JP2012082179A - Method for preventing lowering of optical purity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To inhibit lowering of optical purity of a reduction reaction product caused by a transition metal complex used as a catalyst.SOLUTION: The manufacturing method of a reduction reaction product comprises adding a nitrogen-containing compound to a reaction liquid obtained by a reduction reaction where a transition metal complex is used and subsequently recovering and/or distilling a reaction solvent.

Description

  The present invention relates to a method for deactivating a transition metal complex used as a catalyst without losing the optical purity of a target product when a reduction reaction product is produced by a reduction reaction.

還元機能を有する金属触媒は酸化機能も同時に持ち合わせていることから、生成した２級アルコールの酸化も時としておこり生成物の光学純度低下の要因となる。

これら反応は中性若しくは塩基性条件下で進行することから、反応停止のためには塩酸などの酸を加える方法などがある。 Hydrogenation and hydrogen transfer reactions using metal complexes are important methods in the production of optically active compounds. In general, the reaction is carried out using a prochiral ketone in the presence of a metal catalyst and a secondary alcohol, formic acid, hydrogen, etc. as a hydrogen source. It has been known.

Since the metal catalyst having a reducing function also has an oxidizing function at the same time, oxidation of the produced secondary alcohol sometimes causes reduction of the optical purity of the product.

Since these reactions proceed under neutral or basic conditions, there is a method of adding an acid such as hydrochloric acid to stop the reaction.

  However, when distilling the product, in the presence of hydrochloric acid, the inside of the distillation apparatus becomes hot and acidic, so that the apparatus is easily damaged, and the reaction apparatus and operating method to be used are limited.

The present inventors add a nitrogen-containing compound to the reaction solution of the reduction reaction, so that (i) the nitrogen-containing compound selectively reacts with the metal catalyst, and (ii) eliminates the reduction function and oxidation function of the metal complex. Thus, it was found that the reduction of the optical purity of the reduction reaction product was suppressed, and the present invention was completed.
The present invention includes the following contents [1] to [7].
[1] A method for producing a reduction reaction product, in which a nitrogen-containing compound is added to a reaction solution subjected to a reduction reaction using a transition metal complex, and then a reaction solvent is recovered and / or distilled.
[2] The production method according to [1], wherein the reduction reaction is asymmetric hydrogenation or asymmetric hydrogen transfer.
[3] The production method according to [1] or [2], wherein the transition metal complex is a ruthenium complex, a rhodium complex, or an iridium complex.
[4] The production method according to [3], wherein 1 equivalent or more of a nitrogen-containing compound is added to the transition metal complex.
[5] The production method according to [4], wherein the number of nitrogen atoms in the nitrogen-containing compound is 2 or more.
[6] The production method according to [5], wherein the nitrogen-containing compound is an imidazole.
[7] The above-described [1] to [6], wherein the addition of the nitrogen-containing compound is intended to suppress a reduction in optical purity of the reduction reaction product when performing reaction solvent recovery and / or distillation. Manufacturing method.
[8] The reduction in optical purity of the reduction reaction product is suppressed by adding a nitrogen-containing compound to react the nitrogen-containing compound with a transition metal complex to form a complex containing the nitrogen-containing compound. Production method.

  According to the present invention, an optically active compound can be efficiently produced without causing a decrease in optical purity when the product is purified after a reduction reaction such as asymmetric hydrogenation or asymmetric hydrogen transfer.

Hereinafter, the present invention will be specifically described.
Examples of the transition metal of the transition metal complex used in the present invention include metals of Groups 8 to 10 of the periodic table, among which rhodium, ruthenium and iridium are preferable, and ruthenium is particularly preferable.
Preferable transition metal complexes include diamines, diphosphines, and lower alkyl groups (for example, linear or branched alkyl groups having 1 to 10 carbon atoms, specifically, methyl groups, ethyl groups, Examples thereof include n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, etc., preferably a linear or branched alkyl group having 1 to 6 carbon atoms. And a complex in which a substituted benzene, a halogen atom, pentamethylcyclopentadiene, and the like are coordinated. Diamines and diphosphines as ligands are more preferably optically active substances.

（式中、＊は不斉炭素原子を示し、Ｒ^N1及びＲ^N2は、それぞれ独立して置換基を有してもよいＣ₁〜Ｃ₂₀アルキル基、置換基を有してもよいＣ₃〜Ｃ₈シクロアルキル基、置換基を有してもよいＣ₇〜Ｃ₂₀アラルキル基、置換基を有してもよいＣ₆〜Ｃ₂₀アリール基、又は置換基を有してもよいＣ₃〜Ｃ₂₀ヘテロ環基を表すか、Ｒ^N1とＲ^N2とでアルキレン基又はアルキレンジオキシ基を形成してもよい。Ｒ^N3は水素原子または置換基を有してもよいＣ₁〜Ｃ₂₀アルキル基を示し、Ｒ^N4は炭素数１〜１０のアルキル基；炭素数１〜１０のハロゲン化アルキル基；又は炭素数１〜１０のアルキル基、炭素数１〜１０のハロゲン化アルキル基、若しくはハロゲン原子で置換されていてもよいＣ₅〜Ｃ₂₀アリール基を示す。）
Ｒ^N1及びＲ^N2のＣ₁〜Ｃ₂₀アルキル基、Ｃ₃〜Ｃ₈シクロアルキル基、Ｃ₇〜Ｃ₂₀アラルキル基、アリール基及びヘテロ環基が有することができる置換基としては、メチル基、エチル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、ベンジル、１−フェニルエチル基、フェニル基、ｏ―トルイル基、ｐ−トルイル基、チエニル基、フリル基、ピリジル基、ピペリジニル基、ピペリジノ基等が挙げられる。 Examples of diamines include diamines represented by general formula (A).

(In the formula, * represents an asymmetric carbon atom, and R ^N1 and R ^N2 each independently have a C _{1 to} C ₂₀ alkyl group which may have a substituent, or C ₃ which may have a substituent. -C ₈ cycloalkyl group, an optionally substituted C ₇ -C ₂₀ aralkyl group, an optionally substituted C ₆ -C ₂₀ aryl group, or optionally C ₃ may have a substituent -C ₂₀ heterocycle or represents an group, R ^N1 and R ^N2 and an alkylene group or an alkylenedioxy group may be formed .R ^N3 represents a hydrogen atom or an optionally substituted C ₁ -C ₂₀ an alkyl group, R ^N4 is an alkyl group having 1 to 10 carbon atoms, halogenated alkyl group having 1 to 10 carbon atoms; or an alkyl group having 1 to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon atoms, or (C ₅ -C ₂₀ aryl group optionally substituted with a halogen atom is shown.)
^Examples of the substituent that the C ₁ -C ₂₀ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₇ -C ₂₀ aralkyl group, aryl group and heterocyclic group of R ^N1 and R ^N2 can have include a methyl group, Ethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, benzyl, 1-phenylethyl group, phenyl group, o-toluyl group, p-toluyl group, thienyl group, furyl group, pyridyl group, piperidinyl group And piperidino group.

  Specific examples of optically active diamines include N- (p-toluenesulfonyl) -1,2-diphenylethylenediamine, N-methanesulfonyl-1,2-diphenylethylenediamine, N-trifluoromethanesulfonyl-1,2-diphenyl. Ethylenediamine, N- (p-fluorobenzenesulfonyl) -1,2-diphenylethylenediamine, N-pentafluorobenzenesulfonyl-1,2-diphenylethylenediamine, N- (p-methoxybenzenesulfonyl) -1,2-diphenylethylenediamine, N- (3,5-xylylsulfonyl) -1,2-diphenylethylenediamine, N- (2,4,6-trimethylbenzenesulfonyl) -1,2-diphenylethylenediamine, N-((1R) -camphorsulfonyl) -1,2-Difeni Ethylenediamine, N- (naphthylsulfonyl) -1,2-diphenylethylenediamine, N- (p-toluenesulfonyl) -1,2-cyclohexanediamine, N-methanesulfonyl-1,2-cyclohexanediamine, N-trifluoromethanesulfonyl -1,2-cyclohexanediamine.

