KR102590897B1

KR102590897B1 - Method for producing chiral gamma-lactam compound and metal complex therefor

Info

Publication number: KR102590897B1
Application number: KR1020180174064A
Authority: KR
Inventors: 장석복; 박윤수
Original assignee: 기초과학연구원; 한국과학기술원
Priority date: 2018-12-31
Filing date: 2018-12-31
Publication date: 2023-10-19
Also published as: WO2020141734A1; KR20200082952A

Abstract

본 발명은 키랄 감마-락탐 화합물의 제조방법 및 이를 위한 신규 금속 착체에 관한 것으로, 본 발명의 키랄 감마-락탐 화합물의 제조방법은 키랄 에틸렌디아민 리간드를 포함하는 금속 착체를 촉매로 이용한 온화한 조건 하 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 우수한 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 효율적으로 제조할 수 있다.The present invention relates to a method for producing a chiral gamma-lactam compound and a new metal complex therefor. The method for producing a chiral gamma-lactam compound of the present invention is a process under mild conditions using a metal complex containing a chiral ethylenediamine ligand as a catalyst. A chiral gamma-lactam compound with excellent enantioselectivity can be efficiently prepared from a chiral 1,4,2-dioxazol-5-one compound.

Description

키랄 감마-락탐 화합물의 제조방법 및 이를 위한 금속 착체{METHOD FOR PRODUCING CHIRAL GAMMA-LACTAM COMPOUND AND METAL COMPLEX THEREFOR}Method for producing chiral gamma-lactam compounds and metal complexes therefor {METHOD FOR PRODUCING CHIRAL GAMMA-LACTAM COMPOUND AND METAL COMPLEX THEREFOR}

본 발명은 키랄 감마-락탐 화합물의 제조방법 및 이를 위한 신규 금속 착체에 관한 것으로, 보다 상세하게는 키랄 에틸렌디아민 리간드를 포함하는 금속 착체를 촉매로 이용하여 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 키랄 감마-락탐 화합물을 우수한 거울상이성질선택성으로 효율적으로 제조하는 방법 및 이를 위한 신규 금속 착체에 관한 것이다.The present invention relates to a method for producing a chiral gamma-lactam compound and a new metal complex therefor, and more specifically, to the production of prochiral 1,4,2-dioxazole using a metal complex containing a chiral ethylenediamine ligand as a catalyst. The present invention relates to a method for efficiently preparing a chiral gamma-lactam compound from a -5-one compound with excellent enantioselectivity and a new metal complex therefor.

키랄(chiral) 화합물은 특정 광학 활성을 갖는 화합물로서, 제약업계 및 정밀화학 분야에서 이용되는 중요한 화합물이며, 전 세계 의약품 시장에서 차지하는 비중이 날로 증가하는 추세에 있는 매우 중요한 화합물이다.Chiral compounds are compounds with specific optical activity, and are important compounds used in the pharmaceutical industry and fine chemistry fields, and are very important compounds whose share in the global pharmaceutical market is increasing day by day.

키랄 사이클릭 아미드(chiral cyclic amide)는 다양한 생물학적 활성을 나타내는 중요한 분자 골격이다. 대부분의 항생제에 존재하는 β-락탐과 더불어, γ-키랄 중심을 갖는 5원 락탐은 천연물 및 항암제를 포함한 효과적인 임상 약물 모두에서 기능적 핵심 코어로서 지속적으로 인식되고 있다. 또한, 키랄 감마-락탐 화합물에 대한 수요 역시 지속적으로 증가하고 있는 추세이다.Chiral cyclic amides are important molecular frameworks that exhibit diverse biological activities. In addition to β-lactams present in most antibiotics, five-membered lactams with γ-chiral centers continue to be recognized as the functional core of both natural products and effective clinical drugs, including anticancer drugs. In addition, the demand for chiral gamma-lactam compounds is also continuously increasing.

이러한 구조적 기본단위를 구성하기 위한 효율적이고 선택적인 방법을 개발하기 위한 수많은 연구에도 불구하고, 키랄성 결합(chirality bond)을 형성하기 위한 합성 연구는 찾아보기 어려웠다.Despite numerous studies to develop efficient and selective methods for constructing these basic structural units, synthetic studies to form chirality bonds have been difficult to find.

최근에 이르러서야, 키랄 중심의 직접적인 형성을 위한 다수의 비대칭 합성법(asymmetric synthesis)이 개발되었다. 대표적인 예로는 알릴 알콜의 거울상이성질선택적 고리화(enantioselective cyclization), 불포화 락탐의 수소화 및 N-피리딜 락탐의 C-H 활성화 등이 있다. 그러나 종래 합성법들은 모두 기질에 여러 작용기를 미리 도입시켜야만 하기 때문에, 촉매화학에서 가장 중요하게 주장하는 반응 내의 원자 경제성(atom economy) 및 비용 효율성 측면에서 비효율적이다.Only recently, a number of asymmetric syntheses have been developed for the direct formation of chiral centers. Representative examples include enantioselective cyclization of allyl alcohol, hydrogenation of unsaturated lactams, and C-H activation of N-pyridyl lactams. However, since all conventional synthesis methods require the introduction of multiple functional groups into the substrate in advance, they are inefficient in terms of atom economy and cost efficiency within the reaction, which are the most important aspects in catalytic chemistry.

한편, 지난 20년 동안 많은 연구 그룹에서 C-H 아미드화(C-H amidation) 반응을 통해 설파미데이트(sulfamidate), 설폰아미드(sulfonamide) 및 카바메이트(carbamate)와 같은 키랄 아자시클릭(azacyclic) 화합물의 합성법을 보고했다.Meanwhile, over the past 20 years, many research groups have investigated the synthesis of chiral azacyclic compounds such as sulfamidate, sulfonamide, and carbamate through C-H amidation reaction. reported.

Che 그룹에 의하여 키랄 포피린을 갖는 루테늄 촉매가 키랄 설파미데이트의 거울상이성질선택적 합성을 가능케 함이 처음으로 발견되었다. 이 후, 아미노산 또는 카복사미데이트-기반 리간드, 루테늄-옥사졸린, 이리듐-금속살렌 착체, 및 금속효소(metalloenzyme)를 가진 디로듐(dirhodium) 착체를 포함하는 키랄 촉매가 보고되었다.It was first discovered by the Che group that ruthenium catalysts with chiral porphyrins enable the enantioselective synthesis of chiral sulfamidates. Afterwards, chiral catalysts containing dirhodium complexes with amino acid or carboxamidate-based ligands, ruthenium-oxazoline, iridium-metallosalen complexes, and metalloenzymes were reported.

그러나, 이미노아이오디난(iminoiodinane) 및 유기 아자이드와 같은 관련 나이트렌(nitrene) 전구체의 용이한 접근성과 견고성, 및 반응성이 높은 금속-나이트레노이드(metal-nitrenoid) 중간체로부터 부반응 경로의 부재로 인하여, 설포닐- 또는 카바메이트-기반의 기질에 대한 고리화에 대부분 한정되어 있었다. However, the easy accessibility and robustness of related nitrene precursors, such as iminoiodinane and organic azides, and the absence of side reaction pathways from highly reactive metal-nitrenoid intermediates. For this reason, it was mostly limited to cyclization to sulfonyl- or carbamate-based substrates.

반면, 키랄 락탐, 특히 키랄 감마-락탐 화합물을 합성하기 위한 카복사미드의 비대칭 C-H 아미드화는 견고하지만 반응성이 뛰어난 카보닐나이트렌 전구체의 미개발 및 핵심 금속-나이트레노이드 중간체의 이소시아네이트로의 원치않는 분해로 인하여 아직까지 찾아보기 어렵다.On the other hand, the asymmetric C-H amidation of carboxamides to synthesize chiral lactams, especially chiral gamma-lactam compounds, is robust but leads to the unexploited availability of highly reactive carbonylnitrene precursors and the unwanted conversion of key metal-nitrenoid intermediates to isocyanates. Due to disassembly, it is still difficult to find.

또한, 키랄 감마-락탐 화합물을 제조할 수 있는 금속 촉매에 대한 연구 역시 아직은 미비한 실정이다.In addition, research on metal catalysts capable of producing chiral gamma-lactam compounds is still insufficient.

따라서, 의약 및 화학분야에서 매우 중요한 핵심 중간체인 키랄 감마-락탐 화합물을 자연계에 풍부한 탄화수소 화합물로부터 높은 선택성 및 수율로 효율적으로 제조하는 방법의 개발이 절실히 요구되고 있다.Therefore, there is an urgent need to develop a method for efficiently producing chiral gamma-lactam compounds, which are very important intermediates in the fields of medicine and chemistry, with high selectivity and yield from hydrocarbon compounds abundant in nature.

Org. Lett. 14, 608-611 (2012) Org. Lett. 14, 608-611 (2012) Org. Lett. 19, 1144-1147 (2017) Org. Lett. 19, 1144-1147 (2017) Chem. Comm. 51, 16660-16663 (2015) Chem. Comm. 51, 16660-16663 (2015) Angew. Chem. Int. Ed. 41, 3465-3468 (2002) Angew. Chem. Int. Ed. 41, 3465-3468 (2002) Angew. Chem. Int. Ed. 47, 6825-6828 (2008) Angew. Chem. Int. Ed. 47, 6825-6828 (2008) J. Am. Chem. Soc. 139, 1750-1753 (2017) J. Am. Chem. Soc. 139, 1750-1753 (2017) Org. Lett. 8, 5013-5016 (2006) Org. Lett. 8, 5013-5016 (2006)

이에 본 발명자들은 상기와 같은 문제점을 해결하고자 노력하던 중, 견고하면서 반응성이 뛰어난 카보닐나이트렌 전구체로 프로키랄 1,4,2-디옥사졸-5-온 화합물을 사용하고, 특정 작용기를 가지는 키랄 에틸렌디아민 리간드를 포함하는 금속 착체를 촉매로 사용하는 경우 온화한 조건 하에서 비대칭 C-H 아미드화를 통해 중간체인 금속-카보닐나이트렌을 안정화시켜 부산물의 형성을 억제하여 우수한 거울상이성질선택성을 가진 키랄 감마-락탐 화합물이 제조됨을 발견하고, 본 발명을 완성하였다.Accordingly, while trying to solve the above problems, the present inventors used a prochiral 1,4,2-dioxazol-5-one compound as a robust and highly reactive carbonylnitrene precursor, and used a prochiral 1,4,2-dioxazol-5-one compound with a specific functional group. When a metal complex containing a chiral ethylenediamine ligand is used as a catalyst, the intermediate metal-carbonylnitrene is stabilized through asymmetric C-H amidation under mild conditions and the formation of by-products is suppressed, resulting in chiral gamma with excellent enantioselectivity. -Discovered that lactam compounds could be produced, and completed the present invention.

본 발명은 다양한 천연물, 의약품의 제조를 위한 중간체로 유용하게 이용될 수 있는 키랄 감마-락탐 화합물을 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조하는 방법을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a method for producing a chiral gamma-lactam compound that can be usefully used as an intermediate for the production of various natural products and pharmaceuticals from a prochiral 1,4,2-dioxazol-5-one compound. Do it as

본 발명은 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 키랄 감마-락탐 화합물을 제조하기 위한 촉매로, 신규 금속 착체를 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a novel metal complex as a catalyst for producing chiral gamma-lactam compounds from prochiral 1,4,2-dioxazol-5-one compounds.

상술한 과제를 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 금속 착체 및 염기의 존재 하에 하기 화학식 2로 표시되는 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물을 아미드화하여 하기 화학식 3으로 표시되는 키랄(chiral) 감마-락탐 화합물을 제조하는 방법을 제공한다.In order to solve the above-described problem, the present invention provides a prochiral 1,4,2-dioxazol-5-one compound represented by the following formula 2 in the presence of a metal complex represented by the following formula 1 and a base. A method for producing a chiral gamma-lactam compound represented by the following formula (3) by amidation is provided.

[화학식 1][Formula 1]

(상기 화학식 1에서,(In Formula 1 above,

M은 이리듐(III), 로듐(III) 또는 코발트(III)이며;M is iridium(III), rhodium(III), or cobalt(III);

X₁는 할로겐이며;X ₁ is halogen;

R₁ 내지 R₅는 각각 독립적으로 수소 또는 C1-C20알킬이며;R ₁ to R ₅ are each independently hydrogen or C1-C20 alkyl;

R₆은 -C(=O)-R^a 또는 -S(=O)₂-R^b이며; R ₆ is -C(=O)-R ^a or -S(=O) ₂ -R ^b ;

R^a 및 R^b는 각각 독립적으로 C1-C20알킬, C1-C20알콕시, C6-C20아릴, C6-C20아릴옥시 또는 -NR^cR^d이며, 상기 R^a 및 R^b의 알킬, 알콕시, 아릴 및 아릴옥시는 C1-C20알킬, 할로겐, C1-C20알콕시, 니트로 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며; R ^a and R ^b are each independently C1-C20 alkyl, C1-C20 alkoxy, C6-C20 aryl, C6-C20 aryloxy or -NR ^c R ^d , and the ^alkyl , ^alkoxy , aryl and Aryloxy may be further substituted with one or more selected from C1-C20 alkyl, halogen, C1-C20 alkoxy, nitro and haloC1-C20 alkyl;

R^c 및 R^d는 각각 독립적으로 수소 또는 C1-C20알킬이며;R ^c and R ^d are each independently hydrogen or C1-C20 alkyl;

R₇ 및 R₈은 각각 독립적으로 C1-C20알킬 또는 C6-C20아릴이거나, 상기 R₇과 R₈은 서로 연결되어 고리를 형성할 수 있으며, 상기 R₇ 및 R₈의 알킬 및 아릴은 C1-C20알킬, 할로겐, C1-C20알콕시, 니트로 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있다.)R ₇ and R ₈ are each independently C1-C20 alkyl or C6-C20 aryl, or R ₇ and R ₈ may be connected to each other to form a ring, and the alkyl and aryl of R ₇ and R ₈ are C1- It may be further substituted with one or more selected from C20 alkyl, halogen, C1-C20 alkoxy, nitro and haloC1-C20 alkyl.)

[화학식 2][Formula 2]

[화학식 3][Formula 3]

(상기 화학식 2 및 3에서,(In Formulas 2 and 3 above,

R₂₁은 C1-C20알킬, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬, 시클로알킬, 아릴, 알케닐 또는 알키닐은 C1-C20알킬, 할로겐, 할로C1-C20알킬, 니트로, 시아노, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 및 프탈이미도로부터 선택되는 하나 이상으로 더 치환될 수 있으며;R ₂₁ is C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl or C2-C20 alkynyl, and the alkyl, cycloalkyl, aryl, alkenyl or alkynyl of R ₂₁ is C1 -C20alkyl, halogen, haloC1-C20alkyl, nitro, cyano, C3-C20cycloalkyl, C6-C20aryl, C2-C20alkenyl and phthalimido;

R₂₂ 및 R₂₃은 각각 독립적으로 수소 또는 C1-C20알킬이고, 상기 R₂₃의 알킬은 C6-C20아릴 또는 프탈이미도로 더 치환될 수 있고;R ₂₂ and R ₂₃ are each independently hydrogen or C1-C20 alkyl, and the alkyl of R ₂₃ may be further substituted with C6-C20 aryl or phthalimido;

상기 R₂₁ 내지 R₂₃은 인접한 치환기와 연결되어 고리를 형성할 수 있다.) R ₂₁ to R ₂₃ may be connected to adjacent substituents to form a ring.)

일 실시예에 있어서, 상기 화학식 1에서 R₇과 R₈은 C3-C7알킬렌으로 연결되어 지환족 고리를 형성할 수 있다.In one embodiment, in Formula 1, R ₇ and R ₈ may be connected to C3-C7 alkylene to form an alicyclic ring.

일 실시예에 있어서, 상기 금속 착체는 하기 화학식 1-1로 표시되는 금속 착체일 수 있다.In one embodiment, the metal complex may be a metal complex represented by the following formula 1-1.

[화학식 1-1][Formula 1-1]

(상기 화학식 1-1에서,(In Formula 1-1 above,

X₁는 할로겐이며;X ₁ is halogen;

R₉는 C1-C20알킬 또는 C6-C20아릴이며, 상기 R₉의 아릴은 C1-C20알킬, 할로겐, C1-C20알콕시 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며; R ₉ is C1-C20 alkyl or C6-C20 aryl, and the aryl of R ₉ may be further substituted with one or more selected from C1-C20 alkyl, halogen, C1-C20 alkoxy, and haloC1-C20 alkyl;

R₇ 및 R₈은 각각 독립적으로 C6-C20아릴이거나, 상기 R₇과 R₈은 C3-C7알킬렌으로 연결되어 지환족 고리를 형성할 수 있으며, 상기 R₇ 및 R₈의 아릴은 C1-C20알킬 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있다.)R ₇ and R ₈ are each independently C6-C20 aryl, or R ₇ and R ₈ may be connected by C3-C7 alkylene to form an alicyclic ring, and the aryl of R ₇ and R ₈ is C1- It may be further substituted with one or more selected from C20 alkyl and haloC1-C20 alkyl.)

일 실시예에 있어서, 상기 금속 착체는 하기 화학식 1-2로 표시되는 금속 착체일 수 있다.In one embodiment, the metal complex may be a metal complex represented by the following formula 1-2.

[화학식 1-2][Formula 1-2]

(상기 화학식 1-2에서,(In Formula 1-2 above,

X₁는 할로겐이며;X ₁ is halogen;

R₁ 내지 R₅는 각각 독립적으로 C1-C10알킬이며;R ₁ to R ₅ are each independently C1-C10 alkyl;

R₉는 C1-C10알킬 또는 C6-C12아릴이며, 상기 R₉의 아릴은 C1-C10알킬, 할로겐, C1-C10알콕시 및 할로C1-C10알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며; R ₉ is C1-C10 alkyl or C6-C12 aryl, and the aryl of R ₉ may be further substituted with one or more selected from C1-C10 alkyl, halogen, C1-C10 alkoxy, and haloC1-C10 alkyl;

R₁₀ 및 R₁₁는 각각 독립적으로 C1-C10알킬이며;R ₁₀ and R ₁₁ are each independently C1-C10 alkyl;

c 및 d는 각각 독립적으로 0 내지 5의 정수이다.)c and d are each independently integers from 0 to 5.)

일 실시예에 있어서, 상기 금속 착체는 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰로 사용될 수 있다.In one embodiment, the metal complex may be used in an amount of 0.01 to 0.1 mole per mole of the prochiral 1,4,2-dioxazol-5-one compound.

일 실시예에 있어서, 상기 염기는 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰로 사용될 수 있다. 일 예로, 상기 염기는 NaBAr^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF₆ (Silver hexafluoroantimonate(V)), AgNTf₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF₄ (Silver tetrafluoroborate), AgPF₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate), AgOAc (Silver acetate) 등에서 선택되는 하나 또는 둘 이상일 수 있다.In one embodiment, the base may be used in an amount of 0.01 to 0.1 mol per mole of the prochiral 1,4,2-dioxazol-5-one compound. As an example, the base is NaBAr ^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF ₆ (Silver hexafluoroantimonate(V)), AgNTf ₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF ₄ ( It may be one or more than one selected from Silver tetrafluoroborate), AgPF ₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate), AgOAc (Silver acetate), etc.

일 실시예에 있어서, 상기 아미드화는 20 내지 60℃에서 수행될 수 있다.In one embodiment, the amidation may be performed at 20 to 60°C.

일 실시예에 있어서, 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-1의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-1의 키랄 감마-락탐 화합물일 수 있다.In one embodiment, the prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-1, and the chiral The gamma-lactam compound may be a chiral gamma-lactam compound of the following Chemical Formula 3-1.

[화학식 2-1][Formula 2-1]

[화학식 3-1][Formula 3-1]

(상기 화학식 2-1 및 3-1에서,(In Formulas 2-1 and 3-1 above,

R₂₁은 C1-C20알킬, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬, 시클로알킬, 아릴, 알케닐 또는 알키닐은 C1-C20알킬, 할로겐, 할로C1-C20알킬, 니트로, 시아노, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있다.)R ₂₁ is C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl or C2-C20 alkynyl, and the alkyl, cycloalkyl, aryl, alkenyl or alkynyl of R ₂₁ is C1 -It may be further substituted with any one or more selected from C20 alkyl, halogen, haloC1-C20 alkyl, nitro, cyano, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl and phthalimido.)

일 실시예에 있어서, 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-2의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-2의 키랄 감마-락탐 화합물일 수 있다.In one embodiment, the prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-2, and the chiral The gamma-lactam compound may be a chiral gamma-lactam compound of the following Chemical Formula 3-2.

[화학식 2-2][Formula 2-2]

[화학식 3-2][Formula 3-2]

일 실시예에 있어서, 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-3의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-3의 키랄 감마-락탐 화합물일 수 있다.In one embodiment, the prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-3, and the chiral The gamma-lactam compound may be a chiral gamma-lactam compound of the following formula 3-3.

[화학식 2-3][Formula 2-3]

[화학식 3-3][Formula 3-3]

(상기 화학식 2-3 및 3-3에서,(In Formulas 2-3 and 3-3,

R₂₁은 C1-C20알킬, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬, 시클로알킬, 아릴, 알케닐 또는 알키닐은 C1-C20알킬, 할로겐, 할로C1-C20알킬, 니트로, 시아노, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며;R ₂₁ is C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl or C2-C20 alkynyl, and the alkyl, cycloalkyl, aryl, alkenyl or alkynyl of R ₂₁ is C1 -C20 alkyl, halogen, haloC1-C20 alkyl, nitro, cyano, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl and phthalimido;

R_22a은 C6-C20아릴이다.)R _22a is C6-C20 aryl.)

일 실시예에 있어서, 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-4의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-4의 키랄 감마-락탐 화합물일 수 있다.In one embodiment, the prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-4, and the chiral The gamma-lactam compound may be a chiral gamma-lactam compound of the following formula 3-4.

[화학식 2-4][Formula 2-4]

[화학식 3-4][Formula 3-4]

(상기 화학식 2-4 및 3-4에서,(In Formulas 2-4 and 3-4 above,

L₁은 융합고리를 포함하거나 포함하지 않는 C3-C7알킬렌이고;L ₁ is C3-C7 alkylene with or without a fused ring;

R₂₃은 수소 또는 C1-C20알킬이고, 상기 R₂₃의 알킬은 C6-C20아릴 또는 프탈이미도로 더 치환될 수 있다.)R ₂₃ is hydrogen or C1-C20 alkyl, and the alkyl of R ₂₃ may be further substituted with C6-C20 aryl or phthalimido.)

또한, 본 발명은 하기 화학식 4로 표시되는 금속 착체를 제공한다.Additionally, the present invention provides a metal complex represented by the following formula (4).

[화학식 4][Formula 4]

(상기 화학식 4에서,(In Formula 4 above,

X₂는 할로겐이며;X ₂ is halogen;

R₃₁ 내지 R₃₅는 각각 독립적으로 수소 또는 C1-C20알킬이며;R ₃₁ to R ₃₅ are each independently hydrogen or C1-C20 alkyl;

R₃₆는 C1-C20알콕시 및 할로겐으로부터 선택되는 하나 이상으로 치환된C6-C20아릴, 또는 C1-C20알킬이 치환된 C6-C20아릴이며; R ₃₆ is C6-C20 aryl substituted with one or more C1-C20 alkoxy and halogen, or C6-C20 aryl substituted with C1-C20 alkyl;

R₃₇ 및 R₃₈은 각각 독립적으로 C6-C20아릴이며, 상기 R₃₇ 및 R₃₈의 아릴은 C1-C20알킬 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며;R ₃₇ and R ₃₈ are each independently C6-C20 aryl, and the aryl of R ₃₇ and R ₃₈ may be further substituted with one or more selected from C1-C20 alkyl and haloC1-C20 alkyl;

단, R₃₆이 C1-C20알킬이 치환된 C6-C20아릴인 경우 R₃₇ 및 R₃₈은 C1-C20알킬 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 치환된 C6-C20아릴이다.)However, when R ₃₆ is C6-C20 aryl substituted with C1-C20 alkyl, R ₃₇ and R ₃₈ are C6-C20 aryl substituted with one or more selected from C1-C20 alkyl and haloC1-C20 alkyl.)

일 실시예에 있어서, 상기 금속 착체는 하기 화학식 4-1로 표시될 수 있다.In one embodiment, the metal complex may be represented by the following Chemical Formula 4-1.

[화학식 4-1][Formula 4-1]

(상기 화학식 4-1에서,(In Formula 4-1 above,

X₂는 할로겐이며;X ₂ is halogen;

R₃₁ 내지 R₃₅는 각각 독립적으로 C1-C10알킬이며;R ₃₁ to R ₃₅ are each independently C1-C10 alkyl;

R₃₆는 C1-C10알콕시가 치환된 C6-C12아릴 또는 할로겐이 치환된 C6-C12아릴이다.)R ₃₆ is C6-C12 aryl substituted with C1-C10 alkoxy or C6-C12 aryl substituted with halogen.)

일 실시예에 있어서, 상기 금속 착체는 하기 화학식 4-2로 표시될 수 있다.In one embodiment, the metal complex may be represented by the following Chemical Formula 4-2.

