KR101344077B1 - Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes - Google Patents

Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes Download PDF

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KR101344077B1
KR101344077B1 KR1020110052603A KR20110052603A KR101344077B1 KR 101344077 B1 KR101344077 B1 KR 101344077B1 KR 1020110052603 A KR1020110052603 A KR 1020110052603A KR 20110052603 A KR20110052603 A KR 20110052603A KR 101344077 B1 KR101344077 B1 KR 101344077B1
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alkyl group
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김대영
강영구
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순천향대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/44—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

키랄 팔라듐(chiral palladium) 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있는 베타-인돌릴 에스테르 화합물의 제조방법에 관한 것으로, 베타,감마-불포화된 알파-케토 포스포네이트 화합물을, 키랄 팔라듐 촉매의 존재하에서, 인돌 화합물과 반응시키는 것을 특징으로 한다.
상기와 같은 키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르 화합물의 제조방법을 이용하는 것에 의해, 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다는 효과가 얻어진다.The present invention relates to a method for preparing a beta-indolyl ester compound capable of efficiently preparing an optically active material having high optical purity using a chiral palladium catalyst. The beta, gamma-unsaturated alpha-keto phosphonate compound Is reacted with an indole compound in the presence of a chiral palladium catalyst.
By using the manufacturing method of the beta- indolyl ester compound using the said chiral palladium catalyst, the effect which can manufacture the optically active material of high optical purity efficiently is acquired.

Description

키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르 화합물의 제조방법{Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes}Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes

본 발명은 생명과학적으로 이용 가능한 키랄 베타-인돌릴 에스테르(Beta-indolyl esters)화합물의 제조방법에 관한 것으로, 특히 키랄 팔라듐(chiral palladium) 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있는 베타-인돌릴 에스테르 화합물의 제조방법에 관한 것이다.
The present invention relates to a method of preparing a chiral beta-indolyl ester compound which can be used in a biological science, and particularly, an optically active material having high optical purity is efficiently produced using a chiral palladium catalyst. It relates to a method for producing a beta- indolyl ester compound.

광학이성질체는 밀도, 녹는점, 끓는점 등 대부분의 물리적 성질이 동일하다. 그러나, 편광된 빛을 흡수하는 정도가 다르기 때문에 선형편광된 빛을 조사(照射)했을 때 편광면이 회전하게 되며, 이러한 현상을 광학활성이라고 한다.Optical isomers have almost the same physical properties such as density, melting point, and boiling point. However, since the degree of absorption of polarized light is different, the polarization plane rotates when the linearly polarized light is irradiated. This phenomenon is called optical activity.

물질의 광학활성은 편광계를 사용하여 측정한다. 광학활성은 대칭 중심, 대칭면 또는 회전축 등의 대칭 요소를 갖지 못하는 분자에서 나타난다. 이러한 분자들은, 왼손 또는 오른손과 같이 좌우가 바뀌고 서로 겹쳐지지 않는 거울 상체의 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 symmetry centers, symmetry planes, or rotational axes. These molecules may exist as two isomers with left-handed or right-handed, left-handed, and non-overlapping, enantiomerically related isomers, and molecules of this nature are called chiral compounds.

키랄성 화합물은, 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 모든 아미노산은 비대칭탄소를 가진 키랄성 화합물이다. Chiral compounds are commonly found in carbon compounds having four asymmetric (chiral center) carbons, all of which are linked to carbon, or transition metal complexes having bidentate ligands. Of the 20 kinds of amino acids present in nature, all amino acids except glycine are chiral compounds with asymmetric carbons.

키랄 베타-인돌릴 에스테르 화합물은, 생명과학적으로 이용이 되고 있는 인돌이 포함되어 있기 때문에 많은 연구가 진행되고 있는 분야이다. 키랄 촉매를 이용한 베타-인돌릴 에스테르 화합물을 합성하는 방법은 일부 알려져 있으나(J. Am. Chem. Soc, 2003, 125, 10780; J. Am. Chem. Soc, 2007, 129, 742; J. Am. Chem. Soc. 2010, 132, 2775; Chem. Commun, 2010, 46, 4112.), 현재까지 키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르의 합성 방법은 알려지지 않았으며 알려진 반응은 저온에서 반응을 진행해야 하며 과량의 촉매를 사용해야하는 단점을 가지고 있다. The chiral beta-indolyl ester compound is a field in which a lot of research is being conducted because indole which is used in bioscience is included. Some methods for synthesizing beta-indolyl ester compounds using chiral catalysts are known (J. Am. Chem. Soc, 2003, 125, 10780; J. Am. Chem. Soc, 2007, 129, 742; J. Am Som. 2010, 132, 2775; Chem. Commun, 2010, 46, 4112.), the synthesis of beta-indoleyl esters using chiral palladium catalysts is not known and the reaction proceeds at low temperature. It has the disadvantage of using excess catalyst.

본 발명자들이 개발한 키랄 팔라듐 촉매를 이용한 반응은 대표적으로 비대칭 아민화 반응(Tetrahedron 2009, 65, 5676; Synlett 2008, 1821; Tetrahedron Lett. 2006, 17, 4265.), 알파-플루오로 베타-케토 에스테르의 비대칭 만니히 반응 (Tetrahderon Lett. 2011, 52, 2356.), 시아노 케톤의 비대칭 만니히 반응(Bull. Korean Chem. Soc. 2009, 30, 829.), Diels-Alder 반응(Bull. Korean Chem. Soc. 2008, 29, 2093.), 비대칭 불소화 반응(Bull. Korean Chem. Soc. 2007, 28, 2191; Bull. Korean Chem. Soc. 2007, 28, 2435; Bull. Korean Chem. Soc. 2006, 27, 423; Synlett 2007, 1135; Tetrahedron Lett. 2005, 46, 3115; Org. Lett. 2005, 7, 2309.) 이다.
Reactions using the chiral palladium catalyst developed by the present inventors are typically asymmetric amination reaction (Tetrahedron 2009, 65, 5676; Synlett 2008, 1821; Tetrahedron Lett. 2006, 17, 4265.), alpha-fluoro beta-keto esters Asymmetric Mannich reaction (Tetrahderon Lett. 2011, 52, 2356.), asymmetric Mannich reaction of cyano ketones (Bull. Korean Chem. Soc. 2009, 30, 829.), Diels-Alder reaction (Bull. Korean Chem) Soc. 2008, 29, 2093.), asymmetric fluorination reaction (Bull. Korean Chem. Soc. 2007, 28, 2191; Bull. Korean Chem. Soc. 2007, 28, 2435; Bull. Korean Chem. Soc. 2006, 27, 423; Synlett 2007, 1135; Tetrahedron Lett. 2005, 46, 3115; Org. Lett. 2005, 7, 2309.

