JP5268052B2 - Catalyst for asymmetric amination reaction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an asymmetric catalyst for asymmetric amination and a ligand for manufacturing the catalyst. <P>SOLUTION: This catalyst is a compound represented by general formula (I) (wherein R<SP>1</SP>is a 3-8C alkyl group or aralkyl group; * represents either one of S-configured or R-configured asymmetric carbon), and a rare earth complex having the compound as a ligand, preferably, a lanthanum complex. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to an asymmetric catalyst for use in an asymmetric amination reaction.

  (R)-(-)-2 (4-Bromo-2-fluorobenzyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-4-spiro-3'-pyrrolidine-1, 2 ′, 3,5′-Tetron (hereinafter sometimes referred to as “AS-3201”) has an excellent aldose reductase inhibitory action and is expected as a promising therapeutic agent for diabetes (J Med. Chem., 41, pp. 4118-4129, 1998). AS-3201 is an optically active substance, and the in vitro activity of the optical enantiomer falls below 1/500 (Table 6 on page 4123 of the above document), making AS-3201 stereoselective. Need to be manufactured. Conventionally, AS-3201 is obtained by optical resolution of 3-[(benzyloxycarbonyl) amino] -3- (ethoxycarbonyl) -2,5-dioxopyrrolidine (R)-(-)-3-[( Benzyloxycarbonyl) amino] -3- (ethoxycarbonyl) -2,5-dioxopyrrolidine is deprotected and becomes a key intermediate (R)-(-)-3-amino-3- (ethoxycarbonyl)- It is converted to 2,5-dioxopyrrolidine and synthesized from this compound through several steps (Scheme 5 on page 4121 of the above cited document: The above key intermediate is a compound represented by “Compound 37”. is there).

However, the above method involving optical resolution is disadvantageous in terms of production cost because half of the optical antipodes need to be discarded, and in particular, since cinchonidine used in the optical resolution is difficult to supply in large quantities, This production method is industrially disadvantageous, and development of a method for producing the above key intermediate in a stereoselective manner by means of asymmetric synthesis is required. To stereoselectively produce (R)-(-)-3-amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine, the 3- (ethoxycarbonyl) -2,5-dioxopyrrolidine Although a method of stereoselectively aminating the 3-position is conceivable, the above-mentioned 3- (ethoxycarbonyl) -2,5-dioxopyrrolidine is used as a catalyst that can achieve asymmetric amination known in the art. There was no catalyst capable of achieving enantioselectivity that was practically satisfactory as a raw material.
J. Med. Chem., 41, pp.4118-4129, 1998

  An object of the present invention is to provide an asymmetric catalyst for use in an asymmetric amination reaction and a ligand for the production of the catalyst. Another object of the present invention is to efficiently use (R)-(−)-3-amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine using the above-mentioned catalyst for asymmetric amination reaction. And a method for producing the derivatives thereof.

  As a result of intensive studies to solve the above problems, the present inventors have found that when a rare earth complex such as lanthanum having a ligand represented by the following general formula (I) is used as an asymmetric amination catalyst: It has been found that an amino adduct can be obtained with high enantioselectivity from-(ethoxycarbonyl) -2,5-dioxopyrrolidine and a dialkylazodicarboxylate compound. Also, by chemically converting this amino adduct, the above key intermediate (R)-(−)-3-amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine is produced very efficiently. It was found that AS-3201 can be produced at low cost and in high yield. The present invention has been completed based on these findings.

（式中、R¹はC_3-8アルキル基又はアラルキル基を示し、*はS-配置又はR-配置のいずれかの不斉炭素を示す）で表される化合物、及び該化合物を配位子として有する希土類錯体が提供される。 That is, according to the present invention, the following general formula (I):

(Wherein R ¹ represents a C _3-8 alkyl group or an aralkyl group, * represents an asymmetric carbon in either the S-configuration or the R-configuration), and the compound is coordinated A rare earth complex is provided as a child.

As a preferred embodiment of the above invention, the above compound or the rare earth complex wherein R ¹ is a branched or cyclic C _3-8 alkyl group; the above wherein R ¹ is an isopropyl group, a tert-butyl group, an isobutyl group, or a cyclohexyl group There is provided the compound or the rare earth complex, and the compound or the rare earth complex, wherein R ¹ is an isopropyl group. Lanthanum is preferred as the rare earth element.
The present invention also provides a catalyst for asymmetric amination reaction comprising the above rare earth complex.

（式中、R²、R³、及びR⁴はそれぞれ独立にカルボキシル基の保護基を示す）で表される化合物の製造方法であって、下記の一般式(III)：

（式中、R²は上記と同義である）で表される化合物と下記の一般式(IV)：
R³-O-CO-N=N-CO-O-R⁴
（式中、R³及びR⁴は上記と同義である）で表される化合物とを上記の不斉アミノ化反応用触媒の存在下で反応させる工程を含む方法が提供される。 As a reaction using the asymmetric amination reaction catalyst, according to the present invention, the following general formula (II):

(Wherein R ² , R ³ and R ⁴ each independently represents a protecting group for a carboxyl group), which is a method for producing a compound represented by the following general formula (III):

(Wherein R ² is as defined above) and the following general formula (IV):
R ³ -O-CO-N = N-CO-OR ⁴
There is provided a method comprising a step of reacting a compound represented by the formula (wherein R ³ and R ⁴ have the same meanings as described above) in the presence of the catalyst for asymmetric amination reaction.

In the above method, R ² , R ³ and R ⁴ are preferably an alkyl group, R ² is an ethyl group, and R ³ and R ⁴ are more preferably a tert-butyl group. As a catalyst for asymmetric amination reaction, it is preferable to use a rare earth complex, particularly a lanthanum complex, containing as a ligand the above compound in which R ¹ is an isopropyl group in the above general formula (I). For the preparation of the lanthanum complex, lanthanum triisopropoxide or lanthanum nitrate can be preferably used. When lanthanum nitrate is used, the above reaction is preferably performed in the presence of a base.