Examples of the diphosphine include diphosphine represented by the general formula (B).
R ^P1 R ^P2 P-Q-PR ^P3 R ^P4 (B)
(In the formula, R ^P1 , R ^P2 , R ^P3 and R ^P4 each independently have an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. And R ^P1 and R ^P2 and / or R ^P3 and R ^P4 may form a ring, and Q is a divalent arylene which may have a substituent. Represents a group or a ferrocenediyl group.)
In the above formula, examples of the aryl group which may have a substituent represented by R ^P1 , R ^P2 , R ^P3 and R ^P4 include an aryl group having 6 to 14 carbon atoms. Includes a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group, and the like. These aryl groups may have one or more substituents, and examples of the substituent include an alkyl group, an alkoxy group, an aryl group, and a heterocyclic group.
Examples of the alkyl group as a substituent of the aryl group include linear or branched alkyl groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group and t-butyl group.
Examples of the alkoxy group as the substituent of the aryl group include linear or branched alkoxy groups having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group. Group, n-butoxy group, s-butoxy group, isobutoxy group, t-butoxy group and the like.
Examples of the aryl group as a substituent for the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and a biphenyl group.
Examples of the heterocyclic group as the substituent of the aryl group include an aliphatic heterocyclic group and an aromatic heterocyclic group. The aliphatic heterocyclic group has, for example, 2 to 14 carbon atoms and at least one hetero atom. , Preferably 1 to 3, for example, a 5-8 membered, preferably 5 or 6 membered monocycle containing a hetero atom such as a nitrogen atom, oxygen atom, sulfur atom, etc. A cyclic aliphatic heterocyclic group. Specific examples of the aliphatic heterocyclic group include 2-oxopyrrolidyl group, piperidino group, piperazinyl group, morpholino group, tetrahydrofuryl group, tetrahydropyranyl group, tetrahydrothienyl group and the like. On the other hand, the aromatic heterocyclic group has, for example, 2 to 15 carbon atoms and includes at least one hetero atom, preferably 1 to 3 hetero atoms such as nitrogen, oxygen, and sulfur atoms. ˜8-membered, preferably 5- or 6-membered monocyclic, polycyclic or condensed heteroaryl groups composed of these monocyclic rings, specifically, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl , Pyridazinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, benzofuryl group, benzothienyl group, quinolyl group, isoquinolyl group, quinoxalyl group, phthalazinyl group, quinazolinyl group, naphthyridinyl group, cinnolinyl group, benzoimidazolyl group Group, benzothiazolyl group and the like.

^Examples of the optionally substituted cycloalkyl group represented by R ^P1 , R ^P2 , R ^P3 and R ^P4 include a 5-membered or 6-membered cycloalkyl group. Examples of the alkyl group include a cyclopentyl group and a cyclohexyl group. On the ring of these cycloalkyl groups, 1 to 2 or more may be substituted with a substituent such as an alkyl group or an alkoxy group mentioned as the substituent for the aryl group.
In addition, the alkyl group which may have a substituent represented by R ^P1 , R ^P2 , R ^P3 and R ^P4 is linear or branched, for example, having 1 to 15 carbon atoms, preferably carbon Examples thereof include an alkyl group having 1 to 10, more preferably 1 to 6 carbon atoms. Specific examples include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group. These alkyl groups may have 1 to 2 or more substituents, and examples of the substituent include an alkoxy group and a halogen atom. As an alkoxy group, the alkoxy group described as a substituent of the said aryl group is mentioned.
The ring which may be formed by R ^P1 and R ^P2 and / or R ^P3 and R ^P4 includes a ring including a phosphorus atom to which R ^P1 , R ^P2 , R ^P3 and R ^P4 are bonded, A four-membered ring, a five-membered ring or a six-membered ring is mentioned. Specific examples of the ring include phosphetane ring, phosphorane ring, phosphane ring, 2,4-dimethylphosphetane ring, 2,4-diethylphosphetane ring, 2,5-dimethylphosphorane ring, 2,5-diethyl. A phosphorane ring, a 2,6-dimethylphosphane ring, a 2,6-diethylphosphane ring, etc. are mentioned, These rings may be optically active substances.

  Examples of the divalent arylene group which may have a substituent represented by Q include arylene groups having 6 to 20 carbon atoms such as a phenylene group, a biphenyldiyl group and a binaphthalenediyl group. . Examples of the phenylene group include o or m-phenylene group, and the phenylene group includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group and t-butyl group. An alkyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an s-butoxy group, an isobutoxy group, and a t-butoxy group; 1 to 4 alkoxy groups; may be substituted with a hydroxyl group, an amino group, or a substituted amino group (the substituted amino group is substituted with an alkyl group having 1 to 4 carbon atoms). The biphenyldiyl group and the binaphthalenediyl group preferably have a 1,1′-biaryl-2,2′-diyl type structure, and the biphenyldiyl group and the binaphthalenediyl group are alkyl groups as described above. And an alkoxy group, for example, an alkylenedioxy group such as a methylenedioxy group, an ethylenedioxy group, and a trimethylenedioxy group, a hydroxyl group, an amino group, a substituted amino group, and the like. The ferrocenediyl group may also have a substituent, and examples of the substituent include the alkyl group, alkoxy group, alkylenedioxy group, hydroxyl group, amino group, and substituted amino group described above.

（式中、Ｒ¹及びＲ²は、それぞれ独立して、ハロゲン原子、アルキル基およびアルコキシ基から選ばれる置換基で置換されていてもよいフェニル基を示すか、またはシクロペンチル基もしくはシクロヘキシル基を示す。）
上記のＲ¹及びＲ²における、フェニル基の置換基としてのアルキル基としては、例えば、メチル基、ｔ−ブチル基等の直鎖状又は分岐状の炭素数１〜６のアルキル基が挙げられ、フェニル基の置換基としてのアルコキシ基としては、例えば、メトキシ基、ｔ−ブトキシ基等の直鎖状又は分岐状の炭素数１〜６のアルコキシ基が挙げられ、フェニル基の置換基としてのハロゲン原子としては、例えば、塩素原子、臭素原子、フッ素原子等が挙げられ、これら置換基は該フェニル基上に複数置換していてもよい。 Specific examples of the diphosphine represented by the general formula (B) include known diphosphines, and one of them is a compound represented by the following general formula (C).

(Wherein R ¹ and R ² each independently represents a phenyl group which may be substituted with a substituent selected from a halogen atom, an alkyl group and an alkoxy group, or a cyclopentyl group or a cyclohexyl group) .)
Examples of the alkyl group as a substituent of the phenyl group in the above R ¹ and R ² include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group and a t-butyl group. Examples of the alkoxy group as the substituent of the phenyl group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as a methoxy group and a t-butoxy group. Examples of the halogen atom include a chlorine atom, a bromine atom, and a fluorine atom, and a plurality of these substituents may be substituted on the phenyl group.