[화학식 4-2][Formula 4-2]

(상기 화학식 4-2에서,(In Formula 4-2 above,

X₂는 할로겐이며;X ₂ is halogen;

R₃₆는 C1-C10알킬이 치환된 C6-C12아릴이며; R ₃₆ is C6-C12 aryl substituted with C1-C10 alkyl;

R₃₉ 및 R₄₀는 각각 독립적으로 C1-C10알킬이며;R ₃₉ and R ₄₀ are each independently C1-C10 alkyl;

e 및 f는 각각 독립적으로 1 내지 3의 정수이다.)e and f are each independently integers from 1 to 3.)

일 실시예에 있어서, 상기 금속 착체는 하기 구조에서 선택되는 하나 이상일 수 있다.In one embodiment, the metal complex may be one or more selected from the structures below.

본 발명의 키랄 감마-락탐 화합물의 제조방법은 온화한 조건 하에서 키랄 에틸렌디아민 리간드를 포함하는 금속 착체를 촉매로 사용하여 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 우수한 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 짧은 단계로 효율적으로 합성할 수 있으며, 키랄 감마-락탐 화합물의 대량생산이 가능케하여 상업적으로 이용가능성이 높다.The method for producing a chiral gamma-lactam compound of the present invention uses a metal complex containing a chiral ethylenediamine ligand as a catalyst under mild conditions to obtain excellent enantiomerism from a prochiral 1,4,2-dioxazol-5-one compound. Chiral gamma-lactam compounds with selectivity can be efficiently synthesized in short steps, and mass production of chiral gamma-lactam compounds is possible, making them highly commercially available.

또한, 본 발명의 키랄 감마-락탐 화합물의 제조방법은 키랄 에틸렌디아민 리간드를 도입한 금속 착체를 프로키랄 1,4,2-디옥사졸-5-온 화합물의 아미드화 반응의 촉매로 채용함으로써 아미드화 반응 중 생성되는 중간체인 카보닐나이트렌(carbonylnitrene)의 분해 및 이로 인한 부산물인 이소시아네이트(isocyanate)의 형성을 효과적으로 억제할 수 있다.In addition, the method for producing a chiral gamma-lactam compound of the present invention employs a metal complex into which a chiral ethylenediamine ligand is introduced as a catalyst for the amidation reaction of a prochiral 1,4,2-dioxazol-5-one compound, thereby producing an amide. It can effectively suppress the decomposition of carbonylnitrene, an intermediate produced during the chemical reaction, and the formation of isocyanate, a by-product.

본 발명의 제조방법에 따라 제조된 키랄 감마-락탐 화합물은 다양한 천연물, 의약품 등의 다양한 분야의 중간체 및 합성단위체로 매우 유용하게 적용할 수 있다.The chiral gamma-lactam compound prepared according to the production method of the present invention can be very usefully applied as an intermediate and synthetic unit in various fields such as various natural products and pharmaceuticals.

또한, 본 발명의 금속 착체는 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 키랄 감마-락탐 화합물을 제조하기 위한 촉매로 매우 유용하다.Additionally, the metal complex of the present invention is very useful as a catalyst for producing chiral gamma-lactam compounds from prochiral 1,4,2-dioxazol-5-one compounds.

이하, 본 발명에 대하여 보다 구체적으로 설명한다. 이 때 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.Hereinafter, the present invention will be described in more detail. Unless otherwise defined, the technical and scientific terms used herein have meanings commonly understood by those skilled in the art to which this invention pertains, and the following description will not unnecessarily obscure the gist of the present invention. Descriptions of possible notification functions and configurations are omitted.

본 명세서 내 용어 “알킬”은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소 라디칼을 의미한다. 상기 알킬은 1 내지 20개의 탄소원자를 가질 수 있다. 상기 알킬은 1 내지 10개의 탄소원자를 가질 수 있다. 상기 알킬은 1 내지 7개의 탄소원자를 가질 수 있다. 이러한 알킬 라디칼의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 헥실, 옥틸, 노닐, 데실, 도데실, 테트라데실 등을 포함하지만 이에 한정되지는 않는다.The term “alkyl” herein refers to a monovalent straight-chain or branched saturated hydrocarbon radical consisting of only carbon and hydrogen atoms. The alkyl may have 1 to 20 carbon atoms. The alkyl may have 1 to 10 carbon atoms. The alkyl may have 1 to 7 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, etc.

본 명세서 내 용어 “알콕시”는 -O-알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 구체적인 예로는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시 등을 포함되지만 이에 한정되지는 않는다.The term “alkoxy” in this specification refers to an -O-alkyl radical, where ‘alkyl’ is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, etc.

본 명세서 내 용어 “아릴”은 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 방향족 고리 1가의 유기 라디칼을 의미하는 것으로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합고리계를 포함할 수 있으며, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 포함할 수 있다. 고리 원자로 6 내지 20개의 탄소원자, 바람직하게는 6 내지 12개의 탄소원자를 가질 수 있다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐, 플루오레닐 등을 포함하지만, 이에 한정되지는 않는다. The term “aryl” herein refers to an organic radical with a monovalent aromatic ring derived from an aromatic hydrocarbon by removal of one hydrogen, and each ring contains suitably 4 to 7 ring atoms, preferably 5 or 6 ring atoms. It may include a single or fused ring system including, and may even include a form in which multiple aryls are connected by a single bond. The ring atom may have 6 to 20 carbon atoms, preferably 6 to 12 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, etc.

본 명세서 내 용어 “아릴옥시”는 -O-아릴 라디칼을 의미하는 것으로, 여기서 ‘아릴’은 상기 정의한 바와 같다. 이러한 아릴옥시 라디칼의 예는 페녹시, 나프톡시 등을 포함하지만 이에 한정되지는 않는다.The term “aryloxy” in this specification refers to an -O-aryl radical, where ‘aryl’ is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, etc.

본 명세서 내 용어 “할로” 또는 “할로겐”은 할로겐족 원소를 나타내며, 예컨대, 플루오로, 클로로, 브로모 및 요오도를 포함한다.The term “halo” or “halogen” herein refers to elements of the halogen group and includes, for example, fluoro, chloro, bromo, and iodo.

본 명세서 내 용어 “할로알킬”은 적어도 하나의 할로겐으로 치환된 알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 할로알킬 라디칼의 예는 플루오로메틸, 트리플루오로메틸, 브로모메틸, 퍼플루오로에틸 등을 포함하지만 이에 한정되지는 않는다.The term “haloalkyl” in this specification refers to an alkyl radical substituted with at least one halogen, where ‘alkyl’ is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, etc.

본 명세서 내 용어 “시클로알킬”은 하나 이상의 고리로 구성된 비방향족 카보사이클릭 1가 라디칼로, 포화 또는 불포화된 단일고리, 다중고리 또는 스피로고리 형태를 모두 포함할 수 있다. 구체적인 예로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 노보닐(norbornyl), 바이시클로[3.1.0]헥실(bicyclo[3.1.0]hexyl), 바이시클로[4.1.0]헵틸(bicyclo[4.1.0]heptyl), 바이시클로[2.2.1]헵틸(bicyclo[2.2.1]heptyl), 아다만틸(adamantly), 데칼리닐(decalinyl) 등을 들 수 있으나, 이에 한정되지는 않는다.The term “cycloalkyl” in this specification refers to a non-aromatic carbocyclic monovalent radical consisting of one or more rings, and may include saturated or unsaturated monocyclic, polycyclic, or spiroring forms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3.1.0]hexyl, and bicyclo[4.1.0]heptyl. Examples include, but are not limited to, 4.1.0]heptyl, bicyclo[2.2.1]heptyl, adamantyl, and decalinyl.

본 명세서 내 용어 “알케닐”은 두 개 이상의 탄소 원자들 사이에 하나 이상의 이중 결합을 포함하는 직쇄 또는 분쇄의 불포화 탄화수소 1가 라디칼로, 부분적으로 포화될 수 있다. 구체적으로 에테닐, 프로펜일, 프로프-1-엔-2일, 1-부테닐, 2-부테닐, 이소부틸레닐, 1-펜테닐, 2-펜테닐, 3-메틸-1-부테닐, 2-메틸-2-부테닐, 2,3-디메틸-2-부테닐, 이소프레닐, 제라닐(geranyl), 5-테트라데세닐 등을 포함하지만 이에 한정되지는 않는다.The term “alkenyl” herein refers to a straight-chain or branched unsaturated hydrocarbon monovalent radical containing one or more double bonds between two or more carbon atoms, and may be partially saturated. Specifically, ethenyl, propenyl, prop-1-en-2yl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl. , 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, isoprenyl, geranyl, 5-tetradecenyl, etc., but is not limited thereto.

본 명세서 내 용어 “알키닐”은 두 개 이상의 탄소 원자들 사이에 하나 이상의 삼중 결합을 포함하는 직쇄 또는 분쇄의 불포화 탄화수소 1가 라디칼로, 부분적으로 포화될 수 있다. 구체적으로 에티닐(ethynyl), 프로피닐(propynyl), 부티닐(butynyl) 1,3-부타디이닐(1,3-Butadiynyl) 등을 포함하지만 이에 한정되지는 않는다.The term “alkynyl” herein refers to a straight-chain or branched unsaturated hydrocarbon monovalent radical containing one or more triple bonds between two or more carbon atoms, and may be partially saturated. Specifically, it includes, but is not limited to, ethynyl, propynyl, butynyl, 1,3-butadiynyl, etc.

본 명세서 내 용어 “알킬렌”은 탄소 및 수소 원자만으로 구성된 2가의 직쇄 또는 분쇄 포화 탄화수소 2가 기를 의미하는 것으로, 구체적으로 메틸렌, 에틸렌, 프로필렌, 이소프로필렌, 부틸렌, 이소부틸렌, t-부틸렌, 펜틸렌, 헥실렌, 옥틸렌, 노닐렌 등을 포함하지만 이에 한정되지는 않는다.The term “alkylene” in this specification refers to a divalent straight-chain or branched saturated hydrocarbon divalent group consisting only of carbon and hydrogen atoms, specifically methylene, ethylene, propylene, isopropylene, butylene, isobutylene, and t-butyl. Includes, but is not limited to, lene, pentylene, hexylene, octylene, nonylene, etc.

본 발명은 키랄 감마-락탐 화합물의 제조방법 및 이를 위한 신규 금속 착체에 관한 것으로, 보다 상세하게는 키랄 에틸렌디아민 리간드를 포함하는 금속 착체를 촉매로 이용하여 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 우수한 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 효율적으로 제조하는 방법 및 이를 위한 신규 금속 착체에 관한 것이다.The present invention relates to a method for producing a chiral gamma-lactam compound and a new metal complex therefor, and more specifically, to the production of prochiral 1,4,2-dioxazole using a metal complex containing a chiral ethylenediamine ligand as a catalyst. The present invention relates to a method for efficiently producing a chiral gamma-lactam compound with excellent enantioselectivity from a -5-one compound and a new metal complex therefor.

본 발명의 일 양태에 따르면, 본 발명은 하기 화학식 1로 표시되는 금속 착체 및 염기의 존재 하에 하기 화학식 2로 표시되는 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물을 아미드화하여 하기 화학식 3으로 표시되는 키랄(chiral) 감마-락탐 화합물을 제조하는 방법을 제공한다.According to one aspect of the present invention, the present invention provides a prochiral 1,4,2-dioxazol-5-one compound represented by Formula 2 below in the presence of a metal complex represented by Formula 1 below and a base. A method for producing a chiral gamma-lactam compound represented by the following formula (3) by amidation is provided.

[화학식 1][Formula 1]

(상기 화학식 1에서,(In Formula 1 above,

X₁는 할로겐이며;X ₁ is halogen;

R₆은 -C(=O)-R^a 또는 -S(=O)₂-R^b이며;R ₆ is -C(=O)-R ^a or -S(=O) ₂ -R ^b ;

[화학식 2][Formula 2]

[화학식 3][Formula 3]

(상기 화학식 2 및 3에서,(In Formulas 2 and 3 above,

본 발명의 키랄 감마-락탐 화합물의 제조방법은 종래의 촉매와는 상이한 리간드, 즉 키랄 에틸렌디아민 리간드를 도입한 금속 착체를 촉매로 채용하여 온화한 조건 하에서 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물의 탄소-수소 결합을 탄소-질소 결합으로 바꾸는 질소화 반응, 즉 아미드화를 통해 높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 용이하게 제조할 수 있다. 또한, 키랄 에틸렌디아민 리간드를 도입한 금속 착체를 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물의 아미드화 반응의 촉매로 채용함으로써 아미드화 반응 중 생성되는 중간체인 카보닐나이트렌(carbonylnitrene)의 분해 및 이로 인한 부산물인 이소시아네이트(isocyanate)의 형성을 효과적으로 억제할 수 있다.The method for producing a chiral gamma-lactam compound of the present invention employs a different ligand from the conventional catalyst, that is, a metal complex into which a chiral ethylenediamine ligand is introduced, as a catalyst to produce prochiral 1,4,2-diamine under mild conditions. A chiral gamma-lactam compound with high enantioselectivity can be easily prepared through a nitrogenation reaction, that is, amidation, which changes the carbon-hydrogen bond of the oxazol-5-one compound to a carbon-nitrogen bond. In addition, by employing a metal complex into which a chiral ethylenediamine ligand is introduced as a catalyst for the amidation reaction of a prochiral 1,4,2-dioxazol-5-one compound, the carbonyl intermediate produced during the amidation reaction It can effectively inhibit the decomposition of carbonylnitrene and the formation of isocyanate, a by-product.

본 발명의 키랄 감마-락탐 화합물의 제조방법에서 촉매로 사용되는 상기 금속 착체는 종래의 촉매와는 상이한 리간드, 즉 키랄 에틸렌디아민 리간드를 도입함으로써 종래의 촉매와 대비하여 촉매활성이 우수하며, 거울상이성질선택성 또한 현저하게 향상되어 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물로부터 키랄 감마-락탐 화합물을 높은 선택성 및 수율로 용이하게 제조할 수 있다.The metal complex used as a catalyst in the method for producing a chiral gamma-lactam compound of the present invention has superior catalytic activity compared to the conventional catalyst by introducing a different ligand from the conventional catalyst, that is, a chiral ethylenediamine ligand, and has a mirror image. Property selectivity is also significantly improved, allowing chiral gamma-lactam compounds to be easily prepared from prochiral 1,4,2-dioxazol-5-one compounds with high selectivity and yield.

나아가, 본 발명의 키랄 감마-락탐 화합물의 제조방법에 따르면, 상기 금속 착체를 촉매로 하여 온화한 조건 하에서 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물을 아미드화 반응시킴으로서 다양한 분야의 원료물질, 중간체 등으로 매우 유용하게 사용되는 키랄 감마-락탐 화합물의 대량생산이 가능케하는 장점을 가진다.Furthermore, according to the method for producing a chiral gamma-lactam compound of the present invention, a prochiral 1,4,2-dioxazol-5-one compound is amidated under mild conditions using the metal complex as a catalyst. It has the advantage of enabling mass production of chiral gamma-lactam compounds, which are very useful as raw materials and intermediates in various fields.

일 실시예에 있어서, 상기 화학식 1의 금속 착체는 이리듐(III) 착체일 수 있다.In one embodiment, the metal complex of Formula 1 may be an iridium(III) complex.

일 실시예에 있어서, 상기 화학식 1의 금속 착체에서, R₇과 R₈은 C3-C7알킬렌으로 연결되어 지환족 고리를 형성할 수 있다.In one embodiment, in the metal complex of Formula 1, R ₇ and R ₈ may be connected to C3-C7 alkylene to form an alicyclic ring.

일 실시예에 있어서, 상기 화학식 1의 금속 착체에서, R₂₁ 내지 R₂₃은 서로 연결되어 융합 고리를 형성할 수 있으며, 형성된 융합 고리의 일 예로는 아다만탄 등이 있다. In one embodiment, in the metal complex of Formula 1, R ₂₁ to R ₂₃ may be connected to each other to form a fused ring, and an example of the formed fused ring includes adamantane.

향상된 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 제조하기 위한 측면에서, 상기 금속 착체는 하기 화학식 1-1로 표시되는 금속 착체일 수 있다.In terms of preparing a chiral gamma-lactam compound with improved enantioselectivity, the metal complex may be a metal complex represented by the following formula 1-1.

[화학식 1-1][Formula 1-1]

(상기 화학식 1-1에서,(In Formula 1-1 above,

X₁는 할로겐이며;X ₁ is halogen;

높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 제조함과 동시에 부산물의 형성을 효과적으로 억제하기 위한 측면에서, 상기 금속 착체는 하기 화학식 1-2로 표시되는 금속 착체일 수 있다.In order to produce a chiral gamma-lactam compound with high enantioselectivity and at the same time effectively suppress the formation of by-products, the metal complex may be a metal complex represented by the following formula 1-2.

[화학식 1-2][Formula 1-2]

(상기 화학식 1-2에서,(In Formula 1-2 above,

X₁는 할로겐이며;X ₁ is halogen;

R₉는 C1-C10알킬 또는 C6-C12아릴이며, 상기 R₉의 아릴은 C1-C10알킬, 할로겐, C1-C10알콕시 및 할로C1-C10알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며;R ₉ is C1-C10 alkyl or C6-C12 aryl, and the aryl of R ₉ may be further substituted with one or more selected from C1-C10 alkyl, halogen, C1-C10 alkoxy, and haloC1-C10 alkyl;

높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 고수율로 제조함과 동시에 부산물의 형성을 효과적으로 억제하기 위한 측면에서, 상기 화학식 1-2의 금속 착체에서 X₁는 할로겐이며; R₁ 내지 R₅는 각각 독립적으로 C1-C7알킬이며; R₉는 C1-C7알킬C6-C12아릴이며; R₁₀ 및 R₁₁는 각각 독립적으로 C1-C7알킬이며; c 및 d는 각각 독립적으로 1 내지 5의 정수, 보다 바람직하게는 1 내지 3의 정수일 수 있다.In order to produce a chiral gamma-lactam compound with high enantioselectivity in high yield and at the same time effectively suppress the formation of by-products, in the metal complex of Formula 1-2, X ₁ is a halogen; R ₁ to R ₅ are each independently C1-C7 alkyl; R ₉ is C1-C7alkylC6-C12aryl; R ₁₀ and R ₁₁ are each independently C1-C7 alkyl; c and d may each independently be an integer of 1 to 5, more preferably an integer of 1 to 3.

일 실시예에 있어서, 상기 금속 착체는 하기 구조로 예시될 수 있으나, 이에 한정되는 것은 아니다.In one embodiment, the metal complex may have the following structure, but is not limited thereto.

일 실시예에 있어서, 상기 염기의 사용량은 특별히 제한되지는 않으나, 부산물의 형성을 억제하는 측면에서 바람직하게는 상기 염기를 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰, 보다 바람직하게는 0.04 내지 0.1몰로 사용할 수 있으며, 상기 범위로 염기를 사용하는 경우 부산물의 형성을 현저하게 억제할 수 있다.In one embodiment, the amount of the base used is not particularly limited, but in terms of suppressing the formation of by-products, the base is preferably used in 1 mole of the prochiral 1,4,2-dioxazol-5-one compound. It can be used in an amount of 0.01 to 0.1 mol, more preferably 0.04 to 0.1 mol, and when the base is used in the above range, the formation of by-products can be significantly suppressed.

상기 염기의 구체적인 예로는 NaBAr^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF₆ (Silver hexafluoroantimonate(V)), AgNTf₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF₄ (Silver tetrafluoroborate), AgPF₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate), AgOAc (Silver acetate) 등이 있으며, 이들 단독 또는 둘 이상을 혼합하여 사용할 수 있다. 상기 염기는 바람직하게 NaBAr^F ₄, AgSbF₆, AgNTf₂ 및 AgBF₄ 에서 선택되는 하나 또는 둘 이상일 수 있으며, 보다 바람직하게는 NaBAr^F ₄ 및 AgNTf₂ 에서 선택되는 하나 또는 둘 이상일 수 있다.Specific examples of the base include NaBAr ^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF ₆ (Silver hexafluoroantimonate(V)), AgNTf ₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF ₄ ( Silver tetrafluoroborate), AgPF ₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate), AgOAc (Silver acetate), etc., and these can be used alone or in a mixture of two or more. The base may preferably be one or two or more selected from NaBAr ^F ₄ , AgSbF ₆ , AgNTf ₂ and AgBF ₄ , and more preferably one or two or more selected from NaBAr ^F ₄ and AgNTf ₂ .

일 실시예에 있어서, 상기 금속 착체는 아미드화 반응의 촉매로 사용되며, 사용량은 특별히 제한되지는 않으나, 바람직하게는 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰, 보다 바람직하게는 0.004 내지 0.1 몰로 사용될 수 있다. 상기 범위로 금속 착체를 사용하는 경우 보다 높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 제조할 수 있다.In one embodiment, the metal complex is used as a catalyst for the amidation reaction, and the amount used is not particularly limited, but is preferably used in 1 mole of the prochiral 1,4,2-dioxazol-5-one compound. It can be used in an amount of 0.01 to 0.1 mol, more preferably 0.004 to 0.1 mol. When a metal complex is used in the above range, a chiral gamma-lactam compound with higher enantioselectivity can be prepared.

일 실시예에 있어서, 상기 염기 및 금속 착체는 높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 제조함과 동시에 부산물의 형성을 효과적으로 억제하기 위한 측면에서 동량으로 사용될 수 있다.In one embodiment, the base and metal complex can be used in equal amounts to prepare a chiral gamma-lactam compound with high enantioselectivity and at the same time effectively suppress the formation of by-products.

일 실시예에 있어서, 상기 아미드화 반응은 온화한 조건 하에서 수행될 수 있으며, 바람직하게는 20 내지 60℃, 보다 바람직하게는 30 내지 50℃에서 수행될 수 있다. 상기 아미드화 반응의 반응시간은 반응물질, 반응물질의 양, 용매의 종류 및 용매의 양에 따라 달라질 수 있으며, 특별히 제한되지는 않는다.In one embodiment, the amidation reaction may be performed under mild conditions, preferably at 20 to 60°C, more preferably at 30 to 50°C. The reaction time of the amidation reaction may vary depending on the reactant, amount of reactant, type of solvent, and amount of solvent, and is not particularly limited.

일 실시예에 있어서, 상기 아미드화 반응은 유기용매 하에서 이루어질 수 있으며, 상기 반응물질들과 반응하지 않는 것이라면 유기용매에 제한을 둘 필요는 없다. 일예로, 상기 유기용매로 다이클로로메탄 (dichloromethane), 다이클로로에탄 (dichloroethane), 테트라클로로에탄 (tetrachloroethane), 아세토나이트릴 (acetonitrile), 니트로메탄 (nitromethane), 톨루엔 (toluene), 벤젠 (benzene) 등을 단독 또는 둘 이상 혼합하여 사용할 수 있으며, 반응물의 용해성 및 제거의 용이성을 고려하여 다이클로로메탄, 다이클로로에탄 및 테트라클로로에탄으로부터 선택된 하나 이상을 아미드화 반응 용매로 사용할 수 있다.In one embodiment, the amidation reaction may be performed in an organic solvent, and there is no need to limit the organic solvent as long as it does not react with the reactants. For example, the organic solvents include dichloromethane, dichloroethane, tetrachloroethane, acetonitrile, nitromethane, toluene, and benzene. etc. can be used alone or in combination of two or more, and considering the solubility and ease of removal of the reactant, one or more selected from dichloromethane, dichloroethane, and tetrachloroethane can be used as the amidation reaction solvent.

일 실시예에 있어서, 본 발명에 의해 제조된 키랄 감마-락탐 화합물은 80:20 내지 >99:1의 거울상이성질체 비(enantiomeric ratio, er) 값을 가질 수 있다.In one embodiment, the chiral gamma-lactam compound prepared by the present invention may have an enantiomeric ratio (er) value of 80:20 to >99:1.

일 실시예에 있어서, 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-1의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 이로부터 제조된 키랄 감마-락탐 화합물은 하기 화학식 3-1의 키랄 감마-락탐 화합물일 수 있다.In one embodiment, the prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-1, from which: The prepared chiral gamma-lactam compound may be a chiral gamma-lactam compound of the following formula 3-1.

[화학식 2-1][Formula 2-1]

[화학식 3-1][Formula 3-1]

(상기 화학식 2-1 및 3-1에서,(In Formulas 2-1 and 3-1 above,

일 실시예에 있어서, 상기 화학식 2-1 및 3-1에서, R₂₁은 C1-C20알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬, 아릴, 알케닐 또는 알키닐은 C1-C20알킬, 할로겐, 할로C1-C20알킬, 니트로, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있다.)In one embodiment, in Formulas 2-1 and 3-1, R ₂₁ is C1-C20 alkyl, C6-C20 aryl, C2-C20 alkenyl, or C2-C20 alkynyl, and the alkyl, aryl of R ₂₁ , alkenyl or alkynyl is further substituted with any one or more selected from C1-C20 alkyl, halogen, haloC1-C20 alkyl, nitro, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl and phthalimido. It can be.)