본 발명의 목적은 상술한 바와 같은 문제점을 해결하기 위해 이루어진 것으로서, 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있는 베타-인돌릴 에스테르 화합물의 제조방법을 제공하는 것이다.
An object of the present invention is to solve the problems described above, to provide a method for preparing a beta- indolyl ester compound that can efficiently produce an optically active material of high optical purity using a chiral palladium catalyst. .

상기 목적을 달성하기 위해 본 발명에 따른 베타-인돌릴 에스테르 화합물의 제조방법은 키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르 화합물의 제조방법으로서, 키랄 팔라듐 촉매의 존재하에서, 베타,감마-불포화된 알파-케토 포스포네이트 화합물을, 인돌 화합물과 반응시키는 것을 특징으로 한다.
Method for producing a beta- indolyl ester compound according to the present invention to achieve the above object is a method for preparing a beta- indolyl ester compound using a chiral palladium catalyst, beta, gamma-unsaturated alpha in the presence of a chiral palladium catalyst A keto phosphonate compound is reacted with an indole compound.

상술한 바와 같이, 본 발명에 따른 베타-인돌릴 에스테르 화합물의 제조방법에 의하면, 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다는 효과가 얻어진다.
As described above, according to the method for producing a beta-indoleyl ester compound according to the present invention, an effect of efficiently producing an optically active material having high optical purity using a chiral palladium catalyst is obtained.

본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서의 기술 및 첨부 도면에 의해 더욱 명확하게 될 것이다.These and other objects and novel features of the present invention will become more apparent from the description of the present specification and the accompanying drawings.

먼저 본 발명에 따른 베타-인돌릴 에스테르 화합물의 제조방법의 특징에 대해 설명한다.First, the characteristics of the method for preparing the beta-indoleyl ester compound according to the present invention will be described.

본 발명의 일 실시 예에 따른 베타-인돌릴 에스테르 화합물의 제조방법은, 베타,감마-불포화된 알파-케토 포스포네이트 화합물을, 키랄 팔라듐 촉매(chiral palladium complexes)의 존재하에서, 인돌 화합물과 반응시켜 베타-인돌릴 에스테르 화합물을 제조한다. 상기 제조방법은 키랄 팔라듐 촉매를 이용하여, 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다.Method for producing a beta- indolyl ester compound according to an embodiment of the present invention, the beta, gamma-unsaturated alpha-keto phosphonate compound, in the presence of chiral palladium complexes (chiral palladium complexes), the reaction with the indole compound To prepare a beta-indoleyl ester compound. The above production method is for efficiently producing an optically active substance having high optical purity using a chiral palladium catalyst.

또 다른 일 실시 예에서, 키랄 팔라듐 촉매는, 하기 [화학식 1]의 화합물 또는 그 광학 이성질체인 하기 [화학식 2]의 화합물일 수 있다. In another embodiment, the chiral palladium catalyst may be a compound of the following Chemical Formula 1 or an optical isomer thereof.

Figure 112011041156047-pat00001
Figure 112011041156047-pat00001

Figure 112011041156047-pat00002
Figure 112011041156047-pat00002

상기 [화학식 1 또는 2]에서, 상기 Ar은 페닐(phenyl), 4-메틸페닐(4-methylphenyl) 또는 3,5-디메틸페닐(3,5-dimethylphenyl) 중 어느 하나이며, 상기 X는 BF4, OTf, PF6, 또는 SbF6 중 어느 하나이다.
또 본 발명의 일 실시 예에서, 상기 키랄 팔라듐 촉매의 함량은 반응 물질들의 전체 몰수를 기준으로, 1 내지 20 몰%, 구체적으로는 1 내지 10 몰%, 보다 구체적으로는 5 몰%이다. 상기 범위는, 광학 순도가 높은 베타-인돌릴 에스테르 화합물을 효율적으로 제조하기 위한 것이다. 키랄 팔라듐 촉매의 함량이 상기 범위보다 낮은 경우에는, 합성된 베타-인돌릴 에스테르 화합물의 광학 순도가 저하되고, 상기 범위보다 높은 경우에는, 촉매 첨가로 인한 효율성이 떨어질 수 있다.In [Formula 1 or 2], Ar is phenyl (phenyl), 4-methylphenyl (4-methylphenyl) or 3,5-dimethylphenyl (3,5-dimethylphenyl) any one, wherein X is BF 4 , OTf, PF 6, or SbF 6 .
In addition, in one embodiment of the present invention, the content of the chiral palladium catalyst is 1 to 20 mol%, specifically 1 to 10 mol%, more specifically 5 mol% based on the total moles of the reactants. The said range is for producing the beta- indolyl ester compound with high optical purity efficiently. When the content of the chiral palladium catalyst is lower than the above range, the optical purity of the synthesized beta-indolyl ester compound is lowered, and when higher than the above range, the efficiency due to the addition of the catalyst may be lowered.

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또 본 발명의 일 실시 예에서, 베타, 감마-불포화된 알파-케토 포스포네이트 화합물은 하기의 [화학식 3]의 구조를 갖는 화합물일 수 있다. In addition, in one embodiment of the present invention, the beta, gamma-unsaturated alpha-keto phosphonate compound may be a compound having a structure of the following [Formula 3].