（式中、R⁵は水素原子又はカルボキシル基の保護基を示す）で表される化合物の製造方法であって、下記の工程：
(a)上記一般式(III)で表される化合物と上記一般式(IV)で表される化合物とを上記不斉アミノ化反応触媒の存在下で反応させて上記一般式(II)で表される化合物を得る工程；及び
(b)上記工程(a)で得られた上記一般式(II)で表される化合物からCOOR³及びCOOR⁴を除去した後、N-N結合を切断して上記一般式(V)で表される化合物に変換する工程
を含む方法が提供される。 From another point of view, the following general formula (V):

(Wherein R ⁵ represents a hydrogen atom or a protecting group for a carboxyl group), which is a method for producing a compound represented by the following steps:
(a) A compound represented by the above general formula (III) and a compound represented by the above general formula (IV) are reacted in the presence of the above asymmetric amination reaction catalyst to represent the above general formula (II). Obtaining a compound to be prepared; and
(b) After removing COOR ³ and COOR ⁴ from the compound represented by the general formula (II) obtained in the step (a), the NN bond is cleaved to represent the general formula (V). A method is provided comprising the step of converting to a compound.

  By using the catalyst for asymmetric amination reaction of the present invention, an amination reaction, which cannot achieve practical enantioselectivity with a conventional catalyst, can proceed efficiently and with a high asymmetric yield.

In the present specification, the three-dimensional notation in the general formula indicates an absolute configuration unless otherwise specified.
R ¹ represents a C _3-8 alkyl group or an aralkyl group. As the C _3-8 alkyl group represented by R ¹ , an alkyl group consisting of a linear, branched, cyclic, or combination thereof can be used, but a branched, cyclic, or a combination thereof can be used. An alkyl group consisting of is preferable, and a branched or cyclic alkyl group is more preferable. For example, a branched C _3-4 alkyl group such as an isopropyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, or a cyclic C _5-7 alkyl such as a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group Groups are preferred. Of these, an isopropyl group, an isobutyl group, or a tert-butyl group is more preferable, and an isopropyl group is particularly preferable.

As the aralkyl group represented by R ¹ , for example, a linear or branched C _1-4 alkyl group substituted by one or several, preferably one aryl group or heteroaryl group is used. Can do. As the aryl group constituting the aralkyl group represented by R ¹ , a monocyclic or condensed polycyclic aromatic hydrocarbon group can be used, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthranyl group Or a phenanthryl group and the like, but is not limited thereto. As the heteroaryl group, a monocyclic or condensed polycyclic aromatic heterocyclic group can be used. The number of ring-constituting heteroatoms is not particularly limited, but is about 1 to several, preferably about 1 to 5. When two or more ring heteroatoms are contained, they may be the same or different. Examples of the hetero atom include, but are not limited to, an oxygen atom, a nitrogen atom, or a sulfur atom.

Examples of the monocyclic heteroaryl group constituting the aralkyl group represented by R ¹ include, for example, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1,2,3-oxadiazol) -4-yl group, (1,2,3-oxadiazol) -5-yl group, (1,2,4-oxadiazole) -3-yl group, (1,2,4-oxadiazol) -5-yl group, (1,2,5-oxadiazol) -3-yl group, (1,2,5-oxadiazol) -4-yl group, (1,3,4-oxadiazol) -2-yl group, (1,3,4-oxadiazol) -5-yl group , Furazanyl group, (1,2,3-thiadiazol) -4-yl group, (1,2,3-thiadiazol) -5-yl group, (1,2,4-thiadiazol) -3-yl group, 1,2,4-thiadiazol) -5-yl group, (1,2,5-thiadiazol) -3-yl group, (1,2,5-thiadiazol) -4-yl group, (1,3,4 -Thiadiazolyl) -2-yl group, (1,3,4-thiadiazolyl) -5-yl group, (1H-1,2,3-triazol) -1-yl group, (1H-1,2,3- (Triazol) -4-yl group, (1H-1,2,3-triazol) -5-yl group, (2H-1,2,3-triazol) -2-yl group, (2H-1,2,3 -Triazol) -4-yl group, (1H-1,2,4-triazol) -1-yl group, (1H-1,2,4-triazol) -3-yl group, (1H-1,2, 4-triazol) -5-yl group, (4H-1,2,4-triazol) -3-yl group, (4H-1,2,4-triazol) -4-yl group, (1H-tetrazole)- 1-yl group, (1H-te Razol) -5-yl group, (2H-tetrazol) -2-yl group, (2H-tetrazol) -5-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 2-pyrazinyl group, (1,2,3-triazin) -4-yl group, (1,2,3-triazine)- 5-yl group, (1,2,4-triazine) -3-yl group, (1,2,4-triazine) -5-yl group, (1,2,4-triazine) -6-yl group, (1,3,5-triazine) -2-yl group, 1-azepinyl group, 1-azepinyl group, 2-azepinyl group, 3-azepinyl group, 4-azepinyl group, (1,4-oxazepine) -2- Yl group, (1,4-oxazepine) -3-yl group, (1,4-oxazepine) -5-yl group, (1,4-oxazepine) -6-yl group, (1,4-oxazepine)- 7-yl group, (1,4-thiazepine) -2-yl group, (1,4-thiazepine) -3-yl group, (1,4-thiazepine) -5-yl group, (1,4-thiazepine) ) -6-yl group (1,4-thiazepine) -7-yl, but 5 to 7-membered monocyclic heteroaryl group such groups are not limited thereto.

