JP4845470B2 - Process for producing optically active amino alcohols - Google Patents

Description

  The present invention relates to a process for producing 4-amino-2-hydroxybutyric acids, particularly optically active 4-amino-2-hydroxybutyric acids, which are useful as intermediates for pharmaceuticals or agricultural chemicals.

  As for the method for producing optically active 4-amino-2-hydroxybutyric acid, for example, Non-Patent Document 1 describes that 2-oxobutyric acid is reduced using yeast. Non-Patent Document 2 describes that a reduction reaction of 2-oxobutanoic acid is performed using an enzyme.

  However, the methods described in Non-Patent Documents 1 and 2 are reactions under high dilution conditions of 2-oxobutyric acid, and have a problem that they are unsuitable for industrialization from an economical viewpoint. In addition, the method described in Non-Patent Document 1 has a problem that it requires an excessive amount of yeast and sugar and is expensive.

Patent Document 1 describes a method for producing an optically active amino alcohol by an asymmetric hydrogenation reaction. However, in the method described in Patent Document 1, the substrate for the asymmetric hydrogenation reaction is a ketoalkene, and the reduction reaction of 4-amino-2-oxobutenoic acids is not described.
JP 2004-155770 A Biocatalysis, 1992, Vol. 5, p. 195-201 Journal of the Chemical Society Chemical Communication (J. Chem. Soc. Chem. Commun.), 1995, p. 231-232

  The present invention has been made in view of the above situation, and 4-amino-2-hydroxybutyric acid having high yield and good workability, particularly optically active 4-amino-2-hydroxybutyric acid having high optical purity or It aims at providing the manufacturing method of the salt.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention easily and at a high yield yield the desired 4-amino-2-oxobutenoic acid or a salt thereof by subjecting it to a reduction reaction. It has been found that amino-2-hydroxybutyric acids, in particular, optically active 4-amino-2-hydroxybutyric acids or salts thereof having high optical purity can be obtained, and the present invention has been completed.

（式中、Ｒ¹は（i）置換されていてもよい水酸基、（ii）置換されていてもよいメルカプト基又は（iii）置換されていてもよいアミノ基を示し、Ｒ²及びＲ³は夫々独立して、水素原子、置換基を有していてもよい炭化水素基又は置換基を有していてもよい複素環基を示し、Ｒ⁴及びＲ⁵は夫々独立して、水素原子又は保護基を示す。但し、Ｒ¹とＲ²、Ｒ²とＲ³、Ｒ²とＲ⁵又はＲ⁴とＲ⁵とが結合して環を形成してもよく、二重結合はシス又はトランスである。）で表される４−アミノ−２−オキソブテン酸類であり、得られる光学活性４−アミノ−２−ヒドロキシ酪酸類が一般式（１）

（式中、＊は不斉炭素を示し、Ｒ¹〜Ｒ⁵は前記と同意義である。但し、Ｒ²が水素原子であるときはＲ²が結合している炭素原子は不斉炭素とはならず、またＲ³が水素原子であるときはＲ³が結合している炭素原子は不斉炭素とはならない。）で表される光学活性４−アミノ−２−ヒドロキシ酪酸類であることを特徴とする前記［１］又は［２］に記載の製造方法、
［４］Ｒ¹で示される置換されていてもよい水酸基が、−ＯＲ^1a（式中、Ｒ^1aは水素原子、置換基を有していてもよい炭化水素基又は置換基を有していてもよい複素環基を示す。）で表される基であることを特徴とする前記［３］に記載の製造方法、
［５］Ｒ¹で示される置換されていてもよいメルカプト基が、−ＳＲ^1b（式中、Ｒ^1bは水素原子、置換基を有していてもよい炭化水素基又は置換基を有していてもよい複素環基を示す。）で表される基であることを特徴とする前記［３］に記載の製造方法、
［６］還元反応を不斉触媒の存在下で行うことを特徴とする前記［１］又は［２］に記載の製造方法、
［７］不斉触媒が、遷移金属錯体である、前記［６］に記載の製造方法、
［８］還元反応により生成した４−アミノ−２−ヒドロキシ酪酸類又はその塩を溶媒中で晶析させ、取得することを特徴とする前記［１］〜［７］の何れかに記載の製造方法、
［９］溶媒が、芳香族炭化水素類、脂肪族炭化水素類、アルコール類及び水から選ばれる少なくとも１種であることを特徴とする前記［８］に記載の製造方法、
［１０］４−アミノ−２−オキソブテン酸類又はその塩を不斉触媒の存在下に還元し、還元反応により生成した光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩を溶媒中で晶析させることを特徴とする光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩の製造方法、
［１１］溶媒が、芳香族炭化水素類、脂肪族炭化水素類、アルコール類、ケトン類、エステル類及び水から選ばれる少なくとも１種である、前記［１０］に記載の光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩の製造方法、及び
［１２］４−アミノ−２−オキソブテン酸類又はその塩を不斉触媒の存在下に還元し、還元反応により生成した光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩を溶媒中で晶析させることを特徴とする光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩の光学純度を向上させる方法、
に関する。 That is, the present invention is as follows.
[1] A process for producing 4-amino-2-hydroxybutyric acid or a salt thereof, which comprises subjecting 4-amino-2-oxobutenoic acid or a salt thereof to a reduction reaction,
[2] The reduction reaction is an asymmetric reduction reaction, and the produced 4-amino-2-hydroxybutyric acid or a salt thereof is an optically active 4-amino-2-hydroxybutyric acid or a salt thereof. The production method according to the above [1],
[3] 4-amino-2-oxobutenoic acids are represented by the general formula (2)

(Wherein R ¹ represents (i) an optionally substituted hydroxyl group, (ii) an optionally substituted mercapto group or (iii) an optionally substituted amino group, R ² and R ³ are Each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ and R ⁵ each independently represent a hydrogen atom or A protecting group, provided that R ¹ and R ² , R ² and R ³ , R ² and R ^5, or R ⁴ and R ⁵ may be combined to form a ring, and the double bond is cis or trans 4-amino-2-oxobutenoic acids represented by the general formula (1).

(In the formula, * represents an asymmetric carbon, and R ^{1 to} R ⁵ are as defined above. However, when R ² is a hydrogen atom, the carbon atom to which R ² is bonded is an asymmetric carbon; In addition, when R ³ is a hydrogen atom, the carbon atom to which R ³ is bonded is not an asymmetric carbon.) And is an optically active 4-amino-2-hydroxybutyric acid The production method according to [1] or [2], wherein:
[4] a hydroxy group which may be substituted represented by R ¹ is, in -OR ^1a (wherein, R ^1a is not a hydrogen atom, may be substituted hydrocarbon group or an optionally substituted The production method according to the above [3], which is a group represented by:
[5] An optionally substituted mercapto group represented by R ¹ is —SR ^1b (wherein R ^1b has a hydrogen atom, a hydrocarbon group which may have a substituent, or a substituent. The production method according to the above [3], which is a group represented by the following:
[6] The production method according to [1] or [2], wherein the reduction reaction is performed in the presence of an asymmetric catalyst.
[7] The production method according to the above [6], wherein the asymmetric catalyst is a transition metal complex,
[8] The production according to any one of [1] to [7], wherein 4-amino-2-hydroxybutyric acid or a salt thereof produced by the reduction reaction is crystallized in a solvent and obtained. Method,
[9] The production method according to [8], wherein the solvent is at least one selected from aromatic hydrocarbons, aliphatic hydrocarbons, alcohols and water,
[10] Reduction of 4-amino-2-oxobutenoic acids or salts thereof in the presence of an asymmetric catalyst, and crystallization of optically active 4-amino-2-hydroxybutyric acids or salts thereof generated by the reduction reaction in a solvent A method for producing optically active 4-amino-2-hydroxybutyric acid or a salt thereof,
[11] The optically active 4-amino- described in [10], wherein the solvent is at least one selected from aromatic hydrocarbons, aliphatic hydrocarbons, alcohols, ketones, esters, and water. Process for producing 2-hydroxybutyric acid or its salt, and [12] optically active 4-amino-2 produced by reduction of 4-amino-2-oxobutenoic acid or its salt in the presence of an asymmetric catalyst A method for improving the optical purity of optically active 4-amino-2-hydroxybutyric acid or a salt thereof, characterized by crystallizing hydroxybutyric acid or a salt thereof in a solvent;
About.

  According to the present invention, an asymmetric reduction reaction (hydrogenation reaction) can be performed in one step on both the carbonyl group portion and the carbon-carbon double bond portion of 4-amino-2-oxobutenoic acids used as a substrate. The workability for the production of 4-amino-2-hydroxybutyric acid is improved and economically useful. In addition, according to the production method of the present invention, desired 4-amino-2-hydroxybutyric acid, particularly optically active 4-amino-3-hydroxybutyric acid having a high optical purity or a salt thereof can be obtained in high yield. There is an effect.

  The 4-amino-2-oxobutenoic acids or salts thereof used in the present invention are salts of 4-amino-2-oxobutenoic acids and 4-amino-2-oxobutenoic acids (hereinafter collectively referred to simply as “ 4-amino-2-oxobutenoic acids "), which has a hydrocarbon group or a substituent which may have a substituent at the 1-position adjacent to the 2-position carbonyl group. Any oxobutenoic acid having a group other than a heterocyclic group may be used, and preferably, for example, the following general formula (2)

(Wherein R ¹ represents (i) an optionally substituted hydroxyl group, (ii) an optionally substituted mercapto group or (iii) an optionally substituted amino group, R ² and R ³ are Each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ and R ⁵ each independently represent a hydrogen atom or R ⁴ and R ⁵ each independently represents a hydrogen atom or a protecting group, provided that R ¹ and R ² , R ² and R ³ , R ² and R ⁵ or R ⁴ and R ⁵ May be combined to form a ring, and the double bond is cis or trans.). 4-amino-2-oxobutenoic acids represented by the following formula:

In the general formulas (1) and (2), the optionally substituted hydroxyl group represented by R ¹ is, for example, a group represented by —OR ^1a . Here, R ^1a represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent.