Figure 112011041156047-pat00003
Figure 112011041156047-pat00003

상기 [화학식 3]에서, 상기 R1은 C1~C3의 알킬기 또는 C6-C10인 아릴기이다. 상기 아릴기는 C1~C3의 알킬기 또는 할로겐으로 치환된 아릴기일 수 있다.
상기 R2은 C1-C3의 알킬기이다.
또 본 발명의 일 실시 예에서, 상기 인돌 화합물은 하기 [화학식 4]의 구조를 갖는 화합물일 수 있다. In [Formula 3], the R 1 is C 1 ~ C 3 alkyl group or C 6- C 10 is an aryl group. The aryl group may be an aryl group substituted with an alkyl group or halogen of C 1 ~ C 3 .
R 2 is an alkyl group of C 1 -C 3 .
In addition, in one embodiment of the present invention, the indole compound may be a compound having a structure of the following [Formula 4].

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Figure 112011041156047-pat00004
Figure 112011041156047-pat00004

상기 [화학식 4]에서, 상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1-C3의 알킬기이다.
또 다른 일 실시 예에서, 상기 베타-인돌릴 에스테르 화합물은, [화학식 5]를 갖는 화합물일 수 있다.In [Formula 4], R 3 is any one of F, Cl, Br, I, C 1 ~ C 3 Alkyl group or C 1 ~ C 3 Alkoxy, The R 4 is C 1 -C 3 Alkyl group to be.
In another embodiment, the beta-indolyl ester compound may be a compound having [Formula 5].

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Figure 112011041156047-pat00005
Figure 112011041156047-pat00005

상기 [화학식 5]에서, 상기 R1은 C1~C3의 알킬기 또는 C6~C10인 아릴기이고, 상기 아릴기는 C1-C3의 알킬기 또는 할로겐으로 치환된 아릴기일 수 있다.
상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1-C3의 알킬기이다.
In [Formula 5], wherein R 1 Is an alkyl group of C 1 ~ C 3 or C 6 ~ C 10 It is an aryl group, the aryl group may be an aryl group substituted with an alkyl group or halogen of C 1 -C 3 .
R 3 is any one of F, Cl, Br, I, C 1 -C 3 alkyl group or C 1 -C 3 alkoxy, and R 4 is C 1 -C 3 alkyl group.

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삭제delete

이하, 본 발명의 일 실시 예에 따른 베타-인돌릴 에스테르 화합물의 제조방법에 대하여 보다 구체적으로 설명한다. Hereinafter, a method of preparing the beta-indolyl ester compound according to an embodiment of the present invention will be described in more detail.

본 발명에 따른 베타-인돌릴 에스테르 화합물의 제조방법의 일 실시 예에서, 상기 키랄 팔라듐 촉매는 하기 [반응식 1]의 공정을 통해 제조할 수 있다. In one embodiment of the method for producing a beta-indolyl ester compound according to the present invention, the chiral palladium catalyst may be prepared through the process of [Scheme 1].

[ 반응식 1 ]Scheme 1

Figure 112011041156047-pat00006
Figure 112011041156047-pat00006

또 본 발명의 일 실시 예에서, 베타,감마-불포화된 알파-케토 포스포네이트를 키랄 팔라듐 촉매의 존재하에서 인돌 화합물과 반응시켜 베타-인돌릴 에스테르 화합물을 제조할 수 있다. 구체적인 반응식은, 하기 [반응식 2]와 같다. In addition, in one embodiment of the present invention, beta, gamma-unsaturated alpha-keto phosphonate may be reacted with an indole compound in the presence of a chiral palladium catalyst to prepare a beta-indolyl ester compound. Specific reaction formula is as follows [Scheme 2].

[ 반응식 2 ]Scheme 2

Figure 112011041156047-pat00007
Figure 112011041156047-pat00007

상기 [반응식 2]에서, 상기 R1은 C1~C3의 알킬기 또는 C6-C10인 아릴기이고, 상기 아릴기는 C1~C3의 알킬기 또는 할로겐으로 치환된 아릴기이고, 상기 R2은 C1-C3의 알킬기이고 , R3는 F, Cl, Br, I 또는 C1~C3인 알킬기 또는 C1~C3의 알콕시 중 어느 하나이며, R4는 C1~C3인 알킬기일 수 있다. In Reaction Scheme 2, R 1 is C 1 ~ C 3 Alkyl group or C 6 -C 10 It is an aryl group, The aryl group is C 1 ~ C 3 Alkyl group or an aryl group substituted with halogen, R 2 is C 1 -C 3 is an alkyl group, R 3 is F, Cl, Br, I or And C 1 ~ C 3 alkyl group or C 1 ~ C 3 alkoxy any of one, R 4 may be a C 1 ~ C 3 alkyl group.

반응 중간체인 감마-인돌릴 알파-케토 포스포네이트는 불안정하여 DBU(1,8-Diazabicycloundec-7-ene), 메탄올 처리하여 베타-인돌릴 에스테르 화합물을 합성한다. 상기 친핵체로는 메탄올로 국한된 것은 아니며, C1-C4인 선형 또는 가지형 알코올, C1-C8인 알킬아민, 고리형 아민 또는 헤테로원자가 포함된 고리형 아민(몰포린) 중 어느 하나를 사용할 수 있다.
상기 반응 중간체인 감마-인돌릴 알파-케토 포스포네이트는 하기 [화학식 6]을 갖는 화합물일 수 있다.

Figure 112012107691797-pat00008

상기 [화학식 6]에서, 상기 R1은 C1~C3의 알킬기 또는 C6-C10인 아릴기이고, 상기 아릴기는 C1-C3의 알킬기 또는 할로겐으로 치환된 아릴기이다.
상기 R2은 C1-C3의 알킬기이며, 상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1~C3의 알킬기이다.
The reaction intermediate, gamma-indolyl alpha-keto phosphonate, is unstable and is treated with DBU (1,8-Diazabicycloundec-7-ene), methanol to synthesize beta-indolyl ester compounds. The nucleophile is not limited to methanol, and any one of C 1 -C 4 linear or branched alcohol, C 1 -C 8 alkylamine, cyclic amine or cyclic amine (morpholine) containing heteroatoms Can be used.
The reaction intermediate gamma-indolyl alpha-keto phosphonate may be a compound having the following [Formula 6].
Figure 112012107691797-pat00008
In Chemical Formula 6, R 1 is an alkyl group of C 1 to C 3 or an aryl group of C 6 -C 10 , and the aryl group is an aryl group substituted with an alkyl group or halogen of C 1 -C 3 .
R 2 is a C 1 -C 3 alkyl group, R 3 is F, Cl, Br, I, C 1 ~ C 3 Alkyl group or C 1 ~ C 3 Alkoxy, R 4 is C is an alkyl group of 1 ~ C 3.