구체적으로, 상기 화학식 2-1의 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 구조로 예시될 수 있다.Specifically, the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-1 may be exemplified by the following structure.

또한, 상기 화학식 2-1의 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조된 상기 화학식 3-1의 키랄 감마-락탐 화합물은 하기 구조로 예시될 수 있다.Additionally, the chiral gamma-lactam compound of Formula 3-1 prepared from the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-1 may be exemplified by the following structure.

[화학식 2-2][Formula 2-2]

[화학식 3-2][Formula 3-2]

[화학식 2-3][Formula 2-3]

[화학식 3-3][Formula 3-3]

(상기 화학식 2-3 및 3-3에서, (In Formulas 2-3 and 3-3,

R_22a은 C6-C20아릴이다.)R _22a is C6-C20 aryl.)

일 실시예에 있어서, 상기 화학식 2-3 및 3-3에서, R₂₁은 C1-C20알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬, 아릴, 알케닐 또는 알키닐은 C1-C20알킬, 할로겐, 할로C1-C20알킬, 니트로, C3-C20시클로알킬, C6-C20아릴, C2-C20알케닐 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며; R_22a은 C6-C20아릴일 수 있다.In one embodiment, in Formulas 2-3 and 3-3, R ₂₁ is C1-C20 alkyl, C6-C20 aryl, C2-C20 alkenyl, or C2-C20 alkynyl, and the alkyl, aryl of R ₂₁ , alkenyl or alkynyl is further substituted with any one or more selected from C1-C20 alkyl, halogen, haloC1-C20 alkyl, nitro, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 alkenyl and phthalimido. can be; R _22a may be C6-C20 aryl.

구체적으로, 상기 화학식 2-3의 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 구조로 예시될 수 있다.Specifically, the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-3 may be exemplified by the following structure.

또한, 상기 화학식 2-3의 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조된 상기 화학식 3-3의 키랄 감마-락탐 화합물은 하기 구조로 예시될 수 있다.Additionally, the chiral gamma-lactam compound of Formula 3-3 prepared from the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-3 may be exemplified by the following structure.

[화학식 2-4][Formula 2-4]

[화학식 3-4][Formula 3-4]

(상기 화학식 2-4 및 3-4에서, (In Formulas 2-4 and 3-4 above,

일 실시예에 있어서, 상기 화학식 2-4 및 3-4에서, L₁은 융합고리를 포함하거나 포함하지 않는 C3-C5알킬렌, 구체적으로는

,

,

,

,

,

또는

이고; R₂₃은 수소 또는 프탈이미도로 치환된 C1-C20알킬일 수 있다.In one embodiment, in Formulas 2-4 and 3-4, L ₁ is C3-C5 alkylene with or without a fused ring, specifically

,

or

ego; R ₂₃ may be hydrogen or C1-C20 alkyl substituted with phthalimido.

구체적으로, 상기 화학식 2-4의 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 구조로 예시될 수 있다.Specifically, the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-4 may be exemplified by the following structure.

또한, 상기 화학식 2-4의 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조된 상기 화학식 3-4의 키랄 감마-락탐 화합물은 하기 구조로 예시될 수 있다.Additionally, the chiral gamma-lactam compound of Formula 3-4 prepared from the prochiral 1,4,2-dioxazol-5-one compound of Formula 2-4 may be exemplified by the following structure.

본 발명의 키랄 감마-락탐 화합물을 제조하는 방법은 매우 온화한 조건에서 특정 작용기를 가지는 키랄 에틸렌디아민 리간드, 즉 한쪽 말단 아민은 아미노 기로 존재하고, 다른 쪽 말단 아민은 금속(III)과 결합하되 카보닐 또는 설포닐 작용기가 결합되며, 에틸렌을 구성하는 탄소 원자는 치환되거나 치환되지 않은 알킬이나 아릴 기가 결합되거나 서로 연결되어 고리를 형성한 구조의 리간드를 포함하는 금속 착체를 촉매로 이용하여 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 다양한 천연물, 의약품의 제조를 위한 중간체로 유용하게 이용될 수 있는 높은 거울상이성질선택성을 가진 키랄 감마-락탐 화합물을 원스텝으로 효율적으로 합성할 수 있는 매우 효과적인 방법이다. The method for preparing the chiral gamma-lactam compound of the present invention is a chiral ethylenediamine ligand having a specific functional group under very mild conditions, that is, the amine at one end is an amino group, and the amine at the other end is bonded to metal (III) but forms a carbonyl group. Alternatively, a sulfonyl functional group is bonded, and the carbon atom constituting ethylene is bonded to a substituted or unsubstituted alkyl or aryl group, or a metal complex containing a ligand of a structure formed by linking together is used as a catalyst to produce Prochiral 1, A chiral gamma-lactam compound with high enantioselectivity that can be usefully used as an intermediate for the production of various natural products and pharmaceuticals can be efficiently synthesized in one step from 4,2-dioxazol-5-one compound. It's a very effective method.

따라서, 본 발명의 키랄 감마-락탐 화합물을 제조하는 방법은 특정 금속 착체를 촉매로 이용하고 있어 자연에 풍부한 탄화수소의 프로키랄형 구조를 갖는 전구물질인 프로키랄 1,4,2-디옥사졸-5-온 화합물의 아미드화 반응시 생성되는 중간체인 카보닐나이트렌을 안정화시켜 이의 분해 및 이로 인한 부산물의 형성을 억제하여 의약품이나 화학소재의 원료가 되는 키랄 감마-락탐 화합물을 온화한 조건에서 높은 거울상이성질선택적으로 합성할 수 있다. Therefore, the method for producing a chiral gamma-lactam compound of the present invention uses a specific metal complex as a catalyst to produce prochiral 1,4,2-dioxazole-, a precursor having a prochiral structure of hydrocarbons abundant in nature. It stabilizes carbonylnitrene, an intermediate produced during the amidation reaction of 5-one compounds, and suppresses its decomposition and formation of by-products, thereby producing chiral gamma-lactam compounds, which are raw materials for pharmaceuticals and chemical materials, with a high mirror image under mild conditions. It can be synthesized isomerically selective.

또한, 본 발명은 활성 및 화학적 선택성이 우수한 키랄 감마-락탐 제조용 촉매로 유용하게 사용될 수 있는 하기 화학식 4로 표시되는 신규 금속 착체를 제공한다:In addition, the present invention provides a novel metal complex represented by the following formula 4, which can be usefully used as a catalyst for producing chiral gamma-lactams with excellent activity and chemical selectivity:

[화학식 4][Formula 4]

(상기 화학식 4에서,(In Formula 4 above,

X₂는 할로겐이며;X ₂ is halogen;

상기 화학식 4의 금속 착체는 키랄 감마-락탐 화합물의 제조용 촉매로 촉매활성이 우수하며, 기존의 촉매와 달리 온화한 조건 하에서 프로키랄 1,4,2-디옥사졸-5-온 화합물을 아미드화하여 높은 거울상이성질선택성을 가지는 키랄 감마-락탐을 제조할 수 있다.The metal complex of Formula 4 is a catalyst for the production of chiral gamma-lactam compounds and has excellent catalytic activity. Unlike existing catalysts, it can be produced by amidating a prochiral 1,4,2-dioxazol-5-one compound under mild conditions. Chiral gamma-lactams with high enantioselectivity can be prepared.

우수한 거울상이성질선택적으로 키랄 감마-락탐 화합물을 제조하기 위한 측면에서, 상기 금속 착체는 하기 화학식 4-1로 표시되는 금속착체일 수 있다.In terms of preparing a chiral gamma-lactam compound with excellent enantioselectivity, the metal complex may be a metal complex represented by the following formula 4-1.

[화학식 4-1][Formula 4-1]

(상기 화학식 4-1에서,(In Formula 4-1 above,

X₂는 할로겐이며;X ₂ is halogen;

우수한 거울상이성질선택성을 가지는 키랄 감마-락탐 화합물을 제조하기 위한 보다 바람직한 측면에서, 상기 금속 착체는 하기 화학식 4-2로 표시되는 금속착체일 수 있다.In a more preferred aspect for preparing a chiral gamma-lactam compound having excellent enantioselectivity, the metal complex may be a metal complex represented by the following formula 4-2.

[화학식 4-2][Formula 4-2]

(상기 화학식 4-2에서,(In Formula 4-2 above,

X₂는 할로겐이며;X ₂ is halogen;

높은 거울상이성질 선택성을 가진 키랄 감마-락탐 화합물을 고수율로 제조하기 위한 측면에서, 바람직한 상기 화학식 4-2의 금속 착체는 X₂가 클로로 또는 브로모, 더욱 바람직하게는 클로로이며; R₃₁ 내지 R₃₅는 각각 독립적으로 C1-C7알킬, 더욱 바람직하게는 C1-C4알킬이며; R₃₆는 C1-C7알킬이 치환된 C6-C12아릴, 더욱 바람직하게는 C1-C4알킬이 치환된 페닐, 바이페닐 또는 나프틸이며; R₃₉ 및 R₄₀는 각각 독립적으로 C1-C7알킬, 더욱 바람직하게는 C1-C4알킬이며; e 및 f는 각각 독립적으로 2 또는 3의 정수, 더욱 바람직하게는 3의 정수일 수 있다.In terms of producing a chiral gamma-lactam compound with high enantioselectivity in high yield, the metal complex of Formula 4-2 is preferred, wherein X ₂ is chloro or bromo, more preferably chloro; R ₃₁ to R ₃₅ are each independently C1-C7 alkyl, more preferably C1-C4 alkyl; R ₃₆ is C6-C12 aryl substituted with C1-C7 alkyl, more preferably phenyl, biphenyl or naphthyl substituted with C1-C4 alkyl; R ₃₉ and R ₄₀ are each independently C1-C7 alkyl, more preferably C1-C4 alkyl; e and f may each independently be an integer of 2 or 3, more preferably an integer of 3.

높은 거울상이성질 선택성을 가진 키랄 감마-락탐 화합물을 고수율로 제조함과 동시에 부산물의 형성을 현저히 억제하기 위한 측면에서, 상기 금속 착체는 하기 화학식 4-3으로 표시되는 금속 착체일 수 있다.In order to produce a chiral gamma-lactam compound with high enantioselectivity in high yield and at the same time significantly suppress the formation of by-products, the metal complex may be a metal complex represented by the following formula 4-3.

[화학식 4-3][Formula 4-3]

(상기 화학식 4-3에서, Ts는 토실(tosyl)이고; R₃₁ 내지 R₃₅는 각각 독립적으로 C1-C4알킬이며; R₄₁ 내지 R₄₆은 각각 독립적으로 C1-C4알킬이다.)(In Formula 4-3, Ts is tosyl; R ₃₁ to R ₃₅ are each independently C1-C4 alkyl; R ₄₁ to R ₄₆ are each independently C1-C4 alkyl.)

상기 화학식 4의 금속 착체는 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 높은 거울상이성질선택성(enantioselectivity)을 가진 키랄 감마-락탐 화합물을 용이하게 제조할 수 있는 촉매로 사용될 수 있다.The metal complex of Formula 4 can be used as a catalyst to easily prepare a chiral gamma-lactam compound with high enantioselectivity from a prochiral 1,4,2-dioxazol-5-one compound. there is.

상기 화학식 4의 금속 착체는 구체적으로 하기 구조로 예시될 수 있으나, 이에 한정되는 것은 아니다.The metal complex of Formula 4 may be specifically exemplified by the following structure, but is not limited thereto.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

(준비 및 화학분석)(Preparation and chemical analysis)

달리 명시하지 않는 한, 상업적으로 입수 가능한 모든 시약 및 용매는 추가 정제없이 사용하였다. TCE, DCM 및 THF을 탈기시키고, 활성화된 4Å 분자체 상에서 건조시켰다. Unless otherwise specified, all commercially available reagents and solvents were used without further purification. TCE, DCM and THF were degassed and dried over activated 4Å molecular sieves.

¹H NMR 스펙트럼은 Agilent Technologies DD2 (600 MHz) 또는 Bruker AVHD-400 (400 MHz)를 이용하여 얻었고, ¹³C NMR 스펙트럼은 Agilent Technologies DD2 (150 MHz) 또는 Bruker AVHD-400 (100 MHz)를 이용하여 얻었다. ¹⁹F NMR 스펙트럼은 Agilent Technologies DD2 (564 MHz)를 이용하여 얻었으며, 화학적 이동(chemical shifts)은 C₆H₅CF₃ (¹⁹F, -63.72 ppm)에 대하여 ppm으로 나타내었다. 적외선(IR) 스펙트럼은 Bruker Alpha FT-IR Spectrometer를 이용하여 얻었다. 고분해능 질량스펙트럼(HRMS)은 Agilent technologies 6220 TOF LC/MS 분광기(ESI) 또는 JEOL JMS-AX 505WA(FAB)를 이용하여 얻었다. 고 분해 질량 스펙트럼은 EI 또는 FAB 방법을 사용하여 한국기초과학연구원(대구)에서 얻었으며, 또한 ESI(Electrospray ionization) 방법을 사용하여 KAIST 연구 분석 센터에서 얻었다. 융점(m.p.)은 Buchi Melting Point M-565를 이용하여 측정하였다. HPLC(High pressure liquid chromatography) 분석은 LC20A 펌프와 SPD-M20A 포토다이오드 어레이 검출기로 구성된 Shimadzu Prominence HPLC 시스템을 사용하여 32 ℃에서 수행되었다. 광학 회전은 온도 제어기가 장착된 Jasco P-2000 Polarimeter를 사용하여 확인하였다. ¹ H NMR spectra were obtained using Agilent Technologies DD2 (600 MHz) or Bruker AVHD-400 (400 MHz), and ¹³ C NMR spectra were obtained using Agilent Technologies DD2 (150 MHz) or Bruker AVHD-400 (100 MHz). got it ¹⁹ F NMR spectra were obtained using Agilent Technologies DD2 (564 MHz), and chemical shifts were expressed in ppm for C ₆ H ₅ CF ₃ ( ¹⁹ F, -63.72 ppm). Infrared (IR) spectra were obtained using a Bruker Alpha FT-IR Spectrometer. High-resolution mass spectra (HRMS) were obtained using Agilent technologies 6220 TOF LC/MS spectrometer (ESI) or JEOL JMS-AX 505WA (FAB). High-resolution mass spectra were obtained at the Korea Institute for Basic Science (Daegu) using the EI or FAB method, and were also obtained at the KAIST Research and Analysis Center using the electrospray ionization (ESI) method. Melting point (mp) was measured using Buchi Melting Point M-565. High pressure liquid chromatography (HPLC) analysis was performed at 32 °C using a Shimadzu Prominence HPLC system consisting of an LC20A pump and SPD-M20A photodiode array detector. Optical rotation was confirmed using a Jasco P-2000 Polarimeter equipped with a temperature controller.

리간드Ligand

D-Proline, D-tert-leucine, (1S,2S)-2-amino-1,2-diphenylethan-1-ol, D-prolinamide 및 N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-methylbenzenesulfonamide은 Sigma-Aldrich, TCI chemical company, 및 Strem에서 구입하고, 추가 정제없이 사용하였다.D-Proline, D- tert -leucine, ( 1S , 2S )-2-amino-1,2-diphenylethan-1-ol, D-prolinamide and N -{( 1S , 2S )-2-amino -1,2-diphenylethyl}-4-methylbenzenesulfonamide was purchased from Sigma-Aldrich, TCI chemical company, and Strem, and used without further purification.

N-{(1S,2S)-2-Aminocyclohexyl}-4-methylbenzenesulfonamide, N-{(1S,2S)-2-amino-1,2-diphenylethyl}-methylsulfonamide, N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-methoxybenzenesulfonamide, N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-fluorobenzenesulfonamide 및 N-{(1S,2S)-2-amino-1,2-dimesitylethyl}-4-methylbenzenesulfonamide는 이전에 보고된 방법[J. Org. Chem. 2011, 76, 396-402; Tetrahedron 2009, 65, 5782-5786; Chem. Commun., 2011, 47, 4911-4913]에 따라 합성하여 사용하였다. N -{(1 S ,2 S )-2-Aminocyclohexyl}-4-methylbenzenesulfonamide, N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-methylsulfonamide, N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-4-methoxybenzenesulfonamide, N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-4-fluorobenzenesulfonamide and N -{( 1 S , 2 S )-2-amino-1,2-dimesitylethyl}-4-methylbenzenesulfonamide was prepared using a previously reported method [J. Org. Chem. 2011, 76, 396-402; Tetrahedron 2009, 65, 5782-5786; Chem. Commun., 2011, 47, 4911-4913] was synthesized and used.

실시예Example I : 금속 I: metal 착체의complex 제조 manufacturing

[Cp*IrCl₂]₂ (Cp*: pentamethylcyclopentadienyl) (200 mg, 0.25 mmol, 1 eq), 리간드 (0.50 mmol, 2 eq), TEA (triethylamine, 101 mg, 1.00 mmol, 4 eq) 및 DCM (dichloromethane, 10 mL)를 혼합하고, 실온에서 30분간 교반시켰다. 교반 완료 후, 반응혼합물을 플래쉬 크로마토그래피(용리액: DCM/MeOH = 20/1 v/v) 로 정제하여 목적하는 Ir 착체를 수득하였다.[Cp*IrCl ₂ ] ₂ (Cp*: pentamethylcyclopentadienyl) (200 mg, 0.25 mmol, 1 eq), ligand (0.50 mmol, 2 eq), TEA (triethylamine, 101 mg, 1.00 mmol, 4 eq) and DCM (dichloromethane) , 10 mL) were mixed and stirred at room temperature for 30 minutes. After completion of stirring, the reaction mixture was purified by flash chromatography (eluent: DCM/MeOH = 20/1 v/v) to obtain the desired Ir complex.

[실시예 1] 이리듐 착체 Ir10의 제조[Example 1] Preparation of iridium complex Ir10

리간드로 N-{(1S,2S)-2-amino-1,2-dimesitylethyl}-4-methylbenzenesulfonamide을 사용하여 이리듐 착체 Ir10을 얻었다.Iridium complex Ir10 was obtained using N -{(1 S ,2 S )-2-amino-1,2-dimesitylethyl}-4-methylbenzenesulfonamide as a ligand.

주황색 고체 (218 mg, 93 %, 0.289 mmol scale); m.p. 176-178 ℃ (decomp.); ¹H NMR (599 MHz, CD₂Cl₂) δ 7.25 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 6.1 Hz, 2H), 6.77 (s, 1H), 6.53 (s, 1H), 6.28 (s, 1H), 6.15 (s, 1H), 5.35-5.33 (m, 1H), 5.19 (appt, J = 12.2 Hz, 1H), 4.57-4.47 (m, 1H), 3.99 (d, J = 10.2 Hz, 1H), 2.74 (s, 3H), 2.50 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.77 (s, 15H), 1.69 (s, 3H), 1.56 (s, 3H); ¹³C NMR (101 MHz, CD₂Cl₂, one carbon merged to others) δ 141.64, 139.77, 138.92, 138.34, 138.27, 136.64, 136.31, 132.20, 131.92, 131.65, 130.57, 129.82, 128.81, 127.99, 127.89, 86.18 (C ₅Me₅), 64.90, 61.72, 22.70, 22.00, 21.41, 21.03, 20.90, 20.80, 20.42, 10.06 (C₅ Me ₅); IR (cm^-1) 2956, 2916, 2852, 1739, 1611, 1454, 1376, 1129, 1084, 896, 666, 571, 549; HRMS (EI) m/z calcd. for C₃₇H₄₈ClIrN₂O₂S [M]⁺: 812.2754, found: 812.2752.Orange solid (218 mg, 93%, 0.289 mmol scale); mp 176-178℃(decomp.); ^1H NMR (599 MHz, CD ₂ Cl ₂ ) δ 7.25 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 6.1 Hz, 2H), 6.77 (s, 1H), 6.53 (s, 1H) , 6.28 (s, 1H), 6.15 (s, 1H), 5.35-5.33 (m, 1H), 5.19 (appt, J = 12.2 Hz, 1H), 4.57-4.47 (m, 1H), 3.99 (d, J = 10.2 Hz, 1H), 2.74 (s, 3H), 2.50 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.77 (s, 15H), 1.69 (s, 3H), 1.56 (s, 3H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ , one carbon merged to others ) δ 141.64, 139.77, 138.92, 138.34, 138.27, 136.64, 136.31, 132.20, 131.92, 131.65, 130.57, 129 .82, 128.81, 127.99, 127.89, 86.18 ( C ₅ Me ₅ ), 64.90, 61.72, 22.70, 22.00, 21.41, 21.03, 20.90, 20.80, 20.42, 10.06 (C ₅ Me ₅ ); IR (cm ^-1 ) 2956, 2916, 2852, 1739, 1611, 1454, 1376, 1129, 1084, 896, 666, 571, 549; HRMS (EI) m/z calcd. for C ₃₇ H ₄₈ ClIrN ₂ O ₂ S [M] ⁺ : 812.2754, found: 812.2752.

[실시예 2] 이리듐 착체 Ir7의 제조[Example 2] Preparation of iridium complex Ir7

리간드로 N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-methoxybenzenesulfonamide을 사용하여 이리듐 착체 Ir7을 얻었다.Iridium complex Ir7 was obtained using N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-4-methoxybenzenesulfonamide as a ligand.

주황색 고체 (77 mg, 80 %, 0.13 mmol scale); ¹H NMR (599 MHz, CD₂Cl₂) δ 7.37 (d, J = 8.9 Hz, 2H), 7.18-7.11 (m, 3H), 6.91-6.80 (m, 5H), 6.65 (d, J = 6.9 Hz, 2H), 6.54 (d, J = 8.9 Hz, 2H), 4.39 (appt, J = 12.1 Hz, 1H), 4.31-4.21 (m, 2H), 3.72 (s, 3H), 3.69-3.63 (m, 1H), 1.79 (s, 15H); ¹³C NMR (151 MHz, CD₂Cl₂) δ 160.96, 139.62, 139.31, 136.75, 130.51, 129.42, 129.11, 129.00, 127.63, 127.12, 112.96, 86.08, 74.41, 70.04, 55.80, 9.84; HRMS (ESI) m/z calcd. for C₃₁H₃₆ClIrN₂O₃S [M-Cl]⁺: 709.2076, found: 709.2096.Orange solid (77 mg, 80%, 0.13 mmol scale); ^1H NMR (599 MHz, CD ₂ Cl ₂ ) δ 7.37 (d, J = 8.9 Hz, 2H), 7.18-7.11 (m, 3H), 6.91-6.80 (m, 5H), 6.65 (d, J = 6.9 Hz, 2H), 6.54 (d, J = 8.9 Hz, 2H), 4.39 (appt, J = 12.1 Hz, 1H), 4.31-4.21 (m, 2H), 3.72 (s, 3H), 3.69-3.63 (m) , 1H), 1.79 (s, 15H); ¹³ C NMR (151 MHz, CD ₂ Cl ₂ ) δ 160.96, 139.62, 139.31, 136.75, 130.51, 129.42, 129.11, 129.00, 127.63, 127.12, 112.96, 86.08, 74.4 1, 70.04, 55.80, 9.84; HRMS (ESI) m/z calcd. for C ₃₁ H ₃₆ ClIrN ₂ O ₃ S [M-Cl] ⁺ : 709.2076, found: 709.2096.

[실시예 3] 이리듐 착체 Ir8의 제조[Example 3] Preparation of iridium complex Ir8

리간드로 N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-fluorobenzenesulfonamide을 사용하여 이리듐 착체 Ir8을 얻었다.Iridium complex Ir8 was obtained using N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-4-fluorobenzenesulfonamide as a ligand.

주황색 고체 (221 mg, 85 %); m.p. 239-241 ℃ (decomp.); ¹H NMR (599 MHz, CD₂Cl₂) δ 7.43 (dd, J = 8.6, 5.4 Hz, 2H), 7.22-7.12 (m, 3H), 6.94-6.86 (m, 3H), 6.83 (appt, J = 7.5 Hz, 2H), 6.71 (appt, J = 8.6 Hz, 2H), 6.65 (d, J = 7.5 Hz, 2H), 4.39 (appt, J = 12.1 Hz, 1H), 4.35-4.25 (m, 2H), 3.70 (appt, J = 11.1, 1H), 1.80 (s, 15H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 163.56 (d, J = 248.8 Hz), 141.08 (d, J = 3.1 Hz), 139.18, 139.13, 130.96 (d, J = 8.8 Hz), 129.44, 129.12, 129.04, 127.72, 127.60, 127.25, 114.46 (d, J = 114.5 Hz), 86.11 (C ₅Me₅), 74.19, 69.93, 9.83 (C₅ Me ₅); ¹⁹F NMR (564 MHz, CD₂Cl₂) δ -112.4; IR (cm^-1) 1739, 1579, 1489, 1147, 908, 649, 552; HRMS (EI) m/z calcd. for C₃₀H₃₃ClFIrN₂O₂S [M]⁺: 732.1565, found: 732.1562.Orange solid (221 mg, 85%); mp 239-241℃(decomp.); ^1H NMR (599 MHz, CD ₂ Cl ₂ ) δ 7.43 (dd, J = 8.6, 5.4 Hz, 2H), 7.22-7.12 (m, 3H), 6.94-6.86 (m, 3H), 6.83 (appt, J = 7.5 Hz, 2H), 6.71 (appt, J = 8.6 Hz, 2H), 6.65 (d, J = 7.5 Hz, 2H), 4.39 (appt, J = 12.1 Hz, 1H), 4.35-4.25 (m, 2H) ), 3.70 (appt, J = 11.1, 1H), 1.80 (s, 15H); ¹³ C NMR (150 MHz, CD ₂ Cl ₂ ) δ 163.56 (d, J = 248.8 Hz), 141.08 (d, J = 3.1 Hz), 139.18, 139.13, 130.96 (d, J = 8.8 Hz), 129.44, 129.12 , 129.04, 127.72, 127.60, 127.25, 114.46 (d, J = 114.5 Hz), 86.11 ( C ₅ Me ₅ ), 74.19, 69.93, 9.83 (C ₅ Me ₅ ); ¹⁹ F NMR (564 MHz, CD ₂ Cl ₂ ) δ -112.4; IR (cm ^-1 ) 1739, 1579, 1489, 1147, 908, 649, 552; HRMS (EI) m/z calcd. for C ₃₀ H ₃₃ ClFIrN ₂ O ₂ S [M] ⁺ : 732.1565, found: 732.1562.