Examples of the hydrocarbon group which may have a substituent represented by R ^1a include a hydrocarbon group and a substituted hydrocarbon group. Examples of the hydrocarbon group include an alkyl group, an aryl group, and an aralkyl group.

  As the alkyl group, a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms is preferable. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-methylbutyl, Ethylpropyl, tert-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 1-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylpentan-3-yl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, Decyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like. Among these, an alkyl group having 1 to 10 carbon atoms is more preferable, an alkyl group having 1 to 6 carbon atoms is more preferable, and an alkyl group having 1 to 4 carbon atoms is particularly preferable.

  As the aryl group, an aryl group having 6 to 20 carbon atoms is preferable. Specific examples of the aryl group include phenyl, indenyl, pentarenyl, naphthyl, azulenyl, fluorenyl, phenanthrenyl, anthracenyl, acenaphthylenyl, biphenylenyl, naphthacenyl, and pyrenyl. The aryl group is more preferably an aryl group having 6 to 14 carbon atoms.

  As the aralkyl group, an aralkyl group having 7 to 20 carbon atoms is preferable. Specific examples of the aralkyl group include benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-phenylbutyl, Phenylpentylbutyl, 2-phenylpentylbutyl, 3-phenylpentylbutyl, 4-phenylpentylbutyl, 5-phenylpentylbutyl, 1-phenylhexylbutyl, 2-phenylhexylbutyl, 3-phenylhexylbutyl, 4-phenylhexyl Butyl, 5-phenylhexylbutyl, 6-phenylhexylbutyl, 1-phenylheptyl, 1-phenyloctyl, 1-phenylnonyl, 1-phenyldecyl, 1-phenylundecyl, 1-phenyldodecyl, 1-phenyltridecyl Or 1 Phenyl tetradecyl, and the like. Among them, the aralkyl group is more preferably an aralkyl group having 7 to 12 carbon atoms.

Examples of the substituent that the “hydrocarbon group” represented by R ^1a may have include those described later. Preferable specific examples of the substituted hydrocarbon group include substituted alkyl groups such as trifluoromethyl and methoxymethyl, tolyl (for example, 4-methylphenyl), xylyl (for example, 3,5-dimethylphenyl), 4-methoxy-3, A substituted aryl group or a substituted aralkyl group such as 5-dimethylphenyl or 4-methoxy-3,5-di-t-butylphenyl is exemplified.

^Examples of the heterocyclic group which may have a substituent represented by R ^1a include a heterocyclic group and a substituted heterocyclic group. Examples of the heterocyclic group include an aliphatic heterocyclic group and an aromatic heterocyclic group.
Examples of the aliphatic heterocyclic group include 2 to 14 carbon atoms and at least one hetero atom, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom and / or a sulfur atom. , 3 to 8 membered, preferably 5 or 6 membered monocyclic, polycyclic or condensed ring aliphatic heterocyclic group. Specific examples of the aliphatic heterocyclic group include, for example, pyrrolidyl-2-one group, piperidyl group, piperidino group, piperazinyl group, morpholino group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group, thiolanyl group, and succinimidyl group. Is mentioned.

  As the aromatic heterocyclic group, for example, it has 2 to 15 carbon atoms and contains at least one hetero atom, preferably 1 to 3 hetero atoms such as nitrogen atom, oxygen atom and / or sulfur atom. Examples thereof include 3 to 8 membered, preferably 5 or 6 membered monocyclic, polycyclic or condensed heterocyclic groups. Specific examples thereof include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl and thiazolyl. , Isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 , 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimi Nyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1 , 2-Benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl Phenothiazinyl, phenazinyl, phenoxathiinyl, thianthenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] Ridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] Pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, benzo [1,2,5] thiadiazolyl, benzo [1,2, 5] An oxadiazolyl or phthalimino group is exemplified.

Examples of the substituent that the “heterocyclic group” represented by R ^1a may have include those described later.

The optionally substituted mercapto group represented by R ¹ is, for example, a group represented by —SR ^1b . Here, R ^1b represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Hydrocarbon group represented by R ^1b are as defined hydrocarbon groups represented by R ^1a. Heterocyclic group represented by R ^1b are as defined heterocyclic group represented by R ^1a. Examples of the substituent in the “optionally substituted hydrocarbon group” or “optionally substituted heterocyclic group” represented by R ^1b include the substituents described later.

Examples of the optionally substituted amino group represented by R ¹ include an amino group or a linear or cyclic amino group in which one or two hydrogen atoms of the amino group are substituted with a substituent such as an amino protecting group. Can be mentioned. Any amino protecting group can be used as long as it is usually used as an amino protecting group. For example, amino protecting groups are described in “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS THIRD EDITION [JOHN WILEY & SONS INC. (1999)]”. Preferred examples include a group described as a group, etc. Specific examples of the amino protecting group include, for example, an optionally substituted hydrocarbon group, an optionally substituted acyl group, and a substituted group. And an alkoxycarbonyl group which may have a group, an aryloxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent, and the like.

  The “hydrocarbon group which may have a substituent” in the amino protecting group may have the same meaning as the hydrocarbon group which may have a substituent described above.

  Examples of the acyl group that may have a substituent in the amino protecting group include an acyl group and a substituted acyl group. Examples of the acyl group include a linear, branched or cyclic acyl group having 1 to 20 carbon atoms derived from an acid such as carboxylic acid, sulfonic acid, sulfinic acid, phosphinic acid or phosphonic acid. An acyl group derived from an acid such as sulfonic acid is preferred.

Examples of the acyl group derived from a carboxylic acid include an acyl group derived from a carboxylic acid such as an aliphatic carboxylic acid or an aromatic carboxylic acid. For example, -COR ^a [wherein R ^a has a hydrogen atom or a substituent. A hydrocarbon group which may be substituted or a heterocyclic group which may have a substituent; ]. The “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ^a may have a substituent in the amino protecting group. It is the same meaning as the heterocyclic group which may have a hydrocarbon group and a substituent.
Preferable specific examples of the acyl group derived from carboxylic acid include formyl group, carboxy group, carbamoyl group, alkylcarbonyl group (for example, acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, lauroyl, stearoyl, etc.), cycloalkylcarbonyl group (Eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), aryl-carbonyl groups (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), aralkylcarbonyl groups (eg, phenylacetyl, phenylpropionyl, etc.) and the like. It is done. The acyl group is preferably an acyl group having 1 to 18 carbon atoms, and more preferably an acyl group having 1 to 6 carbon atoms.

A sulfonyl group is mentioned as an acyl group derived from a sulfonic acid. As the sulfonyl group, for example, R ^b —SO ₂ — [R ^b represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. ] The substituted sulfonyl group represented by this is mentioned. Specific examples of the sulfonyl group include alkylsulfonyl groups (for example, methanesulfonyl, trifluoromethanesulfonyl, propanesulfonyl, pentanesulfonyl, heptanesulfonyl, nonanesulfonyl, undecanesulfonyl, tridecanesulfonyl, pentadecanesulfonyl, heptadecanesulfonyl, nonadecanesulfonyl. Etc.) or an arylsulfonyl group (for example, benzenesulfonyl, p-toluenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.) and the like.

  Examples of the substituent in the “acyl group optionally having a substituent” include the substituents described below.

Examples of the alkoxycarbonyl group which may have a substituent in the amino protecting group include an alkoxycarbonyl group and a substituted alkoxycarbonyl group.
The alkoxycarbonyl group may be linear, branched or cyclic, and examples thereof include an alkoxycarbonyl group having 2 to 20 carbon atoms. Specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, 2-propoxycarbonyl group, n-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, 2-ethylhexyloxycarbonyl group, lauryloxycarbonyl group, stearyloxycarbonyl group, cyclohexyloxycarbonyl group, etc. Is mentioned.
Examples of the substituted alkoxycarbonyl group (an alkoxycarbonyl group having a substituent) include an alkoxycarbonyl group in which at least one hydrogen atom of the alkoxycarbonyl group is substituted with a substituent. Examples of the substituent include those described later.

Examples of the aryloxycarbonyl group which may have a substituent in the amino protecting group include an aryloxycarbonyl group and a substituted aryloxycarbonyl group.
Examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 20 carbon atoms, and specific examples thereof include a phenoxycarbonyl group and a naphthyloxycarbonyl group.
Examples of the substituted aryloxycarbonyl group (aryloxycarbonyl group having a substituent) include aryloxycarbonyl groups in which at least one hydrogen atom of the aryloxycarbonyl group is substituted with a substituent. Examples of the substituent include those described later.

Examples of the aralkyloxycarbonyl group which may have a substituent in the amino protecting group include an aralkyloxycarbonyl group and a substituted aralkyloxycarbonyl group.
Examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 20 carbon atoms, and specific examples thereof include a benzyloxycarbonyl group, a phenethyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group.
Examples of the substituted aralkyloxycarbonyl group (aralkyloxycarbonyl group having a substituent) include an aralkyloxycarbonyl group in which at least one hydrogen atom of the aralkyloxycarbonyl group is substituted with a substituent. Examples of the substituent include those described later.

Preferred specific examples of the amino group substituted with the alkyl group represented by R ¹ , that is, the alkyl-substituted amino group include, for example, an N-methylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, Examples thereof include mono- or dialkylamino groups such as N, N-diisopropylamino group and N-cyclohexylamino group.

Preferable specific examples of the amino group substituted with the aryl group represented by R ¹ , that is, the aryl-substituted amino group include, for example, an N-phenylamino group, an N, N-diphenylamino group, an N-naphthylamino group, or an N- Examples thereof include mono- or diarylamino groups such as naphthyl-N-phenylamino group.

Preferable specific examples of the amino group substituted with the aralkyl group represented by R ¹ , that is, the aralkyl-substituted amino group include, for example, mono- or diaralkylamino groups such as N-benzylamino group and N, N-dibenzylamino group Is mentioned. Further, a disubstituted amino group such as an N-methyl-N-phenylamino group or an N-benzyl-N-methylamino group can be mentioned.