이하, 하기 실시 예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시 예 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.

입체 선택적인 베타-인돌릴 에스테르 화합물 합성을 위해 키랄 팔라듐 촉매를 이용한 비대칭 프리델-크래프츠(Friedel-Crafts) 반응을 수행하였으며, 구체적인 반응조건 및 수율은 표 1에 나타내었다. Asymmetric Friedel-Crafts reaction using a chiral palladium catalyst was carried out for the stereoselective beta-indolyl ester compound synthesis. Specific reaction conditions and yields are shown in Table 1.

Figure 112012107691797-pat00009
Figure 112012107691797-pat00009

먼저 키랄 팔라듐 촉매의 구조에 따른 입체 선택성 차이를 확인하였다. 촉매에 구조에 따른 입체 선택성 차이가 큰 것을 볼 수 있으며(entry 1-7), 가장 높은 선택성을 보여준 촉매는 1c 임을 볼 수 있다. 촉매 1c를 이용하여 용매 조건을 확인 한 결과 디클로로메탄이 가장 높은 입체 선택성을 보여주었다.First, the stereoselectivity difference according to the structure of the chiral palladium catalyst was confirmed. It can be seen that the steric selectivity difference according to the structure is large in the catalyst (entry 1-7), and the catalyst showing the highest selectivity is 1c . The solvent condition was confirmed using the catalyst 1c and dichloromethane showed the highest stereoselectivity.

비대칭 프리델-크래프츠 유도체 반응의 결과를 표 2에 나타내었다.The results of the asymmetric Friedel-Crafts derivative reaction are shown in Table 2.

Figure 112012107691797-pat00010
Figure 112012107691797-pat00010

[실시 예 1] [Example 1]

(S)-3-(1H-인돌-3-일)-부트르산 메틸 에스테르{(S)-3-(1H-Indol-3-yl)-butyric acid methyl ester} (S) -3- (1H-indol-3-yl) -butyric acid methyl ester {(S) -3- (1H-Indol-3-yl) -butyric acid methyl ester}

플라스크에 (E)-diethyl 1-oxobut-2-enylphosphonates 0.1 mmol, 키랄 팔라듐 촉매 1c 0.005 mmol을 디클로로메탄 1mL로 녹인 후 인돌 0.12 mmol을 상온에서 가한다. 반응 진행이 완료되면 메탄올 0.15 mL, DBU 0.03 mL 넣고 2시간 상온에서 교반 후 물과 에틸 아세테이트로 추출한다. 유기층을 MgSO4로 건조 후, 농축, 컬럼 크로마토그래피로 분리 정제하여 [화학식 5]를 70% 수율, 93% ee(enantiomeric excess)의 거울상 입체선택성으로 합성하였다.In a flask, 0.1 mmol of (E) -diethyl 1-oxobut-2-enylphosphonates and 0.005 mmol of chiral palladium catalyst 1c were dissolved in 1 mL of dichloromethane, and then 0.12 mmol of indole was added at room temperature. After the reaction was completed, 0.15 mL of methanol and 0.03 mL of DBU were added thereto, stirred at room temperature for 2 hours, and extracted with water and ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and separated and purified by column chromatography. [Formula 5] was synthesized with enantiomeric stereoselectivity of 70% yield and 93% ee (enantiomeric excess).

Figure 112012107691797-pat00011
Figure 112012107691797-pat00011

[α]28D = 7.3 (c = 0.7, CHCl3, 93% ee); 1H NMR (200 MHz, CDCl3) δ = 7.99 (brs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23-7.05 (m, 2H), 6.90 (d, J = 2.5 Hz, 1H), 3.65-3.47 (m, 1H), 3.62 (s, 3H), 2.82 (dd, J = 14.8, 6.0 Hz, 1H), 2.56 (dd, J = 14.7, 8.7 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.0, 136.1, 125.9, 121.5, 120.2, 119.7, 118.8, 118.7, 110.9, 51.1, 41.9, 27.6, 20.6; MS (ESI): m/z = 217.9 [M+H]+, 117.0, 120.9, 123.0 147.0, 176.9; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 0.8 mL/min) Chiralcel OD-H column, tR = 9.0 min (minor), tR = 13.8 (major).
[a] 28 D = 7.3 (c = 0.7, CHCl 3 , 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.99 (brs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23-7.05 (m, 2H ), 6.90 (d, J = 2.5 Hz, 1H), 3.65-3.47 (m, 1H), 3.62 (s, 3H), 2.82 (dd, J = 14.8, 6.0 Hz, 1H), 2.56 (dd, J = 14.7, 8.7 Hz, 1 H), 1.39 (d, J = 6.9 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.0, 136.1, 125.9, 121.5, 120.2, 119.7, 118.8, 118.7, 110.9, 51.1, 41.9, 27.6, 20.6; MS (ESI): m / z = 217.9 [M + H] < + >, 117.0, 120.9, 123.0 147.0, 176.9; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 0.8 mL / min) Chiralcel OD-H column, tR = 9.0 min (minor), tR = 13.8 (major).

[실시 예 2][Example 2]

(S)-3-(1-메틸-1H-인돌-3-일)-부트르산 메틸 에스테르{(S)-3-(1-Methyl-1H-indol-3-yl)-butyric acid methyl ester}(S) -3- (1-methyl-1H-indol-3-yl) -butyric acid methyl ester {(S) -3- (1-Methyl-1H-indol-3-yl) -butyric acid methyl ester}

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 65% 수율, 83% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in 65% yield, enantiomeric stereoselectivity of 83% ee.