Examples of the condensed polycyclic heteroaryl group constituting the aralkyl group represented by R ¹ include a 2-benzofuranyl group, a 3-benzofuranyl group, a 4-benzofuranyl group, a 5-benzofuranyl group, a 6-benzofuranyl group, and a 7-benzofuranyl group. 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 4-benzo [b] thienyl Group, 5-benzo [b] thienyl group, 6-benzo [b] thienyl group, 7-benzo [b] thienyl group, 1-benzo [c] thienyl group, 4-benzo [c] thienyl group, 5-benzo [c] thienyl group, 1-indolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, (2H-iso Indol) -1-yl group, (2H-isoindole) -2-yl group, (2H-isoindole) -4-yl group, (2H-isoi group) Dole) -5-yl group, (1H-indazol) -1-yl group, (1H-indazol) -3-yl group, (1H-indazol) -4-yl group, (1H-indazol) -5-yl Group, (1H-indazol) -6-yl group, (1H-indazol) -7-yl group, (2H-indazol) -1-yl group, (2H-indazol) -2-yl group, (2H-indazole) ) -4-yl group, (2H-indazol) -5-yl group, 2-benzoxazolyl group, 2-benzoxazolyl group, 4-benzoxazolyl group, 5-benzoxazolyl group, 6-benzoxazolyl group, 7-benzoxazolyl group, (1,2-benzisoxazol) -3-yl group, (1,2-benzisoxazol) -4-yl group, (1,2 -Benzoisoxazol) -5-yl group, (1,2-benzisoxazol) -6-yl group, (1,2-benzisoxazol) -7-yl group, (2,1-benzisoxazole) -3-yl group, (2,1-benzoisoxazol) -4-yl group, (2,1- Nzoisoxazol) -5-yl group, (2,1-benzisoxazol) -6-yl group, (2,1-benzisoxazol) -7-yl group, 2-benzothiazolyl group, 4-benzothiazolyl group , 5-benzothiazolyl group, 6-benzothiazolyl group, 7-benzothiazolyl group, (1,2-benzisothiazol) -3-yl group, (1,2-benzisothiazol) -4-yl group, (1,2 -Benzoisothiazol) -5-yl group, (1,2-benzisothiazol) -6-yl group, (1,2-benzisothiazol) -7-yl group, (2,1-benzoisothiazole) -3-yl group, (2,1-benzoisothiazol) -4-yl group, (2,1-benzoisothiazol) -5-yl group, (2,1-benzisothiazol) -6-yl group , (2,1-Benzisothiazol) -7-yl group, (1,2,3-Benzoxadiazol) -4-yl group, (1,2,3-Benzoxadiazol) -5-yl Group, (1,2,3-benzooxadiazole) -6-yl group, (1,2,3 -Benzoxadiazol) -7-yl group, (2,1,3-benzooxadiazol) -4-yl group, (2,1,3-benzooxadiazol) -5-yl group, (1 , 2,3-benzothiadiazol) -4-yl group, (1,2,3-benzothiadiazole) -5-yl group, (1,2,3-benzothiadiazol) -6-yl group, (1,2 , 3-Benzothiadiazole) -7-yl group, (2,1,3-benzothiadiazole) -4-yl group, (2,1,3-benzothiadiazole) -5-yl group, (1H-benzotriazole) -1-yl group, (1H-benzotriazol) -4-yl group, (1H-benzotriazol) -5-yl group, (1H-benzotriazol) -6-yl group, (1H-benzotriazole) -7 -Yl group, (2H-benzotriazol) -2-yl group, (2H-benzotriazol) -4-yl group, (2H-benzotriazol) -5-yl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1- Soquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6- Cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 2-quinoxalinyl group, 5- Quinoxalinyl group, 6-quinoxalinyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group, 3-naphthyridinyl group, 4-naphthyridinyl group, 2-purinyl group, 6-purinyl group, 7- Purinyl group, 8-prinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group, 1-carbazolyl group, 2-carbazolyl group, 3-carbazolyl group , 4-carbazolyl group, 9-carbazolyl group, 2- (α-carbolinyl) group, 3- (α-carbolinyl) group, 4- (α-carbolinyl) group, 5- (α-carbolinyl) group, 6- ( α-Carboninyl) group, 7- (α-Carborinyl) group, 8- (α-Carborinyl) group, 9- (α-Carborinyl) group, 1- (β-Carbonylyl) group, 3- (β-Carbonylyl) group 4- (β-Carbonylyl) group, 5- (β-Carbonylyl) group, 6- (β-Carbonylyl) group, 7- (β-Carbonylyl) group, 8- (β-Carbonylyl) group, 9- (β -Carbonylyl) group, 1- (γ-Carborinyl) group, 2- (γ-Carborinyl) group, 4- (γ-Carborinyl) group, 5- (γ-Carborinyl) group, 6- (γ-Carborinyl) group, 7- (γ-Carborinyl) group, 8- (γ-Carborinyl) group, 9- (γ-Carborinyl) group, 1-Acridinyl group, 2-Acridinyl group, 3-Acridinyl group, 4-Acridinyl group, 9-Acridinyl group Group, 1-phenoxazinyl group, 2-phenoxazinyl group, 3-phenyl Noxazinyl group, 4-phenoxazinyl group, 10-phenoxazinyl group, 1-phenothiazinyl group, 2-phenothiazinyl group, 3-phenothiazinyl group, 4-phenothiazinyl group, 10-phenothiazinyl group, 1-phenazinyl group, 2- Phenazinyl group, 1-phenanthridinyl group, 2-phenanthridinyl group, 3-phenanthridinyl group, 4-phenanthridinyl group, 6-phenanthridinyl group, 7-phenanthridinyl group 8-phenanthridinyl group, 9-phenanthridinyl group, 10-phenanthridinyl group, 2-phenanthrolinyl group, 3-phenanthrolinyl group, 4-phenanthrolinyl group, 5 -Phenanthrolinyl group, 6-phenanthrolinyl group, 7-phenanthrolinyl group, 8-phenanthrolinyl group, 9-phenanthrolinyl group, 10-phenanthrolinyl group, 1-thianthrenyl group Group, 2-thianthenyl group, 1-i Doridinyl group, 2-indolidinyl group, 3-indolidinyl group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-phenoxathinyl group, 2-phenoxathinyl group, 3 -Phenoxathiinyl group, 4-phenoxathiinyl group, thieno [2,3-b] furyl group, pyrrolo [1,2-b] pyridazinyl group, pyrazolo [1,5-a] pyridyl group, imidazo [ 11,2-a] pyridyl group, imidazo [1,5-a] pyridyl group, imidazo [1,2-b] pyridazinyl group, imidazo [1,2-a] pyrimidinyl group, 1,2,4-triazolo [ Examples include, but are not limited to, 8- to 14-membered fused polycyclic heteroaryl groups such as 4,3-a] pyridyl group and 1,2,4-triazolo [4,3-a] pyridazinyl group. There is no.
Examples of the aralkyl group represented by R ¹ include, but are not limited to, a benzyl group or a 3-indolylmethyl group.

