KR101057304B1 - Method for preparing aspartic acid derivative using chiral catalyst - Google Patents

Method for preparing aspartic acid derivative using chiral catalyst Download PDF

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KR101057304B1
KR101057304B1 KR1020080138544A KR20080138544A KR101057304B1 KR 101057304 B1 KR101057304 B1 KR 101057304B1 KR 1020080138544 A KR1020080138544 A KR 1020080138544A KR 20080138544 A KR20080138544 A KR 20080138544A KR 101057304 B1 KR101057304 B1 KR 101057304B1
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aspartic acid
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amine
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김대영
심성보
강영구
강승희
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순천향대학교 산학협력단
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract

하기 화학식 1의 친전자체 화합물을, 키랄 팔라듐 촉매의 존재하에서, 아민과 반응시켜 광학 활성 아스파르트산 유도체를 제조하는 방법이 개시된다:A method for preparing an optically active aspartic acid derivative is disclosed by reacting an electrophilic compound of formula (1) with an amine in the presence of a chiral palladium catalyst:

Figure 112008091093598-pat00001
Figure 112008091093598-pat00001

상기 화학식 1에서, 상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기, 아릴기 또는 치환된 아릴기이고, 상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이다. 또한, 상기 제조방법은, 카이랄 팔라듐 촉매를 이용하여, 수율 및 입체선택성이 우수한 광학 활성 아스파르트산 유도체를 제조할 수 있다는 장점이 있다.In Formula 1, R 1 is C 1 -C 30 Alkyl group, cyclized alkyl group, benzyl group, aryl group or substituted aryl group, Z is C 1 -C 20 Alkoxy, amine, amide, hydroxy Amine or a 5-6 hexacyclic hetero atom compound, wherein the hetero atom is nitrogen, oxygen or sulfur. In addition, the production method has an advantage that an optically active aspartic acid derivative having excellent yield and stereoselectivity can be prepared using a chiral palladium catalyst.

키랄 촉매, 아민, 광학활성, 아스파르트산 유도체 Chiral catalysts, amines, optically active, aspartic acid derivatives

Description

키랄 촉매를 이용한 아스파르트산 유도체의 제조방법{Method for Preparation of Aspartic Acid Derivatives Using Chiral Catalyst}Method for Preparation of Aspartic Acid Derivatives Using Chiral Catalyst

본 발명은 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법에 관한 것이다. The present invention relates to a method for preparing an optically active aspartic acid derivative using a chiral catalyst.

광학 이성질체들은 밀도, 녹는점, 끓는점 등 대부분의 물리적 성질이 동일하지만, 편광된 빛을 흡수하는 정도가 다르기 때문에 선형편광된 빛을 조사(照射)했을 때 편광면이 회전하게 되며, 이러한 현상을 광학활성이라고 한다. Optical isomers have the same physical properties, such as density, melting point, and boiling point, but because they absorb differently polarized light, the plane of polarization rotates when irradiated with linearly polarized light. It is called active.

물질의 광학활성은 편광계를 사용하여 측정한다. 광학활성은 대칭 중심, 대칭면 또는 회전축 등의 대칭 요소를 갖지 못하는 분자에서 나타나며, 이러한 분자들은 왼손 또는 오른손과 같이 좌우가 바뀌고 서로 겹쳐지지 않는 거울상체의 관계를 갖는 2 개의 이성질체로 존재할 수 있으며, 이런 성질을 가진 분자를 키랄성 화합물(chiral compound)이라고 한다. The optical activity of the material is measured using a polarimeter. Optical activity occurs in molecules that do not have symmetrical elements, such as the center of symmetry, the plane of symmetry, or the axis of rotation, and these molecules can exist as two isomers with enantiomers that do not overlap and overlap each other, such as the left or right hand. Molecules with properties are called chiral compounds.

탄소에 연결된 4 개의 원자단(原子團)이 모두 다른 비대칭(키랄중심, chiral center) 탄소를 가진 탄소화합물, 또는 두 자리 리간드를 가진 전이금속착물에서 흔히 볼 수 있다. 자연계에 존재하는 20여 종의 아미노산 중 글리신을 제외한 모 든 아미노산은 비대칭탄소를 가진 키랄성 화합물이다. All four atomic groups linked to carbon are commonly found in carbon compounds with different asymmetric (chiral center) carbons, or in transition metal complexes with bidentate ligands. Of the 20 kinds of amino acids present in nature, all amino acids except glycine are chiral compounds with asymmetric carbons.

특히, 키랄 아스파르트산 유도체는 의약품, 농약 화학 제품의 원료 및 유사약물의 합성에 유용한 중간체이다. 그러나, 낮은 입체선택성을 보완하고, 유도체의 범위를 확대할 수 있는 제조방법에 대한 필요성이 요구되는 실정이다. In particular, chiral aspartic acid derivatives are useful intermediates for the synthesis of pharmaceuticals, raw materials for agrochemical chemicals and analogues. However, there is a need for a manufacturing method that can complement low stereoselectivity and extend the range of derivatives.

본 발명의 일실시예의 목적은 광학 순도가 우수한 아스파르트산 유도체의 제조방법을 제공하는 것이다. An object of one embodiment of the present invention is to provide a method for producing an aspartic acid derivative having excellent optical purity.

본 발명에 따른 제조방법은, 하기 화학식 1의 친전자체 화합물을, 키랄 팔라듐 촉매의 존재하에서, 아민과 반응시켜 광학 활성 아스파르트산 유도체를 제조하는 것을 특징으로 한다:The preparation method according to the invention is characterized in that an electrophilic compound of formula 1 is reacted with an amine in the presence of a chiral palladium catalyst to prepare an optically active aspartic acid derivative:

[화학식 1][Formula 1]

Figure 112008091093598-pat00002
Figure 112008091093598-pat00002

상기 화학식 1에서,In Chemical Formula 1,

상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기, 아릴기 또는 치환된 아릴기이고, 상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이다.R 1 is a C 1 -C 30 alkyl group, a cyclized alkyl group, a benzyl group, an aryl group or a substituted aryl group, and Z is C 1 -C 20 alkoxy, amine, amide, hydroxy amine or 5-6 Each cyclic hetero atom compound is a hetero atom, which is nitrogen, oxygen or sulfur.

본 발명에 따른 제조방법은, 카이랄 팔라듐 촉매를 이용하여, 수율 및 입체선택성이 우수한 광학 활성 아스파르트산 유도체를 제조할 수 있다는 장점이 있다. The production method according to the present invention has an advantage that an optically active aspartic acid derivative having excellent yield and stereoselectivity can be prepared using a chiral palladium catalyst.

본 발명의 일실시예에 따른 제조방법은, 하기 화학식 1의 친전자체 화합물을, 키랄 팔라듐 촉매의 존재하에서, 아민과 반응시켜 광학 활성 아스파르트산 유도체를 제조한다. 상기 제조방법은, 키랄 팔라듐 촉매를 이용하여 높은 수율과 우수한 입체선택성(ee)을 갖는 아스파르트산 유도체를 제조하기 위한 것이다.In the preparation method according to an embodiment of the present invention, an electrophilic compound of formula 1 is reacted with an amine in the presence of a chiral palladium catalyst to prepare an optically active aspartic acid derivative. The preparation method is for producing an aspartic acid derivative having high yield and excellent stereoselectivity (ee) using a chiral palladium catalyst.