Figure 112012107691797-pat00012
Figure 112012107691797-pat00012

[α]29D = 2.7 (c = 0.5, CHCl3, 83% ee); 1H NMR (200 MHz, CDCl3) δ = 7.63 (d, J = 7.7 Hz, 1 H), 7.23-7.03 (m, 3H), 6.82 (s, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.64-3.51 (m, 1H), 2.80 (dd, J = 14.8, 6.1 Hz, 1H), 2.54 (dd, J = 15.4, 8.7 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.2, 137.0, 126.6, 124.7, 121.5, 119.1, 119.0, 118.6, 109.2, 51.4, 42.3, 32.5, 27.8, 21.1; MS (ESI): m/z = 232.1 [M+H]+, 117.0, 120.9, 123.0, 133.9, 147.0, 176.9; HPLC (3 : 2 : 95, iso-PrOH : EtOH : n-hexane, 220 nm, 1.0 mL/min) Chiralcel OD-H column, tR = 8.1 min (minor), tR = 9.5 (major).
[a] 29 D = 2.7 (c = 0.5, CHCl 3 , 83% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.63 (d, J = 7.7 Hz, 1 H), 7.23-7.03 (m, 3H), 6.82 (s, 1H), 3.70 (s, 3H), 3.63 ( s, 3H), 3.64-3.51 (m, 1H), 2.80 (dd, J = 14.8, 6.1 Hz, 1H), 2.54 (dd, J = 15.4, 8.7 Hz, 1H), 1.39 (d, J = 6.9 Hz , 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.2, 137.0, 126.6, 124.7, 121.5, 119.1, 119.0, 118.6, 109.2, 51.4, 42.3, 32.5, 27.8, 21.1; MS (ESI): m / z = 232.1 [M + H] < + >, 117.0, 120.9, 123.0, 133.9, 147.0, 176.9; HPLC (3: 2: 95, iso-PrOH: EtOH: n-hexane, 220 nm, 1.0 mL / min) Chiralcel OD-H column, tR = 8.1 min (minor), tR = 9.5 (major).

[실시 예 3][Example 3]

(S)-3-(5-브로모-1H-인돌-3-일)-부트르산 메틸 에스테르{(S)-3-(5-Bromo-1H-indol-3-yl)-butyric acid methyl ester}(S) -3- (5-Bromo-1H-indol-3-yl) -butyric acid methyl ester {(S) -3- (5-Bromo-1H-indol-3-yl) -butyric acid methyl ester }

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 80% 수율, 99% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in a mirror image stereoselectivity of 80% yield, 99% ee.

Figure 112012107691797-pat00013
Figure 112012107691797-pat00013

[α]29D = -3.3 (c = 1.8, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 8.16 (brs, 1H), 7.74 (d, J = 1.2 Hz 1H), 7.23 (dd, J = 6.2, 3.0 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 3.63 (s, 3H), 3.53-3.45 (m, 1H), 2.76 (dd, J = 14.9, 6.7 Hz, 1H), 2.56 (dd, J = 15.0, 7.9 Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3)δ = 173.1, 135.0, 128.0, 124.7, 121.6, 121.3, 120.3, 112.6, 112.4, 51.5, 42.1, 27.7, 21.0; MS (ESI): m/z = 295.8 [M+H]+, 117.0, 120.9, 122.9, 146.9, 176.9, 222.9, 240.0; HPLC (98 : 2, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 40.5 min (major), tR = 42.2 (minor).
[a] 29 D = -3.3 (c = 1.8, CHCl 3 , 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.16 (brs, 1H), 7.74 (d, J = 1.2 Hz 1H), 7.23 (dd, J = 6.2, 3.0 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 3.63 (s, 3H), 3.53-3.45 (m, 1H), 2.76 (dd, J = 14.9, 6.7 Hz, 1H), 2.56 ( dd, J = 15.0, 7.9 Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.1, 135.0, 128.0, 124.7, 121.6, 121.3, 120.3, 112.6, 112.4, 51.5, 42.1, 27.7, 21.0; MS (ESI): m / z = 295.8 [M + H] < + >, 117.0, 120.9, 122.9, 146.9, 176.9, 222.9, 240.0; HPLC (98: 2, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, tR = 40.5 min (major), tR = 42.2 (minor).

[실시 예 4][Example 4]

(S)-3-(5-메톡시-1H-인돌-3-일)-부트르산 메틸 에스테르{(S)-3-(5-Methoxy-1H-indol-3-yl)-butyric acid methyl ester}(S) -3- (5-methoxy-1H-indol-3-yl) -butyric acid methyl ester {(S) -3- (5-Methoxy-1H-indol-3-yl) -butyric acid methyl ester }

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 75% 수율, 93% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained with a mirror image stereoselectivity of 75% yield, 93% ee.

Figure 112012107691797-pat00014
Figure 112012107691797-pat00014

[α]29D = -2.2 (c = 1.0, CHCl3, 93% ee); 1H NMR (200 MHz, CDCl3) δ = 7.94 (brs, 1H), 7.28 (d, J = 12.0 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.7, 2.0 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 3H), 3.62-3.47 (m, 1H), 2.81 (dd, J = 15.2, 6.2 Hz, 1H), 2.56 (dd, J = 15.0, 8.7 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.6, 154.1, 131.9, 127.0, 121.1, 120.8, 112.4, 112.2, 101.4, 56.2, 51.8, 42.4, 28.1, 21.2; ; MS (ESI): m/z = 247.9 [M+H]+, 117.0, 120.9, 123.0, 147.0, 222.9; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 14.3 min (major), tR = 16.2 (minor).
[a] 29 D = -2.2 (c = 1.0, CHC1 3 , 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.94 (brs, 1H), 7.28 (d, J = 12.0 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.7, 2.0 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 3H), 3.62-3.47 (m, 1H), 2.81 (dd, J = 15.2, 6.2 Hz, 1H), 2.56 (dd, J = 15.0, 8.7 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.6, 154.1, 131.9, 127.0, 121.1, 120.8, 112.4, 112.2, 101.4, 56.2, 51.8, 42.4, 28.1, 21.2; ; MS (ESI): m / z = 247.9 [M + H] < + >, 117.0, 120.9, 123.0, 147.0, 222.9; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, tR = 14.3 min (major), tR = 16.2 (minor).

[실시 예 5][Example 5]

(S)-3-(1H-인돌-3-일)-펜탄산 메틸 에스테르{(S)-3-(1H-Indol-3-yl)-pentanoic acid methyl ester}(S) -3- (1H-Indol-3-yl) -pentanoic acid methyl ester {(S) -3- (1H-Indol-3-yl) -pentanoic acid methyl ester}

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 74% 수율, 97% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained as a mirror image stereoselectivity of 74% yield, 97% ee.

