JPWO2018199146A1 - Catalyst for conversion of ester to amide using oxime / hydroxyamine as substrate - Google Patents

Abstract

A novel method for producing an amide compound with high stereochemical selectivity is provided. The method for producing an amide compound according to the present invention comprises reacting an amino ester compound represented by the following general formula (1) with an amino compound in the presence of a catalyst comprising a metal compound to form an ester group of the amino ester compound. An amidation step of amidating

Description

  The present invention relates to a method for producing an amide compound.

  Conventionally, amide compounds represented by peptides have been used in a wide range of fields, including pharmaceuticals, cosmetics, and functional foods, and the development of their synthetic methods has been vigorously carried out as an important research topic in synthetic chemistry. (Non-Patent Documents 1 to 6). However, there are few effective catalysts for the amidation reaction which is most important for the peptide synthesis. Therefore, the use of an equivalent amount of a reagent that generates a by-product must be used, and peptide synthesis that repeats a multi-step reaction is a very inefficient synthesis from the viewpoint of atom economy (atomic yield). The amount is enormous, and there are few effective purification means. As a result, the costs of disposing and purifying by-products account for most of the necessary costs for peptide synthesis and are one of the biggest barriers in the development of this field.

Annu. Rev .. Biophys. Biomol. Struct. , 2005, 34, 91-118. Tetrahedron, 2005, 6, 10827-10852 Chem. Rev .. , 2007, 107, 5759-5812. Chem. Rev .. , 2011, 111, 6557-6602 Org. Process Res. Dev. , 2016, 20 (2), 140-177. Chem. Rev .. , 2016, 116, 12029-12122

  In peptide synthesis using an amino acid or a derivative thereof as a raw material, it is required to perform an amidation reaction with high stereoselectivity. A highly stereoselective amidation reaction includes an enzymatic reaction in a living body. For example, in vivo, peptides are extremely highly stereoselectively synthesized by skillfully utilizing enzymes and hydrogen bonds. However, enzymatic reactions are not suitable for mass production, and when applied to synthetic chemistry, enormous financial and time costs are required.

  In synthetic chemistry, amidation reaction using a catalyst is also being studied, but in the conventional method, an amide bond is formed mainly by activating a carboxylic acid. It is difficult to synthesize peptides in a stereoselective manner. As described above, in synthetic chemistry, a method for synthesizing peptides in a highly stereoselective manner using a catalyst has not yet been put to practical use. Against this background, development of a highly stereoselective amidation reaction has been desired.

  Under such circumstances, an object of the present invention is to provide a novel method for producing an amide compound with high stereochemical selectivity.

  The present inventors have conducted intensive studies to solve the above problems. As a result, an amidation step of reacting an amino ester compound represented by the following general formula (1) with the amino compound in the presence of a catalyst comprising a metal compound to amidate the ester group of the amino ester compound is performed. It has been found that according to the novel method for producing an amide compound, the amidation reaction proceeds with high stereochemical selectivity. The present invention has been completed by further study based on such findings.

In the general formula (1), the group R ¹ is an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an alicyclic group which may have a substituent. And a heterocyclic group which may have a group or a substituent. The groups R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, and a substituent. It represents an alicyclic group which may be possessed or a heterocyclic group which may be possessed by a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ³ does not exist. The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1. The group R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an alicyclic ring which may have a substituent. It represents a formula group or a heterocyclic group which may have a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ⁴ is an electron pair.

［式（１）中、
基Ｒ¹は、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。基Ｒ²及び基Ｒ³は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。ただし、α位の炭素原子とβ位の窒素原子との結合が二重結合である場合には、基Ｒ³は存在しない。
基Ａは、置換基を有していてもよい炭素数１〜３の直鎖または分岐鎖状のアルキレン基を示す。ｐは、０または１である。
基Ｒ⁴は、水素原子、ハロゲン原子、水酸基、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。ただし、α位の炭素原子とβ位窒素原子との結合が二重結合である場合には、基Ｒ⁴は電子対である。］
項２． 前記アミド化工程の後、得られたアミド化合物において、前記一般式（１）で表されるアミノエステル化合物に由来するβ位の基Ｎ−Ｏ−Ｈをアミノ基に変換する還元工程をさらに備えている、項１に記載のアミド化合物の製造方法。
項３． 金属化合物からなる触媒の存在下に、前記一般式（１）で表されるアミノエステル化合物と、項２で得られたアミノ基を有するアミド化合物とを反応させて、前記アミノエステル化合物のエステル基をアミド化するアミド化工程をさらに備える、項２に記載のアミド化合物の製造方法。
項４． 前記一般式（１）で表される化合物が、下記一般式（１１）で表されるオキシム化合物である、項１〜３のいずれかに記載のアミド化合物の製造方法。

［式（１１）中、基Ｒ¹、基Ｒ²、及び基Ａは、それぞれ、前記一般式（１）と同じである。］
項５． 前記一般式（１）で表される化合物が、下記一般式（１２）で表されるヒドロキシアミノ化合物である、項１〜３のいずれかに記載のアミド化合物の製造方法。

［式（１２）中、基Ｒ¹、基Ｒ²、基Ｒ³、基Ｒ⁴、及び基Ａは、それぞれ、前記一般式（１）と同じである。］
項６． 前記アミノ化合物が、下記一般式（３）で表されるアミノ化合物である、項１〜５のいずれかに記載のアミド化合物の製造方法。

［基Ｒ^a及び基Ｒ^bは、それぞれ独立に、水素原子、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。また、Ｒ^aとＲ^bは、結合する窒素原子と共に飽和または不飽和の複素環を形成してもよい。該複素環基には置換基を有していてもよい。］
項７． 前記アミノ化合物が、アミノ酸もしくはその塩、又はアミノ酸エステルもしくはその塩である、項６に記載のアミド化合物の製造方法。
項８． 前記アミノエステル化合物を１００ｍｏｌ％とした場合に、前記触媒の使用量が、１２ｍｏｌ％以下である、項１〜７のいずれかに記載のアミド化合物の製造方法。
項９． アミド化反応は、塩基の存在下で行われる、項１〜８のいずれかに記載のアミド化合物の製造方法。
項１０． アミド化反応で得られるアミド化合物が、下記一般式（４）である、項１〜９のいずれかに記載のアミド化合物の製造方法。

［式（４）中、基Ｒ²、基Ｒ³、基Ｒ⁴、及び基Ａは、それぞれ、前記一般式（１）と同じであり、基Ｒ^a及び基Ｒ^bは、それぞれ独立に、水素原子、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。また、Ｒ^aとＲ^bは、結合する窒素原子と共に飽和または不飽和の複素環を形成してもよい。該複素環基には置換基を有していてもよい。］
項１１． 下記反応式に従い、酸性溶媒中において、下記一般式（２１）に示される基Ｒ⁵及び基Ｒ⁶の結合する不斉炭素原子を有するオキシム化合物のオキシム基を、立体選択的にアミノ基に変換して、下記一般式（２２）に示されるアミノ化合物を製造する方法。

［式（２１）及び（２２）中、
基Ｒ²は、ハロゲン原子、水酸基、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。
基Ａは、置換基を有していてもよい炭素数１〜３の直鎖または分岐鎖状のアルキレン基を示す。ｐは、０または１である。
基Ｒ⁵及び基Ｒ⁶は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。
基Ｒ⁷は、水酸基、基ＯＲ^7a、アミノ基、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示し、
基Ｒ^7aは、置換基を有していてもよい脂肪族基、置換基を有していてもよい芳香族基、置換基を有していてもよい脂環式基、または置換基を有していてもよい複素環式基を示す。］That is, the present invention provides the following aspects of the invention.
Item 1. An amidation step of reacting an amino ester compound represented by the following general formula (1) with an amino compound in the presence of a catalyst comprising a metal compound to amidate the ester group of the amino ester compound; A method for producing an amide compound.

[In equation (1),
The group R ¹ is an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a group which has a substituent. And a heterocyclic group which may be substituted. The groups R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, and a substituent. It represents an alicyclic group which may be possessed or a heterocyclic group which may be possessed by a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ³ does not exist.
The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1.
The group R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an alicyclic ring which may have a substituent. It represents a formula group or a heterocyclic group which may have a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ⁴ is an electron pair. ]
Item 2. After the amidation step, the obtained amide compound further includes a reduction step of converting a β-position group NOH derived from the amino ester compound represented by the general formula (1) into an amino group. Item 13. The method for producing an amide compound according to Item 1.
Item 3. The amino ester compound represented by the general formula (1) is reacted with the amide compound having an amino group obtained in item 2 in the presence of a catalyst comprising a metal compound to form an ester group of the amino ester compound. Item 3. The method for producing an amide compound according to Item 2, further comprising an amidation step of amidating.
Item 4. Item 4. The method for producing an amide compound according to any one of Items 1 to 3, wherein the compound represented by the general formula (1) is an oxime compound represented by the following general formula (11).