[화학식 1][Formula 1]

Figure 112008091093598-pat00003
Figure 112008091093598-pat00003

상기 화학식 1에서, 상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기, 아릴기 또는 치환된 아릴기이고, 상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이다. In Formula 1, R 1 is C 1 -C 30 Alkyl group, cyclized alkyl group, benzyl group, aryl group or substituted aryl group, Z is C 1 -C 20 Alkoxy, amine, amide, hydroxy Amine or a 5-6 hexacyclic hetero atom compound, wherein the hetero atom is nitrogen, oxygen or sulfur.

또 다른 일실시예에서, 상기 키랄 팔라듐 촉매는, 하기 화학식 2의 화합물 또는 그 광학 이성질체인 화학식 3의 화합물일 수 있다.In another embodiment, the chiral palladium catalyst may be a compound of Formula 3, which is a compound of Formula 2 or an optical isomer thereof.

Figure 112008091093598-pat00004
Figure 112008091093598-pat00004

Figure 112008091093598-pat00005
Figure 112008091093598-pat00005

상기 화학식 2 또는 3에서, In Chemical Formula 2 or 3,

상기 알킬기(Ar)는 페닐(Phenyl), 4-메틸페닐(4-methylphenyl) 또는 3,5-디메틸페닐(3,5-dimethylphenyl)이며,The alkyl group (Ar) is phenyl (Phenyl), 4-methylphenyl (4-methylphenyl) or 3,5-dimethylphenyl (3,5-dimethylphenyl),

상기 X는 BF4, OTf(trifluoromethanesulfonate), SbF6 또는 PF6이다.X is BF 4 , trifluoromethanesulfonate (OTf), SbF 6 or PF 6 .

본 발명의 일실시예에 따른 제조방법은, 하기 반응식 1과 같이 나타낼 수 있다. 하기 반응식 1에 의하면, 친전자체 화합물(1)을, 팔라듐 촉매(2, 3)의 존재하에서, 아민 화합물(4)과 반응시켜 광학 활성 아스파르트산 유도체(5)를 합성하게 된다. Manufacturing method according to an embodiment of the present invention, it can be represented by the following scheme 1. According to Scheme 1, the electrophile compound (1) is reacted with the amine compound (4) in the presence of the palladium catalysts (2, 3) to synthesize the optically active aspartic acid derivative (5).

Figure 112008091093598-pat00006
Figure 112008091093598-pat00006

상기 식에서, Where

상기 R1은 C1-C20의 알킬기, 고리화 알킬기, 벤질기, 아릴기 또는 치환된 아릴기이고, 보다 구체적으로는 메틸, 에틸, 벤질 또는 이소프로필기이고,R 1 is a C 1 -C 20 alkyl group, a cyclized alkyl group, a benzyl group, an aryl group or a substituted aryl group, more specifically methyl, ethyl, benzyl or isopropyl group,

상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이고,Z is a C 1 -C 20 alkoxy, amine, amide, hydroxy amine or 5-hexagonal cyclic hetero atom compound, the hetero atom is nitrogen, oxygen or sulfur,

상기 R2 및 R3는 각각 독립적으로 수소, C1-C30의 알킬기 또는 아릴기이며, R2와 R3는 서로 연결되어 고리를 형성할 수 있고, 상기 아릴기는 치환된 아릴기이며, 상기 치환기는 수소, 알킬기, 알콕시 또는 알콕시 카보닐기이다.R 2 and R 3 are each independently hydrogen, an alkyl group or an aryl group of C 1 -C 30 , R 2 and R 3 may be connected to each other to form a ring, the aryl group is a substituted aryl group, The substituent is hydrogen, an alkyl group, an alkoxy or alkoxy carbonyl group.

또한, 일실시예에서, 상기 팔라듐 촉매는 하기 반응식 2의 공정을 통해 제조할 수 있다. In addition, in one embodiment, the palladium catalyst may be prepared through the process of Scheme 2.

Figure 112008091093598-pat00007
Figure 112008091093598-pat00007

일실시예에서, 상기 아민은, C1-C30의 1, 2차 알킬 아민 또는 헤테로 아민, 또는 벤젠고리의 o-, p-, m- 위치에 알킬, 할로겐 또는 에스터가 치환된 방향족 아민 화합물이다. 보다 구체적으로는, 상기 아민은 하기 화학식 4의 구조를 갖는 화합물들 중에서 하나 이상일 수 있다.In one embodiment, the amine is a C 1 -C 30 primary, secondary alkyl amine or hetero amine, or an aromatic amine compound substituted with alkyl, halogen or ester at o- , p- , m- position of the benzene ring to be. More specifically, the amine may be one or more of the compounds having a structure of formula (4).

Figure 112008091093598-pat00008
Figure 112008091093598-pat00008

일실시예에서, 상기 아스파르트산 유도체는, 하기 화학식 5의 구조를 갖는 화합물이다. In one embodiment, the aspartic acid derivative is a compound having a structure of formula (5).

Figure 112008091093598-pat00009
또는
Figure 112008091093598-pat00010
Figure 112008091093598-pat00009
or
Figure 112008091093598-pat00010

상기 화학식 5에서,In Formula 5,

상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기, 아릴기 또는 치환된 아릴기이고,R 1 is a C 1 -C 30 alkyl group, a cyclized alkyl group, a benzyl group, an aryl group or a substituted aryl group,

상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이고,Z is a C 1 -C 20 alkoxy, amine, amide, hydroxy amine or 5-hexagonal cyclic hetero atom compound, the hetero atom is nitrogen, oxygen or sulfur,

상기 R2 및 R3는 각각 독립적으로 수소, C1-C30의 알킬기 또는 아릴기이며, R2와 R3는 서로 연결되어 고리를 형성할 수 있고, 상기 아릴기는 치환된 아릴기이며, 상기 치환기는 수소, 알킬기, 알콕시 또는 알콕시 카보닐기이다. R 2 and R 3 are each independently hydrogen, an alkyl group or an aryl group of C 1 -C 30 , R 2 and R 3 may be connected to each other to form a ring, the aryl group is a substituted aryl group, The substituent is hydrogen, an alkyl group, an alkoxy or alkoxy carbonyl group.

또한, 상기 Z의 고리형 헤테로 원자 화합물은, 옥사졸리디논(oxazolidinone), 피롤리논(pyrrolinone), 2-아미노 피리딘, 2-아미노 싸이오펜 또는 2-아미노 푸란일 수 있다. In addition, the cyclic hetero atom compound of Z may be oxazolidinone, pyrrolinone, 2-amino pyridine, 2-amino thiophene or 2-amino furan.

일실시예에서, 상기 제조방법은 반응과정에서 극성 또는 비극성 용매가 사용될 수 있으며, 상기 극성 용매로는 알코올 등이 사용될 수 있고, 상기 비극성 용매로는 톨루엔, 자일렌, 헥산, 테트라하이드로퓨란, 다이옥산, 벤젠 또는 디클로로메탄 등이 사용될 수 있다.In one embodiment, the manufacturing method may be a polar or non-polar solvent may be used in the reaction process, alcohol may be used as the polar solvent, toluene, xylene, hexane, tetrahydrofuran, dioxane as the non-polar solvent , Benzene or dichloromethane and the like can be used.