Figure 112012107691797-pat00015
Figure 112012107691797-pat00015

[α]24D = 1.9 (c = 1.3, CHCl3, 84% ee); 1H NMR (200 MHz, CDCl3) δ = 8.03 (brs, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.28-7.12 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 3.65, (s, 3H), 3.53-3.39 (m, 1H), 2.53 (d, J = 7.5 Hz, 2H), 1.94-1.79 (m, 2H), 0.92 (t, J = 7.3, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.4, 136.4, 126.7, 121.8, 120.9, 119.3, 119.1, 118.6, 111.1, 51.4, 40.5, 35.1, 28.2, 11.9; ; MS (ESI): m/z = 231.9 [M+H]+, 117.0, 120.9, 123.0, 146.9, 163.0, 176.9, 222.9; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 9.9 min (major), tR = 10.8 (minor).
[a] 24 D = 1.9 (c = 1.3, CHCl 3 , 84% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.03 (brs, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.28-7.12 (m, 2H ), 7.06 (d, J = 2.4 Hz, 1H), 3.65, (s, 3H), 3.53-3.39 (m, 1H), 2.53 (d, J = 7.5 Hz, 2H), 1.94-1.79 (m, 2H ), 0.92 (t, J = 7.3, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.4, 136.4, 126.7, 121.8, 120.9, 119.3, 119.1, 118.6, 111.1, 51.4, 40.5, 35.1, 28.2, 11.9; ; MS (ESI): m / z = 231.9 [M + H] < + >, 117.0, 120.9, 123.0, 146.9, 163.0, 176.9, 222.9; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, tR = 9.9 min (major), tR = 10.8 (minor).

[실시 예 6][Example 6]

(S)-3-(1-메틸-5-브로모-1H-인돌-3-일)-펜탄산 메틸 에스테르{(S)-3-(1-Methyl-5-bromo-1H-indol-3-yl)-pentanoic acid methyl ester}(S) -3- (1-Methyl-5-bromo-1H-indol-3-yl) -pentanoic acid methyl ester {(S) -3- (1-Methyl-5-bromo-1H-indol-3 -yl) -pentanoic acid methyl ester}

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 68% 수율, 85% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in a mirror image stereoselectivity of 68% yield, 85% ee.

Figure 112012107691797-pat00016
Figure 112012107691797-pat00016

[α]22D = 3.7 (c = 1.3, CHCl3, 85% ee); 1H NMR (200 MHz, CDCl3) δ = 7.72 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 2.67, (dd, J = 7.2, 1.8 Hz, 2H), 1.82-1.67 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.1, 135.7, 128.7, 126.9, 124.2, 121.8, 116.7, 112.0, 110.7, 51.4, 40.6, 34.8, 32.8, 28.4, 11.9; ; MS (ESI): m/z = 323.9 [M+H]+, 116.9, 120.9, 123.0, 147.0, 163.0, 180.0, 222.9, 240.0; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralcel OD-H column, tR = 5.9 min (minor), tR = 7.1 (major).
[a] 22 D = 3.7 (c = 1.3, CHCl 3 , 85% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.72 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.84 ( s, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 2.67, (dd, J = 7.2, 1.8 Hz, 2H), 1.82-1.67 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.1, 135.7, 128.7, 126.9, 124.2, 121.8, 116.7, 112.0, 110.7, 51.4, 40.6, 34.8, 32.8, 28.4, 11.9; ; MS (ESI): m / z = 323.9 [M + H] < + >, 116.9, 120.9, 123.0, 147.0, 163.0, 180.0, 222.9, 240.0; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralcel OD-H column, tR = 5.9 min (minor), tR = 7.1 (major).

[실시 예 7][Example 7]

(S)-3-(5-브로모-1H-인돌-3-일)-펜탄산 메틸 에스테르{(S)-3-(5-bromo-1H-indol-3-yl)-pentanoic acid methyl ester}(S) -3- (5-bromo-1H-indol-3-yl) -pentanoic acid methyl ester {(S) -3- (5-bromo-1H-indol-3-yl) -pentanoic acid methyl ester }

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 79% 수율, 97% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in a mirror image stereoselectivity of 79% yield, 97% ee.

Figure 112012107691797-pat00017
Figure 112012107691797-pat00017

[α]25D = 3.1 (c = 1.3, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3) δ = 8.06 (brs, 1H), 7.75 (s, 1H), 7.27-7.17 (m, 2H), 6.98, (d, J = 2.1 Hz, 1H), 3.58 (s, 3H), 3.39-3.22 (m, 1H) 2.70 (dd, J = 7.4, 1.5 Hz, 2H), 1.84-1.69 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.2, 135.0, 133.7, 128.4, 124.7, 122.2, 121.8, 118.3, 112.6,51.5, 40.4, 34.9, 28.2, 11.9; ; MS (ESI): m/z = 309.9 [M+H]+, 117.0, 120.9, 162.9, 176.9, 222.9, 240.0; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralcel OD-H column, tR = 9.2 min (minor), tR = 11.4 (major).
[a] 25 D = 3.1 (c = 1.3, CHCl 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.06 (brs, 1H), 7.75 (s, 1 H), 7.27-7.17 (m, 2H), 6.98, (d, J = 2.1 Hz, 1H), 3.58 ( s, 3H), 3.39-3.22 (m, 1H) 2.70 (dd, J = 7.4, 1.5 Hz, 2H), 1.84-1.69 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.2, 135.0, 133.7, 128.4, 124.7, 122.2, 121.8, 118.3, 112.6,51.5, 40.4, 34.9, 28.2, 11.9; ; MS (ESI): m / z = 309.9 [M + H] < + >, 117.0, 120.9, 162.9, 176.9, 222.9, 240.0; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralcel OD-H column, tR = 9.2 min (minor), tR = 11.4 (major).