[In the formula (11), the group R ¹ , the group R ² , and the group A are the same as those in the general formula (1). ]
Item 5. Item 4. The method for producing an amide compound according to any one of Items 1 to 3, wherein the compound represented by the general formula (1) is a hydroxyamino compound represented by the following general formula (12).

[In the formula (12), the groups R ¹ , R ² , R ³ , R ⁴ , and A are the same as those in the general formula (1). ]
Item 6. Item 6. The method for producing an amide compound according to any one of Items 1 to 5, wherein the amino compound is an amino compound represented by the following general formula (3).

[The groups ^Ra and ^Rb each independently have a hydrogen atom, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, An alicyclic group or a heterocyclic group which may have a substituent. R ^a and R ^b may form a saturated or unsaturated heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic group may have a substituent. ]
Item 7. Item 7. The method for producing an amide compound according to Item 6, wherein the amino compound is an amino acid or a salt thereof, or an amino acid ester or a salt thereof.
Item 8. Item 10. The method for producing an amide compound according to any one of Items 1 to 7, wherein the amount of the catalyst used is 12 mol% or less when the aminoester compound is 100 mol%.
Item 9. Item 9. The method for producing an amide compound according to any one of Items 1 to 8, wherein the amidation reaction is performed in the presence of a base.
Item 10. Item 10. The method for producing an amide compound according to any one of Items 1 to 9, wherein the amide compound obtained by the amidation reaction has the following general formula (4).

[In the formula (4), the group R ² , the group R ³ , the group R ⁴ , and the group A are respectively the same as those in the general formula (1), and the groups ^Ra and ^Rb are each independently A hydrogen atom, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or Represents a heterocyclic group which may be substituted. R ^a and R ^b may form a saturated or unsaturated heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic group may have a substituent. ]
Item 11. According to the following reaction formula, the oxime group of the oxime compound having an asymmetric carbon atom to which the groups R ⁵ and R ⁶ shown in the following general formula (21) bind in an acidic solvent is stereoselectively converted to an amino group. To produce an amino compound represented by the following general formula (22).

[In the formulas (21) and (22),
The group R ² is a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, Or a heterocyclic group which may have a substituent.
The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1.
The groups R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or a substituent. It represents an alicyclic group which may be possessed or a heterocyclic group which may be possessed by a substituent.
The group R ⁷ is a hydroxyl group, a group OR ^7a , an amino group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an aliphatic group which may have a substituent. A cyclic group, or a heterocyclic group which may have a substituent,
The group R ^7a is an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a group which has a substituent. And a heterocyclic group which may be substituted. ]

  According to the present invention, it is possible to provide a novel method for producing an amide compound in a highly stereochemically selective manner.

  The method for producing an amide compound of the present invention comprises reacting an amino ester compound represented by the following general formula (1) with an amino compound in the presence of a catalyst comprising a metal compound to form an ester group of the amino ester compound. It is characterized by comprising an amidation step of amidating.

  Hereinafter, the method for producing the amide compound of the present invention will be described in detail. As described later, in the present invention, an amide bond is formed by reacting the ester group of the amino ester compound represented by the general formula (1) with the amino group of the amino compound. Thus, the amide compound of the present invention is produced.

  In the present specification, the display of “-” indicating a numerical range indicates that the numerical value is greater than or equal to the numerical value attached to the left side and equal to or less than the numerical value attached to the right side thereof. The notation means that it is X or more and Y or less.

In the amino ester compound represented by the general formula (1) (hereinafter sometimes referred to as the amino ester compound (1)), the group R ¹ is an aliphatic group which may have a substituent, It represents an aromatic group which may have a group, an alicyclic group which may have a substituent, or a heterocyclic group which may have a substituent.

Further, the groups R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, An alicyclic group which may have a group or a heterocyclic group which may have a substituent is shown. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ³ does not exist.

  The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1.

Further, the group R ⁴ may have a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, and a substituent. An alicyclic group or a heterocyclic group which may have a substituent is shown. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ⁴ is an electron pair.

Examples of the substituents (substituents of an aliphatic group, an alicyclic group, and a heterocyclic group) that the group R ¹ , the group R ² , the group R ³ , and the group R ⁴ may have include amidation of the present invention The process is not particularly limited as long as the process proceeds. For example, each independently includes, for example, an alkyl group (for example, a linear or branched alkyl group having 1 to 10 carbon atoms) and an alkenyl group (for example, 1 to 10 carbon atoms). 10 straight-chain or branched alkenyl groups), alkynyl groups (for example, straight-chain or branched-chain alkynyl groups having 1 to 10 carbon atoms), and alkoxy groups (for example, 1 to 10 carbon atoms). straight or branched alkoxy group), a hydroxyl group, a halogen atom, a nitro group, a thiol group, a cyano group, group -COOR1 (R ¹ is the same), and a phenyl group. When the aliphatic group, aromatic group, alicyclic group, or heterocyclic group in the groups R ¹ , R ² , R ³ , and R ⁴ has a substituent, the number of substituents is Is not particularly limited, but each independently includes, for example, 1 to 10, 1 to 5, 1 to 3, 1 to 2, and 1. In the case of having a plurality of substituents, one type of substituent may be used, or two or more types may be used. In addition, the aliphatic group and the aromatic group may each contain a hetero atom. The aliphatic group, alicyclic group, and heterocyclic group may be saturated or unsaturated, respectively.

Examples of the group R ¹ include an aliphatic group having 1 to 20 carbon atoms which may have a substituent, an aromatic group having 4 to 20 carbon atoms which may have a substituent, and a substituent. It is preferably an alicyclic group having 3 to 20 carbon atoms which may be substituted, or a heterocyclic group having 2 to 20 carbon atoms which may be substituted, and having a substituent. An aliphatic group having 1 to 10 carbon atoms, an aromatic group having 4 to 10 carbon atoms which may have a substituent, and 3 to 10 carbon atoms optionally having a substituent. More preferably, it is an alicyclic group or a heterocyclic group having 2 to 10 carbon atoms which may have a substituent. Specific examples of the group R ¹ include a straight-chain or branched group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group and a propargyl group. A linear alkyl group, a phenyl group, a phenylalkyl group having 1 to 10 carbon atoms in an alkyl portion such as a benzyl group or a branched alkyl group, a phenylalkyl group having 1 to 10 linear groups, And a branched alkenyl group. The substituents of the group R ¹ are as described above.

In the general formula (1), the groups R ² and R ³ bonded to the carbon atom at the α-position may each independently have a hydrogen atom, a halogen atom, a hydroxyl group, or a substituent. An aliphatic group having 1 to 20 carbon atoms, an aromatic group having 4 to 20 carbon atoms which may have a substituent, an alicyclic group having 3 to 20 carbon atoms which may have a substituent It is preferably a group or a heterocyclic group having 2 to 20 carbon atoms which may have a substituent, a group -COOR ¹ (R ¹ is the same as described above), and a hydrogen atom, a halogen atom, a hydroxyl group, An aliphatic group having 1 to 10 carbon atoms which may have a substituent, an aromatic group having 4 to 10 carbon atoms which may have a substituent, and a carbon atom which may have a substituent An alicyclic group having 3 to 10 carbon atoms or a heterocyclic group having 2 to 10 carbon atoms which may have a substituent, a group -COOR ¹ (R ¹ Is the same as described above). Specific examples of the groups R ² and R ³ each independently include a hydrogen atom, a hydroxyl group, a nitro group, a thiol group, a cyano group, and a phenyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; A linear or branched alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tert-butyl group; a carbon atom such as an ethylene group, a propylene group and a butylene group; A linear or branched alkenyl group having 1 to 10 carbon atoms; an alkynyl group having 1 to 10 carbon atoms such as a propargyl group; methoxy group, ethoxy group, propoxy group, butoxy group, sec-butoxy group, tert- A linear or branched alkoxy group having 1 to 10 carbon atoms, such as a butoxy group, a 2- (tert-butoxycarbonyl) ethyl group, a 2- (methoxycarbonyl) I) a straight-chain or branched-chain alkoxycarbonylalkyl having 1 to 10 carbon atoms, wherein the alkyl portion such as an ethyl group or a tert-butoxycarbonylmethyl group is a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms; A straight-chain or branched alkoxycarbonyl group having 1 to 10 carbon atoms, such as a tert-butoxycarbonyl group, or a straight-chain or branched alkyl group having 1 to 10 carbon atoms in an alkyl portion such as a benzyl group. And a phenylalkyl group.

The substituents of the groups R ² and R ³ are as described above. Further, as described above, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond (that is, the amino ester compound (1) is an oxime represented by the following general formula (11)) In the case of a compound), the group R ³ is not present.