Preferable specific examples of the amino group substituted with the acyl group represented by R ¹ , that is, the acyl-substituted amino group include, for example, formylamino group, acetylamino group, propionylamino group, pivaloylamino group, pentanoylamino group, hexanoyl An amino group, a benzoylamino group, etc. are mentioned.

Preferable specific examples of the amino group substituted with the alkoxycarbonyl group represented by R ¹ , that is, the alkoxycarbonyl-substituted amino group include, for example, methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, n-butoxy Examples thereof include a carbonylamino group, a tert-butoxycarbonylamino group, a pentyloxycarbonylamino group, and a hexyloxycarbonylamino group.

Preferable specific examples of the amino group substituted with the aryloxycarbonyl group represented by R ¹ , that is, the aryloxycarbonyl-substituted amino group include, for example, that one hydrogen atom of the amino group is substituted with the above-mentioned aryloxycarbonyl group. Specific examples thereof include, for example, a phenoxycarbonylamino group or a naphthyloxycarbonylamino group.

Preferable specific examples of the amino group substituted with the aralkyloxycarbonyl group represented by R ¹ , that is, the aralkyloxycarbonyl-substituted amino group include, for example, benzyloxycarbonylamino group, phenethyloxycarbonylamino group or 9-fluorenylmethyl. An oxycarbonylamino group etc. are mentioned.

Preferable specific examples of the amino group substituted with the substituted sulfonyl group represented by R ¹ include, for example, —NHSO ₂ CH ₃ , —NHSO ₂ C ₆ H ₅ , —NHSO ₂ C ₆ H ₄ CH ₃ or —NHSO _2. CF _{3 and the} like can be mentioned.

Examples of the cyclic amino group represented by R ¹ include a cyclic amino group formed by bonding with an alkylene group which may have a substituent to form a nitrogen-containing ring. The alkylene group may be linear or branched, and examples thereof include an alkylene group having 1 to 6 carbon atoms. Specific examples thereof include, for example, methylene, ethylene, propylene, trimethylene, 2-methylpropylene, , 2-dimethylpropylene or 2-ethylpropylene. The alkylene group may have an oxygen atom, an imino group, a substituted imino group, a carbonyl group, or the like or a double bond at an end of the alkylene group or at any position in the chain. Examples of the substituted imino group include an imino group in which one hydrogen atom of the imino group is substituted with a substituent such as an amino protecting group. The amino protecting group may have the same meaning as the protecting group described for the substituted amino group.
Specific examples of the cyclic amino group include pyrrolidino group, piperazino group, morpholino group and the like.

The “hydrocarbon group which may have a substituent” represented by R ² and R ³ may have the same meaning as the hydrocarbon group which may have a substituent described in the above R ^1a . Examples of the substituent in the “hydrocarbon group which may have a substituent” represented by R ² and R ³ include the substituents described later.

The “heterocyclic group which may have a substituent” represented by R ² and R ³ has the same meaning as the heterocyclic group which may have a substituent described in the above R ^1a .

Examples of the “substituent” in the present invention include a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a halogen atom, a halogenated hydrocarbon group, —OR ^{1a. '} , -SR ^1b' , an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyl group, and a substituted group. Aryloxycarbonyl group which may have a substituent, alkylenedioxy group which may have a substituent, nitro group, amino group, substituted amino group, cyano group, sulfo group, substituted silyl group, hydroxyl group, carboxy group, substituent An alkoxythiocarbonyl group which may have, an aryloxythiocarbonyl group which may have a substituent, an alkylthiocarbonyl group which may have a substituent, and an aryl which may have a substituent. A thiothiocarbonyl group, an optionally substituted carbamoyl group, a substituted phosphino group, an aminosulfonyl group, an alkoxysulfonyl group or an oxo group. The hydrocarbon group that may have a substituent, the heterocyclic group that may have a substituent, the substituted amino group, and the acyl group that may have a substituent may be, It is the same meaning as the group. —OR ^{1a ′} has the same meaning as —OR ^1a . -SR ^{1b '} has the same meaning as -SR ^1b . Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The protecting group for R ⁴ and R ⁵ may have the same meaning as the amino protecting group described above for the optionally substituted amino group.
When R ¹ and R ² , R ² and R ³ , R ² and R ⁵ or R ⁴ and R ⁵ are combined to form a ring, they are bonded with an alkylene group which may have a substituent. To form a ring. In addition, the ring to be formed may be monocyclic, polycyclic, or condensed, and examples thereof include aliphatic rings such as 4- to 8-membered rings.

  The alkylene group may be linear or branched, for example, an alkylene group having 1 to 6 carbon atoms. Preferred specific examples include, for example, methylene, ethylene, propylene, trimethylene, 2-methylpropylene, 2, Examples include 2-dimethylpropylene or 2-ethylpropylene. The alkylene group may have an oxygen atom, an imino group, a substituted imino group, or the like at an end of the alkylene group or at any position in the chain. The substituted imino group has the same meaning as the substituted imino group described above.

  Examples of the substituent in the “alkylene group which may have a substituent” include the above-described substituents.

In the general formula (1), when R ² is a hydrogen atom, the carbon atom to which R ² is bonded is not an asymmetric carbon, and when R ³ is a hydrogen atom, R ³ is bonded. Carbon atoms that are not asymmetric carbons.
Specific examples of 4-amino-2-oxobutenoic acids represented by the general formula (2) include compounds shown in Tables 1 to 3 below.

Examples of salts of 4-amino-2-oxobutenoic acids represented by the general formula (2) include acid salts or amine salts. Specifically, it may be an acid salt when the nitrogen atom part or R ¹ in the molecule of 4-amino-2-oxobutenoic acid is an amino group or a substituted amino group. When R ¹ is a hydroxyl group, it may be a metal salt with an alkali metal or alkaline earth metal or a salt with an amine.

Examples of the acid forming the salt include inorganic acids, organic acids, Lewis acids and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tetrafluoroboric acid, perchloric acid, and periodic acid. Examples of organic acids include formic acid, acetic acid, valeric acid, hexanoic acid, citric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, salicylic acid, oxalic acid, succinic acid, malonic acid, phthalic acid, Examples thereof include carboxylic acids such as tartaric acid, malic acid and glycolic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid. Examples of the Lewis acid include aluminum halides such as aluminum chloride or aluminum bromide, dialkylaluminum halides such as diethylaluminum chloride, diethylaluminum bromide or diisopropylaluminum chloride, triethoxyaluminum, triisopropoxyaluminum or tri-tert. -Trialkoxyaluminum such as butoxyaluminum, titanium halide such as titanium tetrachloride, tetraalkoxytitanium such as tetraisopropoxytitanium, boron trifluoride, boron trichloride, boron tribromide or boron trifluoride diethyl ether complex, etc. Or a halogenated zinc halide such as zinc chloride or zinc bromide.
Examples of the alkali metal that becomes a salt when it is a hydroxyl group include lithium, sodium, potassium, rubidium, and cesium. Examples of the alkaline earth metal include magnesium, calcium, strontium, and barium.
Examples of amines that form salts include ammonia, such as methylamine, ethylamine, propylamine, butylamine, cyclohexylamine, dimethylamine, diethylamine, diisopropylamine, triethylamine, tripropylamine, diisopropylethylamine, di (2-ethylhexyl) amine, Aliphatic amines such as hexadecylamine, tri-n-butylamine or N-methylmorpholine, for example, aromatic amines such as N, N-dimethylaniline, pyridine or 4-dimethylaminopyridine, and saturated heterocycles such as piperidine. And cyclic amines.

  As 4-amino-2-oxobutenoic acids or salts thereof, commercially available products or those appropriately produced may be used.

（式中、Ｒ¹〜Ｒ³及びＲ⁵は前記と同意義である。）で表される化合物である、エノール型の構造をとる場合がある。

The 4-amino-2-oxobutenoic acids or salts thereof represented by the above general formula (2) according to the present invention, for example, when R ⁴ is a hydrogen atom [for example, the following general formula (2-1)], Depending on the type of compound, in the reaction system or in an isolated state, the compound represented by the general formula (2-2)

(Wherein, R ^{1 to} R ³ and R ⁵ have the same meanings as described above) may take an enol-type structure.

  Both are in a so-called keto-enol isomerism relationship, and in the present invention, the compound of the general formula (2-1) and the compound of the general formula (2-2) and the mixture thereof are substantially the same.

  In the present invention, the 4-amino-2-oxobutenoic acids or salts thereof represented by the general formula (2) used in the present invention are the 4-amino-2 represented by the general formula (2-2). -Oxobutenoic acids or salts thereof are also 4-amino-2-oxobutenoic acids or salts thereof represented by the general formula (2-1) and 4-amino-2-form represented by the general formula (2-2). Mixtures with oxobutenoic acids or salts thereof are also encompassed within the scope.

  In the production method of the present invention, the 4-amino-2-oxobutenoic acids represented by the general formula (2-1) and the general formula (2-2) or salts thereof may not be protected with a protecting group. By carrying out an asymmetric reduction reaction, particularly asymmetric hydrogenation, an optically active 4-amino-2-hydroxybutyric acid represented by the general formula (1) or a salt thereof can be obtained with high yield and optical purity. it can. Further, when the 4-amino-2-oxobutenoic acid represented by the general formula (2) or a salt thereof has an enol-type structure, a protective group is introduced into the hydroxyl group in the general formula (2-2). Even if it performs the manufacturing method of this invention, the optically active 4-amino-2-hydroxybutyric acid or its salt represented with General formula (1) with high yield and sufficient optical purity can be obtained.