[실시예 4] 이리듐 착체 Ir5의 제조[Example 4] Preparation of iridium complex Ir5

리간드로 N-{(1S,2S)-2-Aminocyclohexyl}-4-methylbenzenesulfonamide을 사용하여 이리듐 착체 Ir5을 얻었다.Iridium complex Ir5 was obtained using N -{(1 S ,2 S )-2-Aminocyclohexyl}-4-methylbenzenesulfonamide as a ligand.

주황색 고체 (100 mg, 62 %, 0.13 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 7.83 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 4.05 (d, J = 10.3 Hz, 1H), 3.63-3.42 (m, 1H), 2.63-2.53 (m, 1H), 2.36 (s, 3H), 2.37-2.27 (m, 1H), 2.27-2.14 (m, 1H), 2.02 (d, J = 11.8 Hz, 1H), 1.67 (s, 15H), 1.50 (d, J = 13.4 Hz, 1H), 1.37 (d, J = 13.3 Hz, 1H), 1.29-1.15 (m, 1H), 1.12-1.04 (m, 1H), 0.97-0.81 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 146.07, 141.95, 130.32, 129.33, 87.11, 68.01, 65.77, 37.66, 35.45, 26.77, 26.74, 22.90, 11.08.Orange solid (100 mg, 62%, 0.13 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.83 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 4.05 (d, J = 10.3 Hz, 1H), 3.63-3.42 (m, 1H), 2.63-2.53 (m, 1H), 2.36 (s, 3H), 2.37-2.27 (m, 1H), 2.27-2.14 (m, 1H), 2.02 (d, J = 11.8 Hz, 1H ), 1.67 (s, 15H), 1.50 (d, J = 13.4 Hz, 1H), 1.37 (d, J = 13.3 Hz, 1H), 1.29-1.15 (m, 1H), 1.12-1.04 (m, 1H) , 0.97-0.81 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 146.07, 141.95, 130.32, 129.33, 87.11, 68.01, 65.77, 37.66, 35.45, 26.77, 26.74, 22.90, 11.08.

[실시예 5] 이리듐 착체 Ir6의 제조[Example 5] Preparation of iridium complex Ir6

리간드로 N-{(1S,2S)-2-amino-1,2-diphenylethyl}-4-methylbenzenesulfonamide을 사용하여 이리듐 착체 Ir6을 얻었다.Iridium complex Ir6 was obtained using N -{(1 S ,2 S )-2-amino-1,2-diphenylethyl}-4-methylbenzenesulfonamide as a ligand.

주황색 고체 (290 mg, 80 %); ¹H NMR (400 MHz, CD₂Cl₂) δ 7.33 (d, J = 8.0 Hz, 2H), 7.23-7.10 (m, 3H), 6.94-6.77 (m, 7H), 6.66 (d, J = 7.1 Hz, 2H), 4.42 (appt, J = 12.0 Hz, 1H), 4.28 (d, J = 10.9 Hz, 1H), 4.20 (d, J= 10.4 Hz, 1H), 3.68 (ddd, J = 13.8, 10.9, 3.0 Hz, 1H), 2.24 (s, 3H), 1.80 (s, 15H); ¹³C NMR (101 MHz, CD₂Cl₂) δ 141.81, 140.11, 139.53, 139.29, 129.44, 129.13, 129.04, 128.65, 128.36, 127.63, 127.61, 127.01, 86.08, 74.41, 69.92, 21.44, 9.85.Orange solid (290 mg, 80%); ^1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.33 (d, J = 8.0 Hz, 2H), 7.23-7.10 (m, 3H), 6.94-6.77 (m, 7H), 6.66 (d, J = 7.1 Hz, 2H), 4.42 (appt, J = 12.0 Hz, 1H), 4.28 (d, J = 10.9 Hz, 1H), 4.20 (d, J= 10.4 Hz, 1H), 3.68 (ddd, J = 13.8, 10.9 , 3.0 Hz, 1H), 2.24 (s, 3H), 1.80 (s, 15H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 141.81, 140.11, 139.53, 139.29, 129.44, 129.13, 129.04, 128.65, 128.36, 127.63, 127.61, 127.01, 86. 08, 74.41, 69.92, 21.44, 9.85.

[실시예 6] 이리듐 착체 Ir9의 제조[Example 6] Preparation of iridium complex Ir9

리간드로 N-{(1S,2S)-2-amino-1,2-diphenylethyl}-methylsulfonamide을 사용하여 이리듐 착체 Ir9를 얻었다.Iridium complex Ir9 was obtained using N -{( 1S , 2S )-2-amino-1,2-diphenylethyl}-methylsulfonamide as a ligand.

주황색 고체 (290 g, 89 %); ¹H NMR (400 MHz, CD₂Cl₂) δ 7.27-7.17 (m, 3H), 7.17-7.09 (m, 3H), 7.08-7.03 (m, 2H), 7.02-6.96 (m, 2H), 4.52-4.36 (m, 2H), 4.34-4.16 (m, 1H), 3.85-3.71 (m, 1H), 2.28 (s, 3H), 1.72 (s, 15H); ¹³C NMR (101 MHz, CD₂Cl₂) δ 141.32, 139.18, 129.26, 129.20, 129.17, 128.46, 127.80, 127.71, 86.02 (C ₅Me₅), 73.93, 69.79, 44.16, 9.68 (C₅ Me ₅).Orange solid (290 g, 89%); ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.27-7.17 (m, 3H), 7.17-7.09 (m, 3H), 7.08-7.03 (m, 2H), 7.02-6.96 (m, 2H), 4.52 -4.36 (m, 2H), 4.34-4.16 (m, 1H), 3.85-3.71 (m, 1H), 2.28 (s, 3H), 1.72 (s, 15H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 141.32, 139.18, 129.26, 129.20, 129.17, 128.46, 127.80, 127.71, 86.02 ( C ₅ Me ₅ ), 73.93, 69.79, 44.16, 9.68 (C ₅ Me ₅ ) .

비교제조예 1-2 : 이리듐 착체의 제조Comparative Preparation Example 1-2: Preparation of iridium complex

[Cp*IrCl₂]₂ (Cp*: pentamethylcyclopentadienyl) (200 mg, 0.25 mmol), 아미노산 (0.50 mmol), K₂CO₃ (80 mg, 0.58 mmol) 및 MeCN (acetonitrile, 5 mL)을 혼합하고 실온에서 24시간동안 교반시켰다. 교반 완료 후, 감압 하에서 용매를 제거하고, 잔류물을 DCM (10 mL) 중에 현탁시켰다. 현탁액을 셀라이트 패드를 통해 여과시키고, 추가의 DCM (40 mL)으로 더 세정하였다. 합한 황색 여액을 5.0 mL로 농축시키고, 과량의 건조 펜탄 (30 mL)으로 층분리시켰다. 침전물을 모으고, 감압 하에 건조시켜 목적하는 이리듐 착체 Ir-A 또는 Ir-B를 수득하였다.[Cp*IrCl ₂ ] ₂ (Cp*: pentamethylcyclopentadienyl) (200 mg, 0.25 mmol), amino acid (0.50 mmol), K ₂ CO ₃ (80 mg, 0.58 mmol) and MeCN (acetonitrile, 5 mL) were mixed and incubated at room temperature. was stirred for 24 hours. After stirring was complete, the solvent was removed under reduced pressure and the residue was suspended in DCM (10 mL). The suspension was filtered through a pad of Celite and further washed with additional DCM (40 mL). The combined yellow filtrates were concentrated to 5.0 mL and partitioned with excess dry pentane (30 mL). The precipitate was collected and dried under reduced pressure to obtain the desired iridium complex Ir-A or Ir-B.

[비교제조예 1] 이리듐 착체 Ir-A의 제조[Comparative Preparation Example 1] Preparation of iridium complex Ir-A

아미노산으로 D-Proline을 사용하여 이리듐 착체 Ir-A을 얻었다.Iridium complex Ir-A was obtained using D-Proline as the amino acid.

황색 고체 (155 mg, 65 %); ¹H NMR (599 MHz, CD₂Cl₂) δ 4.53-4.30 (m, 1H), 3.98-3.85 (m, 1H), 3.65-3.52 (m, 1H), 3.01-2.84 (m, 1H), 2.28-2.14 (m, 1H), 2.01-1.86 (m, 2H), 1.65 (s, 15H); ¹³C NMR (101 MHz, CD₂Cl₂) δ 184.52, 84.62, 62.84, 55.40, 29.47, 27.55, 9.46.Yellow solid (155 mg, 65%); ^1H NMR (599 MHz, CD ₂ Cl ₂ ) δ 4.53-4.30 (m, 1H), 3.98-3.85 (m, 1H), 3.65-3.52 (m, 1H), 3.01-2.84 (m, 1H), 2.28 -2.14 (m, 1H), 2.01-1.86 (m, 2H), 1.65 (s, 15H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 184.52, 84.62, 62.84, 55.40, 29.47, 27.55, 9.46.

[비교제조예 2] 이리듐 착체 Ir-B의 제조[Comparative Preparation Example 2] Preparation of iridium complex Ir-B

아미노산으로 D-tert-leucine을 사용하여 이리듐 착체 Ir-B를 얻었다.The iridium complex Ir-B was obtained using D- tert -leucine as the amino acid.

황색 고체 (227 mg, 92 %); ¹H NMR (599 MHz, CDCl₃) δ 5.33 (appt, J = 8.4 Hz, 1H), 3.78 (appt, J = 10.8 Hz, 1H), 2.97 (dd, J = 11.3, 6.7 Hz, 1H), 1.70 (s, 15H), 1.10 (s, 9H), Minor isomer: 4.36-4.25 (m, 1H), 4.00-3.87 (m, 1H), 3.18-3.08 (m, 1H), 1.69 (s, 15H), 1.09 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 178.94, 84.27, 65.45, 35.33, 27.07, 9.32, Minor isomer: 83.98, 61.99, 34.64, 27.03, 9.19.Yellow solid (227 mg, 92%); ^1H NMR (599 MHz, CDCl ₃ ) δ 5.33 (appt, J = 8.4 Hz, 1H), 3.78 (appt, J = 10.8 Hz, 1H), 2.97 (dd, J = 11.3, 6.7 Hz, 1H), 1.70 (s, 15H), 1.10 (s, 9H), Minor isomer: 4.36-4.25 (m, 1H), 4.00-3.87 (m, 1H), 3.18-3.08 (m, 1H), 1.69 (s, 15H), 1.09 (s, 9H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.94, 84.27, 65.45, 35.33, 27.07, 9.32, Minor isomer: 83.98, 61.99, 34.64, 27.03, 9.19.

[비교제조예 3] 이리듐 착체 Ir-C의 제조[Comparative Preparation Example 3] Preparation of iridium complex Ir-C

리간드로 (1S,2S)-2-amino-1,2-diphenylethan-1-ol (0.50 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 이리듐 착체 Ir-C를 수득하였다.Iridium complex Ir-C was obtained by reacting in the same manner as in Example 1, except that (1 S ,2 S )-2-amino-1,2-diphenylethan-1-ol (0.50 mmol) was used as a ligand. .

주황색 고체 (201 mg, 70 %); m.p. 164-166 ℃ (decomp.); ¹H NMR (599 MHz, CDCl₃) δ 7.24-7.18 (m, 3H), 7.07-6.97 (m, 7H), 4.85 (d, J = 9.8 Hz, 1H), 4.41 (appt, J = 11.3 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 3.21-3.04 (m, 1H), 1.78 (s, 15H); ¹³C NMR (151 MHz, CDCl₃, one carbon merged to others) δ 143.27, 139.13, 128.72, 128.21, 127.54, 127.41, 126.70, 85.10, 83.05, 73.72, 9.10; IR (cm^-1) 3203, 3025, 2914, 1492, 1376, 1023, 698, 579; HRMS (EI) m/z calcd. for C₂₄H₂₉ClIrNO [M+H]⁺: 576.1645, found: 576.1644.Orange solid (201 mg, 70%); mp 164-166℃(decomp.); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.24-7.18 (m, 3H), 7.07-6.97 (m, 7H), 4.85 (d, J = 9.8 Hz, 1H), 4.41 (appt, J = 11.3 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 3.21-3.04 (m, 1H), 1.78 (s, 15H); ¹³ C NMR (151 MHz, CDCl ₃ , one carbon merged to others ) δ 143.27, 139.13, 128.72, 128.21, 127.54, 127.41, 126.70, 85.10, 83.05, 73.72, 9.10; IR (cm ^-1 ) 3203, 3025, 2914, 1492, 1376, 1023, 698, 579; HRMS (EI) m/z calcd. for C ₂₄ H ₂₉ ClIrNO [M+H] ⁺ : 576.1645, found: 576.1644.

[비교제조예 4] 이리듐 착체 Ir-D의 제조[Comparative Preparation Example 4] Preparation of iridium complex Ir-D

[Cp*IrCl₂]₂ (Cp*: pentamethylcyclopentadienyl) (350 mg, 0.44 mmol), D-prolinamide (100 mg, 0.88 mmol), TEA (93 mg, 0.92 mmol) 및 DCM (8 mL)를 실온에서 12시간동안 교반시켰다. 상기 반응혼합물에 20% NaCl 수용액을 가하고, DCM (10 mL × 2)으로 추출하고, Na₂SO₄으로 건조시키고, 감압 하에서 용매를 제거하였다. 생성된 고체를 THF/diisopropyl ether (1/1 v/v)의 혼합용매 (5 mL)에 재용해시키고, 실온에서 1시간동안 교반시켰다. 오렌지색 침전물을 모으고, 감압 하에 건조시켜 이리듐 착체 Ir-D를 수득하였다.[Cp*IrCl ₂ ] ₂ (Cp*: pentamethylcyclopentadienyl) (350 mg, 0.44 mmol), D-prolinamide (100 mg, 0.88 mmol), TEA (93 mg, 0.92 mmol) and DCM (8 mL) were reacted at room temperature for 12 days. It was stirred for some time. A 20% NaCl aqueous solution was added to the reaction mixture, extracted with DCM (10 mL × 2), dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. The resulting solid was re-dissolved in a mixed solvent of THF/diisopropyl ether (1/1 v/v) (5 mL) and stirred at room temperature for 1 hour. The orange precipitate was collected and dried under reduced pressure to obtain the iridium complex Ir-D.

주황색 고체 (301 mg, 72 %); ¹H NMR (400 MHz, CD₂Cl₂) δ 4.96 (br, 1H), 4.86 (br, 1H), 3.83 (q, J = 8.0 Hz, 1H), 3.58-3.45 (m, 1H), 3.00-2.64 (m, 1H), 2.45-2.22 (m, 1H), 2.22-2.08 (m, 1H), 1.98-1.85 (m, 2H), 1.71 (s, 15H); ¹³C NMR (101 MHz, CD₂Cl₂) δ 184.03, 84.92, 63.26, 55.04, 29.00, 27.61, 9.45; IR (cm^-1) 3119, 2967, 291, 1740, 1583, 1446, 1378, 1032, 923; HRMS (EI) m/z calcd. for C₁₅H₂₄ClIrN₂O [M+H]⁺: 477.1285, found: 477.1281.Orange solid (301 mg, 72%); ^1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 4.96 (br, 1H), 4.86 (br, 1H), 3.83 (q, J = 8.0 Hz, 1H), 3.58-3.45 (m, 1H), 3.00- 2.64 (m, 1H), 2.45-2.22 (m, 1H), 2.22-2.08 (m, 1H), 1.98-1.85 (m, 2H), 1.71 (s, 15H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 184.03, 84.92, 63.26, 55.04, 29.00, 27.61, 9.45; IR (cm ^-1 ) 3119, 2967, 291, 1740, 1583, 1446, 1378, 1032, 923; HRMS (EI) m/z calcd. for C ₁₅ H ₂₄ ClIrN ₂ O [M+H] ⁺ : 477.1285, found: 477.1281.

[비교제조예 5] 이리듐 착체 Ir-E의 제조[Comparative Preparation Example 5] Preparation of iridium complex Ir-E

4-Methyl-N-{(1S,2S)-2-(methylamino)-1,2-diphenylethyl}benzenesulfonamide는 기보고된 방법(J. Am. Chem . Soc.,　2016,　138　(35), pp 11299-11305)에 따라 합성하여 사용하였다.4-Methyl- N -{(1 S ,2 S )-2-(methylamino)-1,2-diphenylethyl}benzenesulfonamide was prepared using a previously reported method ( J. Am. Chem . Soc. , 2016, 138 (35), It was synthesized and used according to pp 11299-11305).

[Cp*IrCl₂]₂ (Cp*: pentamethylcyclopentadienyl) (100 mg, 0.13 mmol), 4-Methyl-N-{(1S,2S)-2-(methylamino)-1,2-diphenylethyl}benzenesulfonamide (96 mg, 0.25 mmol), TEA (50 mg, 0.5 mmol) 및 DCM (5 mL)를 혼합하고, 실온에서 30분간 교반시켰다. 교반 완료 후, 반응혼합물을 플래쉬 크로마토그래피(용리액: DCM/MeOH = 20/1 v/v)로 정제하고, 디클로로메탄/펜탄으로부터 재결정시켜 목적하는 화합물 Ir-E를 수득하였다.[Cp*IrCl ₂ ] ₂ (Cp*: pentamethylcyclopentadienyl) (100 mg, 0.13 mmol), 4-Methyl- N -{(1 S ,2 S )-2-(methylamino)-1,2-diphenylethyl}benzenesulfonamide ( 96 mg, 0.25 mmol), TEA (50 mg, 0.5 mmol) and DCM (5 mL) were mixed and stirred at room temperature for 30 minutes. After completion of stirring, the reaction mixture was purified by flash chromatography (eluent: DCM/MeOH = 20/1 v/v) and recrystallized from dichloromethane/pentane to obtain the desired compound Ir-E.

주황색 고체 (150 mg, 85 %); m.p. 219-221 ℃; ¹H NMR (599 MHz, CD₂Cl₂) δ 7.53 (d, J = 7.9 Hz, 2H), 7.24-7.14 (m, 3H), 7.01-6.91 (m, 5H), 6.83-6.73 (m, 2H), 6.70 (d, J = 7.5 Hz, 2H), 4.41-4.30 (m, 2H), 3.60 (appt, J = 11.4 Hz, 1H), 2.62 (d, J = 6.2 Hz, 3H), 2.29 (s, 3H), 1.74 (s, 15H); ¹³C NMR (151 MHz, CD₂Cl₂) δ 141.61, 140.71, 136.62, 129.29, 129.12, 128.82, 128.77, 128.59, 128.52, 128.12, 127.73, 126.97, 86.78, 82.62, 70.37, 41.28, 21.54, 10.17; IR (cm^-1) 3029, 3031, 2918, 2856, 1739, 1454, 1271, 1135, 928, 699, 580, 546; HRMS (EI) m/z calcd. for C₃₂H₃₈ClIrN₂O₂S [M]⁺: 742.1972, found: 742.1969.Orange solid (150 mg, 85%); mp 219-221℃; ^1H NMR (599 MHz, CD ₂ Cl ₂ ) δ 7.53 (d, J = 7.9 Hz, 2H), 7.24-7.14 (m, 3H), 7.01-6.91 (m, 5H), 6.83-6.73 (m, 2H) ), 6.70 (d, J = 7.5 Hz, 2H), 4.41-4.30 (m, 2H), 3.60 (appt, J = 11.4 Hz, 1H), 2.62 (d, J = 6.2 Hz, 3H), 2.29 (s , 3H), 1.74 (s, 15H); ¹³ C NMR (151 MHz, CD ₂ Cl ₂ ) δ 141.61, 140.71, 136.62, 129.29, 129.12, 128.82, 128.77, 128.59, 128.52, 128.12, 127.73, 126.97, 86. 78, 82.62, 70.37, 41.28, 21.54, 10.17; IR (cm ^-1 ) 3029, 3031, 2918, 2856, 1739, 1454, 1271, 1135, 928, 699, 580, 546; HRMS (EI) m/z calcd. for C ₃₂ H ₃₈ ClIrN ₂ O ₂ S [M] ⁺ : 742.1972, found: 742.1969.

[비교제조예 6] 이리듐 착체 Ir-F의 제조[Comparative Preparation Example 6] Preparation of iridium complex Ir-F

N-{(1S,2S)-2-(dimethylamino)-1,2-diphenylethyl}-4-methylbenzenesulfonamide는 기보고된 방법(Org. Biomol. Chem., 2011, 9, 3290-3294)에 따라 합성하여 사용하였다. N -{(1 S ,2 S )-2-(dimethylamino)-1,2-diphenylethyl}-4-methylbenzenesulfonamide was prepared according to a previously reported method (Org. Biomol. Chem., 2011, 9, 3290-3294). It was synthesized and used.

[Cp*IrCl₂]₂ (Cp*: pentamethylcyclopentadienyl) (76 mg, 0.095 mmol), N-{(1S,2S)-2-(dimethylamino)-1,2-diphenylethyl}-4-methylbenzenesulfonamide (75 mg, 0.19 mmol), K₂CO₃ (43 mg, 0.31 mmol) 및 DCM (5 mL)를 혼합하고, 실온에서 12시간동안 교반시켰다. 교반 완료 후, 반응혼합물을 플래쉬 크로마토그래피(용리액: DCM/MeOH = 1/20 v/v)로 정제하고, 클로로포름/펜탄으로부터 재결정시켜 목적하는 화합물 Ir-F를 수득하였다.[Cp*IrCl ₂ ] ₂ (Cp*: pentamethylcyclopentadienyl) (76 mg, 0.095 mmol), N -{(1 S ,2 S )-2-(dimethylamino)-1,2-diphenylethyl}-4-methylbenzenesulfonamide (75 mg, 0.19 mmol), K ₂ CO ₃ (43 mg, 0.31 mmol) and DCM (5 mL) were mixed and stirred at room temperature for 12 hours. After completion of stirring, the reaction mixture was purified by flash chromatography (eluent: DCM/MeOH = 1/20 v/v) and recrystallized from chloroform/pentane to obtain the desired compound Ir-F.

주황색 고체 (86 mg, 60 %); m.p. 135-137 ℃ (decomp.); ¹H NMR (400 MHz, CDCl₃, -10℃) δ 7.66 (d, J = 8.1 Hz, 2H), 7.47-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.19 (appt, J = 7.4 Hz, 1H), 7.13-7.05 (m, 1H), 7.03-6.88 (m, 3H), 6.86-6.70 (m, 4H), 5.36 (d, J = 10.9 Hz, 1H), 5.29 (d, J = 11.1 Hz, 1H), 3.21 (s, 3H), 2.77 (s, 3H), 2.24 (s, 3H), 1.47 (s, 15H); ¹³C NMR (101 MHz, CDCl₃, -10 ℃) δ 142.73, 140.25, 139.87, 134.68, 130.39, 130.11, 129.80, 128.84, 128.33, 127.57, 126.70, 125.72, 86.86 (C ₅Me₅), 78.09, 67.36, 48.91, 47.70, 21.47, 9.74 (C₅ Me ₅); IR (cm^-1) 3028, 2913, 1739, 1453, 1375, 1262, 1135, 942, 698, 548; HRMS (ESI) m/z calcd. for C₃₃H₄₀IrN₂O₂S [M-Cl]⁺: 721.2440, found: 721.2463.Orange solid (86 mg, 60%); mp 135-137℃(decomp.); ¹ H NMR (400 MHz, CDCl ₃ , -10°C) δ 7.66 (d, J = 8.1 Hz, 2H), 7.47-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.19 (appt, J = 7.4 Hz, 1H), 7.13-7.05 (m, 1H), 7.03-6.88 (m, 3H), 6.86-6.70 (m, 4H), 5.36 (d, J = 10.9 Hz, 1H), 5.29 (d, J = 11.1 Hz, 1H), 3.21 (s, 3H), 2.77 (s, 3H), 2.24 (s, 3H), 1.47 (s, 15H); ¹³ C NMR (101 MHz, CDCl ₃ , -10 ℃) δ 142.73, 140.25, 139.87, 134.68, 130.39, 130.11, 129.80, 128.84, 128.33, 127.57, 126.70, 125.72 , 86.86 ( C ₅ Me ₅ ), 78.09, 67.36 , 48.91, 47.70, 21.47, 9.74 (C ₅ Me ₅ ); IR (cm ^-1 ) 3028, 2913, 1739, 1453, 1375, 1262, 1135, 942, 698, 548; HRMS (ESI) m/z calcd. for C ₃₃ H ₄₀ IrN ₂ O ₂ S [M-Cl] ⁺ : 721.2440, found: 721.2463.