In the general formula (1), the group R ⁴ bonded to the β-position nitrogen atom is a hydrogen atom, a halogen atom, a hydroxyl group, or an aliphatic group having 1 to 20 carbon atoms which may have a substituent. Group, an aromatic group having 4 to 20 carbon atoms which may have a substituent, an alicyclic group having 3 to 20 carbon atoms which may have a substituent, or having a substituent Is preferably a heterocyclic group having 2 to 20 carbon atoms, a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group having 1 to 10 carbon atoms which may have a substituent, An aromatic group having 4 to 10 carbon atoms which may have a group, an alicyclic group having 3 to 10 carbon atoms which may have a substituent, or a substituent More preferably, it is a heterocyclic group having 2 to 10 carbon atoms. Specific examples of the group R ^4, a hydrogen atom, a hydroxyl group, a benzyl group, a phenyl group; a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as iodine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group A linear or branched alkyl group having 1 to 10 carbon atoms, such as an alkyl group; a linear or branched alkenyl group having 1 to 10 carbon atoms, such as an ethylene group, a propylene group, or a butylene group; a propargyl group A linear or branched alkynyl group having 1 to 10 carbon atoms such as methoxy group, ethoxy group, propoxy group, butoxy group, sec-butoxy group, tert-butoxy group; A linear or branched alkoxy group may, for example, be mentioned.

The substituents of the group R ⁴ are as described above. As described above, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond (that is, the amino ester compound (1) is an oxime compound represented by the following general formula (11)) ), The group R ⁴ is an electron pair.

In the group A, examples of the linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent include a methylene group, an ethylene group, and a propylene group. The substituent is the same as the substituent exemplified for the groups R ¹ , R ² , R ³ and R ⁴ .

  In the present invention, the amino ester compound (1) may be subjected to the amidation step in the form of a salt such as a hydrochloride.

  In the amino ester compound represented by the general formula (1), when the bond between the α-position carbon atom and the β-position nitrogen atom is a double bond, the amino ester compound is represented by the following general formula (11). Is an oxime compound.

In the general formula (11), the groups R ¹ , R ² , and A are the same as those in the general formula (1).

  In the amino ester compound (1), when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a single bond, the amino ester compound (1) is a hydroxyamino compound represented by the following general formula (12). Compound.

In the general formula (12), the groups R ¹ , R ² , R ³ , R ⁴ , and A are the same as those in the general formula (1).

  In the present invention, the amino compound is not particularly limited as long as it can react with the amino ester compound (1) to form an amide group. Amines and secondary amines are preferred.

  When a preferred amino compound is represented by the general formula, for example, it can be represented by the following general formula (3).

In the amino compound represented by the general formula (3) (hereinafter sometimes referred to as amino compound (3)), the groups ^Ra and ^Rb each independently have a hydrogen atom or a substituent. It represents a good aliphatic group, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a heterocyclic group which may have a substituent. R ^a and R ^b may form a saturated or unsaturated heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic group may have a substituent.

Examples of the substituent in the heterocyclic ring formed together with the group R ^a and radicals R ^b and bonded to the nitrogen atom is not particularly limited as long as it reacts with the amino ester compound (1) can form an amide group, each independently For example, an alkyl group (for example, a linear or branched alkyl group having 1 to 10 carbon atoms), an alkenyl group (for example, a linear or branched alkenyl group having 1 to 10 carbon atoms) ), An alkynyl group (for example, a linear or branched alkynyl group having 1 to 10 carbon atoms), an alkoxy group (for example, a linear or branched alkoxy group having 1 to 10 carbon atoms), Hydroxyl group, halogen atom, nitro group, thiol group, cyano group, linear or branched alkyl mercapto group having 1 to 10 carbon atoms, linear or branched chain having 1 to 10 carbon atoms in the alkyl group portion Alkyl A phenylalkyl group which is a group, a phenylalkoxycarbonyl group which is a linear or branched alkoxy group having 1 to 10 carbon atoms in an alkoxy group portion, and a straight or branched chain having 1 to 10 carbon atoms in an alkyl group portion. A phenylalkylmercapto group which is a branched alkyl group, an amino group which may have a substituent, an amide group which may have a substituent, a guanidinyl group which may have a substituent, —COOR ¹ (R ¹ is as defined above), an aryl group which may have a substituent, a heterocyclic group which may have a substituent, and the like. (Here, an amino group which may have a substituent, an amide group which may have a substituent, a guanidinyl group which may have a substituent, and an aryl which may have a substituent group, substituent of the heterocyclic group which may have a substituent, wherein the same to the definition of the group R ^a and radicals R ^b. the aryl group, as. heterocyclic group and a phenyl group Represents an indolyl group, an imidazolyl group, or the like.) In addition, an aliphatic group, an aromatic group, an alicyclic group, or a heterocyclic group in the ring structure formed by connecting the groups R ^a and R ^b and When it has a substituent, the number of substituents is not particularly limited, but for example, each independently includes, for example, 1 to 10, 1 to 5, 1 to 3, 1 to 2, and 1. In the case of having a plurality of substituents, one type of substituent may be used, or two or more types may be used. In addition, the aliphatic group and the aromatic group may each contain a hetero atom. The aliphatic group, alicyclic group, and heterocyclic group may be saturated or unsaturated, respectively.

The group R ^a and the group R ^b of the amino compound (3) each independently represent a hydrogen atom, an aliphatic group having 1 to 20 carbon atoms which may have a substituent or a substituent. An aromatic group having 4 to 20 carbon atoms, an alicyclic group having 3 to 20 carbon atoms which may have a substituent, or 2 to 20 carbon atoms which may have a substituent It is preferably a heterocyclic group, a hydrogen atom, an aliphatic group having 1 to 10 carbon atoms which may have a substituent, and an aromatic group having 4 to 10 carbon atoms which may have a substituent. A group, an alicyclic group having 3 to 10 carbon atoms which may have a substituent, or a heterocyclic group having 2 to 10 carbon atoms which may have a substituent is preferable. . However, the case where both the group ^Ra and the group ^Rb are hydrogen atoms (that is, the case where the amino compound (3) is ammonia) is not preferable because it has a low boiling point. The substituents of the groups ^Ra and ^Rb are as described above.

Specific examples of the saturated or unsaturated heterocyclic ring formed together with the nitrogen atom to which R ^a and R ^b are bonded include pyrrolinyl, pyrrolyl, 2,3-dihydro-1H-pyrrolyl, piperidinyl, piperazinyl, homopiperazinyl, morpholino , Thiomorpholino, 1,2,4,6-tetrahydropyridyl, hexahydropyrimidyl, hexahydropyridazyl, 1,2,4,6-tetrahydropyridyl, 1,2,4,6-tetrahydropyridyl , 3,4-dihydropyridyl, imidazolyl, 4,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H-imidazolyl, pyrazolyl, 4,5-dihydro-1H-pyrazolyl, 2,3-dihydro-1H- Pyrazolyl, oxazolyl, 4,5-dihydro-1,3-oxazolyl, 2,3-dihydro-1,3-oxazo Ryl, 2,5-dihydro-1,3-oxazolyl, thiazolyl, 4,5-dihydro-1,3-thiazolyl, 2,3-dihydro-1,3-thiazolyl, 2,5-dihydro-1,3- Examples thereof include a 5- or 6-membered saturated or unsaturated heterocyclic group such as thiazolyl.

  In the present invention, the amino compound is particularly preferably an amino acid or a salt thereof, or an amino acid ester or a salt thereof. The method for producing an amide compound of the present invention can produce an amide compound with high stereochemical selectivity. Therefore, the amino ester compound (1) and an amino acid or a salt thereof, or an amino acid ester or a salt thereof having an asymmetric center are provided. By reacting with a salt, a peptide can be synthesized with high stereochemical selectivity. The amino compound (3) includes an amino acid or a salt thereof, or an amino acid ester or a salt thereof.

  The amino acid is not particularly limited and is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, Known amino acids such as multimers of amino acids containing at least one of these (usually dimers to decamers) are exemplified. Further, as esters of amino acids, the carboxyl group of these amino acids may be a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, such as a propargyl group. Those esterified with a chain alkynyl group, an aryl group, or the like can be given. Examples of the salts of amino acids or salts of amino acid esters include hydrochlorides, sulfates, oxalates, and phosphates of these amino acids or amino acid esters, respectively.

  In the method for producing an amide compound of the present invention, for example, the reaction between the amino ester compound (1) and the amino compound (3) can be represented by the following reaction formula. In the present invention, the amide compound (4) can be suitably produced by the following reaction.

  The molar ratio between the amino ester compound (1) and the amino compound in the method for producing an amide compound of the present invention is not particularly limited, but the molar ratio of the amino compound is 0.1 mol to 1 mol per 1 mol of the amino ester compound (1). About 10 mol, preferably about 0.1 mol to 5 mol, about 1 mol to 10 mol, and about 1 mol to 5 mol may be used.

  However, after the amidation step, in the obtained amide compound (for example, the compound represented by the general formula (4)), the group N at the β-position derived from the aminoester compound represented by the general formula (1) An amino compound is produced through a reduction step of converting —O—H into an amino group, and the amino compound is reacted with the amino ester compound (1) to produce a dipeptide. When an oligopeptide is produced by forming a peptide bond of the above, it is more cost-effective to use an amino ester compound in excess of the amino compound used in the reaction. That is, in the present invention, the amino ester compound (1) can be used as an amino acid unit sequentially bonded to the amino compound, and the amino ester compound (1) (oxime compound or hydroxyamino compound) derived from an amino acid is It can be prepared relatively inexpensively.