[실시 예 8][Example 8]

(S)-3-(5-메톡시-1H-인돌-3-일)-펜탄산 메틸 에스테르{(S)-3-(5-methoxy-1H-indol-3-yl)-pentanoic acid methyl ester}(S) -3- (5-methoxy-1H-indol-3-yl) -pentanoic acid methyl ester }

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 71% 수율, 97% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in the enantiomeric stereoselectivity of 71% yield, 97% ee.

Figure 112012107691797-pat00018
Figure 112012107691797-pat00018

[α]23D = 1.6 (c = 1.0, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3) δ = 7.92 (brs, 1H,) 7.23 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.9, 2.4 Hz, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 3.42-3.28 (m, 1H), 2.71 (d, J = 7.3 Hz, 2H), 1.85-1.71 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ = 173.4, 153.6, 131.5, 127.1, 121.7, 118.3, 111.9, 111.7, 101.2, 55.9, 51.4, 40.4, 34.9, 28.1, 11.8; ; MS (ESI): m/z = 262.0 [M+H]+, 116.7, 120.8, 147.0, 162.8, 179.7. 222.9, 240.1; HPLC (97 : 3, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 49.2 min (major), tR = 56.2 (minor).
[a] 23 D = 1.6 (c = 1.0, CHC1 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.92 (brs, 1H,) 7.23 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.9, 2.4 Hz, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 3.42-3.28 (m, 1H), 2.71 (d, J = 7.3 Hz , 2H), 1.85-1.71 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (50 MHz, CDCl 3 ) δ = 173.4, 153.6, 131.5, 127.1, 121.7, 118.3, 111.9, 111.7, 101.2, 55.9, 51.4, 40.4, 34.9, 28.1, 11.8; ; MS (ESI): m / z = 262.0 [M + H] < + >, 116.7, 120.8, 147.0, 162.8, 179.7. 222.9, 240.1; HPLC (97: 3, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 49.2 min (major), t R = 56.2 (minor).

[실시 예 9][Example 9]

(R)-3-(1H-인돌-3-일)-3-페닐-프로피온산 메틸 에스테르{(R)-3-(1H-Indol-3-yl)-3-phenyl-propionic acid methyl ester}(R) -3- (1H-indol-3-yl) -3-phenyl-propionic acid methyl ester {(R) -3- (1H-Indol-3-yl) -3-phenyl-propionic acid methyl ester}

상기 실시 예 1과 동일한 방법으로 [화학식 5]를 67% 수율, 31% ee의 거울상 입체선택성으로 얻었다.In the same manner as in Example 1, [Formula 5] was obtained in 67% yield, enantioselective stereoselectivity of 31% ee.

Figure 112012107691797-pat00019
Figure 112012107691797-pat00019

1H NMR (400 MHz, CDCl3) δ = 8.01 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30-7.21 (m, 5H), 7.17-7.09 (m, 2H), 7.01-6.97 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 4.80 (t, J = 8.0 Hz,1H), 3.54 (s, 3H), 3.14 (dd, J = 15.2, 8.0 Hz, 1H), 3.01 (dd, J = 15.2, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 172.7, 143.6, 136.4, 128.4, 127.6, 126.4, 126.4, 122.0, 121.1, 119.3, 119.2,118.4, 111.1, 51.6, 41.2, 39.1; HPLC (90 : 10, n-hexane : iso-PrOH, 220 nm, 1.0 mL/min) Chiralcel AD-H column, tR = 17.4 min (major), tR = 20.3 (minor).
1 H NMR (400 MHz, CDCl 3 ) δ = 8.01 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30-7.21 (m, 5H), 7.17-7.09 (m, 2H), 7.01 -6.97 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 4.80 (t, J = 8.0 Hz, 1H), 3.54 (s, 3H), 3.14 (dd, J = 15.2, 8.0 Hz, 1H), 3.01 (dd, J = 15.2, 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ = 172.7, 143.6, 136.4, 128.4, 127.6, 126.4, 126.4, 122.0, 121.1, 119.3, 119.2, 118.4, 111.1, 51.6, 41.2, 39.1; HPLC (90:10, n-hexane: iso-PrOH, 220 nm, 1.0 mL / min) Chiralcel AD-H column, tR = 17.4 min (major), tR = 20.3 (minor).

[실시 예 10][Example 10]

(S)-3-(1-메틸-1H-인돌-3-일)-1-모르폴린-4-일-부탄-1-원{(S)-3-(1-Methyl-1H-indol-3-yl)-1-morpholin-4-yl-butan-1-one}(S) -3- (1-methyl-1H-indol-3-yl) -1-morpholin-4-yl-butane-1-one {(S) -3- (1-Methyl-1H-indol- 3-yl) -1-morpholin-4-yl-butan-1-one}

Figure 112012107691797-pat00020
Figure 112012107691797-pat00020

플라스크에 (E)-diisopropyl 1-oxobut-2-enylphosphonates 0.1 mmol, 팔라듐 촉매 1c 0.005 mmol을 디클로로메탄 1mL로 녹인 후 N-메틸 인돌 0.12 mmol을 상온에서 가한다. 반응 진행이 완료되면 몰포린(morpholine) 0.10 mL 넣고 3시간 상온에서 교반 후 물과 에틸 아세테이트로 추출한다. 유기층을 MgSO4로 건조 후, 농축, 컬럼 크로마토그래피로 분리 정제하여 베타-인돌릴 아마이드 화합물를 83% ee의 거울상 입체선택성으로 합성하였다.
In a flask, 0.1 mmol of (E) -diisopropyl 1-oxobut-2-enylphosphonates and 0.005 mmol of palladium catalyst 1c were dissolved in 1 mL of dichloromethane, and then 0.12 mmol of N-methyl indole was added at room temperature. After the reaction was completed, 0.10 mL of morpholine was added, stirred at room temperature for 3 hours, and extracted with water and ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and separated and purified by column chromatography to synthesize beta-indoleyl amide compound with enantiomeric stereoselectivity of 83% ee.

이상 본 발명자에 의해서 이루어진 발명을 상기 실시 예에 따라 구체적으로 설명하였지만, 본 발명은 상기 실시 예에 한정되는 것은 아니고 그 요지를 이탈하지 않는 범위에서 여러 가지로 변경 가능한 것은 물론이다.
Although the present invention has been described in detail with reference to the above embodiments, it is needless to say that the present invention is not limited to the above-described embodiments, and various modifications may be made without departing from the spirit of the present invention.