The compound represented by the general formula (I) is obtained by condensing an amino group of 2-aminophenol with an optically active L or R-amino acid having R ¹ as a side chain as a raw material. It can be produced by condensing salicylic acid to the resulting compound. If necessary, the amino group of the amino acid or the hydroxyl group of 2-aminophenol can be protected with an appropriate protecting group. For protecting groups, reference can be made to books such as Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. Examples of the amino-protecting group include an alkoxycarbonyl group, an aryloxycarbonyl group, an alkanoyl group, and an arylcarbonyl group (in the above aryloxycarbonyl group or arylcarbonyl group, the aryl ring is substituted or unsubstituted). It may be substituted, and when it has a substituent, examples thereof include a halogen atom and an alkoxy group). Of these, alkoxycarbonyl groups are preferred. The alkoxycarbonyl group is preferably an alkoxycarbonyl group composed of a linear or branched C _1-6 alkoxy group, more preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a tert-butoxycarbonyl group. Particularly preferred is a tert-butoxycarbonyl group. As the hydroxyl-protecting group, an aralkyl group such as a benzyl group, a benzoyl group, a trialkylsilyl group, and the like can be used, and a benzyl group is preferable.

  This condensation reaction can be performed by a normal amide formation reaction in which an amino group and a carboxyl group are reacted. For example, the condensation reaction is performed by an appropriate method such as an active esterification method, a mixed acid anhydride method, or a condensation method. The active esterification method is carried out by reacting a carboxylic acid with an active esterifying agent in a solvent to produce an active ester and then reacting with an amino group. The solvent used is not particularly limited as long as it is inert. For example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, dimethylformamide, dimethylacetamide and the like. Preference is given to amides, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, or mixed solvents thereof. Examples of the active esterifying agent include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide; 1,1′- Diimidazole compounds such as oxalyldiimidazole, N, N'-carbonyldiimidazole; disulfide compounds such as 2,2'-dipyridyl disulfide; such as N, N'-disuccinimidyl carbonate Succinic acid compounds; phosphinic chloride compounds such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; N, N′-disuccinimidyl oxalate (DSO), N , N'-Diphthalimide oxalate (DPO), N, N'-bis (norbornenylsuccinimidyl) oxalate (BNO), 1,1'-bis (benzotriazolyl) oxalate (BBTO), 1 , 1'- screw ( Examples include oxalate compounds such as 6-chlorobenzotriazolyl) oxalate (BCTO) and 1,1′-bis (6-trifluoromethylbenzotriazolyl) oxalate (BTBO). Mention may be made of diimidazole compounds such as N, N′-carbonyldiimidazole.

  The reaction of an active ester with an amino group is, for example, azodicarboxylic acid di-lower alkyl-triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine, N-ethyl-5-phenylisoxazolium-3′- N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as sulfonate, oxydiformates such as diethyloxydiformate (DEPC), N ', N'-dicyclohexylcarbodiimide (DCC ) N ', N'-dicycloalkylcarbodiimides, diheteroaryl diselenides such as di-2-pyridyl diselenide, triaryl phosphines such as triphenylphosphine, p-nitrobenzenesulfonyl Arylsulfonyl triazolides such as triazolide, 2-chloro-1-methylpyridinium 2- B-1-Lower alkyl pyridinium halides and diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA), imidazole derivatives such as N, N'-carbodiimidazole (CDI), and 1-hydroxybenzotriazole (HOBT) Benzotriazole derivatives, dicarboximide derivatives such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) In the presence of a condensing agent such as a phosphonic acid cyclic anhydride such as 1-propanephosphonic acid cyclic anhydride (T3P). Preferably, a carbodiimide derivative such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or a phosphonic acid cyclic anhydride such as 1-propanephosphonic acid cyclic anhydride (T3P) is used. it can. The reaction temperature for the preparation of the active ester is −10 ° C. to room temperature, the reaction between the active ester compound and the amino group is around room temperature, and the reaction time is about 30 minutes to 10 hours.

  The mixed acid anhydride method is carried out by reacting an amino group after producing a mixed acid anhydride of a carboxylic acid. The condensation method can be carried out by directly reacting a carboxylic acid and an amine in the presence of the condensing agent, and is carried out in the same manner as in the reaction for producing the active ester. Condensation can also be carried out by converting the carboxyl group to an acid halide in an inert solvent and then reacting the resulting acid halide with an amine.

  The rare earth complex of the present invention can be prepared by reacting the compound represented by the general formula (I) with a rare earth compound. In general, the compound represented by the above general formula (I) and the rare earth compound can be added to a reaction system for asymmetric amination and prepared in use in the reaction system. Examples of rare earth elements include scandium (Sc), yttrium (Y), and 15 elements belonging to lanthanoids (15 elements of atomic number 57 to 71: lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium ( Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium ( Yb) and lutetium (Lu)), and lanthanoids are preferable, and lanthanum is particularly preferable. The rare earth compound for preparing the rare earth complex of the present invention is not particularly limited. For example, rare earth chloride, rare earth bromide, rare earth fluoride, rare earth carbonate, rare earth sulfate, rare earth nitrate, rare earth phosphate, rare earth oxalate , Rare earth oxides, rare earth nitrides, rare earth sulfides, rare earth iron garnets, rare earth borides, rare earth organic compounds, and the like can be used, but are not limited thereto.