  4-amino-2-hydroxybutyric acids or salts thereof obtained by the production method of the present invention, particularly optically active 4-amino-2-hydroxybutyric acids or salts thereof, are optically active 4-amino-2-hydroxybutyric acids and salts thereof. It is a salt of optically active 4-amino-2-hydroxybutyric acid (hereinafter collectively referred to simply as “4-amino-2-hydroxybutyric acid” or “optically active 4-amino-2-hydroxybutyric acid”). Sometimes it is.) Examples of the optically active 4-amino-2-hydroxybutyric acids or salts thereof include, for example, the following general formula (1)

（式中、＊は不斉炭素を示し、Ｒ¹〜Ｒ⁵は前記と同意義である。しかし、Ｒ²が水素原子であるときはＲ²が結合している炭素原子は不斉炭素とはならず、またＲ³が水素原子であるときはＲ³が結合している炭素原子は不斉炭素とはならない。）で表される光学活性４−アミノ−２−ヒドロキシ酪酸類又はその塩等が挙げられる。
形成する塩は、上記４−アミノ−２−オキソブテン酸類の塩で説明した塩と同様の塩が挙げられ、必要に応じて塩を交換、例えば塩酸塩から硝酸塩に変換してもよい。

(In the formula, * represents an asymmetric carbon, and R ^{1 to} R ⁵ are as defined above. However, when R ² is a hydrogen atom, the carbon atom to which R ² is bonded is an asymmetric carbon; In addition, when R ³ is a hydrogen atom, the carbon atom to which R ³ is bonded is not an asymmetric carbon.) Or an optically active 4-amino-2-hydroxybutyric acid salt or a salt thereof Etc.
Examples of the salt to be formed include the same salts as those described above for the salt of 4-amino-2-oxobutenoic acid, and the salt may be exchanged, for example, converted from hydrochloride to nitrate as necessary.

  Specific examples of the optically active 4-amino-2-hydroxybutyric acid represented by the general formula (1) include compounds shown in Tables 4 to 6 below.

  In the production method of the present invention, the reduction reaction may be performed by reacting 4-amino-2-oxobutenoic acid or a salt thereof with a reducing agent. Such a reducing agent is not particularly limited, but can be usually performed at about 15 to 100 ° C. for about 1 minute to 48 hours at normal pressure. Examples of the reducing agent include, but are not limited to, a reducing agent such as lithium aluminum hydride, sodium borohydride, or borane, or a reducing agent that combines sodium borohydride and a Lewis acid. Preferably, the combination of sodium borohydride and a Lewis acid is mentioned. Preferred Lewis acids include magnesium or calcium compounds. The reduction reaction may be performed in an inert gas atmosphere as necessary. Examples of the inert gas include nitrogen gas and argon gas.

  In the production method of the present invention, in order to produce optically active 4-amino-2-hydroxybutyric acids or salts thereof having high optical purity, a compound represented by the general formula (2) in the presence of an asymmetric catalyst Alternatively, an asymmetric reduction reaction of the salt is preferably performed. The asymmetric reduction reaction refers to a reaction when a product obtained by performing a reduction reaction on a raw material has an asymmetric carbon. The asymmetric reduction reaction is preferably an asymmetric hydrogenation reaction, and the asymmetric reduction reaction is preferably performed in the presence of an asymmetric catalyst.

  The asymmetric hydrogenation reaction can be performed in the presence of a hydrogen source. Examples of the hydrogen source include hydrogen gas and a hydrogen donating substance. That is, examples of the asymmetric hydrogenation reaction used in the present invention include an asymmetric hydrogenation reaction carried out in the presence of hydrogen gas or a hydrogen transfer asymmetric hydrogenation reaction carried out in the presence of a hydrogen donating substance.

  As an asymmetric catalyst, a transition metal complex is preferable, and an asymmetric transition metal complex is more preferable. As the asymmetric transition metal complex, a transition metal complex containing a transition metal and an asymmetric ligand is preferably used. Further, the asymmetric transition metal complex may be used for the asymmetric hydrogenation reaction in situ.

  As the transition metal in the asymmetric transition metal complex, for example, a transition metal of Groups 8 to 10 of the periodic table is preferable.

As an asymmetric transition metal complex, for example, the following general formula (3)
M _m L _n X _p Y _q (3)
Or general formula (4)
[M _m L _n X _p Y _q ] Z _s (4)
Although the transition metal complex represented by these is mentioned, it is not limited to these.

  In the general formula (3) or (4), M represents a transition metal of Groups 8 to 10 of the periodic table, L represents an asymmetric ligand, X represents a halogen atom, a carboxylate group, an allyl group, 1,5-cyclooctadiene or norbornadiene, Y represents a ligand, Z represents an anion or cation, m represents an integer of 1 to 5, and n, p, q and s are each independently An integer of 0 to 5 is shown.

  In the general formulas (3) and (4), examples of the transition metal belonging to Groups 8 to 10 of the periodic table of M are ruthenium (Ru), rhodium (Rh), iridium (Ir), palladium (Pd). Or nickel (Ni) etc. are mentioned. When m is 2 or more, the transition metals may be the same or different.

  Examples of the asymmetric ligand represented by L include a monodentate ligand and a bidentate ligand. Preferred asymmetric ligands include optically active phosphorus ligands, and more preferably optically active bidentate phosphorus ligands. When n is 2 or more, the asymmetric ligands may be the same or different.

The optically active bidentate phosphorus ligand only needs to have an optically active site in the molecule. For example, the following general formula (5)
R ¹¹ R ¹² PQ ¹ -PR ¹³ R ¹⁴ (5)
(Wherein R ^{11 to} R ¹⁴ each independently have a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a substituent. An alkoxy group or an aryloxy group which may have a substituent, Q ¹ represents a spacer, and R ¹¹ and R ¹² and / or R ¹³ and R ¹⁴ may combine to form a ring; R ^{11 to} R ¹⁴ and Q ¹ may be phosphorus compounds represented by general formula (5) as long as the phosphorus compound is an optically active phosphorus compound). In the formula, it suffices to have an optically active site.

In the general formula (5), a hydrocarbon group which may have a substituent represented by R ^{11 to} R ¹⁴ , a heterocyclic group which may have a substituent, or a substituent. The aryloxy group which may have an alkoxy group or a substituent is synonymous with each group demonstrated by the said General formula (1) etc.

Examples of the spacer represented by Q ¹ include a divalent organic group that may have a substituent such as an alkylene group, an arylene group, or a heteroarylene group. The divalent organic group has at least one heteroatom or atomic group such as an oxygen atom, a carbonyl group, a sulfur atom, an imino group, or a substituted imino group at an end of the organic group or at any position in the chain. You may do it. The substituent in the substituted imino group has the same meaning as the substituent in the substituted amino group. Furthermore, the divalent organic group may be substituted with a substituent as described above.

  Examples of the alkylene group include an alkylene group having 1 to 10 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, and an octamethylene group. Group, nonamethylene group, decamethylene group or propylene group.

  Examples of the arylene group include an arylene group having 6 to 20 carbon atoms, and specific examples thereof include a phenylene group, a biphenyldiyl group, a binaphthalenediyl group, and a bisbenzodioxolediyl group.

  Examples of the heteroarylene group include 3 to 8 members having 2 to 20 carbon atoms and containing at least one, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom and / or a sulfur atom, Preferably, a 5- or 6-membered monocyclic heteroarylene group, a polycyclic or condensed ring heteroarylene group can be mentioned, and specific examples thereof include a bipyridinediyl group, a bisbenzothioldiyl group, or a bisthioldiyl group. Is mentioned.

Examples of the divalent organic group having a different atom or atomic group include —CH ₂ —O—CH ₂ — or —C ₆ H ₄ —O—C ₆ H ₄ —.

These divalent organic groups may be substituted with a substituent described later.
Specific examples of the spacer having an optically active site when the spacer has an optically active site include 1,2-dimethylethylene group, 1,2-cyclohexylene group, 1,2-diphenylethylene group, 1, Examples include 2-di (4-methylphenyl) ethylene group, 1,2-dicyclohexylethylene group, 1,3-dioxolane-4,5-diyl group, biphenyldiyl group, or binaphthalenediyl group. Examples of the spacer having an optically active site include (R) isomer, (S) isomer, (R, R) isomer, and (S, S) isomer.

In the case where R ¹¹ and R ¹² and / or R ¹³ and R ¹⁴ are bonded to form a ring, for example, an alkylene group is bonded to form a phosphorus-containing ring. The alkylene group may be linear or branched, for example, an alkylene group having 1 to 6 carbon atoms, and specific examples thereof include, for example, an ethylene group, a propylene group, a trimethylene group, and a 2-methylpropylene group. 2,2-dimethylpropylene group or 2-ethylpropylene group. Specific examples of the ring to be formed include a phospholane ring and a 2,5-dimethylphosphorane ring.

Examples of the optically active phosphorus compound include known or unknown optically active phosphorus compounds that can be used as a ligand. Specific examples thereof include, for example, known specific examples such as 1,2-bis (anisylphenylphosphino). Ethane (DIPAMP), 1,2-bis (alkylmethylphosphino) ethane (BisP *), 2,3-bis (diphenylphosphino) butane (CHIRAPHOS), 1,2-bis (diphenylphosphino) propane (PROPHOS) ), 2,3-bis (diphenylphosphino) -5-norbornene (NORPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane (DIOP), 1-cyclohexyl-1,2-bis (diphenylphosphino) ethane (CYCPHOS), 1-substituted- , 4-bis (diphenylphosphino) pyrrolidine (DEGPHOS), 2,4-bis- (diphenylphosphino) pentane (SKEWPHOS), 1,2-bis (substituted phosphorano) benzene (DuPHOS), 1,2-bis ( Substituted phosphorano) ethane (BPE), 1-((substituted phosphorano) -2- (diphenylphosphino) benzene (UCAP-Ph), 1- (bis (3,5-dimethylphenyl) phosphino) -2- (substituted phosphorano) ) Benzene (UCAP-DM), 1-((substituted phosphorano) -2- (bis (3,5-di (t-butyl) -4-methoxyphenyl) phosphino) benzene (UCAP-DTBM), 1-(( Substituted phosphorano) -2- (di-naphthalen-1-yl-phosphino) benzene (UCAP- (1-Nap)), 2,2 ′ Bis (diphenylphosphino) -1,1′-bicyclopentane (BICP), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2,2′-bis (diphenylphosphino) ) -1,1 ′-(5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydrobinaphthyl) (H ₈ -BINAP), 2,2′-bis (di-p-) Tolylphosphino) -1,1′-binaphthyl (TOL-BINAP), 2,2′-bis (di (3,5-dimethylphenyl) phosphino) -1,1′-binaphthyl (DM-BINAP), 2,2 ′ -Bis (diphenylphosphino) -6,6'-dimethyl-1,1'-biphenyl (BICHEP), (4,4'-bi-1,3-benzodioxole) -5,5'-diylbis ( Diphenylphosphine) (SEGPHOS), (4 4′-bi-1,3-benzodioxole) -5,5′-diylbis [bis (3,5-dimethylphenyl) phosphine] (DM-SEGPHOS) or [(4S)-[4,4′- Bi-1,3-benzodioxole] -5,5′-diyl] bis [bis [3,5-bis (1,1-dimethylethyl) -4-methoxyphenyl] phosphine] (DTBM-SEGPHOS) and the like These optically active substances are mentioned.