상기 제조방법은, 용이하게 이용할 수 있는 출발물질 및 촉매를 사용하여 광학 활성 빌딩 블록을 제조하기 위한 것이다. 또한, 상기 제조방법으로 제조된 광학 활성 아스파르트산 유도체는 입체선택성(ee)이 우수하며, 의약품, 농약, 화학 제품의 원료 및 유사약물의 합성에 대한 유용한 중간체로서 활용될 수 있다.The above production method is for producing optically active building blocks using readily available starting materials and catalysts. In addition, the optically active aspartic acid derivative prepared by the above method has excellent stereoselectivity (ee), and can be used as a useful intermediate for synthesizing raw materials of pharmaceuticals, pesticides, chemical products, and similar drugs.

이하, 하기 실시예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시예 등은 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples and the like are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

본 발명의 실시예 등에서 사용된 팔라듐 촉매는, 하기 화학식 2 또는 3과 같으며, 각 경우에 있어서 실시예 등에 사용된 식별번호는 하기 표 1과 같다.The palladium catalyst used in Examples and the like of the present invention is the same as the following Formula 2 or 3, in each case the identification number used in Examples and the like is shown in Table 1 below.

[화학식 2][Formula 2]

Figure 112008091093598-pat00011
Figure 112008091093598-pat00011

[화학식 3](3)

Figure 112008091093598-pat00012
Figure 112008091093598-pat00012

상기 화학식 2 또는 3에서, In Chemical Formula 2 or 3,

상기 아릴기(Ar)는 페닐(Phenyl), 4-메틸페닐(4-methylphenyl) 또는 3,5-디메틸페닐(3,5-dimethylphenyl)이며,The aryl group (Ar) is phenyl (Phenyl), 4-methylphenyl (4-methylphenyl) or 3,5-dimethylphenyl (3,5-dimethylphenyl),

상기 X는 BF4, OTf(trifluoroborate), SbF6 또는 PF6이다.X is BF 4 , trifluoroborate (OTf), SbF 6 or PF 6 .

식 별
번 호Identification
Number 아릴기(Ar)Aryl group (Ar) XX 식 별
번 호Identification
Number 아릴기(Ar)Aryl group (Ar) XX 2a2a PhenylPhenyl
BF4
BF4 3a3a PhenylPhenyl BF4BF4 2b2b PhenylPhenyl
OTf
OTf 3b3b PhenylPhenyl OTfOTf 2c2c PhenylPhenyl
PF6
PF6 3c3c PhenylPhenyl PF6PF6 2d2d PhenylPhenyl
SbF6
SbF6 3d3d PhenylPhenyl SbF6SbF6 2e2e 4-methylphenyl4-methylphenyl
BF4
BF4 3e3e 4-methylphenyl4-methylphenyl BF4BF4 2f2f 4-methylphenyl4-methylphenyl
OTf
OTf 3f3f 4-methylphenyl4-methylphenyl OTfOTf 2g2 g 4-methylphenyl4-methylphenyl
PF6
PF6 3g3g 4-methylphenyl4-methylphenyl PF6PF6 2h2h 4-methylphenyl4-methylphenyl
SbF6
SbF6 3h3h 4-methylphenyl4-methylphenyl SbF6SbF6 2i2i 3,5-dimethylphenyl3,5-dimethylphenyl
BF4
BF4 3i3i 3,5-dimethylphenyl3,5-dimethylphenyl BF4BF4 2j2j 3,5-dimethylphenyl3,5-dimethylphenyl
OTf
OTf 3j3j 3,5-dimethylphenyl3,5-dimethylphenyl OTfOTf 2k2k 3,5-dimethylphenyl3,5-dimethylphenyl
PF6
PF6 3k3k 3,5-dimethylphenyl3,5-dimethylphenyl PF6PF6 2l2l 3,5-dimethylphenyl3,5-dimethylphenyl
SbF6
SbF6 3l3l 3,5-dimethylphenyl3,5-dimethylphenyl SbF6SbF6

[실시예 1] 에틸 4-옥소-4-(2-옥소피리디-3-닐)-2-페닐아미노부타노에이트 합성 Example 1 Synthesis of ethyl 4-oxo-4- (2-oxopyridin-3-yl) -2-phenylaminobutanoate

N-푸마로일-2-피롤리디논 0.075 mmol에 p-자일렌 0.5 mL를 가한 후, 촉매 (2a, 0.0025 mmol) 를 가하고 5 분간 교반하였다. 아닐린 0.05 mmol을 가한 후, 상온에서 15 시간 동안 교반하였다.0.5 mL of p -xylene was added to 0.075 mmol of N -fumaroyl-2-pyrrolidinone, then a catalyst (2a, 0.0025 mmol) was added and stirred for 5 minutes. After adding 0.05 mmol of aniline, the mixture was stirred at room temperature for 15 hours.

반응 혼합물을 column chromatography (SiO2, EA : Hex = 1 : 2)로 분리, 정제하여 생성물을 85% 수율로 얻었다. Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 25.8 min (minor)과 32.9 min (major))를 이용하여 93% ee(Enantiomeric excess) 값을 얻었다.The reaction mixture was separated and purified by column chromatography (SiO 2 , EA: Hex = 1: 2) to obtain the product in 85% yield. Enantiomeric excess was determined using chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 25.8 min (minor) and 32.9 min (major)) To obtain a 93% ee (Enantiomeric excess) value.

[α]24 D-1.9 (c=1.0, CHCl3) for 93% ee; 1H NMR(200MHz, CDCl3) δ = 7.15 (t,J=7.9Hz, 2H), 6.7 (q, J=7Hz, 3H), 4.52 (br, 2H), 4.18 (q, J=7.4Hz, 2H), 3.51 (ddd, J 1=22.5Hz, J 2=17.7Hz, J 3=22.5Hz, 2H), 2.54 (t, J=7.8Hz, 2H), 2.05-1.9 0(m, 2H), 1.22 (t, J=7.42Hz, 3H) 13C MNR (50MHz, CDCl3) δ = 175.45, 172.39, 170.9, 146.41, 129.1, 117.61, 113.50, 61.25, 52.83, 45.119, 39.40, 33.24, 16.94[α] 24 D -1.9 (c = 1.0, CHCl 3 ) for 93% ee; 1 H NMR (200 MHz, CDCl 3 ) δ = 7.15 (t , J = 7.9 Hz, 2H), 6.7 (q, J = 7 Hz, 3H), 4.52 (br, 2H), 4.18 (q, J = 7.4 Hz, 2H), 3.51 (ddd, J 1 = 22.5Hz, J 2 = 17.7Hz, J 3 = 22.5Hz, 2H), 2.54 (t, J = 7.8Hz, 2H), 2.05-1.9 0 (m, 2H), 1.22 (t, J = 7.42 Hz, 3H) 13 C MNR (50 MHz, CDCl 3 ) δ = 175.45, 172.39, 170.9, 146.41, 129.1, 117.61, 113.50, 61.25, 52.83, 45.119, 39.40, 33.24, 16.94