Specific examples of R ¹ and R ² include, for example, phenyl group, p-tolyl group, m-tolyl group, o-tolyl group, 3,5-xylyl group, 3,5-di-t-butylphenyl group, p-t-butylphenyl group, p-methoxyphenyl group, 3,5-di-t-butyl-4-methoxyphenyl group, p-chlorophenyl group, m-chlorophenyl group, p-fluorophenyl group, m-fluorophenyl Group, cyclobutane group, cyclopentyl group, cyclohexyl group, isopropyl group and the like.
In addition, the binaphthyl ring that is the basic skeleton of the compound represented by the general formula (C) may be substituted with a substituent, and examples of the substituent include C ₁ to C such as a methyl group and a t-butyl group. C ₂₀ alkyl group; methoxy group, t-C ₁ -C ₂₀ alkoxy group or a butoxy group; a trimethylsilyl group, triisopropylsilyl group, t- butyl tri C ₁ -C ₂₀ alkylsilyl group and triphenylmethyl dimethylsilyl group include tri C ₁ -C ₂₀ aryl silyl group such as a silyl group.

（式中、Ｒ³及びＲ⁴は、それぞれ独立して、ハロゲン原子、アルキル基およびアルコキシ基から選ばれる置換基で置換されていてもよいフェニル基、シクロペンチル基又はシクロヘキシル基を示す。Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、同一又は異なっていてもよく、水素原子、アルキル基、アルコキシ基、アシルオキシ基、ハロゲン原子、ハロアルキル基又はジアルキルアミノ基を示し、Ｒ⁵、Ｒ⁶及びＲ⁷のうちの二つで置換基を有していてもよいメチレン鎖又は置換基を有していてもよい（ポリ）メチレンジオキシ基を形成していてもよく、Ｒ⁸、Ｒ⁹及びＲ¹⁰のうちの二つで置換基を有していてもよいメチレン鎖又は置換基を有していてもよい（ポリ）メチレンジオキシ基を形成していてもよい。また、Ｒ⁷とＲ¹⁰とで置換基を有していてもよいメチレン鎖又は置換基を有していてもよい（ポリ）メチレンジオキシ基を形成していてもよい。ただし、Ｒ⁷とＲ¹⁰は水素原子ではない。） Another specific example of the diphosphine represented by the general formula (B) includes a compound represented by the following general formula (D).

(Wherein R ³ and R ⁴ each independently represent a phenyl group, a cyclopentyl group or a cyclohexyl group which may be substituted with a substituent selected from a halogen atom, an alkyl group and an alkoxy group. R ⁵ , ^{R 6, R 7, R 8} , R 9 and R ¹⁰ may be the same or different represents a hydrogen atom, an alkyl group, an alkoxy group, an acyloxy group, a halogen atom, a haloalkyl group or a dialkylamino group, R ⁵ , R ⁶ and R ⁷ may form a methylene chain which may have a substituent or a (poly) methylenedioxy group which may have a substituent, R ⁸ , R ⁹ and R ¹⁰ may form a methylene chain which may have a substituent or a (poly) methylenedioxy group which may have a substituent. the substituents R ⁷ and R ¹⁰ May form which may (poly) methylenedioxy group optionally having a good methylene chain or a substituted group which may. However, R ⁷ and R ¹⁰ are not hydrogen atoms.)

Examples of the alkyl group as a substituent of the phenyl group in the above R ³ and R ⁴ include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group and a t-butyl group. Examples of the alkoxy group as the substituent of the phenyl group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as a methoxy group and a t-butoxy group. Examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom and the like, and these substituents may be substituted on the phenyl group. Specific examples of R ³ and R ⁴ include, for example, phenyl group, p-tolyl group, m-tolyl group, o-tolyl group, 3,5-xylyl group, 3,5-di-t-butylphenyl group, p-t-butylphenyl group, p-methoxyphenyl group, 3,5-di-t-butyl-4-methoxyphenyl group, p-chlorophenyl group, m-chlorophenyl group, p-fluorophenyl group, m-fluorophenyl Group, cyclobutane group, cyclopentyl group, cyclohexyl group, isopropyl group and the like.
In addition, examples of the alkyl group represented by R ^{5 to} R ¹⁰ include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group and a t-butyl group. As the alkoxy group, For example, a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group and a t-butoxy group can be mentioned. Examples of the acyloxy group include an acetoxy group, a propanoyloxy group, a trifluoroacetoxy group, Examples thereof include acyloxy groups having 2 to 10 carbon atoms such as benzoyloxy groups. Examples of halogen atoms include chlorine atoms, bromine atoms and fluorine atoms. Examples of haloalkyl groups include trifluoromethyl groups. include haloalkyl groups having 1 to 4 carbon atoms, a dialkylamino group, for example, dimethylamino group, di-C ₁ -C ₂₀ a, such as a diethylamino group Kiruamino group, and the like.

When forming a methylene chain which may have a substituent at two of R ⁵ , R ⁶ and R ⁷ , and having a substituent at two of R ⁸ , R ⁹ and R ¹⁰ As the methylene chain in the case of forming an optional methylene chain, for example, a methylene chain having 3 to 5 carbon atoms is preferable, and specific examples include a trimethylene group, a tetramethylene group, and a pentamethylene group. Examples of the substituent in the methylene chain which may have the substituent include an alkyl group and a halogen atom. Specific examples thereof include, for example, an alkyl group having 1 to 6 carbon atoms as described above. And a fluorine atom.
Further, when forming a methylene chain which may have a substituent at two of R ⁵ , R ⁶ and R ⁷ , two of R ⁸ , R ⁹ and R ¹⁰ have a substituent. As a specific example of the methylene chain in the case of forming a methylene chain which may be substituted, and in the case of forming a methylene chain which may have a substituent with R ⁷ and R ¹⁰ , a methylene group. Ethylene group. C1-C4 methylene chains, such as a trimethylene group and a propylene group, are mentioned. In addition, examples of the substituent substituted on the methylene chain include an alkyl group and a halogen atom, and specific examples thereof include, for example, the above-described alkyl group having 1 to 6 carbon atoms and a fluorine atom. .
When two of R ⁵ , R ⁶ and R ⁷ may form a (poly) methylenedioxy group which may have a substituent, two of R ⁸ , R ⁹ and R ¹⁰ When forming an optionally substituted (poly) methylenedioxy group, and when forming an optionally substituted (poly) methylenedioxy group with R ⁷ and R ¹⁰ Specific examples of the (poly) methylenedioxy group include (poly) methylenedioxy groups having 1 to 4 carbon atoms such as a methylenedioxy group, an ethylenedioxy group, and a trimethylenedioxy group. In addition, examples of the substituent substituted on the (poly) methylenedioxy group include an alkyl group and a halogen atom. Specific examples thereof include, for example, an alkyl group having 1 to 6 carbon atoms and fluorine as described above. An atom etc. are mentioned.