  As the asymmetric ligand, in addition to the above-mentioned optically active bidentate phosphine ligand, a bisheterocyclic compound can also be used.

  The ligands represented by Y may be the same or different and include neutral ligands such as aromatic compounds or olefin compounds or amines.

  Examples of the aromatic compound include benzene, p-cymene, 1,3,5-trimethylbenzene (mesitylene), hexamethylbenzene and the like. Examples of the olefin compound include ethylene, 1,5-cyclooctadiene, cyclopentadiene, norbornadiene, and the like. Examples of other neutral ligands include N, N-dimethylformamide (DMF), acetonitrile, benzonitrile, acetone or chloroform.

  Examples of amines include 1,2-diphenylethylenediamine (DPEN), 1,2-diaminocyclohexane, ethylenediamine, 1,1-bis (4-methoxyphenyl) -2-isopropylethylenediamine (DAIPEN), 1,2-bis ( 4-methoxyphenyl) ethylenediamine, 1,2-dicyclohexylethylenediamine, 1,2-di (4-N, N-dimethylaminophenyl) ethylenediamine, 1,2-di (4-N, N-diethylaminophenyl) ethylenediamine, 1 , 2-di (4-N, N-dipropylaminophenyl) ethylenediamine, 1,2- (N-benzenesulfonyl) -1,2-di (4-N, N-dimethylaminophenyl) ethylenediamine, 1,2 -(Np-toluenesulfonyl) -1,2-di (4-N, N- Methylaminophenyl) ethylenediamine, 1,2- (N-methanesulfonyl) -1,2-di (4-N, N-dimethylaminophenyl) ethylenediamine, 1,2- (N-trifluoromethanesulfonyl) -1,2 -Di (4-N, N-dimethylaminophenyl) ethylenediamine, 1,2- (N-benzenesulfonyl) -1,2-di (4-N, N-diethylaminophenyl) ethylenediamine, 1,2- (N- Benzenesulfonyl) -1,2-di (4-N, N-dipropylaminophenyl) ethylenediamine, 1,2-di (4-sulfonylphenyl) ethylenediamine, 1,2-di (4-sodiumoxysulfonylphenyl) ethylenediamine 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutane Diamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di (p-methoxyphenyl) Ethylenediamine, 1-isobutyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-benzyl-2,2-di (p-methoxyphenyl) ) Ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-dinaphthylethylenediamine, 1-isopropyl-2,2-dinaphthylethylenediamine, bis [N- (2,4,6- Trimethylphenyl) methyl-1,2-diphenylethylene Diamine, N, N′-bis (phenylmethyl) -1,2-diphenyl-1,2-ethylenediamine, N, N′-bis (mesitylmethyl) -1,2-diphenyl-1,2-ethylenediamine or N, N '-Bis (naphthylmethyl) -1,2-diphenyl-1,2-ethylenediamine and other aromatic diamines and aliphatic diamines and other diamines, triethylamine and other aliphatic amines and pyridine, etc. Aromatic amines and the like.

  These amines preferably use an optically active form of the amines when performing a hydrogen transfer type asymmetric hydrogenation reaction as an asymmetric hydrogenation reaction, among which optically active aromatic diamines or optically active fats are preferred. It is more preferable to use an optically active diamine compound such as an aromatic diamine.

Examples of the halogen atom represented by X include a chlorine atom, a bromine atom or an iodine atom.
In the general formula (4), examples of the anion represented by Z include BF ₄ , ClO ₄ , OTf, NO ₃ , PF ₆ , SbF ₆ , AsF ₆ , BPh ₄ , BH ₄ , BF ₄ , Cl, Br, I, Examples include I ₃ or sulfonate. Here, Tf represents a triflate group (SO ₂ CF ₃ ), and Ph represents phenyl.

Examples of the cation represented by Z include the general formula (6).
[(R ¹⁵ ) ₂ NH ₂ ] ⁺ (6)
(In the formula, two R ^{15 s} may be the same or different and each represents a hydrogen atom or a hydrocarbon group which may have a substituent).

In the general formula (6), the hydrocarbon group which may have a substituent represented by R ¹⁵ is the same as the hydrocarbon group which may have a substituent represented by R ² and R ^3. . The hydrocarbon group which may have a preferable substituent represented by R ¹⁵ is an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group, a phenyl group or a substituent which may have a substituent. Examples thereof include a benzyl group which may have. Specific examples of the cation represented by Z include [Me ₂ NH ₂ ] ⁺ , [Et ₂ NH ₂ ] ^{+ and} [Pr ₂ NH ₂ ] ⁺ . Me, Et and Pr represent methyl, ethyl and propyl, respectively.

Below, the preferable aspect of the said transition metal complex is demonstrated.
[1] General formula (3)
M _m L _n X _p Y _q (3)
1) When M is Ir or Rh, X is Cl, Br or I. When L is a monodentate ligand, m = p = 2, n = 4, q = 0, and L is bidentate In the case of a ligand, m = n = p = 2 and q = 0.
2) When M is Ru, the following (i) to (iv) are preferable.
(I) X is Cl, Br or I, Y represents a trialkylamine, and when L is a monodentate ligand, m = 2, n = p = 4, q = 1, and L is 2 In the case of a bidentate ligand, m = n = 2, p = 4, and q = 1.
(Ii) X represents Cl, Br or I, Y represents a pyridyl group or a substituted pyridyl group, and when L is a monodentate ligand, m = 1, n = p = 2, q = 2, and L is In the case of a bidentate ligand, m = n = 1, p = 2, and q = 2.
(Iii) X is a carboxylate group. When L is a monodentate ligand, m = 1, n = p = 2, q = 0, and when L is a bidentate ligand, m = n = 1, p = 2, and q = 0.
(Iv) X is Cl, Br or I, when L is a monodentate ligand, m = p = 2, n = 4, q = 0, and when L is a bidentate ligand m = n = p = 2 and q = 0.
3) When M is Pd, the following (i) or (ii) is preferable.
(I) X is Cl, Br or I, when L is a monodentate ligand, m = 1, n = 2, p = 2, q = 0, and L is a bidentate ligand M = n = 1, p = 2, and q = 0.
(Ii) X is an allyl group, m = p = 2, n = 4, q = 0 when L is a monodentate ligand, and m = n when L is a bidentate ligand. = P = 2, q = 0.
4) When M is Ni, X is Cl, Br or I. When L is a monodentate ligand, m = 1, n = 2, p = 2, q = 0, and L is bidentate. In the case of a ligand, m = n = 1, p = 2, and q = 0.

[2] General formula (4)
[M _m L _n X _p Y _q ] Z _s (4)
1) When M is Ir or Rh, X is 1,5-cyclooctadiene or norbornadiene, Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , and m = n = p = S = 1, q = 0 or m = s = 1, n = 2, p = q = 0.
2) When M is Ru, the following (i) to (iii) are preferable.
(I) X is Cl, Br or I, Y is a neutral ligand such as an aromatic compound or olefin compound, Z is Cl, Br, I, I ₃ or sulfonate, and L is monodentate In the case of a ligand, m = p = s = q = 1, n = 2, and when L is a bidentate ligand, m = n = p = s = q = 1.
(Ii) When Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ and L is a monodentate ligand, m = 1, n = 2, p = q = 0, s = 2 When L is a bidentate ligand, m = n = 1, p = q = 0, and s = 2.
(Iii) When Z is an ammonium ion and L is a bidentate ligand, m = 2, n = 2, p = 5, and q = 0.
3) When M is Pd and Ni, Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , and when L is a monodentate ligand, m = 1, n = 2, p = Q = 0, s = 2, and when L is a bidentate ligand, m = n = 1, p = q = 0, s = 2.

  The said transition metal complex used by this invention can be manufactured using a well-known method, for example, can be obtained by making an asymmetric ligand and a transition metal complex precursor react. The transition metal complex thus obtained is subjected to post-treatment such as filtration or concentration as necessary, or isolated and / or purified after post-treatment or the like, or post-treatment or It can be used in the reduction reaction as it is without isolation and purification.

As a precursor of the transition metal complex, for example, the general formula (7)
[MX _p Y _q ] Z _s (7)
(Wherein, M, X, Y, Z, p, q and s have the same meanings as described above).