  In the method for producing an amide compound of the present invention, the metal compound used as a catalyst is not particularly limited as long as it can promote the amidation step of amidating the ester group of the aminoester compound. As the metal compound, a metal compound that functions as a Lewis acid is preferable.

  Examples of the metal constituting the metal compound include a wide range of metals located in Groups 2 to 15 of the Periodic Table of the Elements. Specific examples of the metal constituting the metal compound include boron, magnesium, aluminum, gallium, indium, silicon, calcium, lead, bismuth, and mercury, as well as transition metals and lanthanoy elements. Specific examples of transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, Examples include tantalum, tungsten, rhenium, osmium, iridium, platinum, gold and the like. In addition, specific examples of the lanthanoid element include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium, and the like. Among them, tantalum, boron, vanadium, tungsten, hafnium, niobium, neodymium, iron, lead, cobalt, copper, silver exhibit a superior reaction promoting effect and produce an amide compound in a highly stereochemically selective manner. And palladium are particularly preferred.

  The catalyst may contain one of these metal compounds alone, or may contain two or more thereof.

  Particularly, when the amino ester compound (1) is an oxime compound (11), from the viewpoint of exhibiting an excellent reaction promoting effect and producing an amide compound with high stereochemical selectivity, among these, a tantalum compound, The catalyst preferably contains at least one metal compound of a niobium compound, a vanadium compound, a tungsten compound, a hafnium compound, a neodymium compound, an iron compound, a lead compound, a cobalt compound, and a copper compound, and at least one of a tantalum compound and a niobium compound. More preferably, one is included in the catalyst.

  The ligand of the metal compound is appropriately selected according to the type of the metal. Specific examples of the ligand include a linear or branched alkoxy group having 1 to 10 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a fluorine atom, a chlorine atom, a bromine atom and an iodine. A halogen atom such as an atom; an alloxy group having 1 to 10 carbon atoms, an acetylacetonate group (acac), an acetoxy group (AcO), a trifluoromethanesulfonate group (TfO), and a straight or branched chain having 1 to 10 carbon atoms. Examples include a branched alkyl group, a phenyl group, an oxygen atom, a sulfur atom, a group: -SR, a group: -NRR ', and a cyclopentadienyl (Cp) group. R in the group: -SR is an alkyl group, an alkenyl group, an aryl group, or the like, having about 1 to 10 carbon atoms in a straight or branched chain. R and R 'of the group: -NRR' are each independently a hydrogen atom, a linear or branched alkyl group, alkenyl group, aryl group or the like having about 1 to 10 carbon atoms.

For example, specific examples of preferred tantalum compound, TaX ¹ ₅ (where 5 X ¹ is independently a exemplified ligands above. Usually, five X ¹ is the same group) at The tantalum compound represented is mentioned. As the alkoxy group for X ¹ , preferably a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, further preferably A linear or branched alkoxy group having 1 to 3 carbon atoms is exemplified. The aryloxy group is preferably an allyloxy group having 1 to 20 carbon atoms, more preferably an allyloxy group having 1 to 15 carbon atoms, and further preferably an allyloxy group having 1 to 10 carbon atoms. The halogen atom preferably includes a chlorine atom and a bromine atom. Among them, a tantalum alkoxide compound (for example, X ¹ is an alkoxy group) is preferable, and for example, Ta (OMe) ₅ , Ta (OEt) ₅ , Ta (OBu) ₅ , Ta (NMe ₂ ) ₅ , Ta ( Acac) (OEt) ₄ , TaCl ₅ , TaBr ₅ , TaCl ₄ (THF), Ta (OCH ₂ CCH) _{5 and the} like are preferable.

Specific examples of preferred niobium compound, NBX ² ₅ (provided that the five X ² are each independently a a exemplified ligands in. Usually, five X ² are the same group) at The niobium compounds represented are mentioned. As the alkoxy group for X ² , preferably a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, still more preferably A linear or branched alkoxy group having 1 to 3 carbon atoms is exemplified. The aryloxy group is preferably an allyloxy group having 1 to 20 carbon atoms, more preferably an allyloxy group having 1 to 15 carbon atoms, and further preferably an allyloxy group having 1 to 10 carbon atoms. The halogen atom preferably includes a chlorine atom and a bromine atom. Among these, a niobium alkoxide compound (for example, X ² is an alkoxy group) is preferable, and for example, NbCl ₅ , NbCl ₄ (THF), Nb (OEt) _{5 and the} like are preferable.

Specific examples of preferred vanadium compounds, VX ³ ₃ (provided that three X ³ are each independently exemplified ligands above. Usually, three X ³ are the same group), A vanadium compound represented by VO (X ⁴ ) ₅ (provided that five X ^{4 s} are each independently the ligands exemplified above; usually, five X ^{4 s} are the same group). For example, VO (OEt) ₅ is preferable.

Specific examples of preferred hafnium compound, for example, HFX ⁵ ₄ (four X ⁵ are each independently, said a exemplified ligands in. Usually, a four X ⁵ are the same group.) A hafnium compound represented by The alkoxy group for X ⁵ is preferably a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, and still more preferably. A linear or branched alkoxy group having 1 to 4 carbon atoms is exemplified. The aryloxy group is preferably an allyloxy group having 1 to 20 carbon atoms, more preferably an allyloxy group having 1 to 15 carbon atoms, and further preferably an allyloxy group having 1 to 10 carbon atoms. The halogen atom preferably includes a chlorine atom and a bromine atom. Among these, a hafnium alkoxide compound (for example, X ⁵ is an alkoxy group) is preferable, and for example, Hf (OEt) ₄ is preferable.

Specific examples of preferred tungsten compounds, for example, WX ⁶ ₆ (6 X ⁶ are each independently, said a exemplified ligands in. Usually, six X ⁶ are the same group.) And a tungsten compound represented by the following formula: As the alkoxy group for X ⁶ , preferably a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, still more preferably A linear or branched alkoxy group having 1 to 4 carbon atoms is exemplified. The aryloxy group is preferably an allyloxy group having 1 to 20 carbon atoms, more preferably an allyloxy group having 1 to 15 carbon atoms, and further preferably an allyloxy group having 1 to 10 carbon atoms. The halogen atom preferably includes a chlorine atom and a bromine atom. Among these, a tungsten alkoxide compound (for example, X ⁶ is an alkoxy group) is preferable, and for example, W (OEt) ₆ is preferable.

Further, specific examples of preferable neodymium compounds include, for example, NdX ⁷ ₅ (5 X ⁷ are each independently a ligand exemplified above. Usually, 5 X ⁷ are the same group). And a tungsten compound represented by the following formula: The alkoxy group represented by X ⁷ is preferably a straight-chain or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms, and still more preferably. A linear or branched alkoxy group having 1 to 4 carbon atoms is exemplified. The aryloxy group is preferably an allyloxy group having 1 to 20 carbon atoms, more preferably an allyloxy group having 1 to 15 carbon atoms, and further preferably an allyloxy group having 1 to 10 carbon atoms. The halogen atom preferably includes a chlorine atom and a bromine atom. Among these, a neodymium alkoxide compound (for example, X ⁷ is an alkoxy group) is preferable, and for example, Nd (OEt) ₅ is preferable.

Specific examples of preferred iron compound, FeX ⁸ ₂ (provided that the two X ⁸ are each independently exemplified ligands above. Usually, the two X ⁸ are the same group), An iron compound represented by FeX ⁹ ₃ (however, three X ⁹ are each independently the ligand exemplified above; usually, three X ⁹ are the same group). Among these, for example, Fe (OAc) ₂ , Fe (OTf) ₂ , and Fe (OTf) ₃ are preferable.

Specific examples of preferred lead compounds include PbX ¹⁰ ₂ (however, two X ¹⁰ are each independently the ligands exemplified above. Usually, two X ¹⁰ are the same group), A lead compound represented by PbX ¹¹ ₄ (however, four X ¹¹ are each independently the ligands exemplified above; usually, four X ¹¹ are the same group). Among them, for example, Pb (OTf) ₂ and Pb (OAc) ₄ are preferable.

Specific examples of preferred copper compound, CuX ¹² ₂ (provided that the two X ¹² independently wherein an exemplified ligands in. Usually, the two X ¹² are the same group), A copper compound represented by CuX ¹³ (where X ¹³ is a ligand exemplified above) is exemplified. Among these, for example, Cu (Et) ₂ , Cu (OAc) ₂ , Cu (acac) ₂ , CuO, CuOAc, CuS and the like are preferable.

Specific examples of preferred cobalt compounds, CoX ¹⁴ ₂ (provided that the two X ¹⁴ is independently a exemplified ligands above. Usually, the two X ¹⁴ are the same group), A copper compound represented by CoX ¹⁵ ₃ (where X ¹⁵ is the ligand exemplified above, usually three X ¹⁵ are the same group) is exemplified. Among them, for example, CoCl ² and CoBr ₂ are preferable.