출발물질starting material

4-(4-Chlorophenyl)butanoic acid, 4-(p-tolyl)butanoic acid, 4-{4-(tert-butyl)phenyl}butanoic acid, 4-{4-(trifluoromethyl)phenyl}butanoic acid, 4-(naphthalen-2-yl)butanoic acid, 5- cyclohexylpentanoic acid, 6-phenylhexanoic acid, 6-aminohexanoic acid, 5-phenylpentanoic acid, 5-methylhexanoic acid, myristic acid, oleic acid, elaidic acid, 및 2-{1-(aminomethyl)cyclopentyl}acetic acid는 Sigma-Aldrich, Alfa, Enamine 또는 TCI chemical company로부터 구입하여 추가정제없이 사용하였다. 4-(4-Iodophenyl)butanoic acid는 기보고된 방법(Tetrahedron 60 (2004) 6945-6958)에 따라 합성하여 사용하였다. 4-(4-Chlorophenyl)butanoic acid, 4-( p -tolyl)butanoic acid, 4-{4-( tert -butyl)phenyl}butanoic acid, 4-{4-(trifluoromethyl)phenyl}butanoic acid, 4- (naphthalen-2-yl)butanoic acid, 5-cyclohexylpentanoic acid, 6-phenylhexanoic acid, 6-aminohexanoic acid, 5-phenylpentanoic acid, 5-methylhexanoic acid, myristic acid, oleic acid, elaidic acid, and 2-{1- (aminomethyl)cyclopentyl}acetic acid was purchased from Sigma-Aldrich, Alfa, Enamine, or TCI chemical company and used without further purification. 4-(4-Iodophenyl)butanoic acid was synthesized and used according to a previously reported method (Tetrahedron 60 (2004) 6945-6958).

제조예Manufacturing example I: 카복실산I: carboxylic acid 화합물의 제조 Preparation of Compounds

제조예 1-4: 알데히드 화합물로부터 카복실산 화합물의 제조Preparation Example 1-4: Preparation of carboxylic acid compound from aldehyde compound

아르곤(Ar) 대기 하에서 (2-carboxyethyl)triphenylphosphonium bromide (2.41 g, 6 mmol) 및 건조 THF (tetrahydrofuran) (18mL)를 100 mL 둥근 바닥 플라스크에 투입한 후 0℃로 냉각시키고, NaHMDS (sodium bis(trimethylsilyl)amide, 2.29 g, 12.5 mmol)를 첨가하였다. 0℃에서 15분간 교반시킨 후 치환된 벤즈알데히드 화합물 (5 mmol)을 첨가하고 상온에서 밤새 교반시켰다. 교반이 완료되면 감압 하에 농축시키고, 잔류물을 2N NaOH 수용액으로 처리하였다. 반응혼합물을 CH₂Cl₂로 3회 세척하고, 0℃로 냉각한 후 3N HCl 수용액을 첨가하고 교반시켰다. 1시간 후, DCM을 가하여 추출하였다. 얻어진 유기층을 물로 씻어준 다음, 무수 MgSO₄로 건조시키고 여과시켰다. 여액을 감압 농축시킨 후 플래쉬 크로마토그래피(eluent: n-hexane/EtOAc)로 정제하여 올레핀 화합물을 수득하였다.Under argon (Ar) atmosphere, (2-carboxyethyl)triphenylphosphonium bromide (2.41 g, 6 mmol) and dry THF (tetrahydrofuran) (18mL) were added to a 100 mL round bottom flask, cooled to 0°C, and NaHMDS (sodium bis( trimethylsilyl)amide, 2.29 g, 12.5 mmol) was added. After stirring at 0°C for 15 minutes, a substituted benzaldehyde compound (5 mmol) was added and stirred at room temperature overnight. When stirring was complete, it was concentrated under reduced pressure, and the residue was treated with 2N aqueous NaOH solution. The reaction mixture was washed three times with CH ₂ Cl ₂ and cooled to 0°C, then 3N HCl aqueous solution was added and stirred. After 1 hour, DCM was added and extracted. The obtained organic layer was washed with water, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (eluent: n -hexane/EtOAc) to obtain an olefin compound.

올레핀 화합물, 10mol% Pd/C 및 에탄올 (0.1 M)의 용액을 수소 가스(1 atm)로 퍼지하고 밤새 교반시켰다. 이어서, 반응혼합물을 셀라이트 패드를 통해 여과하고, 용매를 감압 하에 제거하여 목적하는 카복실산 화합물을 수득하였다.A solution of olefinic compounds, 10 mol% Pd/C and ethanol (0.1 M) was purged with hydrogen gas (1 atm) and stirred overnight. Then, the reaction mixture was filtered through a Celite pad, and the solvent was removed under reduced pressure to obtain the desired carboxylic acid compound.

출발물질을 달리한 것을 제외하고는 상기와 동일한 방법으로 하기 올레핀 화합물 및 카복실산 화합물을 제조하였다.The following olefin compounds and carboxylic acid compounds were prepared in the same manner as above except that the starting materials were different.

[제조예 1] (E)-4-(3,5-Dimethylphenyl)but-3-enoic acid의 제조[Preparation Example 1] Preparation of ( E )-4-(3,5-Dimethylphenyl)but-3-enoic acid

황색 오일 (290 mg, 30 %, 5 mmol scale); ¹H NMR (400 MHz, CDCl₃) δ 7.00 (s, 2H), 6.89 (s, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.26 (dt, J= 15.9, 7.1 Hz, 1H), 3.29 (dd, J= 7.1, 1.4 Hz, 2H), 2.30 (s, 6H); ¹³C NMR (101 MHz, CD₂Cl₂) δ 177.99, 138.15, 136.66, 134.26, 129.56, 124.35, 120.48, 77.48, 77.16, 76.84, 38.16, 21.38.

Yellow oil (290 mg, 30%, 5 mmol scale); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00 (s, 2H), 6.89 (s, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.26 (dt, J = 15.9, 7.1 Hz, 1H) , 3.29 (dd, J= 7.1, 1.4 Hz, 2H), 2.30 (s, 6H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 177.99, 138.15, 136.66, 134.26, 129.56, 124.35, 120.48, 77.48, 77.16, 76.84, 38.16, 21.38.

[제조예 2] 4-(3,5-Dimethylphenyl)butanoic acid의 제조[Preparation Example 2] Preparation of 4-(3,5-Dimethylphenyl)butanoic acid

Colorless oil (285 mg, 99 %, 1.47 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 12.5-10.6 (br, 1H), 6.84 (s, 1H), 6.81 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.29 (s, 6H), 1.95 (p, J = 7.6 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 179.67, 141.26, 138.04, 127.82, 126.46, 35.00, 33.49, 26.37, 21.39.

Colorless oil (285 mg, 99%, 1.47 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 12.5-10.6 (br, 1H), 6.84 (s, 1H), 6.81 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.29 (s, 6H), 1.95 (p, J = 7.6 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 179.67, 141.26, 138.04, 127.82, 126.46, 35.00, 33.49, 26.37, 21.39.

[제조예 3] (E)-4-(o-Tolyl)but-3-enoic acid의 제조[Preparation Example 3] Preparation of ( E )-4-( o -Tolyl)but-3-enoic acid

흰색 고체 (500 mg, 28 %, 10 mmol scale); ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.51 (m, 1H), 7.19-7.13 (m, 3H), 6.74 (d, J = 15.7 Hz, 1H), 6.18 (dt, J = 15.7, 7.1 Hz, 1H), 3.34 (dd, J= 7.1, 1.6 Hz, 2H), 2.35 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 178.23, 135.92, 135.42, 132.04, 130.38, 127.74, 126.24, 125.88, 122.24, 38.46, 19.91.

White solid (500 mg, 28%, 10 mmol scale); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.51 (m, 1H), 7.19-7.13 (m, 3H), 6.74 (d, J = 15.7 Hz, 1H), 6.18 (dt, J = 15.7, 7.1 Hz, 1H), 3.34 (dd, J= 7.1, 1.6 Hz, 2H), 2.35 (s, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.23, 135.92, 135.42, 132.04, 130.38, 127.74, 126.24, 125.88, 122.24, 38.46, 19.91.

[제조예 4] 4-(o-Tolyl)butanoic acid의 제조[Preparation Example 4] Preparation of 4-( o -Tolyl)butanoic acid

흰색 고체 (400 mg, 87 %); ¹H NMR (599 MHz, CDCl₃) δ 7.20-7.02 (m, 4H), 2.66 (t, J = 7.4 Hz, 2H), 2.43 (t, J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.93 (p, J= 7.5 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 179.73, 139.55, 136.10, 130.43, 129.09, 126.34, 126.12, 33.71, 32.56, 25.14, 19.35.

White solid (400 mg, 87%); ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.20-7.02 (m, 4H), 2.66 (t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H) , 1.93 (p, J= 7.5 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 179.73, 139.55, 136.10, 130.43, 129.09, 126.34, 126.12, 33.71, 32.56, 25.14, 19.35.

[제조예 5] 3-benzyl-4-phenylbutanoic acid의 제조[Preparation Example 5] Preparation of 3-benzyl-4-phenylbutanoic acid

Ethyl 3-benzyl-4-Ethyl 3-benzyl-4- phenylbutphenylbut -2--2- enoate의of enoate 제조 manufacturing

0℃에서 NaH (60% dispersion in mineral oil, 600 mg, 1.5 eq) 및 무수 THF (25 mL)를 함유하는 둥근 바닥 플라스크에 triethylphosphonoacetate (3.70 g, 1.65 eq)를 첨가 한 다음, 실온으로 가온시키고, diphenyl acetone (2.10 g, 10 mmol)을 적가하였다. 반응혼합물을 12시간동안 교반시킨 후 물을 붓고, DCM으로 추출하였다. 유기층을 합한 후 브린(brine)으로 세척하고, MgSO₄로 건조시키고, 여과하고, 감압 하에 농축시켰다. 잔류물을 플래쉬 크로마토그래피(n-헥산/EtOAc)로 정제하여 올레핀 화합물인 Ethyl 3-benzyl-4-phenylbut-2-enoate을 수득하였다.Add triethylphosphonoacetate (3.70 g, 1.65 eq) to a round bottom flask containing NaH (60% dispersion in mineral oil, 600 mg, 1.5 eq) and anhydrous THF (25 mL) at 0°C and then warm to room temperature. diphenyl acetone (2.10 g, 10 mmol) was added dropwise. The reaction mixture was stirred for 12 hours, then water was added and extracted with DCM. The organic layers were combined and washed with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/EtOAc) to obtain an olefin compound, Ethyl 3-benzyl-4-phenylbut-2-enoate.

Colorless oil (720 mg, 25 %); ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.22 (m, 4H), 7.22-7.15 (m, 4H), 7.06 (d, J = 7.2 Hz, 1H), 5.70 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 3.30 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 166.70, 159.95, 138.88, 137.85, 129.49, 129.21, 128.72, 128.65, 126.81, 126.47, 118.54, 60.05, 43.55, 36.88, 14.44.Colorless oil (720 mg, 25%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.31-7.22 (m, 4H), 7.22-7.15 (m, 4H), 7.06 (d, J = 7.2 Hz, 1H), 5.70 (s, 1H), 4.15 ( q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 3.30 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.70, 159.95, 138.88, 137.85, 129.49, 129.21, 128.72, 128.65, 126.81, 126.47, 118.54, 60.05, 43.55, 36.88, 14.44.

3-benzyl-4-3-benzyl-4- phenylbutanoicphenylbutanoic acid acid의 제조 manufacturing of acid

Ethyl 3-benzyl-4-phenylbut-2-enoate (720 mg, 2.57 mmol), Pd/C (270 mg, 10 mol%) 및 에탄올 (0.1 M)의 용액을 수소 가스 (1 atm)로 퍼지하고, 밤새 교반시켰다. 이어서, 상기 반응혼합물을 셀라이트 패드를 통해 여과시킨 후 용매를 감압 하에서 제거하여 원하는 에스테르 화합물을 수득하였다. 추가정제없이 바로 다음 반응에 사용하였다.A solution of ethyl 3-benzyl-4-phenylbut-2-enoate (720 mg, 2.57 mmol), Pd/C (270 mg, 10 mol%) and ethanol (0.1 M) was purged with hydrogen gas (1 atm); Stirred overnight. Subsequently, the reaction mixture was filtered through a Celite pad and the solvent was removed under reduced pressure to obtain the desired ester compound. It was immediately used in the next reaction without additional purification.

상기 수득된 에스테르 화합물에 에탄올 (6 mL)과 H₂O (4 mL) 중의 KOH (413 mg, 4 eq)을 첨가하였다. 상기 반응혼합물을 4시간동안 70 ℃로 가열하고, 실온에서 pH가 2가 될 때까지 1N HCl을 서서히 첨가하였다. 에탄올을 감압 하에 제거하고, 수용액을 EtOAc (3 회)로 추출하였다. 브린(brine)으로 세척한 후, 유기층을 분리하고 MgSO₄로 건조시킨 후, 용매를 제거하여 카복실산 화합물인 3-benzyl-4-phenylbutanoic acid을 수득하였다.To the obtained ester compound was added ethanol (6 mL) and KOH (413 mg, 4 eq) in H ₂ O (4 mL). The reaction mixture was heated to 70° C. for 4 hours, and 1N HCl was slowly added until the pH reached 2 at room temperature. Ethanol was removed under reduced pressure and the aqueous solution was extracted with EtOAc (3 times). After washing with brine, the organic layer was separated, dried over MgSO ₄ , and the solvent was removed to obtain 3-benzyl-4-phenylbutanoic acid, a carboxylic acid compound.

흰색 고체 (653 mg, 99 % combined yield for two steps); ¹H NMR (599 MHz, CDCl₃) δ 7.29 (appt, J = 7.5 Hz, 4H), 7.35-7.23 (m, 6H), 2.72-2.66 (m, 2H), 2.66-2.59 (m, 2H), 2.49 (hept, J = 7.0 Hz, 1H), 2.27 (d, J = 6.6 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 178.87, 139.98, 129.42, 128.53, 126.35, 40.18, 39.00, 37.49.White solid (653 mg, 99% combined yield for two steps); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.29 (appt, J = 7.5 Hz, 4H), 7.35-7.23 (m, 6H), 2.72-2.66 (m, 2H), 2.66-2.59 (m, 2H), 2.49 (hept, J = 7.0 Hz, 1H), 2.27 (d, J = 6.6 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.87, 139.98, 129.42, 128.53, 126.35, 40.18, 39.00, 37.49.

[제조예 6] 6-(1,3-Dioxoisoindolin-2-yl)hexanoic acid의 제조[Preparation Example 6] Preparation of 6-(1,3-Dioxoisoindolin-2-yl)hexanoic acid

Dean-Stark 증류기가 장착된 two-neck round bottom flask에 6-aminohexanoic acid (20 mmol), 무수 프탈산 (3.0 g, 20 mmol), TEA (0.28 mL, 2.0 mmol) 및 톨루엔 (20 mL)을 넣고, 130℃에서 4시간동안 환류교반시켰다. 상온으로 식힌 다음 용매를 감압 하에 제거하고, DCM (150 mL)를 가하고, HCl 수용액 (0.5-1.0 M, 100 mL × 2) 및 브린 (100 mL)로 세척하였다. 얻어진 유기층을 무수 MgSO₄로 건조시키고, 셀라이트 패드를 통해 여과하고, DCM (30 mL)으로 세척하여 6-(1,3-Dioxoisoindolin-2-yl)hexanoic acid 을 수득하였다. Add 6-aminohexanoic acid (20 mmol), phthalic anhydride (3.0 g, 20 mmol), TEA (0.28 mL, 2.0 mmol), and toluene (20 mL) to a two-neck round bottom flask equipped with a Dean-Stark distiller. It was refluxed and stirred at 130°C for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure, DCM (150 mL) was added, and the mixture was washed with HCl aqueous solution (0.5-1.0 M, 100 mL × 2) and brine (100 mL). The obtained organic layer was dried over anhydrous MgSO ₄ , filtered through a Celite pad, and washed with DCM (30 mL) to obtain 6-(1,3-Dioxoisoindolin-2-yl)hexanoic acid.

흰색 고체 (4.96 g, 95 %); ¹H NMR (599 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.02-7.64 (m, 4H), 3.55 (t, J = 7.1 Hz, 2H), 2.18 (t, J = 7.4 Hz, 2H), 1.58 (p, J = 7.4 Hz, 2H), 1.50 (p, J = 7.5 Hz, 2H), 1.27 (p, J= 8.0 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 174.37, 167.93, 134.36, 131.60, 122.99, 37.26, 33.44, 27.68, 25.77, 24.04.White solid (4.96 g, 95%); ^1H NMR (599 MHz, DMSO-d ₆ ) δ 11.98 (s, 1H), 8.02-7.64 (m, 4H), 3.55 (t, J = 7.1 Hz, 2H), 2.18 (t, J = 7.4 Hz, 2H), 1.58 (p, J = 7.4 Hz, 2H), 1.50 (p, J = 7.5 Hz, 2H), 1.27 (p, J = 8.0 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 174.37, 167.93, 134.36, 131.60, 122.99, 37.26, 33.44, 27.68, 25.77, 24.04.

[제조예 7] 2-[1-{(1,3-Dioxoisoindolin-2-yl)methyl}cyclopentyl]acetic acid 의 제조[Preparation Example 7] Preparation of 2-[1-{(1,3-Dioxoisoindolin-2-yl)methyl}cyclopentyl]acetic acid

6-aminohexanoic acid 대신 2-{1-(aminomethyl)cyclopentyl}acetic acid hydrochloride (20 mmol)을 사용한 것을 제외하고는 제조예 6과 동일한 방법으로 반응시켜 2-[1-{(1,3-Dioxoisoindolin-2-yl)methyl}cyclopentyl]acetic acid을 수득하였다.React in the same manner as Preparation Example 6, except that 2-{1-(aminomethyl)cyclopentyl}acetic acid hydrochloride (20 mmol) was used instead of 6-aminohexanoic acid to obtain 2-[1-{(1,3-Dioxoisoindolin- 2-yl)methyl}cyclopentyl]acetic acid was obtained.

흰색 고체 (650 mg, 88 %, 2.58 mmol scale); m.p. 101-103 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.91-7.82 (m, 2H), 7.78-7.70 (m, 2H), 3.81 (s, 2H), 2.45 (s, 2H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 4H), 1.62-1.52 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 176.26, 169.66, 134.29, 132.03, 123.57, 46.65, 44.69, 42.10, 35.91, 24.11; IR (cm^-1) 2945, 2870, 1768, 1701, 1616, 1421, 1336, 875, 712; HRMS (EI) m/z calcd. for C₁₆H₁₇NO₄ [M]⁺: 287.1158, found: 287.1160.White solid (650 mg, 88%, 2.58 mmol scale); mp 101-103℃; ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.91-7.82 (m, 2H), 7.78-7.70 (m, 2H), 3.81 (s, 2H), 2.45 (s, 2H), 1.85-1.75 (m, 2H) ), 1.75-1.65 (m, 4H), 1.62-1.52 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 176.26, 169.66, 134.29, 132.03, 123.57, 46.65, 44.69, 42.10, 35.91, 24.11; IR (cm ^-1 ) 2945, 2870, 1768, 1701, 1616, 1421, 1336, 875, 712; HRMS (EI) m/z calcd. for C ₁₆ H ₁₇ NO ₄ [M] ⁺ : 287.1158, found: 287.1160.

제조예Manufacturing example II: II: 하이드록삼산hydroxamic acid (( hydroxamichydroxamic acid) 화합물의 제조 Preparation of acid) compounds

방법 A.Method A.

카복실산 화합물, oxalyl chloride (2.0 eq), DMF (dimethylformamide) (2 방울) 및 DCM (0.33 M)을 0℃에서 혼합하였다. 실온에서 2시간동안 교반시킨 후, 농축시켜 산 클로라이드 화합물을 수득하였다. 얻어진 산 클로라이드 화합물은 별도의 정제 과정 없이 바로 다음 반응에 사용되었다.A carboxylic acid compound, oxalyl chloride (2.0 eq), DMF (dimethylformamide) (2 drops), and DCM (0.33 M) were mixed at 0°C. After stirring at room temperature for 2 hours, it was concentrated to obtain an acid chloride compound. The obtained acid chloride compound was immediately used in the next reaction without any additional purification process.

EtOAc (0.5 M)과 물 (0.25 M)을 2:1의 부피비로 혼합한 후 K₂CO₃ (2.0 eq)를 첨가하고, Hydroxylamine hydrochloride (1.2 eq)를 가하고 0℃로 냉각시켰다. 0℃에서 상기 얻어진 산 클로라이드 화합물을 적가하였다. 적가가 완료되면, 실온으로 가온하고 12시간동안 교반시켰다. 상 분리 후 수층을 EtOAc로 2회 추출하였다. 유기층을 MgSO₄로 건조시키고, 여과하고, 감압 하에 증발시켰다. 조 생성물을 재결정(DCM + 몇 방울의 메탄올/n-펜탄) 또는 실리카 크로마토그래피(용리액 : DCM/메탄올 = 30 : 1 ~ 10 : 1)에 의해 정제하여 목적하는 하이드록삼산 화합물을 수득하였다.EtOAc (0.5 M) and water (0.25 M) were mixed at a volume ratio of 2:1, K ₂ CO ₃ (2.0 eq) was added, Hydroxylamine hydrochloride (1.2 eq) was added, and the mixture was cooled to 0°C. The acid chloride compound obtained above was added dropwise at 0°C. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 12 hours. After phase separation, the aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by recrystallization (DCM + a few drops of methanol/n-pentane) or silica chromatography (eluent: DCM/methanol = 30:1 to 10:1) to obtain the desired hydroxamic acid compound.

방법 B.Method B.

건조된 THF (0.33 M)에 카복실산 화합물 (1.0 eq)을 첨가하고, 여기에 CDI (1,1'-carbonyldiimidazole, 1.5 eq)을 한번에 첨가한 후 실온에서 1시간동안 교반시켰다. 분말화 hydroxylamine hydrochloride (2 eq)를 첨가하고, 16시간동안 교반시켰다. 반응혼합물을 5% KHSO₄ 수용액 (30 mL)로 희석하고 EtOAc (2 × 30 mL)로 추출하였다. 유기층을 브린(brine)으로 씻고, MgSO₄로 건조시키고, 여과하고, 감압 하에 농축시켜 잔류물을 얻었다. 얻어진 잔류물을 실리카 겔 컬럼 크로마토그래피(용리액 : DCM/methanol = 30:1 ~ 10:1)로 정제하여 목적하는 히드록사믹 산 화합물을 수득하였다.A carboxylic acid compound (1.0 eq) was added to dried THF (0.33 M), and CDI (1,1'-carbonyldiimidazole, 1.5 eq) was added at once and stirred at room temperature for 1 hour. Powdered hydroxylamine hydrochloride (2 eq) was added and stirred for 16 hours. The reaction mixture was diluted with 5% KHSO ₄ aqueous solution (30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent: DCM/methanol = 30:1 to 10:1) to obtain the desired hydroxamic acid compound.

[제조예 8] 4-(4-Chlorophenyl)-N-hydroxybutanamide의 제조[Preparation Example 8] Preparation of 4-(4-Chlorophenyl)- N -hydroxybutanamide

방법 A (3 mmol scale)로 제조; 흰색 고체 (550 mg, 86 %); m.p. 81-83 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (br, 1H), 8.70 (br, 1H), 7.33 (d, J= 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 2.55 (t, J =7.5 Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.76, 140.67, 130.39, 130.20, 128.22, 33.79, 31.60, 26.77; IR (cm^-1) 3198, 3036, 2899, 1621, 1491, 1078, 798, 592; HRMS (EI) m/z calcd. for C₁₀H₁₂ClNO₂ [M]⁺: 213.0557, found: 213.0559.

Prepared by method A (3 mmol scale); White solid (550 mg, 86%); mp 81-83℃; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (br, 1H), 8.70 (br, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H) , 2.55 (t, J =7.5 Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.76, 140.67, 130.39, 130.20, 128.22, 33.79, 31.60, 26.77; IR (cm ^-1 ) 3198, 3036, 2899, 1621, 1491, 1078, 798, 592; HRMS (EI) m/z calcd. for C ₁₀ H ₁₂ ClNO ₂ [M] ⁺ : 213.0557, found: 213.0559.