[실시예 2] 에틸 4-옥소-4-(2-옥소피리디-3-닐)-2-페닐아미노부타노익에시드의 합성(절대배열의 결정)Example 2 Synthesis of Ethyl 4-oxo-4- (2-oxopyridin-3-yl) -2-phenylaminobutanoic acid (determination of absolute configuration)

Figure 112008091093598-pat00013
Figure 112008091093598-pat00013

절대 배열은 에틸 4-옥소-4-(2-옥소피리디-3-닐)-2-페닐아미노부타노에이트를 LiOH와 반응시켜 4-에톡시-4-옥소-3-(페닐아미노)부타노익산으로 가수분해시킨 후, HPLC의 Rt와 광학 회전의 비교에 의하여 결정한 결과 R form이었다(참고문헌: Reboule, I.; Gil ,R.; Collin, J. Tetrahedron : Asymmetry . 2005, 16 , 3881-3886.).The absolute configuration is 4-ethoxy-4-oxo-3- (phenylamino) buta by reacting ethyl 4-oxo-4- (2-oxopyridin-3-yl) -2-phenylaminobutanoate with LiOH. After hydrolysis with noic acid, it was determined by comparison of the optical rotation with Rt of HPLC (Reboule, I .; Gil, R .; Collin, J. Tetrahedron : Asymmetry . 2005 , 16 , 3881 -3886.).

[α]26 D +8.6 (c=1.0, CHCl3 ) for 85%ee1H NMR (200MHz, CDCl3) δ = 7.44 (br, 2H), 7.18 (t, J=7.8Hz, 2H), 6.77 (t, J=7.4Hz, 1H), 6.67 (d, J=7.8Hz, 2H), 4.43 (t, J=5.8, 1H), 4.19 (q, J=7.0Hz, 2H), 2.90 (t, J=5.7Hz, 2H), 1.95 (t, J=7Hz, 3H); 13C MNR (50MHz, CDCl3) δ = 176.19, 172.17, 146.01, 130.87, 119.03, 113.99, 68.16, 64.79, 53.40, 37.10, 13.99; HPLC (AD-H, Hexane/iso-propanol : 90/10, 1.0ml/min, 254nm, tR =11.7 min (minor), tR = 12.4 min (major)[α] 26 D +8.6 (c = 1.0, CHCl 3 ) for 85% ee 1 H NMR (200 MHz, CDCl 3 ) δ = 7.44 (br, 2H), 7.18 (t, J = 7.8 Hz, 2H), 6.77 (t, J = 7.4Hz, 1H), 6.67 (d, J = 7.8Hz, 2H), 4.43 (t, J = 5.8, 1H), 4.19 (q, J = 7.0Hz, 2H), 2.90 (t, J = 5.7 Hz, 2H), 1.95 (t, J = 7 Hz, 3H); 13 C MNR (50 MHz, CDCl 3 ) δ = 176.19, 172.17, 146.01, 130.87, 119.03, 113.99, 68.16, 64.79, 53.40, 37.10, 13.99; HPLC (AD-H, Hexane / iso- propanol: 90/10, 1.0ml / min, 254nm, t R = 11.7 min (minor), t R = 12.4 min (major)

[실시예 3]  Example 3

실시예 1에서의 방법을 사용하여, 하기 반응식 3과 같이, 팔라듐 촉매하에 친전자체 화합물 1a, 1b과 아닐린 4a를 반응시켜, 알파 아미노 에스터 유도체 5a, 5b를 얻었으며, 그 결과를 표 2에 나타내었다.Using the method in Example 1, the electrophile compounds 1a and 1b were reacted with aniline 4a under a palladium catalyst to obtain alpha amino ester derivatives 5a and 5b as shown in Scheme 3 below, and the results are shown in Table 2. It was.

Figure 112008091093598-pat00014
Figure 112008091093598-pat00014

R1 R 1 친전자체
화합물(1)Electrophile
Compound (1) 반응시간Reaction time 화합물 5a, 5b의
수율(%)Of compound 5a, 5b
yield(%) ee (%)
(절대배열)ee (%)
(Absolute arrangement) Me4 Me 4 1a1a 1.5 일1.5 days 8585 45 (nd)45 (nd) Et4 Et 4 1a1a 2 일2 days 9595 71 (R)71 (R) i-Pr4 i-Pr 4 1a1a 6 일6 days 8585 47 (nd)47 (nd) Bn4 Bn 4 1a1a 14 일14 days 5050 73 (nd)73 (nd) Me5 Me 5 1b1b 17 시간17 hours 9898 83 (nd)83 (nd) Et 5 Et 5 1b1b 15 시간15 hours 9494 87 (R)87 (R) i-pr5 i-pr 5 1b1b 28 시간28 hours 8989 89 (nd)89 (nd) Bn5 Bn 5 1b1b 30 시간30 hours 7070 91 (nd)91 (nd)

* Enatiomeric excess(ee)는 HPLC로 확인함.Enatiomeric excess (ee) confirmed by HPLC.

* 4 0.5몰 용액* 4 0.5 molar solution

* 5 0.1몰 용액* 5 0.1 molar solution

* R = 절대배열이 R임을 나타냄. * R = indicates that the absolute array is R

* Nd = 절대배열을 결정하지 않음. Nd = do not determine absolute array

상기 표 2에 의하면, 친전자체 화합물 1a의 경우(즉, 화학식 1에서 Z가 옥사졸리디논(oxazolidinone)인 경우)에 R1이 에틸(ethyl)기일 때, 95% 수율과 71%ee를 얻었다. 또한, 친전자체 화합물 1b의 경우(즉, 화학식 1에서 Z가 피롤리디논(pyrrolidinone)인 경우)에 R1이 에틸(ethyl)기일 때, 94% 수율과 87%ee를 얻었다. 따라서, 반응성, 선택성 및 수율 등을 고려할 때, R1 이 에틸(ethyl)기 일 때, 상대적으로 우수한 결과가 나타나는 것을 알 수 있다.According to Table 2, 95% yield and 71% ee were obtained when R 1 is an ethyl group in the case of the electrophile compound 1a (that is, in the case of Z in the formula (1), Z is oxazolidinone). In addition, in the case of the electrophile compound 1b (that is, when Z in the formula 1 is pyrrolidinone), when R 1 is an ethyl group, 94% yield and 87% ee were obtained. Therefore, considering the reactivity, selectivity and yield, etc., R 1 When this ethyl group, it can be seen that a relatively excellent result appears.

[실시예 4]Example 4

친전자체 화합물과 촉매를 달리하였다는 점을 제외하고는, 실시예 1과 동일한 방법으로 반응을 진행하였다. 반응 생성물에 대한 결과는 하기 표 3에 나타내었다.The reaction was carried out in the same manner as in Example 1, except that the electrophile compound and the catalyst were different. The results for the reaction products are shown in Table 3 below.