  For example, when preparing a lanthanum complex, a lanthanum trialkoxy compound such as lanthanum triisopropoxide or a lanthanum triphenoxy compound such as lanthanum triphenoxide, lanthanum trishexamethyldisilazide or lanthanum hydride, or lanthanum nitrate is used. Can be used. It is known that anhydrous lanthanum nitrate and some kinds of hydrates exist. For example, in addition to anhydrous lanthanum nitrate, any hydrate such as lanthanum nitrate hexahydrate may be used. The rare earth complex can be generally prepared in a solvent in the presence of an inert gas at a temperature of about -50 ° C to room temperature. Examples of the solvent include ether solvents such as diethyl ether, isopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, and aromatic hydrocarbons such as benzene and toluene. System solvents, nitrile solvents such as acetonitrile, ketone solvents such as acetone, and amide solvents such as dimethylformamide and formamide can be used, but are not limited thereto.

  The rare earth complex of the present invention can be used as an asymmetric amination reaction catalyst. The type of asymmetric amination that can be carried out using the catalyst of the present invention is not particularly limited. Generally, however, a β-keto ester compound and an azodicarboxylate compound are used for the α-position of a β-keto ester compound. Examples include a reaction in which two nitrogen atoms are each introduced with a hydrazinyl group protected with a carbonyl protecting group such as an alkoxycarbonyl group.

  As a typical asymmetric reaction that can be carried out using the catalyst of the present invention, the compound represented by the above general formula (III) and the compound represented by the above general formula (IV) are converted into the catalyst of the present invention. A reaction in which a compound represented by the above general formula (II) is obtained by reacting in the presence of can be exemplified. Hereinafter, although this reaction is demonstrated concretely, the use of the catalyst of this invention is not limited to this specific reaction.

In the compounds represented by the above general formulas (II) to (IV), R ² , R ³ , and R ⁴ each independently represent a protecting group for a carboxyl group. References such as Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. can be referred to. The protecting group for the carboxyl group represented by R ² is, for example, a C _1-6 alkyl group (the alkyl group may be any of linear, branched, cyclic, or a combination thereof) , An aralkyl group (such as a benzyl group), an alkylsilyl group (such as a trimethylsilyl group), and the like. Among these, a C _1-6 alkyl group is preferable, a methyl group or an ethyl group is more preferable, and ethyl is particularly preferable. It is a group. As a protecting group for the carboxyl group represented by R ³ and R ⁴ , a C _1-6 alkyl group (the alkyl group may be any of linear, branched, cyclic, or a combination thereof) Aralkyl groups (such as benzyl groups), alkylsilyl groups (such as trimethylsilyl groups), and the like can be used, and tert-butyl groups are particularly preferable. The protective groups for the carboxyl groups represented by R ³ and R ⁴ may be the same or different, but are preferably the same. It is particularly preferred that R ³ and R ⁴ are both tert-butyl groups.

  This reaction can be carried out, for example, in an inert solvent. The type of solvent is not particularly limited. For example, ether solvents such as diethyl ether, isopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, benzene and toluene, etc. Aromatic hydrocarbon solvents, nitrile solvents such as acetonitrile, ketone solvents such as acetone, and amide solvents such as dimethylformamide and formamide can be used. Of these, ester solvents such as ethyl acetate or ether solvents such as tetrahydrofuran are preferred. The reaction temperature is, for example, about −50 ° C. to room temperature, and the reaction time is about several hours to several days.

  This reaction is generally performed by adding a compound represented by the above general formula (I) and a rare earth compound to a reaction system to form a complex, and the general formulas (III) and (IV) serving as reaction raw materials there. However, the order of addition of each reagent is not particularly limited. The ratio of the compound represented by the general formula (I) with respect to the rare earth compound is not particularly limited.For example, a preferred ratio when using the rare earth compound x mol% and the compound y mol% represented by the general formula (I) (x / y) is about 1/1 to 1/5, and is preferably in the range of 1 / 1.5-1 to 1/2 from the viewpoint of increasing the optical yield. In general, the rare earth compound is preferably added to the reaction system at a concentration of about 10 mol% and the compound represented by the general formula (I) is added at a concentration of about 20 mol%. The ratio of the compounds represented by the general formulas (III) and (IV) is not particularly limited, but 1 to 1.5 equivalents of the compound represented by the general formula (IV) with respect to the compound represented by the general formula (III). It is preferable to use within a range.

  You may perform reaction in presence of additives, such as an acid or a base, as needed. Although the kind of additive is not specifically limited, For example, an acid or a base can be used. As the acid, for example, trifluoroacetic acid, benzoic acid, p-tert-butylphenol, m-dimethylaminophenol, or p-aminophenol can be used, and as the base, triethylamine, valine t-butyl ester, or the like is used. be able to. Although the concentration in the case of using an acid or a base is not particularly limited, for example, it can be used at a concentration of about 1 to 30 mol%. In particular, when a complex is formed using a neutral salt such as lanthanum nitrate, the reaction is preferably performed in the presence of a base. As the base, valine t-butyl ester or the like is preferably used. For example, the reaction is preferably performed in the presence of about 3 molar equivalents of the base represented by the compound represented by the general formula (I). Lanthanum nitrate is readily available and is very cheap compared to lanthanum triisopropoxide, and is therefore suitable for industrial reactions. In addition, a reaction prepared by combining a catalyst prepared using lanthanum nitrate with a base can perform an asymmetric amination reaction with high reproducibility, and can be performed in a short time with an extremely small amount of catalyst. be able to.

By subjecting the compound represented by the general formula (II) obtained by the above reaction to NN bond cleavage reaction, it becomes a key intermediate for the production of AS-3201 (R)-(-)-3 A compound represented by the general formula (V) including -amino-3- (ethoxycarbonyl) -2,5-dioxopyrrolidine can be produced. As the protecting group for the carboxyl group represented by R ^{5 in the} compound represented by the general formula (V), those described for R ² above can be used, and an ethyl group can be preferably used. This reaction is carried out, for example, by adding 4N hydrogen chloride ethyl acetate solution to ethyl (R)-(-)-3-amino-3- (ethoxycarbonyl) -2,5-dioxopyrrolidine-3-carboxylate in ethyl acetate solution. And stirred for 24 hours at room temperature, and then reacted with platinum oxide or the like as a catalyst in an acetic acid solvent. By using an R-configuration compound as the compound represented by the general formula (I), a compound having a desired steric structure represented by the general formula (II) can be produced, and then a protecting group on nitrogen can be produced. (R)-(-)-3-Amino-3- (ethoxycarbonyl) -2,5-dioxopyrrolidine is a key intermediate for the production of AS-3201 by performing deprotection and NN bond cleavage reaction A compound represented by the general formula (V) including the above can be produced.