[제조예 9] N-Hydroxy-4-(4-iodophenyl)butanamide의 제조[Preparation Example 9] Preparation of N -Hydroxy-4-(4-iodophenyl)butanamide

방법 A (1.48 mmol scale)로 제조; 흰색 고체 (380 mg, 84 %); m.p. 144-146 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.35 (br, 1H), 8.69 (br, 1H), 7.62 (d, J= 7.8 Hz, 2H), 7.01 (d, J= 7.8 Hz, 2H), 2.52-2.50 (m, 2H), 1.94 (t, J= 7.5 Hz, 2H), 1.75 (p, J= 7.6 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 168.72, 141.44, 136.97, 130.83, 91.28, 33.93, 31.57, 26.6; IR (cm^-1) 3025, 3033, 2898, 1620, 1483, 1081, 1005, 817, 478; HRMS (EI) m/z calcd. for C₁₀H₁₂INO₂ [M]⁺: 304.9913, found: 304.9915.

Prepared by method A (1.48 mmol scale); White solid (380 mg, 84%); mp 144-146℃; ¹ H NMR (599 MHz, DMSO-d ₆ ) δ 10.35 (br, 1H), 8.69 (br, 1H), 7.62 (d, J= 7.8 Hz, 2H), 7.01 (d, J= 7.8 Hz, 2H) , 2.52-2.50 (m, 2H), 1.94 (t, J= 7.5 Hz, 2H), 1.75 (p, J= 7.6 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.72, 141.44, 136.97, 130.83, 91.28, 33.93, 31.57, 26.6; IR (cm ^-1 ) 3025, 3033, 2898, 1620, 1483, 1081, 1005, 817, 478; HRMS (EI) m/z calcd. for C ₁₀ H ₁₂ INO ₂ [M] ⁺ : 304.9913, found: 304.9915.

[제조예 10] N-Hydroxy-4-(p-tolyl)butanamide의 제조[Preparation Example 10] Preparation of N -Hydroxy-4-( p -tolyl)butanamide

방법 A (4 mmol scale)로 제조; 흰색 고체 (690 mg, 89 %); m.p. 100-102 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (br, 1H), 8.68 (br, 1H), 7.14-6.99 (m, 4H), 2.52-2.49 (m, 2H), 2.25 (s, 3H), 1.95 (t, J = 7.4 Hz, 1H), 1.75 (p, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.90, 138.52, 134.63, 128.87, 128.18, 34.18, 31.76, 27.06, 20.62; IR (cm^-1) 3197, 3026, 2908, 2855, 1622, 1074, 806, 482; HRMS (EI) m/z calcd. for C₁₁H₁₅NO₂ [M]⁺: 193.1103, found: 119.1105.

Prepared by method A (4 mmol scale); White solid (690 mg, 89%); mp 100-102℃; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (br, 1H), 8.68 (br, 1H), 7.14-6.99 (m, 4H), 2.52-2.49 (m, 2H), 2.25 (s, 3H) ), 1.95 (t, J = 7.4 Hz, 1H), 1.75 (p, J = 7.4 Hz, 1H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.90, 138.52, 134.63, 128.87, 128.18, 34.18, 31.76, 27.06, 20.62; IR (cm ^-1 ) 3197, 3026, 2908, 2855, 1622, 1074, 806, 482; HRMS (EI) m/z calcd. for C ₁₁ H ₁₅ NO ₂ [M] ⁺ : 193.1103, found: 119.1105.

[제조예 11] 4-{4-(tert-Butyl)phenyl}-N-hydroxybutanamide의 제조[Preparation Example 11] Preparation of 4-{4-( tert -Butyl)phenyl}- N -hydroxybutanamide

방법 A (2 mmol scale)로 제조; 흰색 고체 (386 mg, 82 %); m.p. 78-80 ℃; ¹H NMR (400 MHz, DMSO-d₆, two protons merged to the solvent residual peaks) δ 10.35 (br, 1H), 8.68 (br, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.76 (p, J = 7.5 Hz, 2H), 1.26 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.89, 147.98, 138.54, 127.94, 125.00, 34.08, 34.05, 31.84, 31.22, 26.96; IR (cm^-1) 3234, 3143, 3061, 3019, 2958, 1898, 2862, 1619, 1078, 563; HRMS (EI) m/z calcd. for C₁₄H₂₁NO₂ [M]⁺: 235.1572, found: 235.1573.

Prepared by method A (2 mmol scale); White solid (386 mg, 82%); mp 78-80℃; ¹ H NMR (400 MHz, DMSO-d ₆ , two protons merged to the solvent residual peaks) δ 10.35 (br, 1H), 8.68 (br, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.09 ( d, J = 8.3 Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.76 (p, J = 7.5 Hz, 2H), 1.26 (s, 9H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.89, 147.98, 138.54, 127.94, 125.00, 34.08, 34.05, 31.84, 31.22, 26.96; IR (cm ^-1 ) 3234, 3143, 3061, 3019, 2958, 1898, 2862, 1619, 1078, 563; HRMS (EI) m/z calcd. for C ₁₄ H ₂₁ NO ₂ [M] ⁺ : 235.1572, found: 235.1573.

[제조예 12] N-Hydroxy-4-{4-(trifluoromethyl)phenyl}butanamide의 제조[Preparation Example 12] Preparation of N -Hydroxy-4-{4-(trifluoromethyl)phenyl}butanamide

방법 A (2 mmol scale)로 제조; 흰색 고체 (400 mg, 81 %); m.p. 92-94 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.35 (br, 1H), 8.68 (br, 1H), 7.61 (d, J= 7.9 Hz, 2H), 7.39 (d, J= 7.9 Hz, 2H), 2.62 (t, J= 7.6 Hz, 2H), 1.94 (t, J= 7.4 Hz, 2H), 1.79 (p, J= 7.5 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 168.66, 146.63, 129.12, 126.63 (q, J= 31.9 Hz), 125.10 (q, J= 3.9 Hz), 124.44 (q, J= 271.8 Hz), 34.25, 31.57, 26.50; ¹⁹F NMR (564 MHz, DMSO-d₆) δ -60.75; IR (cm^-1) 3214, 3040, 2929, 2871, 1626, 1322, 1109, 1065, 805, 586; HRMS (EI) m/z calcd. for C₁₁H₁₂F₃NO₂ [M]⁺: 247.0820, found: 247.0823.

Prepared by method A (2 mmol scale); White solid (400 mg, 81%); mp 92-94℃; ¹ H NMR (599 MHz, DMSO-d ₆ ) δ 10.35 (br, 1H), 8.68 (br, 1H), 7.61 (d, J= 7.9 Hz, 2H), 7.39 (d, J= 7.9 Hz, 2H) , 2.62 (t, J= 7.6 Hz, 2H), 1.94 (t, J= 7.4 Hz, 2H), 1.79 (p, J= 7.5 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.66, 146.63, 129.12, 126.63 (q, J= 31.9 Hz), 125.10 (q, J= 3.9 Hz), 124.44 (q, J= 271.8 Hz), 34.25 , 31.57, 26.50; ¹⁹ F NMR (564 MHz, DMSO-d ₆ ) δ -60.75; IR (cm ^-1 ) 3214, 3040, 2929, 2871, 1626, 1322, 1109, 1065, 805, 586; HRMS (EI) m/z calcd. for C ₁₁ H ₁₂ F ₃ NO ₂ [M] ⁺ : 247.0820, found: 247.0823.

[제조예 13] 4-(3-Bromophenyl)-N-hydroxybutanamide의 제조[Preparation Example 13] Preparation of 4-(3-Bromophenyl)- N -hydroxybutanamide

방법 A (2 mmol scale)로 제조; 흰색 고체 (402 mg, 78 %); m.p. 98-100 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.70 (s, 1H), 7.44-7.35 (m, 2H), 7.30-7.10 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.95 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.8 Hz, 2H); ¹³C NMR(101 MHz, DMSO-d₆) δ 168.75, 144.61, 131.06, 130.47, 128.73, 127.49, 121.66, 34.07, 31.61, 26.70; IR (cm^-1) 3170, 3056, 2925, 1627, 1555, 971, 767, 665; HRMS (EI) m/z calcd. for C₁₀H₁₂BrNO₂ [M]⁺: 257.0051, found: 257.0054.

Prepared by method A (2 mmol scale); White solid (402 mg, 78%); mp 98-100℃; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 8.70 (s, 1H), 7.44-7.35 (m, 2H), 7.30-7.10 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.95 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.8 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.75, 144.61, 131.06, 130.47, 128.73, 127.49, 121.66, 34.07, 31.61, 26.70; IR (cm ^-1 ) 3170, 3056, 2925, 1627, 1555, 971, 767, 665; HRMS (EI) m/z calcd. for C ₁₀ H ₁₂ BrNO ₂ [M] ⁺ : 257.0051, found: 257.0054.

[제조예 14] 4-(3,5-Dimethylphenyl)-N-hydroxybutanamide의 제조[Preparation Example 14] Preparation of 4-(3,5-Dimethylphenyl)- N -hydroxybutanamide

방법 A (1.46 mmol scale)로 제조; 흰색 고체 (240 mg, 79 %); m.p. 94-96 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (br, 1H), 8.67 (br, 1H), 6.79 (s, 1H), 6.77 (s, 2H), 2.46 (t, J = 7.7 Hz, 2H), 1.95 (t, J = 7.4 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.90, 141.46, 137.11, 127.21, 126.10, 34.49, 31.84, 26.98, 20.92; IR (cm^-1) 3251, 3011, 2952, 2911, 2858, 1617, 1458, 1077, 1052, 954, 840, 702, 528; HRMS (EI) m/z calcd. for C₁₂H₁₇NO₂ [M]⁺: 207.1259, found: 207.1261.

Prepared by method A (1.46 mmol scale); White solid (240 mg, 79%); mp 94-96℃; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (br, 1H), 8.67 (br, 1H), 6.79 (s, 1H), 6.77 (s, 2H), 2.46 (t, J = 7.7 Hz, 2H), 1.95 (t, J = 7.4 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.90, 141.46, 137.11, 127.21, 126.10, 34.49, 31.84, 26.98, 20.92; IR (cm ^-1 ) 3251, 3011, 2952, 2911, 2858, 1617, 1458, 1077, 1052, 954, 840, 702, 528; HRMS (EI) m/z calcd. for C ₁₂ H ₁₇ NO ₂ [M] ⁺ : 207.1259, found: 207.1261.

[제조예 15] N-Hydroxy-4-(o-tolyl)butanamide의 제조[Preparation Example 15] Preparation of N -Hydroxy-4-( o -tolyl)butanamide

방법 A (2 mmol scale)로 제조; 흰색 고체 (330 mg, 85 %); m.p. 78-80 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.63 (br, 1H), 8.95 (br, 1H), 7.41-7.30 (m, 4H), 3.60 (s, 3H), 2.78 (t, J = 7.4 Hz), 2.27 (t, J = 7.3 Hz, 1H), 1.98 (p, J = 7.5 Hz, 1H); ¹³C NMR (151 MHz, DMSO-d₆, two carbons merged to others) δ 168.89, 139.83, 135.44, 129.95, 128.63, 125.83, 2.01, 25.74, 18.79; IR (cm^-1) 3232, 3020, 2954, 2923, 2864, 1620, 1455, 1071, 939, 737, 545; HRMS (EI) m/zcalcd. for C₁₂H₁₇NO₂ [M]⁺: 207.1259, found: 207.1261.

Prepared by method A (2 mmol scale); White solid (330 mg, 85%); mp 78-80℃; ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.63 (br, 1H), 8.95 (br, 1H), 7.41-7.30 (m, 4H), 3.60 (s, 3H), 2.78 (t, J = 7.4 Hz), 2.27 (t, J = 7.3 Hz, 1H), 1.98 (p, J = 7.5 Hz, 1H); ¹³ C NMR (151 MHz, DMSO-d ₆ , two carbons merged to others) δ 168.89, 139.83, 135.44, 129.95, 128.63, 125.83, 2.01, 25.74, 18.79; IR (cm ^-1 ) 3232, 3020, 2954, 2923, 2864, 1620, 1455, 1071, 939, 737, 545; HRMS (EI) m/zcalcd. for C ₁₂ H ₁₇ NO ₂ [M] ⁺ : 207.1259, found: 207.1261.

[제조예 16] 4-(2-Chlorophenyl)-N-hydroxybutanamide의 제조[Preparation Example 16] Preparation of 4-(2-Chlorophenyl)- N -hydroxybutanamide

방법 A (2 mmol scale)로 제조; 흰색 고체 (307 mg, 72 %); m.p. 86-88 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (br, 1H), 8.71 (br, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.36-7.14 (m, 3H), 2.67 (t, J = 7.8 Hz, 2H), 2.00 (t, J = 7.5 Hz, 2H), 1.78 (p, J = 7.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.68, 138.97, 132.86, 130.67, 129.23, 127.88, 127.29, 32.30, 31.82, 25.31; IR (cm^-1) 3166, 3036, 2973, 2868, 1654, 1428, 1069, 744, 594; HRMS (EI) m/z calcd. for C₁₀H₁₂ClNO₂ [M]⁺: 213.0557, found: 213.0560.

Prepared by method A (2 mmol scale); White solid (307 mg, 72%); mp 86-88℃; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (br, 1H), 8.71 (br, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.36-7.14 (m, 3H), 2.67 ( t, J = 7.8 Hz, 2H), 2.00 (t, J = 7.5 Hz, 2H), 1.78 (p, J = 7.5 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 168.68, 138.97, 132.86, 130.67, 129.23, 127.88, 127.29, 32.30, 31.82, 25.31; IR (cm ^-1 ) 3166, 3036, 2973, 2868, 1654, 1428, 1069, 744, 594; HRMS (EI) m/z calcd. for C ₁₀ H ₁₂ ClNO ₂ [M] ⁺ : 213.0557, found: 213.0560.

[제조예 17] N-Hydroxy-4-(naphthalen-2-yl)butanamide의 제조[Preparation Example 17] Preparation of N-Hydroxy-4-(naphthalen-2-yl)butanamide

방법 A (1.11 mmol scale)로 제조; 흰색 고체 (219 mg, 75 %); m.p. 126-128 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.36 (br, 1H), 8.69 (br, 1H), 7.89-7.80 (m, 3H), 7.68 (s, 1H), 7.52-7.42 (m, 2H), 7.37 (dd, J = 8.4, 1.7 Hz, 1H), 2.73 (t, J = 7.6 Hz, 2H), 2.01 (t, J = 7.4 Hz, 2H), 1.89 (p, J = 7.5 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 168.84, 139.26, 133.15, 131.58, 127.72, 127.42, 127.28, 126.11, 125.91, 125.16, 34.68, 31.75, 26.74; IR (cm^-1) 3167, 3017, 2915, 2853, 1651, 1548, 1361, 1070, 823, 741, 472; HRMS (EI) m/z calcd. for C₁₄H₁₅NO₂ [M]⁺: 229.1103, found: 229.1107.

Prepared by method A (1.11 mmol scale); White solid (219 mg, 75%); mp 126-128℃; ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.36 (br, 1H), 8.69 (br, 1H), 7.89-7.80 (m, 3H), 7.68 (s, 1H), 7.52-7.42 (m, 2H) ), 7.37 (dd, J = 8.4, 1.7 Hz, 1H), 2.73 (t, J = 7.6 Hz, 2H), 2.01 (t, J = 7.4 Hz, 2H), 1.89 (p, J = 7.5 Hz, 2H) ); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.84, 139.26, 133.15, 131.58, 127.72, 127.42, 127.28, 126.11, 125.91, 125.16, 34.68, 31.75, 26.74 ; IR (cm ^-1 ) 3167, 3017, 2915, 2853, 1651, 1548, 1361, 1070, 823, 741, 472; HRMS (EI) m/z calcd. for C ₁₄ H ₁₅ NO ₂ [M] ⁺ : 229.1103, found: 229.1107.

[제조예 18] 5-Cyclohexyl-N-hydroxypentanamide의 제조[Preparation Example 18] Preparation of 5-Cyclohexyl-N-hydroxypentanamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (917 mg, 92 %); m.p. 56-58 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.64 (s, 1H), 1.92 (t, J = 7.4 Hz, 2H), 1.68-1.57 (m, 5H), 1.44 (p, J = 7.4 Hz, 2H), 1.27-1.04 (m, 8H), 0.88-0.77 (m, 2H); ¹³C NMR (151 MHz, DMSO-d₆, one carbon merged to others) δ 169.08, 36.92, 36.57, 32.83, 32.28, 26.19, 25.82, 25.39; IR (cm^-1) 3258, 2918, 2848, 1620, 1542, 1445, 540, 483; HRMS (FAB) m/z calcd. for C₁₁H₂₁NO₂ [M+H]⁺: 200.1651, found: 200.1647.

Prepared by method A (5 mmol scale); White solid (917 mg, 92%); mp 56-58℃; ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.64 (s, 1H), 1.92 (t, J = 7.4 Hz, 2H), 1.68-1.57 (m, 5H), 1.44 ( p, J = 7.4 Hz, 2H), 1.27-1.04 (m, 8H), 0.88-0.77 (m, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ , one carbon merged to others) δ 169.08, 36.92, 36.57, 32.83, 32.28, 26.19, 25.82, 25.39; IR (cm ^-1 ) 3258, 2918, 2848, 1620, 1542, 1445, 540, 483; HRMS (FAB) m/z calcd. for C ₁₁ H ₂₁ NO ₂ [M+H] ⁺ : 200.1651, found: 200.1647.

[제조예 19] N-Hydroxy-6-phenylhexanamide의 제조[Preparation Example 19] Preparation of N-Hydroxy-6-phenylhexanamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (922 mg, 89 %); ¹H NMR (599 MHz, DMSO-d₆) δ 10.33 (br, 1H), 8.66 (br, 1H), 7.26 (appt, J = 7.5 Hz, 2H), 7.20-7.14 (m, 3H), 2.55 (t, J = 7.7 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59-1.46 (m, 4H), 1.25 (p, J = 7.7 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 169.04, 142.21, 128.24, 128.20, 125.59, 35.04, 32.18, 30.70, 28.22, 24.94.

Prepared by method A (5 mmol scale); White solid (922 mg, 89%); ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.33 (br, 1H), 8.66 (br, 1H), 7.26 (appt, J = 7.5 Hz, 2H), 7.20-7.14 (m, 3H), 2.55 ( t, J = 7.7 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59-1.46 (m, 4H), 1.25 (p, J = 7.7 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 169.04, 142.21, 128.24, 128.20, 125.59, 35.04, 32.18, 30.70, 28.22, 24.94.

[제조예 20] 6-(1,3-Dioxoisoindolin-2-yl)-N-hydroxyhexanamide의 제조[Preparation Example 20] Preparation of 6-(1,3-Dioxoisoindolin-2-yl)- N -hydroxyhexanamide

방법 B (5 mmol scale)로 제조; 흰색 고체 (1.28 g, 93 %); m.p. 123-125 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.32 (br, 1H), 8.66 (br, 1H), 7.93-7.75 (m, 4H), 3.54 (t, J = 7.1 Hz, 2H), 1.92 (t, J= 7.4 Hz, 2H), 1.57 (p, J = 7.4 Hz, 2H), 1.50 (p, J= 7.5 Hz, 2H), 1.23 (p, J = 7.8 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 168.95, 167.91, 134.36, 131.58, 122.98, 37.29, 32.04, 27.71, 25.85, 24.67; IR (cm^-1) 3248, 2929, 2861, 1711, 1614, 1395, 1047, 720, 530; HRMS (EI) m/z calcd. for C₁₄H₁₆N₂O₄ [M]⁺: 276.1110, found: 276.1112.

Prepared by method B (5 mmol scale); White solid (1.28 g, 93%); mp 123-125℃; ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.32 (br, 1H), 8.66 (br, 1H), 7.93-7.75 (m, 4H), 3.54 (t, J = 7.1 Hz, 2H), 1.92 ( t, J = 7.4 Hz, 2H), 1.57 (p, J = 7.4 Hz, 2H), 1.50 (p, J = 7.5 Hz, 2H), 1.23 (p, J = 7.8 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.95, 167.91, 134.36, 131.58, 122.98, 37.29, 32.04, 27.71, 25.85, 24.67; IR (cm ^-1 ) 3248, 2929, 2861, 1711, 1614, 1395, 1047, 720, 530; HRMS (EI) m/z calcd. for C ₁₄ H ₁₆ N ₂ O ₄ [M] ⁺ : 276.1110, found: 276.1112.

[제조예 21] N-Hydroxy-5-phenylpentanamide의 제조[Preparation Example 21] Preparation of N -Hydroxy-5-phenylpentanamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (889 mg, 92 %); ¹H NMR (599 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.72 (s, 1H), 7.27 (appt, J = 7.5 Hz, 2H), 7.17 (d, J = 7.6 Hz, 3H), 2.55 (t, J = 7.1 Hz, 2H), 1.97 (t, J = 6.8 Hz, 2H), 1.58-1.46 (m, 4H); ¹³C NMR (151 MHz, DMSO-d₆) δ 169.00, 142.06, 128.26, 128.22, 125.63, 34.82, 32.11, 30.56, 24.78.

Prepared by method A (5 mmol scale); White solid (889 mg, 92%); ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 8.72 (s, 1H), 7.27 (appt, J = 7.5 Hz, 2H), 7.17 (d, J = 7.6 Hz, 3H) , 2.55 (t, J = 7.1 Hz, 2H), 1.97 (t, J = 6.8 Hz, 2H), 1.58-1.46 (m, 4H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 169.00, 142.06, 128.26, 128.22, 125.63, 34.82, 32.11, 30.56, 24.78.

[제조예 22] N-Hydroxy-5-methylhexanamide의 제조[Preparation Example 22] Preparation of N -Hydroxy-5-methylhexanamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (603 mg, 83 %); m.p. 74-76 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.31 (br, 1H), 8.64 (br, 1H), 1.91 (t, J= 7.4 Hz, 2H), 1.54-1.44 (m, 3H), 1.11 (q, J= 7.1 Hz, 2H), 0.84 (d, J= 6.6 Hz, 6H); ¹³C NMR (151 MHz, DMSO-d₆) δ 169.07, 37.86, 32.45, 27.17, 22.94, 22.39; IR (cm^-1) 3197, 2965, 2936, 2868, 1624, 1544, 1121, 1063, 657, 607; HRMS (FAB) m/z calcd. for C₇H₁₅NO₂ [M+H]⁺: 146.1181, found: 146.1183.

Prepared by method A (5 mmol scale); White solid (603 mg, 83%); mp 74-76℃; ¹ H NMR (599 MHz, DMSO-d ₆ ) δ 10.31 (br, 1H), 8.64 (br, 1H), 1.91 (t, J= 7.4 Hz, 2H), 1.54-1.44 (m, 3H), 1.11 ( q, J= 7.1 Hz, 2H), 0.84 (d, J= 6.6 Hz, 6H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 169.07, 37.86, 32.45, 27.17, 22.94, 22.39; IR (cm ^-1 ) 3197, 2965, 2936, 2868, 1624, 1544, 1121, 1063, 657, 607; HRMS (FAB) m/z calcd. for C ₇ H ₁₅ NO ₂ [M+H] ⁺ : 146.1181, found: 146.1183.

[제조예 23] N-Hydroxytetradecanamide의 제조[Preparation Example 23] Preparation of N -Hydroxytetradecanamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (1.13 g, 93 %); m.p.88-90 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (br, 1H), 8.64 (br, 0H), 1.92 (t, J= 7.3 Hz, 2H), 1.54-1.41 (m, 2H), 1.33-1.12 (m, 20H), 0.85 (t, J = 6.6 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆, three carbons merged to others) δ 169.11, 32.26, 31.31, 29.07, 29.04, 28.97, 28.77, 28.73, 28.61, 25.13, 22.11; IR (cm^-1) 3249, 3063, 2954, 2846, 1660, 1620, 1470, 717, 511.

Prepared by method A (5 mmol scale); White solid (1.13 g, 93%); mp88-90℃; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (br, 1H), 8.64 (br, 0H), 1.92 (t, J= 7.3 Hz, 2H), 1.54-1.41 (m, 2H), 1.33- 1.12 (m, 20H), 0.85 (t, J = 6.6 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ , three carbons merged to others) δ 169.11, 32.26, 31.31, 29.07, 29.04, 28.97, 28.77, 28.73, 28.61, 25.13, 22.11; IR (cm ^-1 ) 3249, 3063, 2954, 2846, 1660, 1620, 1470, 717, 511.

[제조예 24] N-Hydroxyoleamide의 제조[Preparation Example 24] Preparation of N -Hydroxyoleamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (1.27 g, 86 %); m.p. 66-68 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.31 (br, 1H), 8.64 (br, 1H), 5.38-5.26 (m, 2H), 1.98 (q, J = 6.5 Hz, 4H), 1.92 (t, J = 7.4 Hz, 2H), 1.46 (p, J = 7.3 Hz, 2H), 1.31-1.20 (m, 20H), 0.85 (t, J = 6.9 Hz, 3H); ¹³C NMR (151 MHz, DMSO-d₆, one carbon merged to others) δ 169.04, 129.60, 129.58, 32.23, 31.25, 29.10, 29.07, 28.80, 28.65, 28.60, 28.57, 28.53, 26.59, 26.55, 25.09, 22.06, 13.90; IR (cm^-1) 3280, 2916, 2848,1664, 1462, 1067, 978, 726; HRMS (EI) m/z calcd. for C₁₈H₃₅NO₂ [M]⁺: 297.2668, found: 297.2664.