Figure 112008091093598-pat00015
Figure 112008091093598-pat00015

화합물 (1)Compound (1) 촉매catalyst 반응시간 Reaction time 화합물 5c, 5d의
수율 (%)Of compound 5c, 5d
Yield (%) ee (%)
(절대배열)ee (%)
(Absolute arrangement) 1c1c 2a2a 74 시간74 hours 9090 81 (R)81 (R) 1c1c 2b2b 80 시간80 hours 9494 80 (R)80 (R) 1c1c 2c2c 82 시간82 hours 9191 75 (R)75 (R) 1c1c 2d2d 82 시간82 hours 9090 61 (R)61 (R) 1c1c 2e2e 3 일3 days 9595 80 (R)80 (R) 1c1c 2g2 g 3 일3 days 9696 69 (R)69 (R) 1c1c 2h2h 3 일3 days 9090 51 (R)51 (R) 1c1c 2i2i 6 일6 days 9191 53 (R)53 (R) 1c1c 2j2j 8 일8 days 9797 34 (R)34 (R) 1c1c 2k2k 6 일6 days 9494 29 (R)29 (R) 1c1c 2l2l 5 일5 days 9090 33 (R)33 (R) 1d1d 2a2a 15 시간15 hours 9090 87 (R)87 (R) 1d1d 2e2e 24 시간24 hours 9090 85 (R)85 (R) 1d1d 2i2i 20 시간20 hours 9191 85 (R)85 (R)

* Enatiomeric excess(ee)는 HPLC로 확인함.Enatiomeric excess (ee) confirmed by HPLC.

* R= 절대배열이 R임을 나타냄.* R = indicates that the absolute array is R

상기 표 3에 의하면, 친전자체 화합물 1d와 촉매 2a를 사용했을 때, 상대적으로 우수한 반응성, 수율 및 입체선택성(ee)를 보여주었다.According to Table 3, when the electrophile compound 1d and the catalyst 2a were used, relatively excellent reactivity, yield and stereoselectivity (ee) were shown.

[실시예 5]Example 5

하기 표 4의 각 아민 화합물을 이용하여, 실시예 1과 동일한 방법으로, 아스파르트산 유도체를 합성하였다. 합성된 아스파르트산 유도체에 대한 결과는 하기 표 4에 나타내었다. Aspartic acid derivatives were synthesized in the same manner as in Example 1 using the respective amine compounds shown in Table 4 below. The results for the synthesized aspartic acid derivatives are shown in Table 4 below.

Figure 112008091093598-pat00016
Figure 112008091093598-pat00016

실시예 No.Example No. 아민 화합물Amine compound 반응 시간 (시간)Reaction time (hours) 화합물 5의 수율 (%)Yield of compound 5 (%) ee(%)
(절대배열)ee (%)
(Absolute arrangement) 5-15-1

Figure 112008091093598-pat00017
Figure 112008091093598-pat00017
2424 6060 89 (nd)89 (nd) 5-25-2
Figure 112008091093598-pat00018
Figure 112008091093598-pat00018
 24 24 9090 95 (nd)95 (nd) 5-35-3
Figure 112008091093598-pat00019
Figure 112008091093598-pat00019
 12 12 9595 89 (nd)89 (nd) 5-45-4
Figure 112008091093598-pat00020
Figure 112008091093598-pat00020
 20 20 8585 96 (nd)96 (nd) 5-55-5
Figure 112008091093598-pat00021
Figure 112008091093598-pat00021
 15 15 9292 91 (nd)91 (nd) 5-65-6
Figure 112008091093598-pat00022
Figure 112008091093598-pat00022
 12 12 8080 83 (nd)83 (nd)

* Enatiomeric excess(ee)는 HPLC로 확인함.Enatiomeric excess (ee) confirmed by HPLC.

* Nd = 절대배열을 결정하지 않음 * Nd = does not determine absolute array

실시예Example 5-1. 에틸 3-( 5-1. Ethyl 3- ( 인돌리Indoli -1-닐)-4-옥소-4-(2--1-Nyl) -4-oxo-4- (2- 옥소피리디Oxopyrididi -3-닐)--3-yl)- 부타노에이트Butanoate

실시예 1에서의 방법을 사용하여, 60%의 수율로 생성물 에틸 3-(인돌리-1-닐)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트을 합성하였다. Using the method in Example 1, the product ethyl 3- (indolin-1-yl) -4-oxo-4- (2-oxopyridin-3-yl) -butanoate was synthesized in a yield of 60%. It was.

Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 11.5 min (minor)과 9.4 min (major))를 이용하여 89% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined using chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 11.5 min (minor) and 9.4 min (major)) 89% ee was obtained. The absolute configuration was not determined.

[α]24 D = +64.7 (c = 1.0, CHCl3) for 89% ee; 1H NMR (200 MHz, CDCl3) δ = 7.03 (t, J = 7.2 Hz, 2H), 6.66 (d, J = 7.3 Hz, 1H), 6.56 (t, J = 7.8 Hz, 1H), 4.84 (dd, J 1 = 8.7 Hz, J 2 = 5.2 Hz, 1H), 4.14 (q, J = 7 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H, 3.71-3.17 (m, 4H), 2.96 (t, J = 8.3 Hz, 2H), 2.59 (t, J = 8 Hz, 2H), 2.10-1.95 (m, 2H), 1.17 (t, J = 7.1, 3H); 13C MNR (50 MHz, CDCl3) δ = 175.2, 171.1, 170.3, 148.4, 129.2, 126.7, 124.1, 117.6, 106.9, 60.1, 54.3, 48.8, 45.1, 35.9, 33.1, 27.9, 16.8, 13.8[a] 24 D = +64.7 (c = 1.0, CHC1 3 ) for 89% ee; 1 H NMR (200 MHz, CDCl 3 ) δ = 7.03 (t, J = 7.2 Hz, 2H), 6.66 (d, J = 7.3 Hz, 1H), 6.56 (t, J = 7.8 Hz, 1H), 4.84 ( dd, J 1 = 8.7 Hz, J 2 = 5.2 Hz, 1H), 4.14 (q, J = 7 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H, 3.71-3.17 (m, 4H), 2.96 (t, J = 8.3 Hz, 2H), 2.59 (t, J = 8 Hz, 2H), 2.10-1.95 (m, 2H), 1.17 (t, J = 7.1, 3H); 13 C MNR (50 MHz, CDCl 3 ) δ = 175.2, 171.1, 170.3, 148.4, 129.2, 126.7, 124.1, 117.6, 106.9, 60.1, 54.3, 48.8, 45.1, 35.9, 33.1, 27.9, 16.8, 13.8

실시예Example 5-2. 에틸 4-(4- 5-2. Ethyl 4- (4- 에톡시Ethoxy -1,4--1,4- 다이옥소Dioxo -1-(2--1- (2- 옥소피리디Oxopyrididi -1-닐)-1-yl) 부타Buta -2--2- 닐아미노Nylamino )) 벤조에이트Benzoate

실시예 1에서의 방법을 사용하여, 90%의 수율로 생성물 에틸 4-(4-에톡시-1,4-다이옥소-1-(2-옥소피리디-1-닐)부타-2-닐아미노)벤조에이트를 합성하였다.Using the method in Example 1, the product ethyl 4- (4-ethoxy-1,4-dioxo-1- (2-oxopyridin-1-yl) butan-2-yl in 90% yield Amino) benzoate was synthesized.