In the compound represented by the general formula (V), ethyl (R)-(−)-3-amino-3- (ethoxycarbonyl) -2,5-dioxopyrrolidine-3- wherein R ⁵ is an ethyl group Carboxylate is a compound represented by “Compound 37” in Scheme 5 on page 4121 of J. Med. Chem., 41, pp. 4118-4129, 1998. From this compound, AS-3201 is incorporated into the above document. It can be easily produced according to the described method.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.
Example 1: Synthesis of a ligand (synthesis of a compound of general formula (I) in which R ¹ is an isopropyl group)
In a 100 mL eggplant-shaped flask, N-tert-butyloxycarbonyl-L-valine (1.400 g, 6.44 mmol), 2- (O-benzyloxy) aminophenol (1.284 g, 6.44 mmol), 1-hydroxybenzotriazole ( 1.017 g, 6.44 mmol) was added and dissolved in 32 mL of methylene chloride. Triethylamine (1.077 mL, 7.73 mmol) was added at room temperature, and the mixture was stirred and cooled to 0 ° C. N-ethyl-N ′-(3-dimethylamino) propylcarbodiimide hydrochloride (1.482 g, 7.73 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 9 hours. 1N Hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the residue obtained after concentration was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-4 / 1), concentrated under reduced pressure and dried to give (2S)- N- (2-benzyloxy) phenyl-2-tert-butoxycarbonylamino-2-isopropylacetamide (2.292 g, yield 89%) was obtained.

  The obtained product (2.292 g, 5.751 mmol) was dissolved in methylene chloride (5 mL) and cooled to 0 ° C. To this solution was added 4N hydrogen chloride dioxane solution, and the mixture was stirred at 0 ° C for 2 hours, and further stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ether was added to the resulting solid residue, insoluble components were collected by filtration, and washed thoroughly with ether. After drying under reduced pressure, (2S) -2-amino-N- (2-benzyloxy) phenyl-2-isopropylacetamide hydrochloride (1.890 g, yield 98%) was obtained as a colorless powder.

  To a suspension of the obtained hydrochloride (1.890 g, 5.644 mmol) in methylene chloride (28 mL), salicylic acid (779.5 mg, 5.644 mmol), 1-hydroxybenzotriazole (1.124 g, 7.34 mmol), triethylamine (1.573 mL) , 11.288 mmol) were added sequentially and cooled to 0 ° C. N-ethyl-N ′-(3-dimethylamino) propylcarbodiimide hydrochloride (1.403 g, 7.34 mmol) was added to the resulting solution, and the mixture was stirred at 0 ° C. for 1 hour and stirred at room temperature for 6 hours. Saturated aqueous citric acid solution was added to the reaction solution, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10 / 1-5 / 1), and (2S) -N- (2-benzyloxy) phenyl-2- Salicyloylamino-2-isopropylacetamide (1.690 g, yield 72%) was obtained as a colorless amorphous crystalline material.

The obtained product (1.690 g, 4.038 mmol) was dissolved in methanol (15 mL), 10% palladium-carbon (169 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The palladium-carbon was filtered through Celite, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography. The resulting colorless solid was recrystallized from ether / hexane to obtain the desired ligand (1.292 g, yield 97%). Was obtained as a white powder.
¹ H NMR (CDCl ₃ ): δ 1.08 (d, J = 2.1 Hz, 3H), 1.10 (d, J = 2.4 Hz, 3H), 2.29-2.36 (m, 1H), 4.65 (dd, J = 7.8, 8.0 Hz, 1H), 6.72 (dd, J = 7.3, 7.8 Hz, 1H), 6.77 (dd, 7.3 Hz, 7,8 Hz 1H), 6.84-6.92 (m, 2H), 6.99 (dd, J = 7.3 , 7.8 Hz, 1H), 7.26 (dd, J = 7.3, 8.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 9.07 (brs, 1H), 11.50 (brs, 1H).

Similarly, a compound in which R ¹ is a sec-butyl group, a cyclohexyl group, a tert-butyl group, a 3-indolylmethyl group, a benzyl group, or an isobutyl group was produced.
Compound in which R ¹ is sec-butyl group
¹ H NMR (CDCl ₃ ): δ 0.98 (dd, J = 6.1, 6.8 Hz, 3H), 1.08 (d, J = 8.4 Hz, 3H), 1.22-1.35 (m, 1H), 1.66-1.73 (m, 1H), 2.11-2.17 (m, 1H), 4.66 (dd, J = 6.9, 8.3 Hz, 1H), 6.85-6.89 (m, 2H), 6.98-7.02 (m, 3H), 7.13 (dd, J = 7.6, 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.40-7.49 (m, 2H), 8.04 (brs, 1H), 8.23 (s, 1H), 11.83 (s, 1H).

A compound in which R ¹ is a cyclohexyl group
¹ H NMR (CDCl ₃ ): δ 1.11-1.25 (m, 5H), 1.64 (brd, J = 12.8 Hz, 1H), 1.73-1.76 (m, 2H), 1.83 (brd, J = 12.2 Hz, 1H) , 1.93 (brd, J = 12.2 Hz, 1H), 1.99-2.03 (m, 1H), 4.63 (dd, J = 8.0, 8.3 Hz, 1H), 6.73 (dd, J = 7.3, 7.3 Hz, 1H), 6.80 (dd, J = 7.3, 7.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.3, 8.3 Hz, 1H) ), 7.29-7.33 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.60 (brs , 1H), 8.77 (s, 1H), 11.6 (s, 1H).