Specific examples of preferred palladium compound, PdX ¹⁵ ₂ (provided that the two X ¹⁵ independently is a exemplified ligands above. Usually, two X ¹⁵ are the same groups) with The palladium compound represented is mentioned. Among them, for example, Pd (OAc) ₂ is preferable.

In addition, specific examples of the metal compound include AgOAc, Pd (OAc) ₂ , Pd (OCOCCF ₃ ) ₂ , Mg (OAc) ₂ , Mg (OTf) ₂ , AlCl ₃ , Ca (OTf) ₂ , Sc (OTf) _{3, In (OTf) 3,} La (OTf) 3, CeCl 3, Gd (OTf) 3, Sm (OTf) 3, Ho (OTf) 3, Er (OTf) 3, Tm (OTf) 3, Bi (OTf ) ₃ , BF ₃ SMe ₂ , Ti (OBu) ₄ , TiCl ₂ (Oi-Pr) ₂ , Fe (OTf) ₂ , ZrCl ₄ , Zr (OEt) ₄ , Sn (OAc) ₂ , SbCl ₃ , SbF ₃ , Sb (OMe) ₃ , Sm (Oi-Pr) _{3 and the} like.

Further, when the amino ester compound (1) is a hydroxyamino compound (12), a metal compound used as a catalyst exhibits a particularly excellent reaction promoting effect, and from the viewpoint of producing an amide compound with high stereochemical selectivity. Is preferably a boron compound. Specific examples of preferred boron _{compounds, 3,4,5-F 3 C 6 H} 2 B (OH) 2, 3,5- (CF 3) 2 C 6 H 3 B (OH) 2, 4- (CF _{3) C 6 H 4 B (} OH) 2, 3-NO 2 C 6 H 4 B (OH) 2, 4-NO 2 C 6 H 4 B (OH) 2, 2-IC 6 H 4 B (OH) ₂ , aromatic boric acid compounds such as PhB (OH) ₂ and dichlorophenylborane (PhBCl ₂ ).

  The catalyst may be supported on a carrier. The carrier for supporting the catalyst is not particularly limited, and a known carrier can be used. In addition, as a method of supporting the catalyst on the carrier, a known method can be adopted.

  The use amount of the catalyst is not particularly limited, but is preferably 20 mol% or less, more preferably about 0.1 mol% to 10 mol%, when the aminoester compound (1) is 100 mol%.

The method for producing an amide compound of the present invention may be performed in the presence of a base from the viewpoint of increasing the reaction efficiency. The base is not particularly limited, for example, triethylamine (Et ₃ N), diisopropylamine (i-Pr ₂ NH), straight-chain or branched having 1 to 10 carbon atoms, such as diisopropylethylamine (i-Pr ₂ EtN) Examples thereof include amines having 1 to 3 chain alkyl groups.

  The amount of the base used is not particularly limited, but is preferably about 20 to 120 mol%, more preferably about 50 to 100 mol%, when the amount of the amino ester compound (1) is 100 mol%.

The method for producing an amide compound of the present invention may be performed in an organic solvent from the viewpoint of increasing the reaction efficiency. The organic solvent is not particularly restricted but includes, for example, aromatic hydrocarbons such as toluene and xylene, pentane, petroleum ether, 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr ₂ O), diethyl ether (Et ₂ O), ethers such as cyclopentyl methyl ether (CPME), and esters such as ethyl acetate (AcOEt). One organic solvent may be used alone, or two or more organic solvents may be used in combination. The concentration of the amino ester compound (1) in the reaction system is not particularly limited, but is preferably 2% by volume to 70% by volume from the viewpoint of increasing the reaction efficiency.

  The reaction temperature in the method for producing an amide compound of the present invention is not particularly limited, but is preferably about 0 ° C to 150 ° C from the viewpoint of increasing the reaction efficiency. The reaction time is not particularly limited, but may be, for example, about 10 minutes to 50 hours.

  The method for producing the amide compound of the present invention can be carried out under normal pressure, under reduced pressure, or under increased pressure. From the viewpoint of performing the reaction simply, it may be carried out under normal pressure. The production of the amide compound is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.

  Thus, the amide compound is suitably produced by the production method of the present invention.

  The amide compound produced by the method for producing an amide compound of the present invention can be purified according to a conventional method, isolated and used for various purposes.

  Further, in the method for producing an amide compound of the present invention, after the above-mentioned amidation step, in the obtained amide compound, the β-group NOH derived from the aminoester compound (1) is converted to an amino group. A reduction step for converting may be further provided. By the reduction step, an amino group can be introduced into the amide compound.

  Further, using an amide compound having an amino group introduced in the reduction step (that is, an amide compound having an amino group), the amino ester compound (1) and the amino group are reacted in the presence of the catalyst comprising the metal compound described above. The amidation step of amidating the ester group of the amino ester compound (1) by reacting the amide compound with the amide compound can be performed.

  As described above, in the present invention, the structure of the amino ester compound (1) to be repeatedly added is variously selected and the amidation step is performed, whereby the amino compound having the desired structure is linked by a peptide bond. Can be synthesized to produce a desired oligopeptide with high stereochemical selectivity.

  In the reduction step of converting the group N—O—H into an amino group, the reduction method is not particularly limited, and a known reduction method can be employed. For example, when the amino ester compound (1) is the oxime compound (11), a method of reducing with the use of a reduction catalyst in the presence of hydrogen gas may be mentioned. Examples of the reduction catalyst include metal catalysts such as palladium, palladium hydroxide-carbon, palladium oxide, platinum oxide, platinum-carbon, Rh-carbon, and iridium black. Similarly, when the amino ester compound (1) is a hydroxyamino compound (12), a method of reducing the compound using a metal catalyst such as palladium as a reducing catalyst in the presence of hydrogen gas may be used. Further, when the amino ester compound (1) is an oxime compound (11), the oxime group can be stereoselectively converted to an amino group as described below.

In the present invention, an oxime compound having an asymmetric carbon atom to which groups R ⁵ and R ⁶ represented by the following general formula (21) are bonded in an acidic solvent according to the following reaction formula (hereinafter referred to as oxime compound (21)) The oxime group of the formula (1) may be stereoselectively converted to an amino group to produce an amino compound represented by the following general formula (22) (hereinafter sometimes referred to as amino compound (22)). Can be provided. The obtained amino compound (22) can also be used as an amino compound to be reacted with the amino ester compound (1) in the method for producing an amide compound of the present invention.

  In the present invention, since the reduction reaction can be carried out in an acidic solvent according to the above reaction formula, even when the solubility of the oxime compound to be subjected to the reduction in a solvent (a common organic solvent such as alcohol) is low, the acidic For those highly soluble in the solvent, the reduction reaction can be favorably advanced. In addition, since the acidic solvent generally has a high boiling point, the reaction can be performed in a high-temperature environment. Further, after the completion of the reduction reaction, if the reaction solution is mixed with water, the product is precipitated, which facilitates purification.

The acidic solvent is not particularly limited as long as the reduction reaction can proceed in an acidic environment, and examples thereof include a mineral acid such as hydrochloric acid, a solvent containing an organic acid having a carboxy group, and a solvent containing an organic acid having a carboxy group. And the like. Specific examples of preferred acidic solvents include organic acids such as hydrochloric acid, acetic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, and pivalic acid. The acidic solvent may be used alone or as a mixture of two or more.
The reduction reaction includes D-tartaric acid, D, L-tartaric acid, L-tartaric acid, D-lactic acid, D, L-lactic acid, L-lactic acid, D-mandelic acid, D, L-mandelic acid, L-mandelic acid And the like may be used as additives. The additive is preferably used in an amount of about 0.1 to 10 equivalents to the compound to be reduced.

Further, another organic solvent may be contained in the acidic solvent. Other organic solvents include lower alcohols such as methanol and ethanol, esters such as ethyl acetate, petroleum ether, 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr ₂ O), and diethyl ether (Et). ₂ O), and the like ethers such as cyclopentyl methyl ether (CPME). One organic solvent may be used alone, or two or more organic solvents may be used in combination.

  In the reduction reaction, as described above, a metal catalyst such as palladium, palladium hydroxide-carbon, palladium oxide, platinum oxide, platinum-carbon, Rh-carbon, or iridium black is used as a reduction catalyst in the presence of hydrogen gas. Can be used.

In the reduction reaction, the steric structure of the asymmetric carbon atom to which the groups R ⁵ and R ⁶ of the oxime compound (21) are bonded changes to the steric structure of the carbon atom at the α-position during the reduction of the oxime group. Affected, and an amino group can be introduced stereoselectively at the α-position. Further, in the reduction step, by using an asymmetric catalyst as the reduction catalyst, the three-dimensional structure of the asymmetric carbon atom at the α-position together with the three-dimensional structure of the asymmetric carbon atom to which the groups R ⁵ and R ⁶ are bonded. Can also be controlled. For example, when the asymmetric carbon atom to which the groups R ⁵ and R ⁶ are bonded is an R-form, an amino group can be introduced with the α-position carbon atom as an R-form or an S-form. Similarly, when the asymmetric carbon atom to which the groups R ⁵ and R ⁶ are bonded is an S-form, an amino group can be introduced with the α-position carbon atom as the R-form or the S-form. As the asymmetric catalyst used for reduction with hydrogen, known catalysts can be easily obtained.