Prepared by method A (5 mmol scale); White solid (1.27 g, 86%); mp 66-68℃; ^1H NMR (599 MHz, DMSO-d ₆ ) δ 10.31 (br, 1H), 8.64 (br, 1H), 5.38-5.26 (m, 2H), 1.98 (q, J = 6.5 Hz, 4H), 1.92 ( t, J = 7.4 Hz, 2H), 1.46 (p, J = 7.3 Hz, 2H), 1.31-1.20 (m, 20H), 0.85 (t, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, DMSO-d ₆ , one carbon merged to others) δ 169.04, 129.60, 129.58, 32.23, 31.25, 29.10, 29.07, 28.80, 28.65, 28.60, 28.57, 28.53, 26.5 9, 26.55, 25.09, 22.06 , 13.90; IR (cm ^-1 ) 3280, 2916, 2848,1664, 1462, 1067, 978, 726; HRMS (EI) m/z calcd. for C ₁₈ H ₃₅ NO ₂ [M] ⁺ : 297.2668, found: 297.2664.

[제조예 25] (E)-N-Hydroxyoctadec-9-enamide의 제조[Preparation Example 25] Preparation of ( E ) -N -Hydroxyoctadec-9-enamide

방법 A (5 mmol scale)로 제조; 흰색 고체 (1.27 g, 86 %); m.p. 90-92 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (br, 1H), 8.64 (br, 1H), 5.43-5.29 (m, 2H), 2.03-1.81 (m, 6H), 1.46 (p, J = 7.2 Hz, 2H), 1.33-1.17 (m, 20H), 0.85 (t, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆, three carbons merged to others) δ 169.08, 130.07, 130.05, 32.25, 31.96, 31.28, 29.01, 28.82, 28.70, 28.59, 28.50, 28.43, 25.12, 22.10, 13.95; IR (cm^-1) 3249, 2913, 2847, 1659, 1468, 1065, 963, 718; HRMS (FAB) m/z calcd. for C₁₈H₃₅NO₂ [M+H]⁺: 298.2746, found: 298.2748.

Prepared by method A (5 mmol scale); White solid (1.27 g, 86%); mp 90-92℃; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (br, 1H), 8.64 (br, 1H), 5.43-5.29 (m, 2H), 2.03-1.81 (m, 6H), 1.46 (p, J = 7.2 Hz, 2H), 1.33-1.17 (m, 20H), 0.85 (t, J = 6.7 Hz, 3H); ¹³ C NMR (101 MHz, DMSO-d ₆ , three carbons merged to others) δ 169.08, 130.07, 130.05, 32.25, 31.96, 31.28, 29.01, 28.82, 28.70, 28.59, 28.50, 28.43, 25. 12, 22.10, 13.95; IR (cm ^-1 ) 3249, 2913, 2847, 1659, 1468, 1065, 963, 718; HRMS (FAB) m/z calcd. for C ₁₈ H ₃₅ NO ₂ [M+H] ⁺ : 298.2746, found: 298.2748.

[제조예 26] 3-Benzyl-N-hydroxy-4-phenylbutanamide의 제조[Preparation Example 26] Preparation of 3-Benzyl- N -hydroxy-4-phenylbutanamide

방법 A (2.4 mmol scale)로 제조; 흰색 고체 (550 mg, 84 %); m.p. 89-91 ℃; ¹H NMR (599 MHz, DMSO-d₆) δ 10.41 (br, 1H), 8.74 (br, 1H), 7.29 (appt, J= 7.6 Hz, 4H), 7.19 (appt, J = 7.4 Hz, 2H), 7.13 (d, J= 7.5 Hz, 4H), 2.54-2.43 (m, 4H), 2.37 (hept, J= 6.6 Hz, 1H), 1.84 (d, J= 6.8 Hz, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 168.27, 140.10, 128.98, 128.25, 125.89, 38.83, 38.43, 35.79; IR (cm^-1) 3220, 3026, 2912, 1626, 747, 738, 504; HRMS (EI) m/z calcd. for C₁₇H₁₉NO₂ [M]⁺: 269.1416, found: 269.1419.

Prepared by method A (2.4 mmol scale); White solid (550 mg, 84%); mp 89-91℃; ¹ H NMR (599 MHz, DMSO-d ₆ ) δ 10.41 (br, 1H), 8.74 (br, 1H), 7.29 (appt, J = 7.6 Hz, 4H), 7.19 (appt, J = 7.4 Hz, 2H) , 7.13 (d, J= 7.5 Hz, 4H), 2.54-2.43 (m, 4H), 2.37 (hept, J= 6.6 Hz, 1H), 1.84 (d, J= 6.8 Hz, 2H); ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.27, 140.10, 128.98, 128.25, 125.89, 38.83, 38.43, 35.79; IR (cm ^-1 ) 3220, 3026, 2912, 1626, 747, 738, 504; HRMS (EI) m/z calcd. for C ₁₇ H ₁₉ NO ₂ [M] ⁺ : 269.1416, found: 269.1419.

[제조예 27] 2-[1-{(1,3-Dioxoisoindolin-2-yl)methyl}cyclopentyl]-N-hydroxyacetamide의 제조[Preparation Example 27] Preparation of 2-[1-{(1,3-Dioxoisoindolin-2-yl)methyl}cyclopentyl]- N -hydroxyacetamide

방법 B (0.21 mmol scale)로 제조; 흰색 고체 (455 mg, 72 %); ¹H NMR (599 MHz, CD₃OD) δ 7.91-7.84 (m, 2H), 7.84-7.79 (m, 2H), 3.73 (s, 2H), 2.20 (s, 2H), 1.76-1.59 (m, 8H); ¹³C NMR(151 MHz, CD₃OD, one carbonyl missing) δ 170.91, 135.46, 133.30, 124.19, 48.45, 46.57, 41.39, 35.88, 25.01.

Prepared by method B (0.21 mmol scale); White solid (455 mg, 72%); ¹ H NMR (599 MHz, CD ₃ OD) δ 7.91-7.84 (m, 2H), 7.84-7.79 (m, 2H), 3.73 (s, 2H), 2.20 (s, 2H), 1.76-1.59 (m, 8H); ¹³ C NMR (151 MHz, CD ₃ OD, one carbonyl missing) δ 170.91, 135.46, 133.30, 124.19, 48.45, 46.57, 41.39, 35.88, 25.01.

제조예Manufacturing example III: 3-치환된-1,4,2- III: 3-substituted-1,4,2- 디옥사졸dioxazole -5-온(3-substituted-1,4,2--5-on(3-substituted-1,4,2- dioxazoldioxazol -5-one) 화합물의 제조-5-one) Preparation of compounds

실온에서 DCM (50 mL)에 하이드록삼산 화합물 (5.0 mmol)를 녹인 후 CDI (0.81 g, 5.0 mmol)을 한꺼번에 첨가하였다. 30분간 교반시킨 후, 1N HCl (30 mL)로 켄칭시키고, 디클로로메탄 (50 mL × 3)으로 추출하고, 무수 MgSO₄로 건조시키고, 용매를 감압 하에 제거하였다. 조 혼합물을 실리카 패드를 통해 여과시키고, 디클로로메탄으로 세척하였다. 여액을 감압 하에 농축시켜 목적하는 3-치환된 1,4,2-디옥사졸-5-온 화합물을 수득하였다.After dissolving the hydroxamic acid compound (5.0 mmol) in DCM (50 mL) at room temperature, CDI (0.81 g, 5.0 mmol) was added all at once. After stirring for 30 minutes, it was quenched with 1N HCl (30 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The crude mixture was filtered through a pad of silica and washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain the desired 3-substituted 1,4,2-dioxazol-5-one compound.

출발물질을 달리한 것을 제외하고는 상기와 같은 방법으로 하기의 화합물을 제조하였다.The following compounds were prepared in the same manner as above except that the starting materials were different.

[제조예 28] 3-(3-Phenylpropyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 28] Preparation of 3-(3-Phenylpropyl)-1,4,2-dioxazol-5-one

무색의 액체 (0.82 g, 80 %); ¹H NMR (600 MHz, CDCl₃) δ 7.32 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.07 (p, J = 7.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 166.4, 154.0, 139.7, 128.6, 128.4, 126.5, 34.5, 25.9, 24.0; IR (cm^-1) 3207, 2913, 1827, 1634, 1452, 980; HRMS (EI) m/z calcd. for C₁₁H₁₁NO₃ [M]⁺: 205.0739, found: 205.0737.

Colorless liquid (0.82 g, 80%); ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.32 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 2.75 (t , J = 7.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.07 (p, J = 7.4 Hz, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 166.4, 154.0, 139.7, 128.6, 128.4, 126.5, 34.5, 25.9, 24.0; IR (cm ^-1 ) 3207, 2913, 1827, 1634, 1452, 980; HRMS (EI) m/z calcd. for C ₁₁ H ₁₁ NO ₃ [M] ⁺ : 205.0739, found: 205.0737.

[제조예 29] 3-{3-(4-fluorophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 29] Preparation of 3-{3-(4-fluorophenyl)propyl}-1,4,2-dioxazol-5-one

무색의 액체 (0.41 g, 90 %); ¹H NMR (600 MHz, CD₂Cl₂) δ 7.22-7.12 (m, 2H), 7.07-6.95 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 166.6, 161.5 (d, J = 243.4 Hz), 154.1, 135.9 (d, J = 3.1 Hz), 129.9 (d, J = 7.8 Hz), 115.2 (d, J = 21.3 Hz), 33.7, 26.0, 24.0; ¹⁹F NMR (564 MHz, CD₂Cl₂) δ -117.7 (m); IR (cm^-1) 2934, 1870, 1825, 1508, 1218, 1150, 981; HRMS (EI) m/z calcd. for C₁₁H₁₀FNO₃ [M]⁺: 223.0645, found: 223.0646.

Colorless liquid (0.41 g, 90%); ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 7.22-7.12 (m, 2H), 7.07-6.95 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H); ¹³ C NMR (150 MHz, CD ₂ Cl ₂ ) δ 166.6, 161.5 (d, J = 243.4 Hz), 154.1, 135.9 (d, J = 3.1 Hz), 129.9 (d, J = 7.8 Hz), 115.2 (d) , J = 21.3 Hz), 33.7, 26.0, 24.0; ¹⁹ F NMR (564 MHz, CD ₂ Cl ₂ ) δ -117.7 (m); IR (cm ^-1 ) 2934, 1870, 1825, 1508, 1218, 1150, 981; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ FNO ₃ [M] ⁺ : 223.0645, found: 223.0646.

[제조예 30] 3-{3-(4-Chlorophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 30] Preparation of 3-{3-(4-Chlorophenyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (516 mg, 94 %, 2.3 mmol scale); m.p. 37-39 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.28 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.38, 154.14, 138.37, 132.51, 129.91, 128.95, 34.01, 25.92, 24.08; IR (cm^-1) 2926, 1899, 1866, 1828, 1788, 1633, 1492, 1392, 1353, 1217, 1094, 991, 801, 757, 516; HRMS (EI) m/z calcd. for C₁₁H₁₀ClNO₃ [M]⁺: 239.0349, found: 239.0352.

White solid (516 mg, 94%, 2.3 mmol scale); mp 37-39℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.28 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.62 (t , J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.38, 154.14, 138.37, 132.51, 129.91, 128.95, 34.01, 25.92, 24.08; IR (cm ^-1 ) 2926, 1899, 1866, 1828, 1788, 1633, 1492, 1392, 1353, 1217, 1094, 991, 801, 757, 516; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ ClNO ₃ [M] ⁺ : 239.0349, found: 239.0352.

[제조예 31] 3-(3-(4-Bromophenyl)propyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 31] Preparation of 3-(3-(4-Bromophenyl)propyl)-1,4,2-dioxazol-5-one

흰색 고체 (1.3 g, 93 %); ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 166.2, 154.0, 138.7, 131.8, 130.1, 120.4, 33.9, 25.7, 23.9; IR (cm^-1) 2925, 1867, 1826, 1631, 1152, 985; HRMS (EI) m/z calcd. for C₁₁H₁₀BrNO₃ [M]⁺: 282.9844, found: 282.9843.

White solid (1.3 g, 93%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.44 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.62 (t , J = 7.4 Hz, 2H), 2.04 (p, J = 7.4 Hz, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 166.2, 154.0, 138.7, 131.8, 130.1, 120.4, 33.9, 25.7, 23.9; IR (cm ^-1 ) 2925, 1867, 1826, 1631, 1152, 985; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ BrNO ₃ [M] ⁺ : 282.9844, found: 282.9843.

[제조예 32] 3-{3-(4-Iodophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 32] Preparation of 3-{3-(4-Iodophenyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (350 mg, 78%, 1.5 mmol scale); m.p. 57-59 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 2.69 (t, J = 7.5 Hz, 1H), 2.61 (t, J = 7.5 Hz, 1H), 2.04 (p, J = 7.5 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 166.36, 154.14, 139.55, 137.89, 130.63, 91.83, 34.16, 25.82, 24.09; IR (cm^-1) 2923, 1897, 1828, 1631, 1152, 989, 793, 758, 503; HRMS (EI) m/z calcd. for C₁₁H₁₀INO₃ [M]⁺: 330.9705, found: 330.9707.

White solid (350 mg, 78%, 1.5 mmol scale); mp 57-59℃; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 2.69 (t, J = 7.5 Hz, 1H), 2.61 (t , J = 7.5 Hz, 1H), 2.04 (p, J = 7.5 Hz, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.36, 154.14, 139.55, 137.89, 130.63, 91.83, 34.16, 25.82, 24.09; IR (cm ^-1 ) 2923, 1897, 1828, 1631, 1152, 989, 793, 758, 503; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ INO ₃ [M] ⁺ : 330.9705, found: 330.9707.

[제조예 33] 3-[3-{4-(Trifluoromethyl)phenyl}propyl]-1,4,2-dioxazol-5-one의 제조[Preparation Example 33] Preparation of 3-[3-{4-(Trifluoromethyl)phenyl}propyl]-1,4,2-dioxazol-5-one

무색의 액체 (401 mg, 92 %, 1.6 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 7.57 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.08 (p, J = 7.5 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.36, 154.14, 144.25, 128.89, 128.89 (q, J = 32.2 Hz), 125.63 (q, J = 3.7 Hz), 124.33 (q, J = 271.8 Hz), 34.36, 25.61, 24.03; ¹⁹F NMR (564 MHz, CDCl₃) δ -62.45; IR (cm^-1) 1871, 1827, 1322, 1156, 1108, 1066, 980, 761; HRMS (EI) m/z calcd. for C₁₂H₁₀F₃NO₃ [M]⁺: 273.0613, found: 273.0610.

Colorless liquid (401 mg, 92%, 1.6 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.57 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.64 (t , J = 7.5 Hz, 2H), 2.08 (p, J = 7.5 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.36, 154.14, 144.25, 128.89, 128.89 (q, J = 32.2 Hz), 125.63 (q, J = 3.7 Hz), 124.33 (q, J = 271.8 Hz), 34.36 , 25.61, 24.03; ¹⁹ F NMR (564 MHz, CDCl ₃ ) δ -62.45; IR (cm ^-1 ) 1871, 1827, 1322, 1156, 1108, 1066, 980, 761; HRMS (EI) m/z calcd. for C ₁₂ H ₁₀ F ₃ NO ₃ [M] ⁺ : 273.0613, found: 273.0610.

[제조예 34] 3-{3-(4-nitrophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 34] Preparation of 3-{3-(4-nitrophenyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (1.0 g, 81 %); ¹H NMR (600 MHz, CDCl₃) δ 8.18 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.12 (p, J = 7.5 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 165.9, 153.8, 147.5, 146.9, 129.2, 124.0, 34.4, 25.4, 24.1; IR (cm^-1) 1828, 1536, 1346, 1152, 990, 948; HRMS (EI) m/z calcd. for C₁₁H₁₀N₂O₅ [M]⁺: 250.0590, found: 250.0592.

White solid (1.0 g, 81%); ^1H NMR (600 MHz, CDCl ₃ ) δ 8.18 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.67 (t , J = 7.4 Hz, 2H), 2.12 (p, J = 7.5 Hz, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 165.9, 153.8, 147.5, 146.9, 129.2, 124.0, 34.4, 25.4, 24.1; IR (cm ^-1 ) 1828, 1536, 1346, 1152, 990, 948; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ N ₂ O ₅ [M] ⁺ : 250.0590, found: 250.0592.

[제조예 35] 3-{3-(p-Tolyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 35] Preparation of 3-{3-( p -Tolyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (720 mg, 96 %, 3.4mmol scale); m.p. 42-44 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.33 (s, 3H), 2.04 (p, J = 7.4 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 166.63, 154.25, 136.80, 136.24, 129.47, 128.47, 34.24, 26.11, 24.13, 21.14; IR (cm^-1) 2921, 1898, 1866, 1829, 1630, 1515, 1393, 1153, 990, 802, 750, 530; HRMS (EI) m/z calcd. for C₁₂H₁₃NO₃ [M]⁺: 219.0895, found: 219.0898.

White solid (720 mg, 96%, 3.4mmol scale); mp 42-44℃; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.61 (t , J = 7.5 Hz, 2H), 2.33 (s, 3H), 2.04 (p, J = 7.4 Hz, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.63, 154.25, 136.80, 136.24, 129.47, 128.47, 34.24, 26.11, 24.13, 21.14; IR (cm ^-1 ) 2921, 1898, 1866, 1829, 1630, 1515, 1393, 1153, 990, 802, 750, 530; HRMS (EI) m/z calcd. for C ₁₂ H ₁₃ NO ₃ [M] ⁺ : 219.0895, found: 219.0898.

[제조예 36] 3-[3-{4-(tert-Butyl)phenyl}propyl]-1,4,2-dioxazol-5-one의 제조[Preparation Example 36] Preparation of 3-[3-{4-( tert -Butyl)phenyl}propyl]-1,4,2-dioxazol-5-one

흰색 고체 (237mg, 91 %, 1.0 mmol scale); m.p. 47-49 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.07 (p, J = 7.4 Hz, 2H), 1.32 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 166.64, 154.23, 149.58, 136.78, 128.28, 125.68, 34.55, 34.15, 31.49, 25.97, 24.21; IR (cm^-1) 2957, 2864, 1882, 1867, 1821, 1761, 1653, 1163, 1149, 1000, 752, 543; HRMS (EI) m/z calcd. for C₁₅H₁₉NO₃ [M]⁺: 261.1365, found: 261.1362.

White solid (237 mg, 91%, 1.0 mmol scale); mp 47-49℃; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.63 (t , J = 7.5 Hz, 2H), 2.07 (p, J = 7.4 Hz, 2H), 1.32 (s, 9H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.64, 154.23, 149.58, 136.78, 128.28, 125.68, 34.55, 34.15, 31.49, 25.97, 24.21; IR (cm ^-1 ) 2957, 2864, 1882, 1867, 1821, 1761, 1653, 1163, 1149, 1000, 752, 543; HRMS (EI) m/z calcd. for C ₁₅ H ₁₉ NO ₃ [M] ⁺ : 261.1365, found: 261.1362.

[제조예 37] 3-{3-(3-Bromophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 37] Preparation of 3-{3-(3-Bromophenyl)propyl}-1,4,2-dioxazol-5-one

무색의 액체 (498 mg, 88 %, 2 mmol scale);¹H NMR (599 MHz, CDCl₃) δ 7.36 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.18 (appt, J = 7.8 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 2.71 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.05 (p, J = 7.5 Hz, 2H); IR (cm^-1) 1870, 1823, 1146, 978, 778, 760, 693; HRMS (EI) m/z calcd. for C₁₁H₁₀BrNO₃ [M]⁺: 282.9844, found: 282.9844.

Colorless liquid (498 mg, 88%, 2 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.36 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.18 (appt, J = 7.8 Hz, 1H), 7.11 (d, J = 7.6 Hz) , 1H), 2.71 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.05 (p, J = 7.5 Hz, 2H); IR (cm ^-1 ) 1870, 1823, 1146, 978, 778, 760, 693; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ BrNO ₃ [M] ⁺ : 282.9844, found: 282.9844.

[제조예 38] 3-{3-(3,5-Dimethylphenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 38] Preparation of 3-{3-(3,5-Dimethylphenyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (221 mg, 94 %, 1.0 mmol scale); m.p. 34-36 ℃; ¹H NMR (400 MHz, CDCl₃) δ 6.87 (s, 1H), 6.79 (s, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 166.67, 154.27, 139.82, 138.34, 128.27, 126.42, 34.55, 26.03, 24.23, 21.38; IR (cm^-1) 2919, 1869, 1825, 1635, 1606, 1146, 978, 760, 701; HRMS (EI) m/z calcd. for C₁₃H₁₅NO₃ [M]⁺: 233.1052, found: 233.1049.

White solid (221 mg, 94%, 1.0 mmol scale); mp 34-36℃; ^1H NMR (400 MHz, CDCl ₃ ) δ 6.87 (s, 1H), 6.79 (s, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.67, 154.27, 139.82, 138.34, 128.27, 126.42, 34.55, 26.03, 24.23, 21.38; IR (cm ^-1 ) 2919, 1869, 1825, 1635, 1606, 1146, 978, 760, 701; HRMS (EI) m/z calcd. for C ₁₃ H ₁₅ NO ₃ [M] ⁺ : 233.1052, found: 233.1049.

[제조예 39] 3-{3-(o-Tolyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 39] Preparation of 3-{3-( o -Tolyl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (260 mg, 84 %, 1.4 mmol scale); m.p. 44-46 ℃; ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.05 (m, 4H), 2.74 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.03 (p, J = 7.5 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 166.58, 154.22, 138.15, 136.03, 130.69, 129.06, 126.81, 126.31, 32.14, 24.74, 24.49, 19.38; IR (cm^-1) 2955, 1880, 1818, 1750, 1631, 1160, 986, 757, 456; HRMS (EI) m/z calcd. for C₁₂H₁₃NO₃ [M]⁺: 219.0895, found: 219.0896.

White solid (260 mg, 84%, 1.4 mmol scale); mp 44-46℃; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.21-7.05 (m, 4H), 2.74 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.32 (s, 3H) , 2.03 (p, J = 7.5 Hz, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.58, 154.22, 138.15, 136.03, 130.69, 129.06, 126.81, 126.31, 32.14, 24.74, 24.49, 19.38; IR (cm ^-1 ) 2955, 1880, 1818, 1750, 1631, 1160, 986, 757, 456; HRMS (EI) m/z calcd. for C ₁₂ H ₁₃ NO ₃ [M] ⁺ : 219.0895, found: 219.0896.

[제조예 40] 3-{3-(2-Chlorophenyl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 40] Preparation of 3-{3-(2-Chlorophenyl)propyl}-1,4,2-dioxazol-5-one

황색 오일 (208 mg, 87 %, 1.0 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 7.37 (d, J = 7.6 Hz, 1H), 7.25-7.12 (m, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.72-2.60 (m, 2H), 2.08 (p, J = 7.5, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.46, 154.19, 137.68, 134.10, 130.64, 129.95, 128.26, 127.19, 32.50, 24.47, 24.31; IR (cm^-1) 1870, 1825, 1146, 979, 751; HRMS (EI) m/z calcd. for C₁₁H₁₀ClNO₃ [M]⁺: 239.0349, found: 239.0347.

Yellow oil (208 mg, 87%, 1.0 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.37 (d, J = 7.6 Hz, 1H), 7.25-7.12 (m, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.72-2.60 (m, 2H), 2.08 (p, J = 7.5, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.46, 154.19, 137.68, 134.10, 130.64, 129.95, 128.26, 127.19, 32.50, 24.47, 24.31; IR (cm ^-1 ) 1870, 1825, 1146, 979, 751; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ ClNO ₃ [M] ⁺ : 239.0349, found: 239.0347.

[제조예 41] 3-{3-(Naphthalen-2-yl)propyl}-1,4,2-dioxazol-5-one의 제조[Preparation Example 41] Preparation of 3-{3-(Naphthalen-2-yl)propyl}-1,4,2-dioxazol-5-one

흰색 고체 (157 mg, 96 %, 0.64 mmol scale); m.p. 46-48 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.86-7.77 (m, 3H), 7.63 (s, 1H), 7.52-7.42 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.16 (p, J = 7.4 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.57, 154.22, 137.36, 133.70, 132.41, 128.58, 127.82, 127.60, 126.98, 126.92, 126.40, 125.76, 34.83, 25.91, 24.17; IR (cm^-1) 1870, 1819, 1629, 1155, 1134, 986, 935, 820, 754, 473; HRMS (EI) m/z calcd. for C₁₅H₁₃NO₃ [M]⁺: 255.0895, found: 255.0897.