  Specific examples of the optically active diphosphine include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2,2′-bis [di (p-tolyl) phosphino] -1,1′-binaphthyl. (Tolbinap), 2,2'-bis [di (m-tolyl) phosphino] -1,1'-binaphthyl, 2,2'-bis [di (3,5-xylyl) phosphino] -1,1'- Xylbinap, 2,2′-bis [di (pt-butylphenyl) phosphino] -1,1′-binaphthyl, 2,2′-bis [di (p-methoxyphenyl) phosphino] -1, 1'-binaphthyl, 2,2'-bis [di (3,5-di-t-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl, 2,2'-bis [di (cyclopentyl) Phosphino] -1,1 -Binaphthyl, 2,2'-bis [di (cyclohexyl) phosphino] -1,1'-binaphthyl, 2,2'-bis (diphenylphosphino) -5,5 ', 6,6', 7,7 ' , 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (di-p-tolylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro -1,1'-binaphthyl, 2,2'-bis (di-m-tolylphosphino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1, 1'-binaphthyl (Xylyl-H8-binap), 2,2′-bis (di-3,5-xylylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro-1 1′-binaphthyl, 2,2′-bis (di-pt-butylphenylphosphino) -5,5 ′ 6,6 ′, 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (di-p-methoxyphenylphosphino) -5,5 ′, 6,6 ′ , 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (di-p-chlorophenylphosphino) -5,5 ′, 6,6 ′, 7,7 ′ , 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (dicyclopentylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro- 1,1′-binaphthyl, 2,2′-bis (dicyclohexylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl, (( 4,4′-bi-1,3-benzodioxole) -5,5′-diyl) bis (diphenylphosphine) (s egphos), (4,4′-bi-1,3-benzodioxole) -5,5′-diyl) bis (di (3,5-xylyl) phosphine) (dm-segphos), ((4, 4'-bi-1,3-benzodioxole) -5,5'-diyl) bis (di (3,5-di-t-butyl-4-methoxyphenyl) phosphine), ((4,4 ' -Bi-1,3-benzodioxole) -5,5'-diyl) bis (di (4-methoxyphenyl) phosphine), ((4,4'-bi-1,3-benzodioxole) -5,5'-diyl) bis (dicyclohexylphosphine), ((4,4'-bi-1,3-benzodioxole) -5,5'-diyl) bis (bis (3,5-di-) t-butylphenyl) phosphine), 2,2′-bis (di-3,5-xylylphosphino) -6,6'-dimethoxy-1,1'-biphenyl (xylyl-MeO-biphep), 2,2'-bis (diphenylphosphino) -6,6'-dimethyl-1,1-biphenyl, 2,2 '-Bis (di-p-tolylphosphino) -6,6'-dimethyl-1,1'-biphenyl, 2,2'-bis (di-o-tolylphosphino) -6,6'-dimethyl-1,1' -Biphenyl, 2,2'-bis (di-m-fluorophenylphosphino) -6,6'-dimethyl-1,1'-biphenyl, 2,2'-bis (diphenylphosphino) -6,6 ' -Dimethoxy-1,1'-biphenyl, 2,2'-bis (di-p-tolylphosphino) -6,6'-dimethoxy-1,1'-biphenyl, 2,2 ', 6,6'-tetramethoxy -4,4'-bis (di-3,5 Xylylphosphino) -3,3'-bipyridine (xylyl-p-phos), 2,2 ', 6,6'-tetramethoxy-4,4'-bis (diphenylphosphino) -3,3'- Bipyridine, 2,2 ′, 6,6′-tetramethoxy-4,4′-bis (di-p-tolylphosphino) -3,3′-bipyridine, 2,2 ′, 6,6′-tetramethoxy-4 , 4′-bis (di-o-tolylphosphino) -3,3′-bipyridine, 4,12-bis (di-3,5-xylylphosphino)-[2.2] -paracyclophane, 4, 12-bis (diphenylphosphino)-[2.2] -paracyclophane, 4,12-bis (di-p-tolylphosphino)-[2.2] -paracyclophane, 4,12-bis (di-) o-Tolylphosphino)-[2.2] -paracycloph 1,1′-bis (2,4-diethylphosphatano) ferrocene, 1,13-bis (diphenylphosphino) -7,8-dihydro-6H-dibenzo [f, h] [1,5 ] Dioxonine, 1,13-bis (bis (3,5-dimethylphenyl) phosphino) -7,8-dihydro-6H-dibenzo [f, h] [1,5] dioxonine (xylyl-C3-tunephos), 6 , 6′-bis (bis (3,5-dimethylphenyl) phosphino) -2,2 ′, 3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin (xylyl-synphos) and the like Can be mentioned.