In the general formulas (21) and (22), the group R ² and the group A are the same as those in the general formula (1).

Further, the groups R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, An alicyclic group which may have a group or a heterocyclic group which may have a substituent is shown.

Further, the group R ⁷ is a hydroxyl group, a group OR ^7a , an amino group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or a group which has a substituent. A good alicyclic group or a heterocyclic group which may have a substituent, and the group R ^7a is an aliphatic group which may have a substituent or may have a substituent; It represents an aromatic group, an alicyclic group which may have a substituent, or a heterocyclic group which may have a substituent.

The substituents (substituents of an aliphatic group, an alicyclic group, and a heterocyclic group) that the groups R ⁵ , R ⁶ , and R ⁷ may have are not particularly limited as long as the reduction reaction proceeds. Independently, for example, an alkyl group (for example, a linear or branched alkyl group having 1 to 10 carbon atoms) and an alkenyl group (for example, a linear or branched chain group having 1 to 10 carbon atoms) Alkenyl group), an alkynyl group (for example, a linear or branched alkynyl group having 1 to 10 carbon atoms), an alkoxy group (for example, a linear or branched chain having 1 to 10 carbon atoms) An alkoxy group), a hydroxyl group, a halogen atom, a nitro group, a thiol group, a cyano group, a phenylalkyl group which is a straight-chain or branched alkyl group having 1 to 10 carbon atoms in the alkyl group portion, and having 1 to 1 carbon atoms. 10 linear or branched alkyl mercapto groups, A phenylalkoxycarbonyl group, which is a linear or branched alkoxy group having 1 to 10 carbon atoms in a alkoxy group portion, a linear or branched alkyl group having 1 to 10 carbon atoms in an alkyl group portion; A phenylalkyl mercapto group, an amino group which may have a substituent, an amide group which may have a substituent, a guanidinyl group which may have a substituent, a group -COOR ¹ (R ¹ is The same applies to the above), an aryl group which may have a substituent, a heterocyclic group which may have a substituent, and the like. (Here, an amino group which may have a substituent, an amide group which may have a substituent, a guanidinyl group which may have a substituent, and an aryl which may have a substituent The substituents in the group and the heterocyclic group which may have a substituent are the same as the definitions of the groups R ⁵ , R ⁶ and the group R ^7. Examples of the aryl group include a phenyl group. Examples of the cyclic group include an indolyl group and an imidazolyl group.) Further, the aliphatic group, the aromatic group, the alicyclic group, or the heterocyclic group in the groups R ⁵ , R ⁶ , and R ⁷ is When it has a substituent, the number of substituents is not particularly limited, but for example, each independently includes, for example, 1 to 10, 1 to 5, 1 to 3, 1 to 2, and 1. In the case of having a plurality of substituents, one type of substituent may be used, or two or more types may be used. In addition, the aliphatic group and the aromatic group may each contain a hetero atom. The aliphatic group, alicyclic group, and heterocyclic group may be saturated or unsaturated, respectively.

As the groups R ⁵ and R ⁶ , each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group having 1 to 20 carbon atoms which may have a substituent or a substituent. An aromatic group having 4 to 20 carbon atoms, an alicyclic group having 3 to 20 carbon atoms which may have a substituent, or 2 to 20 carbon atoms which may have a substituent It is preferably a heterocyclic group, a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group having 1 to 10 carbon atoms which may have a substituent, and a carbon number which may have a substituent. An aromatic group having 4 to 10 carbon atoms, an alicyclic group having 3 to 10 carbon atoms which may have a substituent, or a heterocyclic group having 2 to 10 carbon atoms which may have a substituent Is more preferable. Specific examples of the group R ⁵ and the group R ⁶ each independently include a hydrogen atom, a hydroxyl group, a nitro group, a thiol group, a cyano group, and a phenyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; A linear or branched alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group; a carbon atom having 1 to 10 carbon atoms such as an ethylene group, a propylene group or a butylene group; A linear or branched alkenyl group having 1 to 10 carbon atoms such as a propargyl group; a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a sec-butoxy group And a tert-butoxy group, such as a linear or branched alkoxy group having 1 to 10 carbon atoms.

Examples of the group R ⁷ include a hydroxyl group, a group OR ^7a , an amino group, an aliphatic group having 1 to 20 carbon atoms which may have a substituent, and an aliphatic group having 4 to 20 carbon atoms which may have a substituent. An aromatic group, an alicyclic group having 3 to 20 carbon atoms which may have a substituent, or a heterocyclic group having 2 to 20 carbon atoms which may have a substituent Is preferably a hydroxyl group, a group OR ^7a , an amino group, an aliphatic group having 1 to 10 carbon atoms which may have a substituent, and an aromatic group having 4 to 10 carbon atoms which may have a substituent. It is more preferable that the group is an alicyclic group having 3 to 10 carbon atoms which may have a substituent or a heterocyclic group having 2 to 10 carbon atoms which may have a substituent. .

^Examples of R ^{7a in the} group OR ^7a include a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group, and a phenyl group.

Specific examples of the group R ⁷ include, independently of each other, a hydroxyl group, an amino group, a phenyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. A linear or branched alkyl group having 1 to 10 carbon atoms such as a group; a linear or branched alkenyl group having 1 to 10 carbon atoms such as an ethylene group, a propylene group or a butylene group; a propargyl group A linear or branched alkynyl group having 1 to 10 carbon atoms such as methoxy group, ethoxy group, propoxy group, butoxy group, sec-butoxy group, tert-butoxy group; A straight-chain or branched alkoxy group, a phenyl group and the like can be mentioned.

  In the production of the amino compound (22), the amount of the reduction catalyst to be used is not particularly limited. % Is more preferable.

  The concentration of the oxime compound (21) in the reaction system is not particularly limited, but is preferably 2% by volume to 70% by volume from the viewpoint of increasing the reaction efficiency.

  The reaction temperature in the production of the amino compound (22) is not particularly limited, but is preferably about 0 ° C to 150 ° C from the viewpoint of increasing the reaction efficiency. The reaction time is not particularly limited, but may be, for example, about 10 minutes to 60 hours.

  The method for producing the amide compound of the present invention can be carried out under normal pressure, under reduced pressure, or under increased pressure. From the viewpoint of performing the reaction simply, it may be carried out under normal pressure.

Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples. However, the present invention is not limited to the embodiments. In the following examples, cat is a catalyst and r. t. Means room temperature (about 23 ° C.). Unless otherwise specified, the yield was determined by GC analysis using dodecane as an internal standard, ¹ H NMR analysis using tetramethylsilane or deuterated chloroform as an internal standard, or chromatography. It is a value obtained by performing The product was identified by ¹ H NMR analysis and liquid chromatography mass spectrometry (LC-MS).

<Example 1: Amidation reaction between oxime compound and alanine methyl ester (examination of catalyst)>
As shown in the following formula, in a nitrogen gas atmosphere, in the presence of a metal compound (10 mol%) shown in Table 1 as a catalyst and a toluene solvent (2.5 mL), an oxime compound 1 (0.5 mmol) and an amino compound Was reacted with 3.0 equivalents of L-alanine methyl ester (L-Ala-OMe) at 100 ° C. for 24 hours to synthesize an amide compound (dipeptide precursor) represented by the following formula 6a. The yield is shown in Table 1.

<Example 2: Amidation reaction between oxime compound and alanine t-butyl ester hydrochloride (examination of catalyst)>
Oxime compound 1 (1) of the following formula under the conditions shown in the following formula under a nitrogen gas atmosphere in the presence of Ta (OEt) ₅ (2 mol%) as a catalyst and 1 equivalent of triethylamine (Et ₃ N) as a base. 0.05 equivalents) and 1.0 mmol of L-alanine t-butyl ester hydrochloride (HL-Ala-Ot-Bu.HCl) as an amino compound were reacted at 50 ° C for 24 hours to obtain the following formula An amide compound (dipeptide precursor) represented by 6b was synthesized. The yield is shown in Table 2.

<Example 3: Amidation reaction between oxime compound and phenylalanine methyl ester (examination of catalyst)>
As shown in the following formula, in a nitrogen gas atmosphere, in the presence of a metal compound (10 mol%) shown in Table 3 as a catalyst and a toluene solvent (2.5 mL), an oxime compound 1 (0.5 mmol) and an amino compound And 3.0 equivalents of L-phenylalanine methyl ester (L-Phe-OMe) were reacted at 100 ° C. for 24 hours to synthesize an amide compound (dipeptide precursor) represented by the following formula 6c. The yield is shown in Table 3.