Compound in which R ¹ is tert-butyl group
¹ H NMR (CDCl ₃ ): δ 1.17 (s, 9H), 4.67 (d, J = 9.2 Hz, 1H), 6.91 (dd, J = 7.3, 8.0 Hz, 2H), 6.98-7.05 (m, 3H) , 7.15-7.23 (m, 3H), 7.44-7.49 (m, 2H), 7.74-7.77 (m, 2H).
Compound in which R ¹ is 3-indolylmethyl group
¹ H NMR (CDCl ₃ ): δ 3.30 (dd, J = 8.5, 14.5 Hz, 1H), 3.60 (dd, J = 9.9, 14.5 Hz, 1H), 5.12-5.17 (m, 1H), 6.59 (s, 8.0 Hz, 1H), 6.75 (dd, J = 8.0, 8.0 Hz, 1H), 6.80 (dd, J = 7.8, 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz.1H), 7.02-7.08 (m, 1H), 7.12-7.20 (m, 3H), 7.22-7.26 (m, 1H), 7.37-7.42 (m, 2H), 7.72 (brs, 1H) , 7.79 (d, J = 6.6 Hz, 1H), 8.10 (s, 1H), 8.17 (brs, 1H), 11.98 (s, 1H).

A compound in which R ¹ is a benzyl group
¹ H NMR (DMSO): δ 3.12 (dd, J = 9.3, 13.5 Hz, 1H), 3.24 (dd, 4.6, 13.5 Hz, 1H), 5.04 (brs, 1H), 6.77 (dd, J = 7.5, 7.5 Hz, 1H), 6.84-6.95 (m, 4H), 7.17 (dd, J = 7.0, 7.0 Hz, 1H), 7.26 (dd, J = 7.5, 7.5 Hz, 2H), 7.37 (d, J = 6.4 Hz , 3H), 7.82 (brd, J = 8.0 Hz, 1H), 7.89 (brd, J = 7.3 Hz, 1H), 9.03 (brs, 1H), 9.45 (brs, 1H), 9.82 (brs, 1H), 11.9 (brs, 1H).
Compound in which R ¹ is an isobutyl group
¹ H NMR (CDCl ₃ ): δ 1.00 (d, J = 6.7 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 1.22-1.30 (m, 1H), 1.76-1.83 (m, 2H) , 1.92-1.95 (m, 1H), 4.87 (brd, J = 6.4 Hz, 1H), 6.83-6.89 (m, 3H), 6.98 (d, J = 8.3 Hz, 2H), 7.09-7.11 (m, 1H ), 7.18 (d, J = 7.9 Hz, 1H), 7.40-7.47 (m, 2H), 8.54 (brs, 1H).

Example 2: Asymmetric amination reaction In general formula (II), a compound in which R ² is an ethyl group and R ³ and R ⁴ are both tert-butyl groups was synthesized by the following method.
A 20 mL test tube was dried by heating under reduced pressure, allowed to cool, and then placed in an argon atmosphere. 50 mL (0.01 mmol) of 0.2 M lanthanum triisopropoxide in tetrahydrofuran (THF), R ¹ obtained in Example ¹ was After adding 200 mL (0.02 mmol) of a 0.1 M THF solution of the compound of the general formula (I) which is an isopropyl group, the mixture was stirred at room temperature for 1 hour. After about 30 minutes, the reaction solution became cloudy. Thereafter, the THF solvent was distilled off under reduced pressure in an argon atmosphere, followed by drying under reduced pressure at room temperature for 1 hour. Next, 700 mL of ethyl acetate (AcOEt) was added, and 0.1 mmol of 3-ethoxycarbonylsuccinimide was dissolved in 150 mL of AcOEt. The resulting cloudy solution was cooled to 0 ° C., and 0.12 mmol of di-tert-butylazodicarboxylate was dissolved in 150 ml of AcOEt and added. The reaction was usually completed in about 10 hours, and the completion of the reaction was confirmed by TLC. About 3 mL of 1N aqueous hydrochloric acid solution was added, and the mixture was extracted 3 times with 5 mL of ethyl acetate. Subsequently, the organic phase was washed with 10 mL of saturated aqueous sodium hydrogen carbonate solution and 10 mL of saturated brine, and the obtained organic phase was dried over sodium sulfate, evaporated under reduced pressure, and dried under reduced pressure to obtain a crude product. .

From the obtained crude product, the disappearance rate of the raw material was determined by ¹ H NMR (CDCl ₃ ) using dibenzyl ether as an internal standard substance. A portion of the crude product was purified by PTLC to determine optical purity (ee) and optical purity was determined by HPLC (85-92% ee). The conditions are as follows.
Column: Daicel Chemical CHIRALPAK AD-H (4.6Φx250mm)
Solvent: n-hexane / methanol = 95/5
Flow rate: 1.0ml / min
Column temperature: 40 ° C
Peak detection: 210 nm
Retention time: 9.0 min ((-) enantiomer), 12.5 min ((+) enantiomer)

Similarly, the above reaction was performed using a lanthanum complex prepared using each of the above ligands as an asymmetric amination catalyst, and the results shown in Table 1 below were obtained (in the table, cyclohexyl represents a cyclohexyl group). CH ₂ -3-indole represents a 3-indolylmethyl group).

Example 3
A rare earth complex in which R ¹ is isopropyl was prepared in the same manner as in Example 2, and an asymmetric amination reaction was carried out in the same manner as in Example 2. The results are shown in Table 2.

Example 4
The asymmetric amination reaction similar to Example 2 was performed in the presence of various additives, and the influence of the additives was examined. The results are shown in Table 3. The concentration of each additive is in the range of 5-10 mol%.