In addition to the above, specific examples of diphosphines that can be used in the present invention include N, N-dimethyl-1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethylamine, 2,3-bis (diphenyl). Phosphino) butane, 1-cyclohexyl-1,2-bis (diphenylphosphino) ethane, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane, 1, 2-bis [(o-methoxyphenyl) phenylphosphino] ethane, 1,2-bis (2,5-dimethylphosphorano) ethane, N, N′-bis (diphenylphosphino) -N, N′-bis (1-phenylethyl) ethylenediamine, 1,2-bis (diphenylphosphino) propane, 2,4-bis (diphenylphosphino) pentane, cycl Hexylanisylmethylphosphine, 2,3-bis (diphenylphosphino) -5-norbornene, 3,4-bis (diphenylphosphino) -1-benzylpyrrolidine, 1- [1 ′, 2-bis (diphenylphosphino) ) Ferrocenyl] ethyl alcohol, 2,2′-bis (diphenylphosphino) -1,1′-dicyclopentane, 2,2′-bis (diphenylphosphino) -1,1-binaphthyl-5,5′- Sodium disulfonate, 2,2′-bis (di (3,5-xylyl) phosphino) -1,1-binaphthyl-5,5′-sodium disulfonate, 1,1- (2,2′-bis (diphenyl) Phosphino) -1,1′-binaphthyl-6,6′-diyl) bis (methylene) guanidine, 1,1- (2,2′-bis (di (3,5-xylyl) phosphino) -1, 1'-binaphthyl-6,6'-diyl) bis (methylene) guanidine, (6,6'-bis (tris (3,3,4,4,5,5,6,6,7,7,8, 8,8-tridecafluorooctyl) silyl) -1,1′-binaphthyl-2,2′-diyl) bis (diphenylphosphine), (6,6′-bis (tris (3,3,4,4,4)) 5,5,6,6,7,7,8,8,8-tridecafluorooctyl) silyl) -1,1'-binaphthyl-2,2'-diyl) bis (di (3,5-xylyl) Phosphine), (2,2′-bis (diphenylphosphino) -1,1′-binaphthyl-4,4′-diyl) dimethanamine hydrobromide, (2,2′-bis (di (3, 5-xylyl) phosphino) -1,1′-binaphthyl-4,4′-diyl) dimethanamine hydrobromide, (4 4'-bis (trimethylsilyl) -1,1'-binaphthyl-2,2'-diyl) bis (diphenylphosphine), (4,4'-bis (trimethylsilyl) -1,1'-binaphthyl-2,2 ' -Diyl) bis (di (3,5-xylyl) phosphine), (4,4'-bis (triisopropylsilyl) -1,1'-binaphthyl-2,2'-diyl) bis (diphenylphosphine), ( 4,4′-bis (triisopropylsilyl) -1,1′-binaphthyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), 2,2′-bis (diphenylphosphino) -1,1'-binaphthyl-4,4'-diyldiphosphonic acid, 2,2'-bis (di (3,5-xylyl) phosphino) -1,1'-binaphthyl-4,4'-diyldiphosphonic acid, tetraethyl 2,2'-bis (Gif Nylphosphino) -1,1′-binaphthyl-4,4′-diyl diphosphonate, tetraethyl 2,2′-bis (di (3,5-xylyl) phosphino) -1,1′-binaphthyl-4,4′- Diyl diphosphonate, (4,4′-diphenyl-1,1′-binaphthyl-2,2′-diyl) bis (diphenylphosphine), (4,4′-diphenyl-1,1′-binaphthyl-2,2 '-Diyl) bis (di (3,5-xylyl) phosphine), (4,4'-dichloro-1,1'-binaphthyl-2,2'-diyl) bis (diphenylphosphine), (4,4'-Dichloro-1,1'-binaphthyl-2,2'-diyl) bis (di (3,5-xylyl) phosphine), (4,4'-dibromo-1,1'-binaphthyl-2,2'- Diyl) bis (diphenylphosphine), (4,4′-di Lomo-1,1′-binaphthyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (4,4′-dimethyl-1,1′-binaphthyl-2,2′-diyl) ) Bis (diphenylphosphine), (4,4′-dimethyl-1,1′-binaphthyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (2,2′-bis ( Diphenylphosphino) -1,1′-binaphthyl-4,4′-diyl) bis (diphenylmethanol), (2,2′-bis (di (3,5-xylyl) phosphino) -1,1′-binaphthyl -4,4'-diyl) bis (diphenylmethanol), (4,4'-bis (1,1,1,2,2,3,3,4,4,5,5,6,6,8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13, 13-hexacosafluoro-7- Perfluorohexyl) tridecan-7-yl) -1,1′-binaphthyl-2,2′-diyl) bis (diphenylphosphine), (4,4′-bis (1,1,1,2,2,3,3) 3,4,4,5,5,6,6,8,8,9,9,10,10,11,11,12,12,13,13,13-hexacosafluoro-7- (perfluorohexyl) Tridecan-7-yl) -1,1′-binaphthyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (7,7′-dimethoxy-1,1′-binaphthyl-2) , 2′-diyl) bis (diphenylphosphine), (7,7′-dimethoxy-1,1′-binaphthyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), 4,4 '-Di-tert-butyl-4,4', 5,5'-tetrahydro-3H, 3 ' H-3,3′-bizinaft [2,1-c: 1 ′, 2′-e] phosphapine, 1,2-bis (3H-dinaphth [2,1-c: 1 ′, 2′-e] phosphapine -4 (5H) -yl) benzene, 3,3'-bis (diphenylphosphino) -4,4'-biphenanthrene, 3,3'-bis (di (3,5-xylyl) phosphino) -4,4 '-Biphenanthrene, (3,3'-diphenyl-1,1'-binaphthyl-2,2'-diyl) bis (methylene) bis (diphenylphosphine), (3,3'-diphenyl-1,1'-binaphthyl) -2,2'-diyl) bis (methylene) bis (di (3,5-xylyl) phosphine), 2,2'-bis (diphenylphosphinooxy) -1,1'-binaphthyl, 2,2'- Bis (di (3,5-xylyl) phosphinooxy) -1,1′-binaphthy (3,3′-dimethyl-1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis (diphenylphosphine), (3,3′-dimethyl-1,1′-binaphthyl-2) , 2′-diyl) bis (oxy) bis (di (3,5-xylyl) phosphine), (3,3′-diphenyl-1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis (Diphenylphosphine), (3,3′-diphenyl-1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis (di (3,5-xylyl) phosphine), (3,3′- Bis (3,5-dimethylphenyl) -1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis (diphenylphosphine), (3,3′-bis (3,5-dimethylphenyl)- 1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis Di (3,5-xylyl) phosphine), (3,3′-diphenyl-1,1′-binaphthyl-2,2′-diyl) bis (oxy) bis (bis (3,5-dimethylphenyl) phosphine) N2, N2′-bis (diphenylphosphino) -1,1′-binaphthyl-2,2′-diamine, N2, N2′-bis (di (3,5-xylyl) phosphino) -1,1′- Binaphthyl-2,2′-diamine, (SP) -1-[(S) -α- (dimethylamino) -2- (diphenylphosphino) benzyl] -2-diphenylphosphinoferrocene, (RP) -1- [(R) -α- (dimethylamino) -2- (diphenylphosphino) benzyl] -2-diphenylphosphinoferrocene, (R) -1-{(RP) -2- [2- (diphenylphosphino) Phenyl] ferrocenyl Ethyldiphenylphosphine, (S) -1-{(SP) -2- [2- (diphenylphosphino) phenyl] ferrocenyl} ethyldiphenylphosphine, (R) -1-{(RP) -2- [2- ( Diphenylphosphino) phenyl] ferrocenyl} ethyldicyclophosphine, (S) -1-{(SP) -2- [2- (diphenylphosphino) phenyl] ferrocenyl} ethyldicyclophosphine, (R) -1- { (RP) -2- [2- (diphenylphosphino) phenyl] ferrocenyl} ethyldi (2-norbornyl) phosphine, (S) -1- {SP) -2- [2- (diphenylphosphino) phenyl] ferrocenyl} Ethyl di (2-norbornyl) phosphine, (R) -1-{(RP) -2- [2- (diphenylphosphino) phenyl] phen Senyl} ethyldi (3,5-xylyl) phosphine, (S) -1-{(SP) -2- [2- (diphenylphosphino) phenyl] ferrocenyl} ethyldi (3,5-xylyl) phosphine, (R) -1-{(RP) -2- [2- [di (3,5-xylyl) phosphino] phenyl] ferrocenyl} ethyldi (3,5-xylyl) phosphine, (S) -1-{(SP) -2 -[2- [di (3,5-xylyl) phosphino] phenyl] ferrocenyl} ethyldi (3,5-xylyl) phosphine, (R) -1-{(RP) -2- [2- (diphenylphosphino) Phenyl] ferrocenyl} ethyl bis [3,5-bis- (trifluoromethyl) phenyl] phosphine, (S) -1-{(SP) -2- [2- (diphenylphosphino) phenyl] ferroce Nil} ethylbis [3,5-bis- (trifluoromethyl) phenyl] phosphine, (R) -1-{(RP) -2- [2- [bis (4-methoxy-3,5-dimethylphenyl) phosphino ] Phenyl] ferrocenyl} ethylbis [3,5-bis (trifluoromethyl) phenyl] phosphine, (S) -1-{(SP) -2- [2- [bis (4-methoxy-3,5-dimethylphenyl) ) Phosphino] phenyl] ferrocenyl} ethylbis [3,5-bis (trifluoromethyl) phenyl] phosphine, 3,3 ′, 4,4′-tetramethyl-1,1′-diphenyl-2,2 ′, 5 5′-tetrahydro-1H, 1′H-2,2′-biphosphole, 1,1′-di-tert-butyl-2,2′-biphospholane, 2,2′-di-tert-butyl-2,2 ', 3,3' Tetrahydro-1H, 1′H-1,1′-bisisophosphoindole, 1,2-bis (2,4-dimethylphosphetan-1-yl) ethane, 1,2-bis (2,5-dimethyl) Phosphoran-1-yl) ethane, 1,2-bis (2,4-dimethylphosphetan-1-yl) benzene, 1,2-bis (2,5-dimethylphosphoran-1-yl) benzene, 3,4-bis (2,5-dimethylphosphoran-1-yl) furan-2,5-dione, 3,4-bis (2,5-diethylphosphoran-1-yl) furan-2,5- Dione, 3,4-bis (2,5-dimethylphosphoran-1-yl) -1-phenyl-1H-pyrrole-2,5-dione, 1- (3,5-bis (trifluoromethyl) phenyl) -3,4-bis (2,5-dimethylphosphoran-1-yl) -1H-pyrrole-2,5-dione, 1-((1R, 2S, 4R, 5S) -2,5-dimethyl-7-phosphabicyclo [2.2.1] heptan-7-yl) -2 -((2R, 5S) -2,5-dimethyl-7-phosphabicyclo [2.2.1] heptan-7-yl) benzene, 1,1 '-(benzo [b] thiophene-2,3- Diyl) bis (2,5-dimethylphosphorane), (2,2 ′, 4,4′-tetramethyl-3,3 ′, 4,4′-tetrahydro-2H, 2′H-6,6′- Bibenzo [b] [1,4] dioxepin-7,7′-diyl) bis (diphenylphosphine), (2,2 ′, 4,4′-tetramethyl-3,3 ′, 4,4′-tetrahydro- 2H, 2′H-6,6′-bibenzo [b] [1,4] dioxepin-7,7′-diyl) bis (di (3,5-xy Le)
Phosphine), ((6R) -6,7-dimethyl-6,7-dihydrodibenzo [e, g] [1,4] dioxocin-1,12-diyl) bis (diphenylphosphine), ((6R) -6 , 7-dimethyl-6,7-dihydrodibenzo [e, g] [1,4] dioxocin-1,12-diyl) bis (di (3,5-xylyl) phosphine), (4,4 ', 5, 5 ', 6,6'-Hexamethylbiphenyl-2,2'-diyl) bis (diphenylphosphine), (4,4', 5,5 ', 6,6'-hexamethylbiphenyl-2,2'- Diyl) bis (di (3,5-xylyl) phosphine), (4,4 ′, 5,5 ′, 6,6′-hexamethoxybiphenyl-2,2′-diyl) bis (diphenylphosphine), (4 , 4 ′, 5,5 ′, 6,6′-hexamethoxybiphenyl-2, '-Diyl) bis (di (3,5-xylyl) phosphine), (5,5'-dichloro-4,4', 6,6'-tetramethylbiphenyl-2,2'-diyl) bis (diphenylphosphine) ), (5,5′-dichloro-4,4 ′, 6,6′-tetramethylbiphenyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (5,5′- Dimethoxy-4,4 ′, 6,6′-tetramethylbiphenyl-2,2′-diyl) bis (diphenylphosphine), (5,5′-dimethoxy-4,4 ′, 6,6′-tetramethylbiphenyl) -2,2'-diyl) bis (di (3,5-xylyl) phosphine), 2,2'-bis (diphenylphosphino) -6,6'-dimethoxybiphenyl-3,3'-diol, 2'-bis (di (3,5-xylyl) phosphino) -6,6'-di Toxibiphenyl-3,3′-diol, (3,3 ′, 6,6′-tetramethoxybiphenyl-2,2′-diyl) bis (diphenylphosphine), (3,3 ′, 6,6′-tetra Methoxybiphenyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (3,3′-diisopropyl-6,6′-dimethoxybiphenyl-2,2′-diyl) bis (diphenylphosphine) ), (3,3′-diisopropyl-6,6′-dimethoxybiphenyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (6,6′-dimethoxy-3,3 ′) -Bis (p-tolyloxy) biphenyl-2,2'-diyl) bis (diphenylphosphine), (6,6'-dimethoxy-3,3'-bis (p-tolyloxy) biphenyl-2,2'-diyl) Screw (Di (3 -Xylyl) phosphine), 2,2'-bis (diphenylphosphino) -6,6'-dimethoxybiphenyl-3,3'-diyl bis (2,2-dimethylpropanoate), 2,2'-bis (Di (3,5-xylyl) phosphino) -6,6′-dimethoxybiphenyl-3,3′-diylbis (2,2-dimethylpropanoate), (5,5′-dichloro-6,6′- Dimethoxybiphenyl-2,2′-diyl) bis (diphenylphosphine), (5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine ), 6,6′-bis (diphenylphosphino) biphenyl-2,2′-diyl diacetate, 6,6′-bis (di (3,5-xylyl) phosphino) biphenyl-2,2′-diyl diacetate Acetate, 6 6'-bis (diphenylphosphino) biphenyl-2,2'-diylbis (2,2-dimethylpropanoate), 6,6'-bis (di (3,5-xylyl) phosphino) biphenyl-2,2 '-Diylbis (2,2-dimethylpropanoate), 6,6'-bis (diphenylphosphino) biphenyl-2,2'-diylbis (2-methylpropanoate), 6,6'-bis (di (3,5-xylyl) phosphino) biphenyl-2,2′-diylbis (2-methylpropanoate, 6,6′-bis (diphenylphosphino) biphenyl-2,2′-diyl dicyclohexanecarboxylate, 6 , 6′-bis (di (3,5-xylyl) phosphino) biphenyl-2,2′-diyl dicyclohexanecarboxylate, (4,4 ′, 6,6′-tetrakis (trif) (Olomethyl) biphenyl-2,2′-diyl) bis (diphenylphosphine), (4,4 ′, 6,6′-tetrakis (trifluoromethyl) biphenyl-2,2′-diyl) bis (di (3,5 -Xylyl) phosphine), (5-methoxy-4,6-dimethyl-4 ', 6'-bis (trifluoromethyl) biphenyl-2,2'-diyl) bis (diphenylphosphine), (5-methoxy-4) , 6-Dimethyl-4 ′, 6′-bis (trifluoromethyl) biphenyl-2,2′-diyl) bis (di (3,5-xylyl) phosphine), (2,2,2 ′, 2′- Tetramethyl-4,4′-bibenzo [d] [1,3] dioxol-5,5′-diyl) bis (diphenylphosphine), (2,2,2 ′, 2′-tetramethyl-4,4 ′ -Bibenzo [d] [1,3] dioxole -5,5'-diyl) bis (di (3,5-xylyl) phosphine), 6,6'-bis (diphenylphosphino) -2,2 ', 3,3'-tetrahydro-7,7'- Bibenzofuran, 6,6′-bis (di (3,5-xylyl) phosphino) -2,2 ′, 3,3′-tetrahydro-7,7′-bibenzofuran, (2,2,2 ′, 2 '-Tetrafluoro-4,4'-bibenzo [d] [1,3] dioxol-5,5'-diyl) bis (diphenylphosphine), (2,2,2', 2'-tetrafluoro-4, 4'-bibenzo [d] [1,3] dioxol-5,5'-diyl) bis (di (3,5-xylyl) phosphine), 2- (naphthyl) -8-diphenylphosphino-1- [3 , 5-Diosa-4-phospha-cyclohepta [2,1-a; 3,4-a ′] dinaphthalene-4 Yl] -1,2-dihydroquinoline, 4,12-bis (di (3,5-xylyl) phosphino)-[2.2] -paracyclophane, 7,7′-bis (di (3,5- Xylyl) phosphino) -2,2 ′, 3,3′-tetrahydro-1,1′-spirobiindane (Xyl-SDP), 7,7′-bis (diphenylphosphino) -2,2 ′, 3,3 ′ -Tetrahydro-1,1'-spirobiindane (SDP), bis (2-diphenylphosphinophenyl) ether (DPEphos), 4,5-bis (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane (DIOP), 1,2-bis (diphenylphosphino) propane (PROPHOS), 2,3-bis (diphenylphosphino) butane (CHIRAPHOS), 1,2-bis [(2-meso Toxiphenyl) (phenyl) phosphino] ethane (DIPAMP), 3,4-bis (diphenylphosphino) -1-benzylpyrrolidine (DEGUPHOS), 2,3-bis (diphenylphosphino) -bicyclo [2.2.1 ] Hept-5-ene (NORPHOS), 1-tertiary butoxycarbonyl-4-diphenylphosphino-2- (diphenylphosphinomethyl) pyrrolidine (BPPM), (2,2'-bis- (dibenzofuran-3,3) -Diyl) -bis-diphenylphosphine (BIBFUP), 2,2-bis (diphenylphosphino) -3,3-binaphtho [b] furan (BINAPFu), 2,2'-bis (diphenylphosphino) -3 3′-bi [benzo [b] thiophene] (BITIANP), N, N′-dimethyl-7,7 ′ Bis (di (3,5-xylyl) phosphino) -3,3 ′, 4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine (Xyl-Sophos), 2,3- Bis (tertiarybutylmethylphosphino) quinoxaline (QuinoxP ^* ), 2,4-bis (diphenylphosphino) pentane (SKEWPHOS), 2,4-bis (di (3,5-xylyl) phosphino) pentane (XylSKEWPHOS) 4,4′-bis (diphenylphosphino) -2,2 ′, 5,5′-tetramethyl-3,3′-bithiophene (TMBTP), 3,3′-bis (diphenylphosphonyl) -1, 1′-2,2′-biindole (N-Me-2-BINPO), (2,2 ′, 5,5′-tetramethyl-3,3′-bithiophene-4,4′-diyl) bis ( Gif Nilphosphine) (BITIANP), (4,4 ′, 6,6′-tetramethyl-3,3′-bibenzo [b] thiophene-2,2′-diyl) bis (diphenylphosphine) (tetraMe-BITIANP), 1,1′-bis (diphenylphosphino) -3,3′-dimethyl-1H, 1′H-2,2′-biindole (BISCAP), 2,2′-bis (diphenylphosphino) -3, 3′-bibenzofuran (BICUMP), 2,2′-bis (diphenylphosphino) -1,1′-bibenzo [d] imidazole (BIMIP) and the like can be mentioned.