<Comparative Example 1: Amidation reaction between oxime compound and L-phenylalanine methyl ester (without catalyst)>
When the amidation reaction of the oxime compound and L-phenylalanine methyl ester was carried out in the same manner as in Example 3 except that the catalyst was not used in Example 3, the yield of the amide compound was less than 1%. Was.

  In Table 3, for annotation a, 2.0 mL of toluene as a reaction solvent was used. For annotation b, 1.5 mL of the reaction solvent toluene was used.

<Example 4: Amidation reaction of oxime compound and L-alanine t-butyl ester hydrochloride using microwave>
As shown in the following formula, Nb (OEt) ₅ (2.0 mol%) as a catalyst and triethylamine (Et ₃ N) 1 as a base under a nitrogen gas atmosphere under the reaction conditions (additional conditions) shown in Table 4 In the presence of an equivalent amount, the oxime compound 1 and 1.0 mmol of L-alanine t-butyl ester hydrochloride (HL-Ala-Ot-Bu.HCl) as an amino compound were subjected to microwave treatment at 50 ° C under a microwave ( MW) to synthesize an amide compound (dipeptide precursor) represented by the following formula 6b. The yield is shown in Table 4.

  In Table 4, for annotation a, 0.5 mmol of HL-Ala-Ot-Bu.HCl was used. CPME means cyclopentyl methyl ether.

<Example 5: Amidation reaction between oxime compound and L-alanine t-butyl ester hydrochloride (examination of base)>
As shown in the following formula, Ta (OEt) ₅ (2 mol%) as a catalyst under a nitrogen gas atmosphere
And oxime compound 1 (1.05 eq.) And L-alanine t-butyl ester hydrochloride (HL-Ala-Ot-Bu) in the presence of 1 eq. Of diisopropylamine (i-Pr ₂ NH) as a base -HCl) was reacted with 1.0 mmol at 50 ° C for 24 hours to synthesize an amide compound represented by the following formula 6b.

<Example 6: Amidation reaction between oxime compound and L-alanine t-butyl ester hydrochloride (examination of substrate)>
As shown in the following formula, in the presence of Nb (OEt) ₅ as a catalyst (amount shown in Table 5) and 1 equivalent of triethylamine (Et ₃ N) as a base under an atmosphere of nitrogen gas, an oxime compound 1b and an amino acid An amide compound represented by the following formula 6b is reacted with 1.0 mmol of L-alanine t-butyl ester hydrochloride (HL-Ala-Ot-Bu.HCl) as a compound at 50 ° C for 24 hours. Was synthesized. The yield is shown in Table 5.

<Example 7: Amidation reaction between oxime compound and amino acid t-butyl ester hydrochloride (examination of substrate 1)>
As shown in the following reaction formula, in a nitrogen gas atmosphere, in the presence of Nb (OEt) ₅ (2 mol%) as a catalyst and 1 equivalent of triethylamine (Et ₃ N) as a base, various oxime compounds of the following formulas (each 1.05 equivalents) and 1.0 mmol of various amino acid t-butyl ester hydrochlorides of the following formula were reacted at 50 ° C. for 24 hours to synthesize various amide compounds 2 (dipeptide precursors). The synthesized amide compounds (2b) to (2sc) are as shown below. Note that in the following formulas, the radicals R ¹ of R ² and the amino compound of the oxime compound used as the starting material, respectively, correspond to the radicals R ² and groups R ¹ of the amide compound produced (2b) ~ (2sc) are doing. The yield is shown together with each amide compound produced.

In the above formulas of the amide compounds (2b) to (2sc), the respective annotations are as follows. For a, the reaction was carried out at 80 ° C. For b, the yield was measured by ¹ H NMR analysis. For c, 4 mol% of the catalyst was used. As for d, the amino acid: H-Tyr-Ot-Bu was used as the amino compound without using a base, and the hydrochloride of the amino acid was not used. Regarding e, the reaction was carried out at 70 ° C. For f, 3 mol% of the catalyst was used. For g, the rotamer ratio was determined by ¹ H NMR analysis. For h, the catalyst was used at 5 mol%.

<Example 8: Amidation reaction between oxime compound and amino acid t-butyl ester hydrochloride (examination of substrate 2)>
As shown in the following reaction formula, in a nitrogen gas atmosphere, in the presence of Nb (OEt) ₅ (2 mol%) as a catalyst and 1 equivalent of triethylamine (Et ₃ N) as a base, various oxime compounds of the following formulas (each 1.05 equivalents) and 1.0 mmol of various amino acid t-butyl ester hydrochlorides of the following formula were reacted at 50 ° C. for 24 hours to synthesize various amide compounds 2 (dipeptide precursors). The synthesized amide compounds (2t) to (2y) are as shown below. Note that in the following formulas, the radicals R ¹ of R ₂ and the amino compound of the oxime compound used as the starting material, respectively, correspond to the radicals R ² and groups R ¹ of the amide compound produced (2t) ~ (2y) are doing. The yield is shown together with each amide compound produced.

  For annotation a, the catalyst was 5 mol%, the reaction time was 48 hours, and the reaction temperature was 80 ° C.

<Example 9: Amidation reaction between oxime compound and amino acid t-butyl ester hydrochloride (examination of substrate 3)>
As shown in the following reaction formula, in a nitrogen gas atmosphere, in the presence of Nb (OEt) ₅ (5 mol%) as a catalyst and 1 equivalent of triethylamine (Et ₃ N) as a base, various oxime compounds of the following formulas (each 1.05 equivalents) and 1.0 mmol of various amino acid t-butyl ester hydrochlorides of the following formula were reacted at 50 ° C. for 24 hours to synthesize various amide compounds 21 (dipeptide precursors). Note that in the following formulas, radical R ⁴ of the oxime compound used as the starting material corresponds to the group R ⁴ of the resulting amide compound. The yield is shown together with each amide compound produced.

<Example 10: Amidation reaction between oxime compound and amino acid t-butyl ester hydrochloride (examination of substrate 4)>
As shown in the following reaction formula, in a nitrogen gas atmosphere, in the presence of Nb (OEt) ₅ (5 mol%) as a catalyst and 1 equivalent of triethylamine (Et ₃ N) as a base, various oxime compounds (1 (0.05 equivalents) and 1.0 mmol of the amino acid t-butyl ester hydrochloride of the following formula were reacted at 50 ° C. for 24 hours to synthesize an amide compound 23 (dipeptide precursor). Note that in the following formulas, radical R ⁴ of the oxime compound used as the starting material corresponds to the group R ⁴ of the resulting amide compound. The yield is shown together with each amide compound produced.

<Example 11: Synthesis of amino compound (dipeptide) from oxime compound (dipeptide derivative) (investigation of stereoselective hydrogenation reaction)>
Under the conditions shown in the following reaction formula, a stereoselective hydrogenation reaction is carried out on an oxime group of the oxime compound 2 of the following formula in an acetic acid solution under an atmosphere of Pd (OH) ₂ / C as a catalyst and hydrogen gas (1 atm). Then, amino compound 5 was synthesized. The synthesized amino compounds (5a) to (5r) are as shown below. In the following formula, the group R ¹ of the oxime compound used as a raw material corresponds to the group R ¹ of each of the generated amino compounds (5a) to (5r). The yield is shown with each amino compound produced.

Regarding annotation a, the diastereomeric ratio of each of the above amino compounds (5a) to (5r) was measured by ¹ H NMR analysis. For annotation b, the resulting dipeptide was isolated as acetate. The annotation c was analyzed after purification by silica gel chromatography. The annotation d was analyzed after recrystallization from diethyl ether. For annotation e, the solvent was 4N HCl / CPME: acetic acid = 1: 9.

<Example 12: Amidation reaction between hydroxyamine compound and L-alanine methyl ester (examination of catalyst)>
As shown in the following formula, a hydroxyamine compound 7 (0.25 mmol, er = 98.5: 1.5) of the following formula and L as an amino compound in the presence of the catalyst (10 mol%) shown in Table 6 -Alanine methyl ester 8 (0.375 mmol, 1.5 equivalents) was reacted in toluene solvent (1 mL) at 100 ° C. for 16 hours to synthesize an amide compound (dipeptide precursor) represented by the following formula 9. did. The yield is shown in Table 6.

In Table 6, the yields are isolation yields except for Entry 6. Entry 6 was measured by ¹ H NMR analysis. The diastereomer ratio is a value measured by chiral HPLC analysis. For Entry 1, the er of the hydroxyamine compound is 95: 5.

<Comparative Example 2: Amidation reaction between hydroxyamine compound and L-alanine methyl ester (without catalyst)>
In Example 9, an amidation reaction between the hydroxyamine compound and L-alanine methyl ester was performed in the same manner as in Example 9 except that no catalyst was used. As a result, the yield of the amide compound was less than 1%. there were.