Example 5: Deamination reaction The compound obtained in Example 2 (a compound in which R ² is an ethyl group and R ³ and R ⁴ are both tert-butyl groups in general formula (II)) is subjected to an NN bond cleavage reaction. Then, a compound in which R ⁵ is an ethyl group in the general formula (V) was synthesized as follows.
Ethyl 3- [N, N'-bis (tert-butyloxycarbonyl) hydrazino] -2,5-dioxypyrrolidine-3-carboxylate (67.4 mg) in ethyl acetate (0.5 mL) in 4N hydrogen chloride acetic acid Ethyl solution (1 mL) was added, and the mixture was stirred at room temperature for 11 and a half hours. The insoluble component was collected by filtration and washed with ether to give ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate monohydrochloride (19.3 mg, 48%) as a powder.

  Platinum oxide (3.7 mg) was added to a mixture of the obtained ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate monohydrochloride (19.2 mg), acetic acid (1 mL), and water (0.5 mL). In addition, this was vigorously stirred at 50 ° C. for 2 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through celite, and the celite was washed with a small amount of acetic acid. Sodium acetate (12 mg) was added to the mixed solution of the filtrate and the washing solution and concentrated. To remove residual acetic acid and water, toluene was added to the residue and concentrated again. Ethyl acetate was added to the residue, insoluble matter was collected by filtration, and the combined product obtained by concentrating the ethyl acetate solution was purified by PTLC (methylene chloride / methanol = 20/1) to obtain the desired product (S)-( +)-3-Amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine (9.3 mg, 62%) was obtained.

In Example 2, the asymmetric amino group was prepared by using the compound of the general formula (I) in which R ¹ is an isopropyl group obtained from N-tert-butyloxycarbonyl-L-valine in Example 1 as a ligand. (S)-(+)-3-amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine is obtained by cleaving the NN bond of the amination product by the above method. It has been. Therefore, (R)-(−)-3-amino- (ethoxycarbonyl) -2,5-dioxopyrrolidine, the key intermediate for the production of AS-3201, is N-tert-butyloxycarbonyl-D A ligand was produced by the method of Example 1 using -valine as a starting material, and asymmetric amination of 3-ethoxycarbonylsuccinimide was carried out using the ligand. By deamination according to the method, in principle the same chemical and optical yields can be obtained.

Example 6: Asymmetric amination reaction
In a 500 mL eggplant-shaped flask, lanthanum nitrate hexahydrate (La (NO ₃ ) ₃ · 6H ₂ O, 126 mg, 0.292 mmol), represented by general formula (I) derived from D-valine, in an air atmosphere An R-configuration compound (a compound in which R ¹ is an isopropyl group, 96 mg, 0.292 mmol) was introduced, and ethyl acetate (1.46 mL) was added and stirred. When D-valine-tert-butyl ester (167 μL, 0.876 mmol) was added to the obtained transparent solution, the reaction solution gradually became cloudy. A solution of 3-ethoxycarbonylsuccinimide (10 g, 58.4 mmol) in ethyl acetate (60 ml) was then added to give a clear solution. The resulting solution was cooled to 0 ° C., and a reaction was started by adding an ethyl acetate solution (50 mL) of di-tert-butylazodicarboxylate (16.1 g, 70.08 mmol). After confirming the disappearance of the raw materials by TLC (60 minutes), about 80 mL of a 1N hydrochloric acid aqueous solution was added for liquid separation, and the aqueous phase was extracted once with 100 mL of ethyl acetate. Subsequently, the organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, evaporated under reduced pressure, and dried under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (methylene chloride / cyclohexane / ethyl acetate = 4/4/1), and the target product (-)-enantiomer (R ² in general formula (II) was A compound having an ethyl group and R ³ and R ⁴ are both tert-butyl groups) (23.4 g, yield 99%). Optical purity was determined by HPLC (90% ee). The conditions are as follows.
Column: Daicel Chemical CHIRALPAK AD-H (4.6Φ x 250 mm)
Solvent: n-hexane / methanol = 95/5
Flow rate: 1.0 ml / min
Column temperature: 40 ° C
Peak detection: 210 nm
Retention time: 9.0 min ((-)-enantiomer), 12.5 min ((+)-enantiomer).

Claims (11)

The following general formula (I):

(Wherein R ¹ represents a C _3-8 alkyl group or an aralkyl group, and * represents an asymmetric carbon in either the S-configuration or the R-configuration). The compound according to claim 1, wherein R ¹ is a branched chain or a cyclic C _3-8 alkyl group. A rare earth complex having the compound according to claim 1 or 2 as a ligand. The rare earth complex according to claim 3, wherein the rare earth element is lanthanum. The catalyst for asymmetric amination reaction containing the rare earth complex of Claim 3. The catalyst for asymmetric amination according to claim 5, comprising a lanthanum complex containing, as a ligand, an R-configuration compound in which R ¹ is an isopropyl group. The following general formula (II):

(Wherein R ² , R ³ and R ⁴ each independently represents a protecting group for a carboxyl group), which is a method for producing a compound represented by the following general formula (III):

(Wherein R ² is as defined above) and the following general formula (IV):
R ³ -O-CO-N = N-CO-OR ⁴
A method comprising a step of reacting a compound represented by the formula (wherein R ³ and R ⁴ are as defined above) in the presence of the catalyst for asymmetric amination reaction according to claim 6. The method according to claim 7, wherein R ² , R ³ , and R ⁴ are alkyl groups. The method according to claim 7 or 8, wherein the catalyst for asymmetric amination reaction is prepared using lanthanum triisopropoxide. The method according to claim 7 or 8, wherein the catalyst for asymmetric amination reaction is prepared using lanthanum nitrate, and the asymmetric amination reaction is carried out in the presence of a base. The following general formula (V):

(Wherein R ⁵ represents a hydrogen atom or a protecting group for a carboxyl group), which is a method for producing a compound represented by the following steps:
(a) The asymmetric amination catalyst according to claim 6, wherein the compound represented by general formula (III) according to claim 7 and the compound represented by general formula (IV) according to claim 7 are combined. And a step of obtaining a compound represented by the general formula (II) according to claim 7; and
(b) After removing COOR ³ and COOR ⁴ from the compound represented by the general formula (II) obtained in the step (a), the NN bond is cleaved to represent the general formula (V). A method comprising the step of converting to a compound.