Specific examples of the precursor of the transition metal complex represented by the general formula (7) used in the present invention include a case where the transition metal represented by M in the general formula (7) is ruthenium, rhodium, and iridium. For example, [RuCl ₂ (benzene)] ₂ , [RuBr ₂ (benzene)] ₂ , [RuI ₂ (benzene)] ₂ , [RuCl ₂ (p-cymene)] ₂ , [RuBr ₂ (p-cymene) )] ₂ , [RuI ₂ (p-cymene)] ₂ , RuCl ₂ (hexamethylbenzene)] ₂ , [RuBr ₂ (hexamethylbenzene)] ₂ , [RuI ₂ (hexamethylbenzene)] ₂ , [RuCl ₂ (mesitylene)] ₂ , _{[RuBr 2 (mesitylene)] 2} , [RuI 2 (mesitylene)] 2, [RuCl 2 (pentamethylcyclopentadiene)] 2, [RuBr 2 (pentamethylcyclopentadiene)] 2, [RuI 2 (pentamethylcyclopentadiene)] 2, [RuCl 2 (co _{)] N, [RuBr 2 (} cod)] n, [RuI 2 (cod)] n, [RuCl 2 (nbd)] n, [RuBr 2 (nbd)] n, [RuI 2 (nbd)] n, RuCl _trihydrate, RuBr ₃ hydrate, RuI _{3 hydrate, [RhCl 2 (cyclopentadiene)]} 2, [RhBr 2 (cyclopentadiene)] 2, [RhI 2 (cyclopentadiene)] 2, [RhCl 2 (pentamethylcyclopentadiene) ] ₂ , [RhBr ₂ (pentamethylcyclopentadiene)] ₂ , [RhI ₂ (pentamethylcyclopentadiene)] ₂ , [RhCl ₂ (cod)] _n , [RhBr ₂ (cod)] _n , [RhI ₂ (cod)] _n , [RhCl ₂ (nbd)] _n , [RhBr ₂ (nbd)] _n , [RhI ₂ (nbd)] _n , [Rh (cod) ₂ ] SbF ₆ , RhCl ₃ hydrate, RhBr ₃ hydrate, RhI ₃ water Japanese, [IrCl ₂ (cyclo pentadiene)] ₂ , [IrBr ₂ (cyclopentadiene)] ₂ , [IrI ₂ (cyclopentadiene)] ₂ , [IrCl ₂ (pentamethylcyclopentadiene)] ₂ , [IrBr ₂ (pentamethylcyclopentadiene)] ₂ , [IrI ₂ (pentamethylcyclopentadiene) ₂ [IrCl ₂ (cod)] _n , [IrBr ₂ (cod)] _n , [IrI ₂ (cod)] _n , [IrCl ₂ (nbd)] _n , [IrBr ₂ (nbd)] _n , [IrI ₂ (nbd )] _N , IrCl ₃ hydrate, IrBr ₃ hydrate or IrI ₃ hydrate. In the above formula, n represents a positive number.

Below, the manufacturing method of the transition metal complex used by this invention is demonstrated concretely.
The symbols used in the following transition metal complex formulas are: L is an asymmetric ligand, cod is 1,5-cyclooctadiene, nbd is norbornadiene, and Tf is a triflate group. (SO ₂ CF ₃ ), Ph represents a phenyl group, and Ac represents an acetyl group. Specific examples include those using a bidentate ligand as an asymmetric ligand in order to avoid complexity.

Rhodium complex:
The rhodium complex can be produced according to the method described in “Chemical Course of 4th edition” edited by The Chemical Society of Japan, Vol. 18, Organometallic Complex, 339-344, 1991 (Maruzen). Specifically, it can be obtained by reacting bis (cycloocta-1,5-diene) rhodium (I) tetrafluoroborate with an asymmetric ligand.
Specific examples of the rhodium complex include the following.
_{[Rh (L) Cl] 2} , [Rh (L) Br] 2, [Rh (L) I] 2, [Rh (cod) (L)] BF 4, [Rh (cod) (L)] ClO 4 , [Rh (cod) (L)] PF ₆ , [Rh (cod) (L)] BPh ₄ , [Rh (cod) (L)] OTf, [Rh (nbd) (L)] BF ₄ , [Rh (Nbd) (L)] ClO ₄ , [Rh (nbd) (L)] PF ₆ , [Rh (nbd) (L)] BPh ₄ , [Rh (nbd) (L)] OTf, [Rh (L) ₂ ] ClO ₄ , [Rh (L) ₂ ] PF ₆ , [Rh (L) ₂ ] OTf, [Rh (L) ₂ ] BF ₄

Ruthenium complex:
Ruthenium complexes are described in T.W. Ikariya et al. Chem. Soc. , Chem. Commun. , 1985, 922 and the like. Specifically, it can be produced by heating and refluxing [Ru (cod) Cl ₂ ] _n and an asymmetric ligand in a toluene solvent in the presence of triethylamine.

K.K. Masima et al., J. MoI. Chem. Soc. , Chem. Commun. , 1989, 1208, the ruthenium complex can also be obtained. Specifically, it can be obtained by heating and stirring [Ru (p-cymene) I ₂ ] ₂ and an asymmetric ligand in methylene chloride and ethanol. Specific examples of the ruthenium complex include the following.
Ru (OAc) ₂ (L), Ru ₂ Cl ₄ (L) ₂ NEt ₃ , [RuCl (benzone) (L)] Cl, [RuBr (benzone) (L)] Br, [RuI (benzene) (L) ] I, [RuCl (p-cymene) (L)] Cl, [RuBr (p-cymene) (L)] Br, [RuI (p-cymene) (L)] I, [Ru (L)] (BF _{4) 2, [Ru (L} )] (ClO 4) 2, [Ru (L)] (PF 6) 2, [Ru (L)] (BPh 4) 2, [Ru (L)] (OTf) 2 , Ru (OCOCF ₃ ) ₂ (L), [{RuCl (L) ₂ } (μ-Cl) ₃ ] [Me ₂ NH ₂ ], [{RuCl (L)} ₂ (μ-Cl) ₃ ] [Et _{2 NH 2], [{RuBr} (L) 2} (μ-Cl) 3] [Me 2 NH 2], [{RuBr (L) 2} (μ-Cl) 3] [ _{t 2 NH 2], RuCl 2} (L), RuBr 2 (L), RuI 2 (L), RuCl 2 (L) (diamine), RuBr 2 (L) (diamine), RuI 2 (L) (diamine) , [{RuI (L)} ₂ (μ-I) ₃ ] [Me ₂ NH ₂ ], [{RuI (L)} ₂ (μ-I) ₃ ] [Et ₂ NH ₂ ], RuCl ₂ (L) (Pyridine), RuBr ₂ (L) (pyridine), RuI ₂ (L) (pyridine)

Iridium complex:
Iridium complexes are described in K.K. Masima et al., J. MoI. Organomet. Chem. , 1992, 428, 213 and the like. Specifically, the asymmetric ligand and [Ir (cod) (CH ₃ CN) ₂ ] BF ₄ can be obtained by stirring and reacting in tetrahydrofuran.
Specific examples of the iridium complex include the following.
_{[Ir (L) Cl] 2} , [Ir (L) Br] 2, [Ir (L) I] 2, [Ir (cod) (L)] BF 4, [Ir (cod) (L)] ClO 4 , [Ir (cod) (L)] PF ₆ , [Ir (cod) (L)] BPh ₄ , [Ir (cod) (L)] OTf, [Ir (nbd) (L)] BF ₄ , [Ir (Nbd) (L)] ClO ₄ , [Ir (nbd) (L)] PF ₆ , [Ir (nbd) (L)] BPh ₄ , [Ir (nbd) (L)] OTf

Palladium complex:
Palladium complexes are described in Y.W. Uozumi et al. Am. Chem. Soc. , 1991, 9887 and the like. Specifically, it can be obtained by reacting an asymmetric ligand with π-allyl palladium chloride.
Specific examples of the palladium complex include the following.
PdCl ₂ (L), (π-allyl) Pd (L), [(Pd (L)] BF ₄ , [(Pd (L)] ClO ₄ , [(Pd (L)) PF ₆ , [(Pd ( L)] BPh ₄ , [(Pd (L)] OTf

Nickel complex:
The nickel complex can be obtained by the method described in the Chemical Society of Japan, “Fourth Edition, Experimental Chemistry Course,” Volume 18, Organometallic Complex, page 376, 1991 (Maruzen). It can also be obtained by dissolving the asymmetric ligand and nickel chloride in a mixed solvent of 2-propanol and methanol and stirring with heating.
Specific examples of the nickel complex include the following.
NiCl ₂ (L), NiBr ₂ (L), NiI ₂ (L)

As the transition metal complex used in the production method of the present invention, a commercially available product or a product produced by a known method may be used.
The transition metal complex used in the present invention may be used in an asymmetric hydrogenation reaction as it is without being isolated or purified by mixing an asymmetric ligand and a precursor of the transition metal complex. This is a so-called in situ asymmetric hydrogenation reaction.

  The amount of the asymmetric catalyst used varies depending on the 4-amino-2-oxobutenoic acids to be used, the reaction vessel used, the type of reaction or economy, but is usually in a molar ratio with respect to the 4-amino-2-oxobutenoic acids. It is appropriately selected from the range of about 1/10 to 1 / 100,000, preferably about 1/50 to 1 / 10,000.

  When the asymmetric hydrogenation reaction is performed in the presence of hydrogen gas, the reaction can be performed under a hydrogen atmosphere, and a hydrogen gas pressure of about 0.1 MPa is sufficient. It is appropriately selected from the range of about 0.1 to 20 MPa, preferably about 0.2 to 10 MPa. In consideration of economy, it is possible to maintain high activity even at about 1 MPa or less.

  When the asymmetric hydrogenation reaction is performed in the presence of a hydrogen donating substance, examples of the hydrogen donating substance include an organic compound and / or an inorganic compound. In the reaction system, for example, hydrogen is generated by thermal action or catalytic action. Any compound that can donate can be used.

  Examples of the hydrogen-donating substance include formic acid or a salt thereof, a combination of formic acid and a base, hydroquinone, cyclohexadiene, phosphorous acid or alcohols. Among these, formic acid or a salt thereof, a combination of formic acid and a base, alcohols, and the like are particularly preferable.

  Examples of formic acid salts in formic acid or salts thereof include metal salts of formic acid such as alkali metal salts or alkaline earth metal salts of formic acid, ammonium salts, substituted amine (for example, trimethylamine) salts, and the like. Examples of the combination of formic acid and base include those in which formic acid is in the form of a formic acid salt in the reaction system, or those in which the formic acid is substantially in the form of a formic acid salt.

  These bases that form metal salts of formic acid such as alkali metal salts or alkaline earth metal salts of formic acid, ammonium salts or substituted amine salts, etc., and bases in the combination of formic acid and bases include ammonia, inorganic bases or An organic base etc. are mentioned.

  Examples of the alkali metal that forms a salt with formic acid include lithium, sodium, potassium, rubidium, and cesium. Examples of the alkaline earth metal include magnesium, calcium, strontium, and barium.

  Examples of the inorganic base include potassium carbonate, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydroxide, magnesium carbonate, calcium carbonate, and other alkali metal salts or alkaline earth metal salts, Examples thereof include metal hydrides such as sodium hydride.