<Example 13: Amidation reaction between hydroxyamine compound and L-alanine t-butyl ester (examination of catalyst)>
As shown in the following formula, in the presence of dichlorophenylborane (PhBCl ₂ ) (10 mol%) as a catalyst, a hydroxyamine compound (0.25 mmol, er = 95: 5) of the following formula and L-alanine t as an amino compound -Butyl ester (3.0 equivalents) was reacted in a toluene solvent (1 mL) at 100 ° C. for 18 hours to synthesize an amide compound 11a (dipeptide precursor) represented by the following formula. In the hydroxyamine compound 11a of the following formula, Bn means a benzyl group.

<Example 14: Amidation reaction between hydroxyamine compound and various amino acid t-butyl esters (investigation of amino compound)>
As shown in the following formula, in the presence of 3,4,5-trifluorophenylboronic acid (12 mol%) as a catalyst, a hydroxyamine compound 7 (0.25 mmol, er = 95: 5) The t-butyl esters 10a, 10b, and 10c ((0.75 mmol, 3 equivalents)) of various kinds of aluminum acids as compounds are reacted in a toluene solvent (1 mL) at 100 ° C. for 16 hours, and represented by the following formula. Each of the amide compounds 11a, 11b, 11c (dipeptide precursor) was synthesized, and in the hydroxyamine compound of the following formula, Bn represents a benzyl group.

<Example 15: Synthesis of amino compound (dipeptide) from hydroxyamine compound (dipeptide derivative) (investigation of stereoselective hydrogenation reaction)>
Under the conditions shown in the following reaction formula, the hydroxyamino group of the hydroxyamine compound 11a of the following formula was converted into an amino group in an acetic acid solution under an atmosphere of Pd (OH) ₂ / C as a catalyst and hydrogen gas (1 atm). Thus, the amino compound 12a (dipeptide) was synthesized. In the hydroxyamine compound of the following formula, Bn means a benzyl group.

<Example 16: Amidation reaction between oxime compound and amino acid methyl ester (examination of catalyst)>
As shown in the following reaction formula, in an atmosphere of nitrogen gas, in the presence of Nb (OEt) ₅ (4 mol%) as a catalyst and one equivalent of triethylamine (Et ₃ N) as a base, an oxime compound 1 (1 0.05 equivalent) and 1.0 mmol of various amino acid t-butyl ester hydrochlorides of the following formula were reacted at 50 ° C. for 24 hours to synthesize various amide compounds 24 (dipeptide precursors). The synthesized amide compounds (24a) to (24b) are as shown below. Note that in the following formulas, the radicals R ⁵ of the oxime compound used as the starting material corresponds to the group R ⁵ each, each amide compound produced (24a) ~ (24b). The yield is shown together with each amide compound produced.

<Example 17: Amidation reaction of oxime compound and amino acid methyl ester using palladium catalyst>
As shown in the following reaction formula, in a nitrogen gas atmosphere, in the presence of Pd (OAc) ₂ (10 mol%) as a catalyst, 1.0 mol of an oxime compound represented by the following formula and 2.0 mmol of alanine methyl ester represented by the following formula: By reacting at 80 ° C. for 24 hours, an amide compound was synthesized in a yield of 86%.

<Example 18: Synthesis of amino compound (dipeptide) from oxime compound (dipeptide derivative) (examination of asymmetric hydrogenation reaction)>
Under the conditions shown in the following reaction formula, an additive (1 equivalent) was added under an atmosphere of Pd (OH) ₂ / C as a catalyst and hydrogen gas (1 atm), and an oxime group of an oxime compound 2a of the following formula was added in an acetic acid solution. Was subjected to an asymmetric hydrogenation reaction to synthesize amino compound 5a.

<Example 19: Synthesis of cosmetic peptide (tripeptide-3)>
As shown in the following formula, Ta (OMe) ₅ (10 mol%), Cbz serine methyl ester (4.67 mmol, 1.18 g), and valine t-butyl ester (7 mol, 1.20 g) were used as catalysts at 60 ° C. for 24 hours. The reaction was allowed to proceed for a period of time to quantitatively obtain dipeptide 25 (1.84 g). Then, in the presence of Pd (OH) _{2 /} C (0.8 mmol, 562 mg), 25 was hydrogenated (1 atm) in a methanol solvent for 1.5 hours to deprotect the Cbz group to obtain 26 ( 76%, 786 mg). Next, Ta (OMe) ₅ (10 mol%), 26 (0.50 mmol, 130 mg), and an oxime compound (0.525 mmol, 54.1 mg) were reacted at 60 ° C. for 24 hours as a catalyst under a nitrogen gas atmosphere. The tripeptide precursor 27 was obtained (60%, 100 mg). Thereafter, 27 (0.3 mmol, 100 mg) was hydrogenated (1 atm) in acetic acid solvent for 1 hour in the presence of Pd (OH) _{2 /} C (0.06 mmol, 42.3 mg), and then 4N hydrogen chloride / acetic acid The t-butyl ester was deprotected by adding an ethyl solution (3.0 mmol) and stirring for 2 hours to obtain the desired tripeptide-3 (89%, 79.2 mg).

Claims (11)

An amidation step of reacting an amino ester compound represented by the following general formula (1) with an amino compound in the presence of a catalyst comprising a metal compound to amidate the ester group of the amino ester compound; A method for producing an amide compound.

[In equation (1),
The group R ¹ is an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a group which has a substituent. And a heterocyclic group which may be substituted. The groups R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, and a substituent. It represents an alicyclic group which may be possessed or a heterocyclic group which may be possessed by a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ³ does not exist.
The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1.
The group R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an alicyclic ring which may have a substituent. It represents a formula group or a heterocyclic group which may have a substituent. However, when the bond between the carbon atom at the α-position and the nitrogen atom at the β-position is a double bond, the group R ⁴ is an electron pair. ]   After the amidation step, the obtained amide compound further includes a reduction step of converting a β-position group NOH derived from the amino ester compound represented by the general formula (1) into an amino group. The method for producing an amide compound according to claim 1, wherein   An ester of the amino ester compound is reacted by reacting the amino ester compound represented by the general formula (1) with the amide compound having an amino group obtained in claim 2 in the presence of a catalyst comprising a metal compound. The method for producing an amide compound according to claim 2, further comprising an amidation step of amidating the group. The method for producing an amide compound according to any one of claims 1 to 3, wherein the compound represented by the general formula (1) is an oxime compound represented by the following general formula (11).

[In the formula (11), the group R ¹ , the group R ² , and the group A are the same as those in the general formula (1). ] The method for producing an amide compound according to any one of claims 1 to 3, wherein the compound represented by the general formula (1) is a hydroxyamino compound represented by the following general formula (12).

[In the formula (12), the group R ¹ , the group R ² , the group R ³ , the group R ⁴ , and the group A are the same as those in the general formula (1). ] The method for producing an amide compound according to any one of claims 1 to 5, wherein the amino compound is an amino compound represented by the following general formula (3).

[The groups ^Ra and ^Rb each independently have a hydrogen atom, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, An alicyclic group or a heterocyclic group which may have a substituent. R ^a and R ^b may form a saturated or unsaturated heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic group may have a substituent. ]   The method for producing an amide compound according to claim 6, wherein the amino compound is an amino acid or a salt thereof, or an amino acid ester or a salt thereof.   The method for producing an amide compound according to any one of claims 1 to 7, wherein the amount of the catalyst used is 12 mol% or less when the aminoester compound is 100 mol%.   The method for producing an amide compound according to any one of claims 1 to 8, wherein the amidation reaction is performed in the presence of a base. The method for producing an amide compound according to any one of claims 1 to 9, wherein the amide compound obtained by the amidation reaction has the following general formula (4).

[In the formula (4), the group R ² , the group R ³ , the group R ⁴ , and the group A are respectively the same as those in the general formula (1), and the group ^Ra and the group ^Rb are each independently Having a hydrogen atom, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a substituent Represents an optionally substituted heterocyclic group. R ^a and R ^b may form a saturated or unsaturated heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic group may have a substituent. ] According to the following reaction formula, the oxime group of the oxime compound having an asymmetric carbon atom to which the groups R ⁵ and R ⁶ shown in the following general formula (21) bind in an acidic solvent is stereoselectively converted to an amino group. To produce an amino compound represented by the following general formula (22).

[In the formulas (21) and (22),
The group R ² is a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, Or a heterocyclic group which may have a substituent.
The group A represents a linear or branched alkylene group having 1 to 3 carbon atoms which may have a substituent. p is 0 or 1.
The groups R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or a substituent. It represents an alicyclic group which may be possessed or a heterocyclic group which may be possessed by a substituent.
The group R ⁷ is a hydroxyl group, a group OR ^7a , an amino group, an aliphatic group which may have a substituent, an aromatic group which may have a substituent, or an aliphatic group which may have a substituent. A cyclic group, or a heterocyclic group which may have a substituent,
The group R ^7a is an aliphatic group which may have a substituent, an aromatic group which may have a substituent, an alicyclic group which may have a substituent, or a group which has a substituent. And a heterocyclic group which may be substituted. ]