Specific examples of the transition metal complex include the following.

Examples of the nitrogen-containing compound added in the present invention include aliphatic amines, aromatic amines, and nitrogen-containing heterocyclic compounds. Among these, nitrogen-containing compounds having two or more nitrogen atoms are preferable.
An aliphatic amine means one in which an aliphatic group is substituted for a hydrogen atom of ammonia (NH ₃ ). Examples of the aliphatic group include a linear or branched alkyl group having 1 to 10 carbon atoms or an alicyclic group. Preferably, it is a C1-C6 linear or branched alkyl group or alicyclic group. Specific aliphatic amines include, for example, methylamine, ethylamine, propylamine, butylamine, isopropylamine, 2-ethylhexylamine, tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine, diethylenetriamine, triethylenetetramine, tris ( 2,2 ′, 2 ″ -aminoethyl) amine, N, N′-bis (2-aminoethyl) -1,3-propanediamine, N, N′-bis (3-aminopropyl) ethylenediamine, bis ( 3-aminopropyl) amine, 1,2-bis (3-aminopropylamino) ethane, 1,4-bis (3-aminopropyl) piperidine, cyclopropylamine, cyclohexylamine and the like. Preferably, the aliphatic amine is diethylenetriamine, triethylenetetramine, tris (2,2 ′, 2 ″ -aminoethyl) amine, N, N′-bis (2-aminoethyl) -1,3-propanediamine, N, N′-bis (3-aminopropyl) ethylenediamine, bis (3-aminopropyl) amine, 1,2-bis (3-aminopropylamino) ethane, 1,4-bis (3-aminopropyl) piperidine, etc. Diethylenetriamine and triethylenetetramine are more preferable.

An aromatic amine means one in which an aromatic group is substituted in place of a hydrogen atom of ammonia. Examples of the aromatic group include aromatic groups composed of a single ring or a plurality of rings (condensed rings) exhibiting aromaticity. Specific examples of the aromatic amine include aniline, toluidine, xylidine, anisidine, naphthylamine, diphenylamine, triphenylamine, benzidine, 1,2-phenylenediamine, 4-fluoro-1,2-phenylenediamine, and 2,3-diamino. Pyridine, 3,4-diaminopyridine, 2,3-diaminotoluene, 3,4-diaminotoluene, 3,3′-diaminobenzine, 3,4-diaminobenzophenone, 2,5-diamino-5-bromopyridine, 6 , 6'-diamino-2,2'-bipyridyl, 4,5-dichloro-1,2-phenylenediamine, 3,4-diaminobenzoic acid, 2,2'-bipyridyl, 2,2'-bi-4- Examples include picoline, 6,6′-bi-3-picoline, 2,2′-biquinoline, and the like. Preferred aromatic amines include 1,2-phenylenediamine, 4-fluoro-1,2-phenylenediamine, 2,3-diaminopyridine, 3,4-diaminopyridine, 2,3-diaminotoluene, 3,4-diamino. Toluene, 3,3′-diaminobenzine, 3,4-diaminobenzophenone, 2,5-diamino-5-bromopyridine, 6,6′-diamino-2,2′-bipyridyl, 4,5-dichloro-1, 2-phenylenediamine, 3,4-diaminobenzoic acid, 2,2′-bipyridyl, 2,2′-bi-4-picoline, 6,6′-bi-3-picoline, 2,2′-biquinoline and the like Yes, 1,2-phenylenediamine and 3,4-diaminobenzoic acid are more preferable.
Examples of the nitrogen-containing heterocyclic compound include pyrrole, pyridine, imidazole, 2-methylimidazole, 1-methylimidazole, 1,3-thiazole, oxazole, pyrazole, 1,2,4-triazole, pyrazine, pyrimidine, pyridazine, indole, Examples thereof include aromatic compounds such as quinoline and purine, and endocyclic alicyclic amines such as diazabicycloundecane (DBU), piperidine, diazabicyclooctane (DABCO), and sparteine. Preferred nitrogen-containing heterocyclic compounds include imidazole, 2-methylimidazole, 1-methylimidazole, 1,3-thiazole, 1,3-oxazole, pyrazole, 1,2,4-triazole, etc., and 2-methylimidazole More preferred are imidazoles such as 1-methylimidazole and imidazole.

The amount of the nitrogen-containing compound added is, in the case of a compound having one nitrogen atom in the nitrogen-containing compound, equimolar or more, preferably 2 times or more, more preferably 3 times the transition metal complex. In the case of a compound that is at least mol and the number of nitrogen atoms in the nitrogen-containing compound is 2 or more, it is at least equimolar, preferably at least 1.5 times mol.
According to the present invention, a decrease in the optical purity of the product can be avoided without separating the catalyst after an asymmetric reduction reaction using an optically active transition metal complex as a catalyst.

Examples of the asymmetric reduction method performed in the production method of the present invention include an asymmetric hydrogenation reaction and an asymmetric hydrogen transfer reaction.
Although it does not specifically limit as asymmetric hydrogenation reaction, The manufacturing method of the optically active alcohol by asymmetric hydrogenation of a carbonyl group (For example, literature (5th edition Experimental Chemistry Lecture 19 Synthesis of organic compounds VII Maruzen Co., Ltd.) p122) and the like, and methods for producing optically active compounds by asymmetric hydrogenation such as carbon-carbon double bonds and imino groups (for example, literature (Asymmetric Catalysis In Organic Synthesis, p16-p94)).
Although it does not specifically limit as asymmetric hydrogen transfer reaction, For example, literature (J.Am.Chem.Soc., 1997,119,8378, J.Am.Chem.Soc.1996,118,2521, etc.) And the like, and a method for producing an optically active alcohol by asymmetric reduction of a carbonyl group.
In the production method of the present invention, a nitrogen-containing compound is added to a reaction solution subjected to a reduction reaction using a transition metal complex, and then reaction solvent recovery and / or distillation is performed.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these. In the following Examples and Comparative Examples, MS spectra were measured with an LCMS-IT-TOF type apparatus manufactured by SHIMADZU. The GC analysis was performed with GC: Chirasil Dex-CB (0.25 mm × 25 m, DF = 0.25).