Enantiomeric excess의 결정은 chiral HPLC (chiralcell OD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 32.6 min (minor)과 23.7 min(major)) 이용하여 95% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined by chiral HPLC (chiralcell OD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 32.6 min (minor) and 23.7 min (major)). 95% ee was obtained. The absolute configuration was not determined.

mp : 119.5-121 [α]25 D = -3.9 (c = 1.0, CHCl3) for 95% ee; 1H NMR (200 MHz, CDCl3) δ = 7.87 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.99 (d, J = 8.7 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.79 (t, J = 7 Hz, 2H), 3.53 (ddd, J 1 = 25.3 Hz, J 2 = 17.6Hz, J 3 = 5.0 Hz, 2H), 2.59 (t, J = 7.9 Hz, 2H), 2.11-1.96 (m, 2H), 1.35 (t, J = 6.9, 3H), 1.25(t, 3H, J = 7.0); 13C MNR (50 MHz, CDCl3) δ = 175.5, 171.7, 170.7, 166.4, 150.2, 131.3, 119.5, 111.9, 61.5, 60.1, 51.9, 45.1, 39.1, 33.2, 16.9, 14.2, 13.9mp: 119.5-121 [a] 25 D = -3.9 (c = 1.0, CHCl 3 ) for 95% ee; 1 H NMR (200 MHz, CDCl 3 ) δ = 7.87 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.99 (d, J = 8.7 Hz, 1H), 4.30 ( q, J = 6.9 Hz, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.79 (t, J = 7 Hz, 2H), 3.53 (ddd, J 1 = 25.3 Hz, J 2 = 17.6 Hz, J 3 = 5.0 Hz, 2H), 2.59 (t, J = 7.9 Hz, 2H), 2.11-1.96 (m, 2H), 1.35 (t, J = 6.9, 3H), 1.25 (t, 3H, J = 7.0 ); 13 C MNR (50 MHz, CDCl 3 ) δ = 175.5, 171.7, 170.7, 166.4, 150.2, 131.3, 119.5, 111.9, 61.5, 60.1, 51.9, 45.1, 39.1, 33.2, 16.9, 14.2, 13.9

실시예Example 5-3. 에틸 2-(4- 5-3. Ethyl 2- (4- 에틸페닐아미노Ethylphenylamino )-4-옥소-4-(2-) -4-oxo-4- (2- 옥소피리디Oxopyrididi -3-닐)--3-yl)- 부타노에이트Butanoate

실시예 1에서의 방법을 사용하여,95%의 수율로 생성물 실시예 6 에틸 2-(4-에틸페닐아미노)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트을 합성하였다. Using the method in Example 1, Product Example 6 Ethyl 2- (4-ethylphenylamino) -4-oxo-4- (2-oxopyridin-3-yl) -butano in a yield of 95% Eates were synthesized.

Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 30.8 min (minor)과 23.9 min(major)를 이용하여 89% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined using chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 30.8 min (minor) and 23.9 min (major)). An 89% ee value was obtained, the absolute configuration was not determined.

[α]26 D = -3.8 (c = 1.0, CHCl3) for 89% ee; 1H NMR (200 MHz, CDCl3): δ = 7.01 (d, J = 8.2 Hz, 2H), 6.61(d, J = 8.1 Hz, 2H), 4.46-4.43 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.78 (t, J = 7.2 Hz, 2H), 3.49 (ddd, , J 1 = 23.1 Hz, J 2 = 17.5 Hz, J 3= 5.3 Hz, 2H), 2.62-2.47 (m, 4H), 2.09-1.98 (m, 2H), 1.27-1.13 (m, 6H); 13C MNR (50 MHz, CDCl3): δ = 175.4, 172.5, 171.1, 144.4, 134.1, 128.4, 114.5, 61.2, 53.3, 45.1, 39.5, 28.1, 16.9, 15.7, 13.0[a] 26 D = -3.8 (c = 1.0, CHC1 3 ) for 89% ee; 1 H NMR (200 MHz, CDCl 3 ): δ = 7.01 (d, J = 8.2 Hz, 2H), 6.61 (d, J = 8.1 Hz, 2H), 4.46-4.43 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.78 (t, J = 7.2 Hz, 2H), 3.49 (ddd,, J 1 = 23.1 Hz, J 2 = 17.5 Hz, J 3 = 5.3 Hz, 2H), 2.62-2.47 ( m, 4H), 2.09-1.98 (m, 2H), 1.27-1.13 (m, 6H); 13 C MNR (50 MHz, CDCl 3 ): δ = 175.4, 172.5, 171.1, 144.4, 134.1, 128.4, 114.5, 61.2, 53.3, 45.1, 39.5, 28.1, 16.9, 15.7, 13.0

실시예 5-4. 부틸 4-(4-에톡시-1,4-다이옥소-1-(2-옥소피리디-1-닐)부타-2-닐아미노)벤조에이트Example 5-4. Butyl 4- (4-ethoxy-1,4-dioxo-1- (2-oxopyridin-1-yl) buta-2-ylamino) benzoate

실시예 1에서의 방법을 사용하여, 85%의 수율로 생성물 부틸 4-(4-에톡시-1,4-다이옥소-1-(2-옥소피리디-1-닐)부타-2-닐아미노)벤조에이트를 합성하였다.Using the method in Example 1, the product butyl 4- (4-ethoxy-1,4-dioxo-1- (2-oxopyridin-1-yl) butan-2-yl in a yield of 85% Amino) benzoate was synthesized.

Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 79.5 min (minor)과 52.2 min(major)를 이용하여 96% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined by chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 79.5 min (minor) and 52.2 min (major)). A 96% ee value was obtained, the absolute configuration was not determined.

[α]26 D = 7.1 (c = 1.0, CHCl3) for 96% ee; 1H NMR (200 MHz, CDCl3): δ = 7.87 (d, J = 8.7 Hz, 2H), 6.63(d, J = 8.7 Hz, 2H), 5.0 (d, J = 8.5 Hz, 1H), 4.59-4.49 (m, 1H), 4.29-4.09 (m, 4H), 3.79 (t, J = 7.2Hz, 2H), 3.53 (ddd, J 1= 24 Hz, J 2 = 17 Hz, J 3 = 5.4 Hz, 2H), 2.59-2.47 (t, J = 8.1 Hz, 2H), 2.11-1.96 (m, 2H), 1.78-1.65 (m, 2H), 1.55-1.36 (m, 2H), 1.26 (t, J = 8 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C MNR (50 MHz, CDCl3): δ = 175.3, 171.5, 170.5, 166.3, 150.1, 131.1, 119.2, 111.7, 63.7, 61.2, 51.6, 44.9, 38.9, 32.9, 30.5, 18.9, 16.7, 13.7, 13.4[a] 26 D = 7.1 (c = 1.0, CHC1 3 ) for 96% ee; 1 H NMR (200 MHz, CDCl 3 ): δ = 7.87 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.0 (d, J = 8.5 Hz, 1H), 4.59 -4.49 (m, 1H), 4.29-4.09 (m, 4H), 3.79 (t, J = 7.2 Hz, 2H), 3.53 (ddd, J 1 = 24 Hz, J 2 = 17 Hz, J 3 = 5.4 Hz , 2H), 2.59-2.47 (t, J = 8.1 Hz, 2H), 2.11-1.96 (m, 2H), 1.78-1.65 (m, 2H), 1.55-1.36 (m, 2H), 1.26 (t, J = 8 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13 C MNR (50 MHz, CDCl 3 ): δ = 175.3, 171.5, 170.5, 166.3, 150.1, 131.1, 119.2, 111.7, 63.7, 61.2, 51.6, 44.9, 38.9, 32.9, 30.5, 18.9, 16.7, 13.7, 13.4