  Examples of the organic base include alkali metal alkoxides such as potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide, sodium acetate , Alkali metal / alkaline earth metal acetates such as potassium acetate, magnesium acetate or calcium acetate, triethylamine, diisopropylethylamine, N, N-dimethylaniline, piperidine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [ 4.3.0] Non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, tri-n-butylamine or N-methylmorpholine , Methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, tert-butyl lithium, etc. Organic metal compounds or quaternary ammonium salts.

  As the alcohol as a hydrogen-donating substance, lower alcohols having a hydrogen atom at the α-position are preferable, and specific examples include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and the like. Among them, isopropanol is preferable.

  The amount of the hydrogen-donating substance to be used is appropriately selected from the range of usually about 0.1 to 100 equivalents, preferably about 0.5 to 20 equivalents, relative to 4-amino-2-oxobutenoic acids.

  The asymmetric hydrogenation reaction can be performed in a solvent as necessary. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as pentane, hexane, heptane and octane, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane. , Diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane, dioxolane and other ethers, methanol, ethanol, 2-propanol, n-butanol, 2-butanol, tert-butanol or Alcohols such as benzyl alcohol, polyhydric alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol or glycerin, vinegar Esters such as methyl, ethyl acetate, n-butyl acetate or methyl propionate, amides such as N, N-dimethylformamide or N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, cyano-containing organic compounds such as acetonitrile , N-methylpyrrolidone or water. These solvents may be used alone or in appropriate combination of two or more.

  The amount of the solvent used is determined by the solubility and economics of 4-amino-2-oxobutenoic acids, which are reaction substrates used. For example, when an alcohol is used as a solvent, depending on the reaction substrate used, 4-amino-2-oxobutenoic acid, an asymmetric hydrogenation reaction can be performed in a solvent-free or solvent-free state from a low concentration of about 1% or less. It can be carried out. What is necessary is just to select the usage-amount of a solvent suitably so that it may become normally about 5-50 mass% with respect to the solvent to be used, and about 10-40 mass% with respect to the solvent to use.

  The reaction temperature varies depending on the type and amount of the asymmetric catalyst used, but is suitably selected from the range of usually about 15 to 100 ° C., preferably about 20 to 80 ° C. in consideration of economy and the like. The reaction can be carried out even at a low temperature of about -30 to 0 ° C or a high temperature of about 100 to 250 ° C.

  The reaction time varies depending on the type and amount of the asymmetric catalyst used, the type and concentration of the 4-amino-2-oxobutenoic acid represented by the general formula (5) used, the reaction temperature, the reaction conditions such as the hydrogen pressure, and the like. However, the reaction is completed within a few minutes to a few hours, but it is usually selected from the range of about 1 minute to 48 hours, preferably about 10 minutes to 24 hours.

  The asymmetric hydrogenation reaction can be carried out regardless of whether the reaction mode is batch or continuous. Moreover, it can carry out in reaction containers used in this field, such as a flask, a reaction kettle, and an autoclave.

  The asymmetric hydrogenation reaction can be performed in the presence of an additive as necessary. Examples of the additive include an acid, a fluorine-containing alcohol, a base, a quaternary ammonium salt, a quaternary phosphonium salt, and a halogen.

Examples of the acid include inorganic acids, organic acids, Lewis acids, and the like.
Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tetrafluoroboric acid, perchloric acid, and periodic acid.

  Examples of organic acids include formic acid, acetic acid, valeric acid, hexanoic acid, citric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, salicylic acid, oxalic acid, succinic acid, malonic acid, phthalic acid, Examples thereof include carboxylic acids such as tartaric acid, malic acid and glycolic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid.

  Examples of Lewis acids include aluminum halides such as aluminum chloride or aluminum bromide, dialkylaluminum halides such as diethylaluminum chloride, diethylaluminum bromide or diisopropylaluminum chloride, triethoxyaluminum, triisopropoxyaluminum or tri-tert. -Trialkoxyaluminum such as butoxyaluminum, titanium halide such as titanium tetrachloride, tetraalkoxytitanium such as tetraisopropoxytitanium, boron trifluoride, boron trichloride, boron tribromide or boron trifluoride diethyl ether complex And boron halides such as zinc chloride or zinc bromide.

These acids may be used alone or in appropriate combination of two or more.
The amount of the acid used is appropriately selected from the range of usually about 0.0001 to 100 equivalents, preferably about 0.001 to 10 equivalents, relative to the unsaturated compound.

  As the fluorinated alcohol, a fluorinated aliphatic alcohol is preferred. Specific examples of the fluorinated aliphatic alcohol include saturated or unsaturated fluorinated aliphatic alcohols having 2 to 10 carbon atoms. Specific examples of the fluorine-containing aliphatic alcohol include, for example, 2,2,2-trifluoroethanol, 2,2-difluoroethanol, 3,3,3-trifluoropropanol, 2,2,3,3,3- Pentafluoropropanol, 2,2,3,3-tetrafluoropropanol, 3,3,4,4,4-pentafluorobutanol, 4,4,5,5,5-pentafluoropentanol, 5,5,6 , 6,6-pentafluorohexanol, 3,3,4,4,5,5,6,6,6-nonafluorohexanol or 1,1,1,3,3,3-hexafluoro-2-propanol Is mentioned. These fluorine-containing aliphatic alcohols may be used alone or in appropriate combination of two or more.

  The amount of the fluorinated alcohol used is appropriately selected from the range of usually about 0.01 to 100 equivalents, preferably about 0.1 to 10 equivalents, relative to the unsaturated compound.

  Examples of the base include inorganic bases and organic bases. Examples of inorganic bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, etc. Metal hydrogen carbonates, metal hydrides such as lithium hydride, sodium hydride or potassium hydride, or ammonia. Examples of the organic base include lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, potassium naphthalene. Sodium acetate, potassium acetate, magnesium acetate, calcium acetate, lithium diethylamide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diphenylphosphide, sodium diphenylphosphine Alkali metal / alkaline earth metal salts such as fido or potassium diphenylphosphide, triethylamine, diisopropylethylamine, N, N-di Tyraniline, piperidine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, tri- organic amines such as n-butylamine or N-methylmorpholine, methyllithium, ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, s-butyllithium, t-butyllithium, phenyllithium, methylmagnesium chloride, Ethylmagnesium chloride, n-propylmagnesium chloride, isopropylmagnesium chloride, n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, phenylmagnesium chloride, methylmagnesium bromide Organometallic compounds such as amide, ethylmagnesium bromide, n-propylmagnesium bromide, isopropylmagnesium bromide, n-butylmagnesium bromide, s-butylmagnesium bromide, t-butylmagnesium bromide or phenylmagnesium bromide or the above asymmetric ligands Examples of the optically active substance (optically active diamine compound) and racemic body of the diamine compound exemplified above.

  The amount of the base used is appropriately selected from the range of usually about 0 to 100 equivalents, preferably about 0 to 10 equivalents, relative to the unsaturated compound.

  Examples of the quaternary ammonium salt include quaternary ammonium salts having 4 to 24 carbon atoms. Specific examples of the quaternary ammonium salt include tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium chloride or tetrabutylammonium triphenyldifluorosilicate.

  The amount of the quaternary ammonium salt used is appropriately selected from the range of usually about 0 to 100 equivalents, preferably about 0 to 10 equivalents, relative to the asymmetric catalyst.

  Examples of the quaternary phosphonium salt include quaternary phosphonium salts having 4 to 36 carbon atoms. Specific examples of the quaternary phosphonium salt include tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium iodide, methyltriphenylphosphonium chloride, methyltriphenylphosphonium bromide, and methyltriphenylphosphonium iodide.

  The amount of the quaternary phosphonium salt to be used is appropriately selected from the range of usually about 0 to 100 equivalents, preferably about 0 to 10 equivalents, relative to the asymmetric catalyst.

Examples of the halogen include bromine and iodine.
The amount of halogen used is appropriately selected from the range of usually about 0 to 100 equivalents, preferably about 0 to 10 equivalents, relative to the unsaturated compound.

The above additives may be used alone or in combination of two or more as appropriate.
In addition, when a group bonded to a nitrogen atom, for example, a protecting group of an amino group is deprotected by the reduction reaction of the present invention, the system may be used in the system after completion of the reduction reaction or after the post treatment, if necessary. A similar group or a different group may be introduced into the amino group.

  The obtained 4-amino-2-hydroxybutyric acid or a salt thereof, particularly optically active 4-amino-2-hydroxybutyric acid or a salt thereof, may be purified by post-treatment or the like, if necessary. Specific methods for the post-treatment include means known per se, such as solvent extraction, salting out, crystallization, recrystallization, various types of chromatography and the like.

  In addition, the optically active 4-amino-2-hydroxybutyric acid obtained as described above is subjected to various operations as necessary to obtain an optical purity of the optically active 4-amino-2-hydroxybutyric acid or a salt thereof. Thus, the optical purity and / or chemical purity of 4-amino-2-hydroxybutyric acid or a salt thereof can be further improved.

Examples of various operations include crystallization, optical resolution using an optical resolution agent and microorganisms, and the like.
Crystallization may be performed by a conventional method performed in this field. When performing these operations, when an optically active 4-amino-2-hydroxybutyric acid salt or a salt thereof is used as the optically active 4-amino-2-hydroxybutyric acid salt, a salt formed as necessary is used. Desalting may be performed as free optically active 4-amino-2-hydroxybutyric acids.

  The solvent used for crystallization may be any solvent that dissolves the obtained optically active 4-amino-2-hydroxybutyric acid or a salt thereof, for example, an aromatic hydrocarbon such as benzene, toluene or xylene. , Aliphatic hydrocarbons such as pentane, hexane, heptane or octane, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or dichloroethane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran , Ethers such as dioxane or dioxolane, alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2-butanol, tert-butanol or benzyl alcohol, ethylene glycol, propylene Recall, polyhydric alcohols such as 1,2-propanediol or glycerin, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, esters such as methyl acetate, ethyl acetate, n-butyl acetate or methyl propionate, Examples include amides such as formamide, N, N-dimethylformamide or N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, cyano-containing organic compounds such as acetonitrile, N-methylpyrrolidone, water, and the like. These solvents may be used alone or in appropriate combination of two or more. Among these solvents, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols or water are preferable.