Example 1
Nitrogen substitution was performed by adding 0.5 g (4.15 mmol) of acetophenone, 250 mg (0.415 mmol) of [Ru (R, R) -Tsdpen (p-cymene)] and 42 mg of 2-propanol to a 200 ml reaction vessel. This solution was reacted at room temperature for 2 hours. The conversion to (R) -phenylethanol was 86% and the optical purity was 91% ee.
Furthermore, when 67.3 mg (0.622 mmol) of α-phenylenediamine was added to the reaction solution and stirred, the color of the solution changed from reddish brown to purple. The solvent was distilled off under reduced pressure, and a heptane slurry was further removed to remove acetophenone and phenylethanol. After drying and mass spectrometry, the result was 679.1438. From mass spectrometry, the resulting compound is presumed to be Ru [(R, R) -Tsdpen] (phenylenediamine) ₂ .

得られた結果を表１に示す。表１からＲｕ［（Ｒ，Ｒ）−Ｔｓｄｐｅｎ］（フェニレンジアミン）₂又は［Ｒｕ（Ｒ，Ｒ）−Ｔｓｄｐｅｎ（ｐ-ｃｙｍｅｎｅ）］＋α−フェニレンジアミンの存在下ではラセミ化は進行しないことが分かる。

((R) -Phenylic alcohol racemization experiment)
In the presence of 0.5 equivalents of Ru [(R, R) -Tsdpen] (phenylenediamine) ₂ relative to the substrate (phenylethanol whose optical purity of (R) -phenylethanol is 94.5% ee) Reaction was performed. Further, the following reaction was similarly performed in the presence of [Ru (R, R) -Tsdpen (p-cymene)] instead of Ru [(R, R) -Tsdpen] (phenylenediamine) ₂ . Furthermore, in addition to [Ru (R, R) -Tsdpen (p-cymene)], 1.5 equivalents of α-phenylenediamine was added and the following reaction was carried out in the same manner.

The obtained results are shown in Table 1. Table 1 shows that racemization does not proceed in the presence of Ru [(R, R) -Tsdpen] (phenylenediamine) ₂ or [Ru (R, R) -Tsdpen (p-cymene)] + α-phenylenediamine. .

(Reference Example 1: Asymmetric hydrogen transfer reaction of acetophenone)
In a 200 ml reaction vessel, 10 g (8.32 mmol) of acetophenone, 1.06 g (1.6646 mmol) of [RuCl (S, S) -Tsdpen (p-cymene)] and formic acid / triethylamine (5/2 (volume ratio)) 41. Nitrogen substitution was performed by adding 5 ml. After stirring this solution at 30 ° C. for 17 hours, 45 ml of methylene chloride and 40 ml of water were added to separate the organic layer. Methylene chloride was distilled off from the organic layer to obtain 13.5 g of (S) -phenylethanol concentrate. When this concentrate was stored at 5 ° C. for 4 days, the change in optical purity from the end of the reaction was as follows.

(Comparative Example 1)
When 1 g of (S) -phenylethanol concentrate with optical purity of 79.5% ee obtained in Reference Example 1 and stored at 5 ° C for 4 days was heated at 80 ° C for 16 hours, the optical purity was 13.6% ee. It dropped to.

(Example 2-5)
A nitrogen-containing compound was added to 1 g (Ru: 0.123 mmol) of (S) -phenylethanol having an optical purity of 79.5% ee obtained in Reference Example 1 and stored at 5 ° C. for 4 days, and then at 80 ° C. for 16 hours. The results of heating are as shown in the table below.

(Example 6: Synthesis of (R) -4- (1-hydroxyethyl) benzonitrile)
To a 200 mL four-necked flask, 15.0 g (103.3 mmol) of 4-acetylbenzonitrile, 30 ml of MeOH, and 126 mg (0.2 mmol) of [RuCl (R, R) -Tsdpen (p-cymene)] were added. While maintaining the temperature at 15 ° C., 75 ml of formic acid / triethylamine (5/2 (volume ratio)) was added dropwise at 20 ° C. or lower over 30 minutes, and the mixture was heated to 25 ° C. and stirred for 64 hours. After completion of the reaction, the mixture was cooled to 15 ° C., added with 30 ml of water, extracted with 90 ml of ethyl acetate, and washed twice with 30 ml of water. Subsequently, 75.5 mg (0.5 mmol) of triethylenetetramine was weighed in a 300 ml eggplant flask, and an ethyl acetate extraction solution was added thereto, and the ethyl acetate was distilled off under reduced pressure. 14.4 g (95.9% ee) of the obtained concentrated liquid was purified by distillation under reduced pressure (118 to 120 ° C./1 torr) to obtain the desired (R) -4- (1-hydroxyethyl) benzonitrile. 7 g (yield 76.9%) was obtained. The optical purity was 95.6% ee.

(Comparative Example 2)
When a similar operation was performed except that triethylenetetramine was not added in Example 6, the optical purity of the distillate was 86.2% ee.

(Reference Example 2: Asymmetric hydrogen transfer reaction of acetophenone)
In a 200 ml reaction vessel, 10 g (8.30 mmol) of acetophenone, [RuCl (S, S) -Tsdpen (p-cymene)] 1.00 g (1.5712 mmol), 300 ml of 2-propanol and 300 mg (7.500 mmol) of sodium hydroxide And nitrogen substitution was performed. This solution was stirred at 40 ° C. for 22 hours, and then the solvent was distilled off to obtain 11.3 g of (S) -phenylethanol concentrate. The change in optical purity from the end of the reaction was as follows.

(Comparative Example 2)
When 1 g of (S) -phenylethanol concentrate having an optical purity of 83.9% ee obtained in Reference Example 2 was heated at 80 ° C. for 17 hours, the optical purity decreased to 78.2% ee.

(Example 7-9)
A nitrogen-containing compound was added to 1 g (Ru: 0.138 mmol) of (S) -phenylethanol concentrate (Ru: 0.138 mmol) having an optical purity of 83.9% ee obtained in the same manner as in Reference Example 2, and heated at 80 ° C. for 17 hours. The results are shown in the table below.

(Reference Example 3: Racemization of optically active (R) -phenylethanol)
In a 200 ml reaction vessel, 94.5% ee (R) -phenylethanol 100 mg (0.819 mmol), [Ru (R, R) -Tsdpen (p-cymene)] 24.6 mg (0.041 mmol) and formic acid / triethylamine Nitrogen substitution was performed by adding 2 ml (5/2 (volume ratio)). When this solution was stirred at 80 ° C. for 17 hours, the optical purity was 55.4% ee.

(Examples 10-15)
The same operation as in Reference Example 3 was performed except that the nitrogen-containing compound was added to the reaction vessel. The results are shown in the table below.

Claims (8)

  A method for producing a reduction reaction product, in which a nitrogen-containing compound is added to a reaction solution subjected to a reduction reaction using a transition metal complex, and then a reaction solvent is recovered and / or distilled.   The production method according to claim 1, wherein the reduction reaction is asymmetric hydrogenation or asymmetric hydrogen transfer.   The production method according to claim 1 or 2, wherein the transition metal complex is a ruthenium complex, a rhodium complex, or an iridium complex.   The manufacturing method of Claim 3 which adds a nitrogen-containing compound 1 equivalent or more with respect to a transition metal complex.   The production method according to claim 4, wherein the number of nitrogen atoms in the nitrogen-containing compound is 2 or more.   The production method according to claim 5, wherein the nitrogen-containing compound is an imidazole.   The production method according to any one of claims 1 to 6, wherein the addition of the nitrogen-containing compound is intended to suppress a reduction in optical purity of the reduction reaction product when the reaction solvent is recovered and / or distilled.   The production method according to claim 7, wherein the addition of the nitrogen-containing compound causes the nitrogen-containing compound to react with the transition metal complex to form a complex containing the nitrogen-containing compound, thereby suppressing a reduction in optical purity of the reduction reaction product.