실시예 5-5. 에틸 2-(4-클로로페닐아미노)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트Example 5-5. Ethyl 2- (4-chlorophenylamino) -4-oxo-4- (2-oxopyridin-3-yl) -butanoate

실시예 1에서의 방법을 사용하여, 92%의 수율로 생성물 실시예 8 에틸 2-(4-클로로페닐아미노)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트을 합성하였다. Using the method in Example 1, the product Example 8 ethyl 2- (4-chlorophenylamino) -4-oxo-4- (2-oxopyridin-3-yl) -butano in a yield of 92% Eates were synthesized.

Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 53.8 min (minor)과 32.9 min(major)를 이용하여 91% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined using chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 53.8 min (minor) and 32.9 min (major)). A 91% ee value was obtained, the absolute configuration was not determined.

[α]24 D = -13 (c = 1.0, CHCl3) for 91% ee; 1H NMR (200 MHz, CDCl3): δ = 7.12 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 4.51-4.44 (m, 2H), 4.19 (q, J = 7 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H), 3.49 (ddd, J 1 = 27.5 Hz, J 2 = 17.4 Hz, J 3 = 5.0 Hz, 2H), 2.60 (t, J = 7.9 Hz, 2H), 2.11-1.96 (m, 2H) 1.24 (t, J = 7 Hz, 3H); 13C MNR (50 MHz, CDCl3): δ = 175.2, 171.8, 170.6, 144.8, 128.6, 122.5, 114.4, 61.1, 52.6, 44.8, 39.3, 32.9, 16.6, 13.6[a] 24 D = -13 (c = 1.0, CHC1 3 ) for 91% ee; 1 H NMR (200 MHz, CDCl 3 ): δ = 7.12 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 4.51-4.44 (m, 2H), 4.19 (q, J = 7 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H), 3.49 (ddd, J 1 = 27.5 Hz, J 2 = 17.4 Hz, J 3 = 5.0 Hz, 2H), 2.60 (t, J = 7.9 Hz, 2H), 2.11-1.96 (m, 2H) 1.24 (t, J = 7 Hz, 3H); 13 C MNR (50 MHz, CDCl 3 ): δ = 175.2, 171.8, 170.6, 144.8, 128.6, 122.5, 114.4, 61.1, 52.6, 44.8, 39.3, 32.9, 16.6, 13.6

실시예 5-6. 에틸 2-(3-트리플로로메틸페닐아미노)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트Example 5-6. Ethyl 2- (3-Trifluoromethylphenylamino) -4-oxo-4- (2-oxopyridin-3-yl) -butanoate

실시예 1에서의 방법을 사용하여, 80%의 수율로 생성물 에틸 2-(3-트리플로로메틸페닐아미노)-4-옥소-4-(2-옥소피리디-3-닐)-부타노에이트을 합성하였다. Using the method in Example 1, the product ethyl 2- (3-trifluoromethylphenylamino) -4-oxo-4- (2-oxopyridin-3-yl) -butanoate was obtained in a yield of 80%. Synthesized.

Enantiomeric excess의 결정은 chiral HPLC (chiralpak AD-H, iso-PrOH : Hex = 2 : 8, flow rate: 1.0 mL / min, detector : 254 nm, 20.5 min (minor)과 14.7 min(major)를 이용하여 83% ee값을 얻었다. 절대배열은 결정하지 않았다. Enantiomeric excess was determined using chiral HPLC (chiralpak AD-H, iso-PrOH: Hex = 2: 8, flow rate: 1.0 mL / min, detector: 254 nm, 20.5 min (minor) and 14.7 min (major)). A 83% ee value was obtained, the absolute configuration was not determined.

mp : 96-97.5 [α]24 D = -7.0 (c = 1.0, CHCl3) for 83% ee; 1H NMR (200 MHz, CDCl3): δ = 7.26 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 8 Hz, 2H), 4.74 (d, J = 8.7 Hz, 1H), 4.54-4.45 (m, 1H) , 4.20 (q, J = 7.2 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H), 3.51 (ddd, J 1 = 30.4, J 2 = 17.4, J 3 = 5.6, 2H) 2.60 (t, J = 8.1 Hz, 2H), 2.11-1.96 (m, 1.24); 13C MNR (50 MHz, CDCl3) δ = 175.5, 146.8, 131.2 (q, J = 31.5 Hz), 129.5, 124.1 (q, J = 270 Hz), 116.2, 114.3, 119.1, 61.3, 52.4, 45.1, 33.1, 16.8mp: 96-97.5 [a] 24 D = -7.0 (c = 1.0, CHC1 3 ) for 83% ee; 1 H NMR (200 MHz, CDCl 3 ): δ = 7.26 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 8 Hz, 2H), 4.74 (d, J = 8.7 Hz, 1H), 4.54-4.45 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H), 3.51 (ddd, J 1 = 30.4, J 2 = 17.4, J 3 = 5.6, 2H) 2.60 (t, J = 8.1 Hz, 2H), 2.11-1.96 (m, 1.24); 13 C MNR (50 MHz, CDCl 3 ) δ = 175.5, 146.8, 131.2 (q, J = 31.5 Hz), 129.5, 124.1 (q, J = 270 Hz), 116.2, 114.3, 119.1, 61.3, 52.4, 45.1, 33.1, 16.8

[실시예 6] 팔라듐 촉매의 제조Example 6 Preparation of Palladium Catalyst

(MeCN)2PdCl2 (0.1556 g, 0.6 mmol)를 벤젠에 녹인 용액에 (R)-BINAP (0.3736 g, 0.6 mmol)을 벤젠 1 mL에 녹인 후 적가하였다. 상온에서 14 시간 반응 후, 노란색 침전물을 여과하였다. 조 생성물을 아세톤 5 mL과 헥산 10 mL로 고체화하여, 주황색 고체 0.35 g을 73% 수율로 얻었다.(MeCN) 2 PdCl 2 (0.1556 g, 0.6 mmol) was added dropwise after dissolving (R) -BINAP (0.3736 g, 0.6 mmol) in 1 mL of benzene in a solution of benzene. After reaction for 14 hours at room temperature, the yellow precipitate was filtered off. The crude product was solidified with 5 mL of acetone and 10 mL of hexanes to give 0.35 g of an orange solid in 73% yield.

