yield of 11.9 g (44.7 mmol), a yield of 37% (from isocyanate), and a diastereomeric excess> 97% de.

<Step II> Production of optically active hydrogen-phosphine borane compound [(S) -tert-butylmethylphosphine-borane] (S _P ) -tert-butyl (methyl) [N-((S) -1-phenylethyl) Instead of 10.03 g of carbamoyl] phosphine-borane, 10.03 g of (R _P ) -tert-butyl (methyl) [N-((R) -1-phenylethyl) carbamoyl] phosphine-borane obtained in Step I A colorless powder was obtained in the same procedure as in Step II of Example 1, except that was used.
The colorless powder obtained was identified as the title compound by NMR analysis. The NMR analysis results are shown below. The obtained colorless powder had a yield of 3.01 g (25.5 mmol) and a yield of 67%.

(result of analysis)
¹ H-NMR (CDCl ₃ );
-0.5-1 (3H, m), 1.22 (9H, d, 14.7Hz), 1.32 (3H, dd, 10.5Hz, 6.0Hz), 4.4 (1H, dm, 355 Hz).

<Step III> Optically active 2,3-bisphosphinopyrazine derivative [(R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline (abbreviation: (R, R) -QuinoxP ^* )] Preparation of (R) -tert-butylmethylphosphine-borane 3.01 g (25.5 mmol) and 2,3-dichloroquinoxaline 1,703 mg obtained in step II Instead of 236 mg (2.0 mmol) and 2,3-dichloroquinoxaline 133 mg (0.67 mmol), an orange cubic crystal was obtained in the same manner as in Step III of Example 1, except that the reaction scale was adjusted accordingly. Crystal was obtained. The obtained orange cubic crystals had a yield of 179 mg (0.535 mmol) and a yield of 80%. As a result of analysis, the obtained orange cubic crystals were identified as the title compound. The analysis results are shown below.

(result of analysis)
¹ H-NMR (CDCl ₃ );
1.02 (18 H, t, 6.0 Hz), 1.4 (6 H, t, 3.2 Hz), 7.68-7.75 (2 H, m), 8.07-8.14 (2 H, m ).
¹³ C-NMR (CDCl ₃ );
4.8 (d), 27.6 (t), 31.9 (t), 129.6 (d), 141.6, 165.1 (d), 165.2 (d).
³¹ P-NMR (CDCl ₃ );
-16.6.
Specific rotation: -54.3 ° ([α] ^D ₂₂ (c = 1, CHCl ₃ )
Melting point: 102-103 ° C

Claims (4)

A method for producing an optically active 2,3-bisphosphinopyrazine derivative represented by the following general formula (A), which comprises the following steps I, II and III.
[Process I]
General formula (1)

(In the formula, R ¹ and R ² are a pair of groups that cause asymmetry on the phosphorus atom due to their presence, or the phosphorus atom forms one point on the asymmetric surface, respectively, a hydrogen atom, a hydrocarbon, Group or substituted hydrocarbon group.)
And a hydrogen-phosphine borane compound represented by the general formula (2)

(In the formula, R ³ represents an asymmetric hydrocarbon group or a substituted asymmetric hydrocarbon group.)
And an optically active isocyanate compound represented by general formula (3)

(In the formula, R ¹ , R ² and R ³ are as defined above.)
Then, the phosphine borane compound represented by the general formula (3) is purified by optical resolution to obtain the general formula (3 ′).

(In the formula, R ¹ , R ² and R ³ are as defined above, and * indicates asymmetry.)
An optically active phosphine borane compound represented by the formula:
[Process II]
The phosphine borane compound represented by the general formula (3 ′) obtained in the step I is subjected to a decomposition reaction, and the general formula (1 ′)

(Wherein R ^1, R ² and * are as defined above.)
An optically active hydrogen-phosphine borane compound represented by the formula:
[Step III]
An optically active hydrogen-phosphine borane compound represented by the general formula (1 ′) obtained in the step II, and the general formula (4)

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or an alkyl group, and may be the same group or different groups, and may be bonded to each other to form a saturated or unsaturated ring. Well, the saturated or unsaturated ring may have a substituent, and X represents a halogen atom.)
Is reacted with 2,3-dihalogenopyrazine represented by the general formula (5)

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ and * are as defined above.)
After obtaining the optically active bis (phosphine-borane) pyrazine compound represented by general formula (A), the bis (phosphine-borane) pyrazine compound is deboraneated.

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ and * are as defined above.)
An optically active 2,3-bisphosphinopyrazine derivative represented by the formula: The method for producing a pyrazine derivative according to claim 1, wherein R ¹ is a tert-butyl group or an adamantyl group, and R ² is a methyl group. The method for producing a pyrazine derivative according to claim 1 or 2, wherein R ³ is a (S) -1-phenylethyl group or a (R) -1-phenylethyl group. The method for producing a pyrazine derivative according to any one of claims 1 to 3, wherein R ⁴ and R ⁵ are bonded to each other to form an optionally substituted benzene ring.