The amount of solvent used for crystallization is not particularly limited because it varies depending on the type of solvent used and the type of optically active 4-amino-2-hydroxybutyric acid or its salt, but is optically active at least below the boiling point of the solvent used. What is necessary is just to use the quantity which melt | dissolves 4-amino-2-hydroxybutyric acid or its salt, and the quantity corresponded to become a saturated solution at the temperature which optically active 4-amino-2-hydroxybutyric acid or its salt dissolves. 1 to 1.5 times the amount, preferably 1 to 1.2 times the amount, more preferably 1 to 1.1 times the range. It should be noted that the amount of solvent used is preferably as small as possible.
The crystallization temperature, that is, the temperature at which the optically active 4-amino-2-hydroxybutyric acid or its salt is dissolved in the solvent is determined depending on the type of solvent used or the optically active 4-amino-2-hydroxybutyric acid or its salt. Although it is not particularly limited because it differs depending on the etc., it may be set below the boiling point of the solvent used. Moreover, after dissolving optically active 4-amino-2-hydroxybutyric acid or its salt in a solvent, you may cool a solvent as needed. Cooling may be performed at a constant speed, continuously changed, or changed stepwise.
Crystallization may be performed by adding seed crystals as necessary.
As the seed crystal, it is preferable to use an optically active 4-amino-2-hydroxybutyric acid or a salt thereof that is usually crystallized, and an optically active substance having an optical purity of substantially 100% ee is used. Is preferred.
When seed crystals are added during crystallization, the timing of addition is not particularly limited, but the cooling operation is performed even after optically active 4-amino-2-hydroxybutyric acid or a salt thereof is dissolved in a solvent. When performing, it may be either during cooling or after cooling.
The amount of seed crystals to be added is not particularly limited because it varies depending on the type of solvent used and the optically active 4-amino-2-hydroxybutyric acid or its salt, but it may be only a small amount and is optically active 4 that dissolves in the solvent. -Amino-2-hydroxybutyric acid or a salt thereof is suitably selected from the range of 0.00001% by mass or more, preferably 0.00001-0.2% by mass, more preferably 0.0001-0.1% by mass. Is done.

Here, “improvement of optical purity” means higher optical purity (high optical purity) than the optical purity of optically active 4-amino-2-hydroxybutyric acids before crystallization obtained by the above-described production method. It can be said that the optical purity is substantially 100% ee. Note that “substantially 100% ee” means an optical purity such that the other mirror body is hardly detected with respect to one mirror body. In the present invention, when “substantially 100% ee” is specifically shown, it means an optical purity of 90% ee or higher, preferably 95% ee or higher, more preferably 96% ee or higher. The high optical purity is preferably the optical purity of the present invention, for example, the optical purity of carbon bonded to a hydroxyl group, but when R ² or R ³ represented by the general formula (1) is not hydrogen, R ² Alternatively, the optical purity of the carbon to which R ³ is bonded is also combined with the optical purity of the carbon to which the hydroxyl group is bonded in order to determine the optical purity in the present invention. More preferably, the purity is determined.

  Further, “improvement in chemical purity” means to make the chemical purity higher than the chemical purity of the optically active 4-amino-2-hydroxybutyric acid before crystallization obtained by the above-described production method. In other words, it can be said that the chemical purity is 100%. Here, “substantially 100%” means a chemical purity such that impurities such as raw materials and the other enantiomer with respect to one enantiomer are hardly detected. In the present invention, when “substantially 100%” is specifically indicated, it is 90% or more, preferably 93% or more, more preferably 95% or more, still more preferably 97% or more, and most preferably 99%. % Chemical purity.

  In addition, the present invention reduces 4-amino-2-oxobutenoic acids or salts thereof in the presence of the above-mentioned asymmetric catalyst, and optically active 4-amino-2-hydroxybutyric acids or salts thereof produced by a reduction reaction. Provided is a method for further improving the optical purity of optically active 4-amino-2-hydroxybutyric acid or a salt thereof by crystallization in a solvent.

  The 4-amino-2-hydroxybutyric acids obtained by the production method of the present invention, particularly optically active 4-amino-3-hydroxybutyric acids, are useful as intermediates for pharmaceuticals and agricultural chemicals.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
In the following examples, the apparatus used for measuring physical properties and the like is as follows.
NMR: Varian GEMINI-2000 (300 MHz)
Gas chromatography (GC): Hewlett Packard 5890-II

[Example 1]
Preparation of ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate 10 g (41.1 mmol) of ethyl-4-t-butyroxycarbonylamino-2-oxo-3-butenate, [RuCl ( R) -segphos] ₂ (μ-Cl) ₃ [Et ₂ NH ₂ ] 189 mg and 2-butanol 60 mL were mixed and reacted at 70 ° C. under a hydrogen pressure of 3 MPa. After 7 hours, after confirming disappearance of the raw material by GC, the solvent was distilled off, and crude ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate (optical purity: 79.2% ee). )

[Example 2]
Crude ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate obtained in Example 1 and toluene-heptane mixed solution [toluene: heptane = 1: 1 (v / v)] 30 mL And crystallization at 5 ° C. gave the desired ethyl-4-t-butyoxycarbonylamino-2- (R) -hydroxybutyrate (MW: 247.29, 28.4 mmol). It was. Yield: 69%, optical purity 96.9% ee.
¹ H-NMR: δ (CDCl ₃ ) 1.30 (3H, t), 1.43 (9H, s), 1.81 (1H, m), 2.01 (1H, m), 3.28 ( 2H, m), 4.23 (1H, m), 4.24 (2H, q), 4.88 (1H, br)

Example 3
Preparation of ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate 200 mg (0.8 mmol) of ethyl-4-t-butyroxycarbonylamino-2-oxo-3-butenate, Ru (p -Cymene) [(R, R) -Tsdpen] 4 mg, formic acid-triethylamine azeotrope 2 mL and tetrahydrofuran (THF) 2 mL were mixed and reacted at 30 ° C. with stirring. After confirming disappearance of the raw material by GC after 16 hours, the solvent was distilled off and the desired ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate 171 mg (MW: 247.29, 0.69 mmol) was obtained. Yield: 87%, optical purity: 66.1% ee. ^{The 1} H-NMR data was consistent with the ¹ H-NMR data of Example 1.

[Examples 4 to 10]
250 mg of ethyl-4-t-butyroxycarbonylamino-2-oxo-3-butenate, and the catalyst shown in the following Table 7 is 1 to the amount of ethyl-4-t-butyoxycarbonylamino-2-oxo-3-butenate. / 100 mol and a solution mixed with 1.5 mL of the solvent shown in Table 7 were subjected to an asymmetric hydrogenation reaction at 80 ° C. under a hydrogen pressure of 3 MPa for 7 hours. After confirming disappearance of the raw material by GC, the solvent was distilled off to obtain the desired ethyl-4-t-butyroxycarbonylamino-2-hydroxybutyrate. The results are shown in Table 7.

[Examples 11 to 14]
3 g of ethyl-4-t-butyloxycarbonylamino-2- (R) -hydroxybutyrate having an optical purity of 79.2% ee obtained by the same method as in Example 1 was used as the solvent A and the solvent shown in Table 8 below. Crystallization was performed using the mixed solution with B under the conditions shown in Table 8 below to obtain the desired ethyl-4-t-butoxycarbonylamino-2- (R) -hydroxybutyrate. The results are shown in Table 8.

  From the above results, the optical purity of ethyl-4-t-butyroxycarbonylamino-2- (R) -hydroxybutyrate was improved under any crystallization conditions.

The present invention is a method for producing 4-amino-2-hydroxybutyric acid or a salt thereof useful as an intermediate for pharmaceuticals, agricultural chemicals or the like, particularly an optically active 4-amino-2-hydroxybutyric acid or a salt thereof having high optical purity. As industrially very useful. According to the present invention, since it can be produced in one step as compared with the conventional method, the workability is improved, and the desired 4-amino-2-hydroxybutyric acid, particularly optical activity 4 having a high optical purity is obtained with high yield. -Amino-2-hydroxybutyric acids can be produced.

Claims (3)

General formula (2)

(In the formula, R ¹ is a group represented by —OR ^1a , and R ^1a represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. R ² and R ³ each independently represents a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s), R ⁴ and R ⁵ being Each independently represents a hydrogen atom or a protecting group, provided that R ¹ and R ² , R ² and R ³ , R ² and R ^5, or R ⁴ and R ⁵ may combine to form a ring. , A double bond is cis or trans.) (Wherein the substituent is a hydrocarbon group, a heterocyclic group, a halogen atom, a halogenated hydrocarbon group) ^{, -OR 1a ', -SR 1b'} , an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, alkylene Oki Group, nitro group, amino group, cyano group, sulfo group, silyl group, hydroxyl group, carboxy group, alkoxythiocarbonyl group, aryloxythiocarbonyl group, alkylthiocarbonyl group, arylthiocarbonyl group, carbamoyl group, phosphino group, aminosulfonyl A group, an alkoxysulfonyl group or an oxo group, R ^{1a ′} represents a hydrogen atom, a hydrocarbon group or a heterocyclic group, and R ^{1b ′} represents a hydrogen atom, a hydrocarbon group or a heterocyclic group). The general formula (1)

(In the formula, * represents an asymmetric carbon, and R ^{1 to} R ⁵ are as defined above. However, when R ² is a hydrogen atom, the carbon atom to which R ² is bonded is an asymmetric carbon; In addition, when R ³ is a hydrogen atom, the carbon atom to which R ³ is bonded is not an asymmetric carbon.) A process for producing an optically active 4-amino-2-hydroxybutyric acid compound .   The production method according to claim 1, wherein the reduction reaction is performed in the presence of an asymmetric catalyst. The 4-amino-2-hydroxybutyric acid compound produced | generated by the reductive reaction is crystallized in a solvent, and it acquires, The manufacturing method of Claim 1 or 2 characterized by the above-mentioned.