상기 반응에서 얻어진 고체 [(R)-BINAP]PdCl2 (0.29 g, 0.3625 mmol)를 CH2Cl2 13.5 mL에 녹인 용액에 CH3CN 7 mL, AgBF4 (0.1764, 0.9062 mmol)을 가한 후 상온에서 30분 교반하였다. 반응 혼합물을 celite 여과, 여액을 농축한 후, 여기에 CH2Cl2 15 mL과 diethyl ether 60 mL로 고체화하여, 팔라듐 촉매 2a를 81% 수율로 (0.284 g) 얻었다.Solid [(R) -BINAP] PdCl 2 obtained in the above reaction 7 mL of CH 3 CN and AgBF 4 (0.1764, 0.9062 mmol) were added to a solution of (0.29 g, 0.3625 mmol) in 13.5 mL of CH 2 Cl 2 , followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered through celite, the filtrate was concentrated, and then solidified with 15 mL of CH 2 Cl 2 and 60 mL of diethyl ether to obtain a palladium catalyst 2a in 81% yield (0.284 g).

Claims (7)

하기 화학식 1의 친전자체 화합물을, 키랄 팔라듐 촉매의 존재하에서, 아민과 반응시켜 광학 활성 아스파르트산 유도체를 제조하는 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법:A method for preparing an optically active aspartic acid derivative using a chiral catalyst, comprising reacting an electrophilic compound of Formula 1 with an amine in the presence of a chiral palladium catalyst to produce an optically active aspartic acid derivative: [화학식 1][Formula 1]
Figure 112011004398178-pat00023
Figure 112011004398178-pat00023
 상기 화학식 1에서,In Chemical Formula 1, 상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기 또는 아릴기이고,R 1 is a C 1 -C 30 alkyl group, a cyclized alkyl group, a benzyl group or an aryl group, 상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황임.Z is a C 1 -C 20 alkoxy, amine, amide, hydroxy amine or 5-hexagonal cyclic hetero atom compound, wherein the hetero atom is nitrogen, oxygen or sulfur. 제 1 항에 있어서,The method of claim 1, 상기 키랄 팔라듐 촉매는, 하기 화학식 2의 화합물 또는 그 광학 이성질체인 화학식 3의 화합물인 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법:The chiral palladium catalyst is a compound of the formula (2) or an optical isomer thereof is a method for producing an optically active aspartic acid derivative using a chiral catalyst characterized in that: [화학식 2][Formula 2]
Figure 112008091093598-pat00024
Figure 112008091093598-pat00024
 [화학식 3](3)
Figure 112008091093598-pat00025
Figure 112008091093598-pat00025
 상기 화학식 2 또는 3에서, In Chemical Formula 2 or 3, 상기 Ar은 페닐, 4-메틸페닐(4-methylphenyl) 또는 3,5-디메틸페닐(3,5-dimethylphenyl)이며,Ar is phenyl, 4-methylphenyl or 3,5-dimethylphenyl; 상기 X는 BF4, OTf(trifluoromethanesulfonate), SbF6 또는 PF6임.X is BF 4 , trifluoromethanesulfonate (OTf), SbF 6 or PF 6 . 제 1 항에 있어서,The method of claim 1, 상기 아민은, C1-C30의 1, 2 차 알킬아민 또는 헤테로아민, 또는 벤젠고리의 o-, p-, m- 위치에 알킬, 할로겐 또는 에스터가 치환된 방향족 아민 화합물인 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법.The amine is a C 1 -C 30 primary, secondary alkylamine or heteroamine, or an aromatic amine compound in which alkyl, halogen or ester is substituted at o- , p- , m- position of the benzene ring Method for preparing optically active aspartic acid derivative using chiral catalyst. 제 3 항에 있어서,The method of claim 3, wherein 상기 아민은, 하기 화학식 4의 구조를 갖는 화합물들 중 하나 이상인 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법:The amine is a method of producing an optically active aspartic acid derivative using a chiral catalyst, characterized in that at least one of the compounds having a structure of formula (4): [화학식 4][Formula 4]
Figure 112008091093598-pat00026
Figure 112008091093598-pat00026
 제 1 항에 있어서,The method of claim 1, 상기 아스파르트산 유도체는, 하기 화학식 5의 구조를 갖는 화합물인 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법:The method for producing an optically active aspartic acid derivative using a chiral catalyst, characterized in that the aspartic acid derivative is a compound having a structure of formula (5): [화학식 5][Chemical Formula 5]
Figure 112011004398178-pat00027
또는
Figure 112011004398178-pat00028
Figure 112011004398178-pat00027
or
Figure 112011004398178-pat00028
 상기 화학식 5에서,In Formula 5, 상기 R1은 C1-C30의 알킬기, 고리화 알킬기, 벤질기 또는 아릴기이고,R 1 is a C 1 -C 30 alkyl group, a cyclized alkyl group, a benzyl group or an aryl group, 상기 Z는 C1-C20의 알콕시, 아민, 아마이드, 하이드록시 아민 또는 5-6각 고리형 헤테로 원자 화합물이며, 상기 헤테로 원자는 질소, 산소 또는 황이고,Z is a C 1 -C 20 alkoxy, amine, amide, hydroxy amine or 5-hexagonal cyclic hetero atom compound, the hetero atom is nitrogen, oxygen or sulfur, 상기 R2 및 R3는 각각 독립적으로 수소, C1-C30의 알킬기 또는 아릴기이며, R2와 R3는 서로 연결되어 고리를 형성할 수 있고, 상기 아릴기는 치환된 아릴기이며, 상기 치환기는 수소, 알킬기, 알콕시 또는 알콕시 카보닐기임.R 2 and R 3 are each independently hydrogen, an alkyl group or an aryl group of C 1 -C 30 , R 2 and R 3 may be connected to each other to form a ring, the aryl group is a substituted aryl group, Substituents are hydrogen, alkyl, alkoxy or alkoxy carbonyl groups. 제 1 항에 있어서,The method of claim 1, 상기 Z의 고리형 헤테로 원자 화합물은, 옥사졸리디논(oxazolidinone), 피롤리논(pyrrolinone), 2-아미노 피리딘, 2-아미노 싸이오펜 또는 2-아미노 푸란인 것을 특징으로 하는 키랄 촉매를 이용한 광학 활성 아스파르트산 유도체의 제조방법.The cyclic heteroatomic compound of Z is oxazolidinone, pyrrolinone, 2-amino pyridine, 2-amino thiophene or 2-amino furan, and is optically active using a chiral catalyst. Method for preparing aspartic acid derivatives. 제 1 항에 있어서,The method of claim 1, 상기 제조방법은, 반응과정에서 극성 또는 비극성 용매를 사용할 수 있으며, 상기 극성 용매는 알코올이고, 상기 비극성 용매는 톨루엔, 자일렌, 헥산, 테트라하이드로퓨란, 다이옥산, 벤젠 또는 디클로로메탄인 것을 특징으로 하는 키랄 촉매 를 이용한 광학 활성 아스파르트산 유도체의 제조방법.In the production method, a polar or nonpolar solvent may be used in the reaction process, the polar solvent is an alcohol, and the nonpolar solvent is toluene, xylene, hexane, tetrahydrofuran, dioxane, benzene or dichloromethane. Method for preparing optically active aspartic acid derivative using chiral catalyst.
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