Claims (6)

키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르 화합물의 제조방법으로서, 하기 [화학식 3]의 구조를 갖는 베타, 감마-불포화된 알파 케토 포스포네이트 화합물을, 키랄 팔라듐 촉매 존재하에서, 하기 [화학식 4]의 구조를 갖는 인돌 화합물과 반응시켜, 하기 [화학식 6]의 감마-인돌릴 알파-케토 포스포네이트 중간체를 합성 후, 1,8-Diazabicycloundec 7-ene, 알코올 처리하여, 하기 [화학식 5]의 구조를 갖는 베타-인돌릴 에스테르 화합물을 제조하는 것을 특징으로 하는 키랄 팔라듐 촉매를 이용한 베타-인돌릴 에스테르 화합물을 제조하는 방법.
[화학식 3]
Figure 112013062365134-pat00021

상기 [화학식 3]에서, 상기 R1은 C1~C3의 알킬기 또는 C6-C10인 아릴기이고, 상기 아릴기는 C1~C3의 알킬기 또는 할로겐으로 치환된 아릴기이고, 상기 R2은 C1-C3의 알킬기임.
[화학식 4]
Figure 112013062365134-pat00027

상기 [화학식 4]에서, 상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1-C3의 알킬기이다.
[화학식 5]
Figure 112013062365134-pat00022

상기 [화학식 5]에서, 상기 R1은 C1~C3의 알킬기 또는 C6~C10인 아릴기이고, 상기 아릴기는 C1-C3의 알킬기 또는 할로겐으로 치환된 아릴기이다. 상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1-C3의 알킬기이며, 상기 R5는 C1-C3의 알킬기임.
[화학식 6]
Figure 112013062365134-pat00023

상기 [화학식 6]에서, 상기 R1은 C1~C3의 알킬기 또는 C6-C10인 아릴기이고, 상기 아릴기는 C1-C3의 알킬기 또는 할로겐으로 치환된 아릴기이다. 상기 R2은 C1-C3의 알킬기이며, 상기 R3는 F, Cl, Br, I, C1~C3의 알킬기 또는 C1~C3의 알콕시 중 어느 하나이고, 상기 R4는 C1~C3의 알킬기임.As a method for producing a beta-indolyl ester compound using a chiral palladium catalyst, a beta, gamma-unsaturated alpha keto phosphonate compound having a structure of the following Chemical Formula 3 is used in the presence of a chiral palladium catalyst. Reacted with an indole compound having the structure of to synthesize the gamma-indolyl alpha-keto phosphonate intermediate of Formula 6, followed by treatment with 1,8-Diazabicycloundec 7-ene and alcohol, A method for producing a beta-indoleyl ester compound using a chiral palladium catalyst, characterized by producing a beta-indoleyl ester compound having a structure.
(3)
Figure 112013062365134-pat00021

In [Formula 3], the R 1 is C 1 ~ C 3 alkyl group or C 6- C 10 is an aryl group, wherein the aryl group is a C 1 ~ C 3 Alkyl group or an aryl group substituted with halogen, wherein R 2 is a C 1 -C 3 Alkyl group.
[Chemical Formula 4]
Figure 112013062365134-pat00027

In [Formula 4], R 3 is any one of F, Cl, Br, I, C 1 ~ C 3 Alkyl group or C 1 ~ C 3 Alkoxy, The R 4 is C 1 -C 3 Alkyl group to be.
[Chemical Formula 5]
Figure 112013062365134-pat00022

In [Formula 5], wherein R 1 Is an alkyl group of C 1 ~ C 3 or C 6 ~ C 10 It is an aryl group, wherein the aryl group is a C 1 -C 3 alkyl group or an aryl group substituted with halogen. R 3 is any one of F, Cl, Br, I, C 1 -C 3 alkyl group or C 1 -C 3 alkoxy, R 4 is C 1 -C 3 alkyl group, and R 5 is C An alkyl group of 1 -C 3 .
[Chemical Formula 6]
Figure 112013062365134-pat00023

In Chemical Formula 6, R 1 is an alkyl group of C 1 to C 3 or an aryl group of C 6 -C 10 , and the aryl group is an aryl group substituted with an alkyl group or halogen of C 1 -C 3 . R 2 is a C 1 -C 3 alkyl group, R 3 is F, Cl, Br, I, C 1 ~ C 3 Alkyl group or C 1 ~ C 3 Alkoxy, R 4 is C 1 ~ C 3 is an alkyl group. 삭제delete 삭제delete 제1항에 있어서,
상기 키랄 팔라듐 촉매는, 하기 [화학식 1]의 화합물 또는 그 광학 이성질체인 [화학식 2]의 화합물인 것을 특징으로 하는 베타-인돌릴 에스테르 화합물의 제조방법.
[ 화학식 1 ]
Figure 112013062365134-pat00025

[ 화학식 2 ]
Figure 112013062365134-pat00026

상기 [화학식 1] 또는 [화학식 2]에서,
상기 Ar은 페닐(phenyl), 4-메틸페닐(4-methylphenyl) 또는 3,5-디메틸페닐(3,5-dimethylphenyl) 중 어느 하나이며, 상기 X는 BF4, OTf, PF6, 또는 SbF6 중 어느 하나임.The method of claim 1,
The chiral palladium catalyst is a compound of the formula [1] or a compound of the formula [2] which is an optical isomer thereof.
[Chemical Formula 1]
Figure 112013062365134-pat00025

[Formula 2]
Figure 112013062365134-pat00026

In [Formula 1] or [Formula 2],
Ar is any one of phenyl, 4-methylphenyl, or 3,5-dimethylphenyl, and X is BF 4 , OTf, PF 6, or SbF 6 . Which one. 제1항에 있어서,
상기 키랄 팔라듐 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 1 내지 20 몰%인 것을 특징으로 하는 베타-인돌릴 에스테르 화합물의 제조방법. The method of claim 1,
The content of the chiral palladium catalyst, based on the total number of moles of the reactant, characterized in that 1 to 20 mol% method for producing a beta- indolyl ester compound. 삭제delete
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