White solid (157 mg, 96%, 0.64 mmol scale); mp 46-48℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.86-7.77 (m, 3H), 7.63 (s, 1H), 7.52-7.42 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 2.91 ( t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.16 (p, J = 7.4 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.57, 154.22, 137.36, 133.70, 132.41, 128.58, 127.82, 127.60, 126.98, 126.92, 126.40, 125.76, 34.83 , 25.91, 24.17; IR (cm ^-1 ) 1870, 1819, 1629, 1155, 1134, 986, 935, 820, 754, 473; HRMS (EI) m/z calcd. for C ₁₅ H ₁₃ NO ₃ [M] ⁺ : 255.0895, found: 255.0897.

[제조예 42] 3-(4-Cyclohexylbutyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 42] Preparation of 3-(4-Cyclohexylbutyl)-1,4,2-dioxazol-5-one

무색의 액체 (419 mg, 93 %, 2.0 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 2.62 (t, J = 7.6 Hz, 2H), 1.75-1.61 (m, 7H), 1.40 (p, J = 7.9 Hz, 2H), 1.27-1.09 (m, 6H), 0.86 (q, J = 10.4 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.88, 154.36, 37.52, 36.84, 33.43, 26.76, 26.46, 26.14, 24.96, 24.90; IR (cm^-1) 2920, 2849, 1867, 1826, 1636, 1448, 1146, 978, 978, 761; HRMS (FAB) m/z calcd. for C₁₂H₁₉NO₃ [M+H]⁺: 226.1443, found: 226.1444.

Colorless liquid (419 mg, 93%, 2.0 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 2.62 (t, J = 7.6 Hz, 2H), 1.75-1.61 (m, 7H), 1.40 (p, J = 7.9 Hz, 2H), 1.27-1.09 (m, 6H), 0.86 (q, J = 10.4 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.88, 154.36, 37.52, 36.84, 33.43, 26.76, 26.46, 26.14, 24.96, 24.90; IR (cm ^-1 ) 2920, 2849, 1867, 1826, 1636, 1448, 1146, 978, 978, 761; HRMS (FAB) m/z calcd. for C ₁₂ H ₁₉ NO ₃ [M+H] ⁺ : 226.1443, found: 226.1444.

[제조예 43] 3-(5-Phenylpentyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 43] Preparation of 3-(5-Phenylpentyl)-1,4,2-dioxazol-5-one

무색의 액체 (720 mg, 91 %); ¹H NMR (599 MHz, CDCl₃) δ 7.29 (t, J = 7.7 Hz, 1H), 7.23-7.14 (m, 3H), 2.66-2.59 (m, 4H), 1.75 (p, J = 7.6 Hz, 2H), 1.68 (p, J = 7.7 Hz, 2H), 1.45 (p, J = 7.7 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 166.72, 154.30, 142.06, 128.52, 128.48, 126.03, 35.64, 30.81, 28.36, 24.82, 24.52; IR (cm^-1) 2934, 2858, 1862, 1825, 1635, 1149, 980, 747, 698; HRMS (EI) m/z calcd. for C₁₃H₁₅NO₃ [M]⁺: 233.1052, found: 233.1056.

Colorless liquid (720 mg, 91%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.29 (t, J = 7.7 Hz, 1H), 7.23-7.14 (m, 3H), 2.66-2.59 (m, 4H), 1.75 (p, J = 7.6 Hz, 2H), 1.68 (p, J = 7.7 Hz, 2H), 1.45 (p, J = 7.7 Hz, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.72, 154.30, 142.06, 128.52, 128.48, 126.03, 35.64, 30.81, 28.36, 24.82, 24.52; IR (cm ^-1 ) 2934, 2858, 1862, 1825, 1635, 1149, 980, 747, 698; HRMS (EI) m/z calcd. for C ₁₃ H ₁₅ NO ₃ [M] ⁺ : 233.1052, found: 233.1056.

[제조예 44] 2-{5-(5-Oxo-1,4,2-dioxazol-3-yl)pentyl}isoindoline-1,3-dione의 제조[Preparation Example 44] Preparation of 2-{5-(5-Oxo-1,4,2-dioxazol-3-yl)pentyl}isoindoline-1,3-dione

흰색 고체 (670 mg, 95 %, 3.0 mmol scale); m.p. 83-85 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.84 (dd, J = 5.4, 3.0 Hz, 1H), 7.72 (dd, J = 5.4, 3.0 Hz, 1H), 3.70 (t, J = 7.1 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.79 (p, J = 7.4 Hz, 2H), 1.74 (p, J = 7.4 Hz, 2H), 1.51 -1.42 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 168.57, 166.49, 154.27, 134.16, 132.19, 123.42, 37.42, 28.04, 25.93, 24.78, 24.07; IR (cm^-1) 2930, 1892, 1860, 1771, 1714, 1393, 1372, 982, 721, 712; HRMS (EI) m/z calcd. for C₁₅H₁₄N₂O₅ [M]⁺: 302.0903, found: 302.0906.

White solid (670 mg, 95%, 3.0 mmol scale); mp 83-85℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.84 (dd, J = 5.4, 3.0 Hz, 1H), 7.72 (dd, J = 5.4, 3.0 Hz, 1H), 3.70 (t, J = 7.1 Hz, 2H) , 2.63 (t, J = 7.5 Hz, 2H), 1.79 (p, J = 7.4 Hz, 2H), 1.74 (p, J = 7.4 Hz, 2H), 1.51 -1.42 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 168.57, 166.49, 154.27, 134.16, 132.19, 123.42, 37.42, 28.04, 25.93, 24.78, 24.07; IR (cm ^-1 ) 2930, 1892, 1860, 1771, 1714, 1393, 1372, 982, 721, 712; HRMS (EI) m/z calcd. for C ₁₅ H ₁₄ N ₂ O ₅ [M] ⁺ : 302.0903, found: 302.0906.

[제조예 45] 3-(4-Methylpentyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 45] Preparation of 3-(4-Methylpentyl)-1,4,2-dioxazol-5-one

무색의 액체 (630 mg, 89 %, 4.1 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 2.60 (t, J = 7.6 Hz, 2H), 1.72 (p, J = 7.7 Hz, 2H), 1.63-1.55 (m, 1H), 1.32-1.22 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H); ¹³C NMR (151 MHz, CDCl₃) δ 166.85, 154.35, 37.99, 27.71, 25.13, 22.60, 22.44; IR (cm^-1) 2957, 1867, 1827, 1636, 1366, 1148, 980, 761; HRMS (FAB) m/z calcd. for C₈H₁₃NO₃ [M+H]⁺: 172.0974, found: 172.0973.

Colorless liquid (630 mg, 89%, 4.1 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 2.60 (t, J = 7.6 Hz, 2H), 1.72 (p, J = 7.7 Hz, 2H), 1.63-1.55 (m, 1H), 1.32-1.22 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.85, 154.35, 37.99, 27.71, 25.13, 22.60, 22.44; IR (cm ^-1 ) 2957, 1867, 1827, 1636, 1366, 1148, 980, 761; HRMS (FAB) m/z calcd. for C ₈ H ₁₃ NO ₃ [M+H] ⁺ : 172.0974, found: 172.0973.

[제조예 46] 3-(4-Phenylbutyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 46] Preparation of 3-(4-Phenylbutyl)-1,4,2-dioxazol-5-one

무색의 액체 (604 mg, 92 %, 3.0 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 7.30 (appt, J = 7.5 Hz, 2H), 7.21 (appt, J = 7.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 1.81-1.71 (m, 4H); ¹³C NMR (151 MHz, CDCl₃) δ 166.61, 154.26, 141.31, 128.60, 128.45, 126.22, 35.26, 30.46, 24.76, 24.10; IR (cm^-1) 1870, 1825, 1149, 980, 759, 748, 699; HRMS (EI) m/z calcd. for C₁₂H₁₃NO₃ [M]⁺: 219.0895, found: 219.0895.

Colorless liquid (604 mg, 92%, 3.0 mmol scale); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.30 (appt, J = 7.5 Hz, 2H), 7.21 (appt, J = 7.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 2H), 2.67 (t , J = 6.7 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 1.81-1.71 (m, 4H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.61, 154.26, 141.31, 128.60, 128.45, 126.22, 35.26, 30.46, 24.76, 24.10; IR (cm ^-1 ) 1870, 1825, 1149, 980, 759, 748, 699; HRMS (EI) m/z calcd. for C ₁₂ H ₁₃ NO ₃ [M] ⁺ : 219.0895, found: 219.0895.

[제조예 47] 3-[{(3r,5r,7r)-adamantan-1-yl}methyl]-1,4,2-dioxazol-5-one의 제조[Preparation Example 47] Preparation of 3-[{(3r,5r,7r)-adamantan-1-yl}methyl]-1,4,2-dioxazol-5-one

흰색 고체 (1.13 g, 96 %); ¹H NMR (600 MHz, CDCl₃) δ 2.36 (s, 2H), 2.01 (s, 3H), 1.72 (d, J = 12.2 Hz, 3H), 1.65-1.58 (m, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 165.0, 154.3, 42.1, 38.8, 36.3, 33.2, 28.3; IR (cm^-1) 2903, 2885, 2848, 1813, 1152, 985; HRMS (EI) m/z calcd. for C₁₃H₁₇NO₃ [M]⁺: 235.1208, found:235.1206.

White solid (1.13 g, 96%); ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.36 (s, 2H), 2.01 (s, 3H), 1.72 (d, J = 12.2 Hz, 3H), 1.65-1.58 (m, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 165.0, 154.3, 42.1, 38.8, 36.3, 33.2, 28.3; IR (cm ^-1 ) 2903, 2885, 2848, 1813, 1152, 985; HRMS (EI) m/z calcd. for C ₁₃ H ₁₇ NO ₃ [M] ⁺ : 235.1208, found:235.1206.

[제조예 48] 3-Tridecyl-1,4,2-dioxazol-5-one의 제조[Preparation Example 48] Preparation of 3-Tridecyl-1,4,2-dioxazol-5-one

Colorless resin (792 mg, 98 %, 3.0 mmol scale); ¹H NMR (400 MHz, CDCl₃) δ 2.62 (t, J = 7.5 Hz, 2H), 1.72 (p, J = 7.5 Hz, 2H), 1.44-1.36 (m, 2H), 1.33-1.21 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃, one carbon merged to others) δ 166.88, 154.38, 32.06, 29.78, 29.73, 29.65, 29.49, 29.44, 29.07, 28.85, 24.90, 24.67, 22.84, 14.26; IR (cm^-1) 2922, 2853, 1869, 1820, 1146, 979, 762; HRMS (FAB) m/z calcd. for C₁₅H₂₇NO₃ [M+H]⁺: 270.2069, found: 270.2067.

Colorless resin (792 mg, 98 %, 3.0 mmol scale); ^1H NMR (400 MHz, CDCl ₃ ) δ 2.62 (t, J = 7.5 Hz, 2H), 1.72 (p, J = 7.5 Hz, 2H), 1.44-1.36 (m, 2H), 1.33-1.21 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ , one carbon merged to others) δ 166.88, 154.38, 32.06, 29.78, 29.73, 29.65, 29.49, 29.44, 29.07, 28.85, 24.90, 24.67, 22.84, 14.26; IR (cm ^-1 ) 2922, 2853, 1869, 1820, 1146, 979, 762; HRMS (FAB) m/z calcd. for C ₁₅ H ₂₇ NO ₃ [M+H] ⁺ : 270.2069, found: 270.2067.

[제조예 49] (Z)-3-(Heptadec-8-en-1-yl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 49] Preparation of ( Z )-3-(Heptadec-8-en-1-yl)-1,4,2-dioxazol-5-one

무색의 액체 (901 mg, 93 %, 3.0 mmol scale); ¹H NMR (599 MHz, CDCl₃) δ 5.45-5.30 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.06-1.96 (m, 4H), 1.71 (p, J = 7.6 Hz, 2H), 1.44-1.36 (m, 2H), 1.37-1.21 (m, 18H), 0.87 (t, J = 6.9 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃, one carbon merged to others) δ 166.84, 154.35, 130.33, 129.68, 32.05, 29.90, 29.73, 29.66, 29.47, 29.05, 28.98, 28.83, 27.38, 27.23, 24.89, 24.65, 22.82, 14.24; IR (cm^-1) 3004, 2923, 2853, 1870, 1820, 1146, 979, 761; HRMS (EI) m/z calcd. for C₁₉H₃₃NO₃ [M]⁺: 323.2460, found: 323.2458.

Colorless liquid (901 mg, 93%, 3.0 mmol scale); ¹ H NMR (599 MHz, CDCl ₃ ) δ 5.45-5.30 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.06-1.96 (m, 4H), 1.71 (p, J = 7.6 Hz, 2H), 1.44-1.36 (m, 2H), 1.37-1.21 (m, 18H), 0.87 (t, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCl ₃ , one carbon merged to others) δ 166.84, 154.35, 130.33, 129.68, 32.05, 29.90, 29.73, 29.66, 29.47, 29.05, 28.98, 28.83, 27.38 , 27.23, 24.89, 24.65, 22.82 , 14.24; IR (cm ^-1 ) 3004, 2923, 2853, 1870, 1820, 1146, 979, 761; HRMS (EI) m/z calcd. for C ₁₉ H ₃₃ NO ₃ [M] ⁺ : 323.2460, found: 323.2458.

[제조예 50] (E)-3-(Heptadec-8-en-1-yl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 50] Preparation of ( E )-3-(Heptadec-8-en-1-yl)-1,4,2-dioxazol-5-one

Colorless resin (267 mg, 91 %, 0.91 mmol scale); ¹H NMR (400 MHz, CD₂Cl₂) δ 5.47-5.32 (m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.05-1.91 (m, 4H), 1.70 (p, J = 7.4 Hz, 2H), 1.41-1.23 (m, 20H), 0.88 (t, J = 6.8, 3H); ¹³C NMR (101 MHz, CD₂Cl₂, two carbons merged to others) δ 167.60, 154.93, 131.12, 130.68, 33.16, 33.05, 32.48, 30.24, 30.06, 29.90, 29.74, 29.35, 29.22, 25.28, 25.05, 23.26, 14.46; IR (cm^-1) 2922, 2853, 1869, 1820, 1464, 1146, 977, 762; HRMS (EI) m/z calcd. for C₁₉H₃₃NO₃ [M]⁺: 323.2460, found: 323.2463.

Colorless resin (267 mg, 91%, 0.91 mmol scale); ^1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 5.47-5.32 (m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.05-1.91 (m, 4H), 1.70 (p, J = 7.4 Hz, 2H), 1.41-1.23 (m, 20H), 0.88 (t, J = 6.8, 3H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ , two carbons merged to others) δ 167.60, 154.93, 131.12, 130.68, 33.16, 33.05, 32.48, 30.24, 30.06, 29.90, 29.74, 29.35, 29 .22, 25.28, 25.05, 23.26 , 14.46; IR (cm ^-1 ) 2922, 2853, 1869, 1820, 1464, 1146, 977, 762; HRMS (EI) m/z calcd. for C ₁₉ H ₃₃ NO ₃ [M] ⁺ : 323.2460, found: 323.2463.

[제조예 51] 3-(5-phenylpent-4-yn-1-yl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 51] Preparation of 3-(5-phenylpent-4-yn-1-yl)-1,4,2-dioxazol-5-one

무색의 오일 (1.0 g, 88 %); ¹H NMR (400 MHz, CD₂Cl₂) δ 7.42-7.36 (m, 2H), 7.32-7.27 (m, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 6.7 Hz, 2H), 2.02 (p, J = 7.0 Hz, 2H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 166.5, 154.2, 131.4, 128.3, 127.9, 123.3, 87.4, 82.0, 23.8, 23.5, 18.5; IR (cm^-1) 1870, 1823, 1634, 1146, 979, 754, 691; HRMS (EI) m/z calcd. for C₁₃H₁₁NO₃ [M]⁺: 229.0739, found: 229.0741.

Colorless oil (1.0 g, 88%); ^1H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.42-7.36 (m, 2H), 7.32-7.27 (m, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 6.7 Hz, 2H), 2.02 (p, J = 7.0 Hz, 2H); ¹³ C NMR (150 MHz, CD ₂ Cl ₂ ) δ 166.5, 154.2, 131.4, 128.3, 127.9, 123.3, 87.4, 82.0, 23.8, 23.5, 18.5; IR (cm ^-1 ) 1870, 1823, 1634, 1146, 979, 754, 691; HRMS (EI) m/z calcd. for C ₁₃ H ₁₁ NO ₃ [M] ⁺ : 229.0739, found: 229.0741.

[제조예 52] (E)-3-(5-Phenylpent-4-en-1-yl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 52] Preparation of ( E )-3-(5-Phenylpent-4-en-1-yl)-1,4,2-dioxazol-5-one

무색의 오일 (0.36 g, 96 %, 2.6 mmol scale); ¹H NMR (600 MHz, CDCl₃) δ 7.35 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.15 (dt, J = 15.7, 6.9 Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.35 (q, J = 7.0 Hz, 2H), 1.93 (q, J = 7.3 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 166.5, 154.1, 137.0, 132.0, 128.6, 127.7, 127.4, 126.0, 31.8, 24.1, 24.1; IR (cm^-1) 1868, 1824, 1633, 1146, 965, 740; HRMS (EI) m/z calcd. for C₁₃H₁₃NO₃ [M]⁺: 231.0895, found: 231.0896.

Colorless oil (0.36 g, 96%, 2.6 mmol scale); ^1H NMR (600 MHz, CDCl ₃ ) δ 7.35 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 6.45 (d , J = 15.8 Hz, 1H), 6.15 (dt, J = 15.7, 6.9 Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.35 (q, J = 7.0 Hz, 2H), 1.93 (q , J = 7.3 Hz, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 166.5, 154.1, 137.0, 132.0, 128.6, 127.7, 127.4, 126.0, 31.8, 24.1, 24.1; IR (cm ^-1 ) 1868, 1824, 1633, 1146, 965, 740; HRMS (EI) m/z calcd. for C ₁₃ H ₁₃ NO ₃ [M] ⁺ : 231.0895, found: 231.0896.

[제조예 53] 3-(2-Benzyl-3-phenylpropyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 53] Preparation of 3-(2-Benzyl-3-phenylpropyl)-1,4,2-dioxazol-5-one

무색의 오일 (480 mg, 94 %, 1.7 mmol scale); ¹H NMR (400 MHz, CDCl₃) δ 7.36 (appt, J = 7.4 Hz, 4H), 7.29 (d, J = 7.3 Hz, 2H), 7.21 (d, J = 7.7 Hz, 4H), 2.92-2.81 (m, 2H), 2.70-2.62 (m, 2H), 2.61-2.51 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 165.92, 154.01, 138.73, 129.24, 128.80, 126.88, 40.40, 39.00, 28.45; IR (cm^-1) 1872, 1825, 1143, 980, 751, 739,698; HRMS (EI) m/z calcd. for C₁₈H₁₇NO₃ [M]⁺: 295.1208, found: 295.1205.

Colorless oil (480 mg, 94%, 1.7 mmol scale); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.36 (appt, J = 7.4 Hz, 4H), 7.29 (d, J = 7.3 Hz, 2H), 7.21 (d, J = 7.7 Hz, 4H), 2.92-2.81 (m, 2H), 2.70-2.62 (m, 2H), 2.61-2.51 (m, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 165.92, 154.01, 138.73, 129.24, 128.80, 126.88, 40.40, 39.00, 28.45; IR (cm ^-1 ) 1872, 1825, 1143, 980, 751, 739,698; HRMS (EI) m/z calcd. for C ₁₈ H ₁₇ NO ₃ [M] ⁺ : 295.1208, found: 295.1205.

[제조예 54] 3-((2,3-Dihydro-1H-inden-2-yl)methyl)-1,4,2-dioxazol-5-one의 제조[Preparation Example 54] Preparation of 3-((2,3-Dihydro-1 H -inden-2-yl)methyl)-1,4,2-dioxazol-5-one

무색의 오일 (0.43 g, 40 %); ¹H NMR (600 MHz, CDCl₃) δ 7.24-7.19 (m, 2H), 7.19-7.14 (m, 2H), 3.21 (dd, J = 15.6, 7.8 Hz, 2H), 2.91 (hept, J = 7.8, 7.2 Hz, 1H), 2.78 (d, J = 7.4 Hz, 2H), 2.75 (dd, J = 15.6, 6.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 165.9, 154.0, 141.3, 126.8, 124.6, 38.7, 35.5, 30.3; IR (cm^-1) 1878, 1820, 1353, 1143, 990, 744; HRMS (EI) m/z calcd. for C₁₂H₁₁NO₃ [M]⁺: 217.0739, found: 217.0740.

Colorless oil (0.43 g, 40%); ^1H NMR (600 MHz, CDCl ₃ ) δ 7.24-7.19 (m, 2H), 7.19-7.14 (m, 2H), 3.21 (dd, J = 15.6, 7.8 Hz, 2H), 2.91 (hept, J = 7.8) , 7.2 Hz, 1H), 2.78 (d, J = 7.4 Hz, 2H), 2.75 (dd, J = 15.6, 6.4 Hz, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 165.9, 154.0, 141.3, 126.8, 124.6, 38.7, 35.5, 30.3; IR (cm ^-1 ) 1878, 1820, 1353, 1143, 990, 744; HRMS (EI) m/z calcd. for C ₁₂ H ₁₁ NO ₃ [M] ⁺ : 217.0739, found: 217.0740.

[제조예 55] 2-((1-((5-Oxo-1,4,2-dioxazol-3-yl)methyl)cyclohexyl)methyl)isoindoline-1,3-dione의 제조[Preparation Example 55] Preparation of 2-((1-((5-Oxo-1,4,2-dioxazol-3-yl)methyl)cyclohexyl)methyl)isoindoline-1,3-dione

흰색 고체 (0.36 g, 52 %, 2.0 mmol scale); ¹H NMR (400 MHz, CDCl₃) δ 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 3.76 (s, 2H), 2.72 (s, 2H), 1.74-1.63 (m, 2H), 1.52-1.42 (m, 8H); ¹³C NMR (100 MHz, CDCl₃) δ 169.2, 165.2, 154.1, 134.4, 131.8, 123.6, 45.4, 38.7, 33.5, 32.0, 25.4, 21.4; IR (cm^-1) 2922, 1824, 1707, 1390, 984, 711; HRMS (EI) m/z calcd. for C₁₈H₁₈N₂O₅ [M]⁺: 342.1216, found: 342.1212.

White solid (0.36 g, 52%, 2.0 mmol scale); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 3.76 (s, 2H), 2.72 (s, 2H), 1.74-1.63 (m, 2H), 1.52-1.42 (m, 8H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 165.2, 154.1, 134.4, 131.8, 123.6, 45.4, 38.7, 33.5, 32.0, 25.4, 21.4; IR (cm ^-1 ) 2922, 1824, 1707, 1390, 984, 711; HRMS (EI) m/z calcd. for C ₁₈ H ₁₈ N ₂ O ₅ [M] ⁺ : 342.1216, found: 342.1212.

[제조예 56] 2-[[1-{(5-Oxo-1,4,2-dioxazol-3-yl)methyl}cyclopentyl]methyl]isoindoline-1,3-dione의 제조[Preparation Example 56] Preparation of 2-[[1-{(5-Oxo-1,4,2-dioxazol-3-yl)methyl}cyclopentyl]methyl]isoindoline-1,3-dione

흰색 고체 (50 mg, 90 %, 0.17 mmol scale); m.p. 105-107 ℃; ¹H NMR (599 MHz, CD₂Cl₂) δ 7.92-7.81 (m, 2H), 7.79-7.68 (m, 2H), 3.75 (s, 2H), 2.75 (s, 2H), 1.92-1.74 (m, 4H), 1.73-1.65 (m, 2H), 1.61-1.51 (m, 2H); ¹³C NMR (151 MHz, CD₂Cl₂) δ 169.76, 166.15, 154.74, 134.84, 132.47, 123.87, 47.30, 44.96, 36.15, 33.91, 24.61; IR (cm^-1) 1836, 1773, 1708, 1631, 1390, 1341, 1155, 991, 918, 712, 529; HRMS (EI) m/z calcd. for C₁₇H₁₆N₂O₅ [M]⁺: 328.1059, found: 328.1057.

White solid (50 mg, 90%, 0.17 mmol scale); mp 105-107℃; ¹ H NMR (599 MHz, CD ₂ Cl ₂ ) δ 7.92-7.81 (m, 2H), 7.79-7.68 (m, 2H), 3.75 (s, 2H), 2.75 (s, 2H), 1.92-1.74 (m , 4H), 1.73-1.65 (m, 2H), 1.61-1.51 (m, 2H); ¹³ C NMR (151 MHz, CD ₂ Cl ₂ ) δ 169.76, 166.15, 154.74, 134.84, 132.47, 123.87, 47.30, 44.96, 36.15, 33.91, 24.61; IR (cm ^-1 ) 1836, 1773, 1708, 1631, 1390, 1341, 1155, 991, 918, 712, 529; HRMS (EI) m/z calcd. for C ₁₇ H ₁₆ N ₂ O ₅ [M] ⁺ : 328.1059, found: 328.1057.

실시예Example II : II: 프로키랄Prochiral 디옥사졸dioxazole -온 화합물로부터 키랄 감마-락탐 화합물의 제조Preparation of chiral gamma-lactam compounds from -one compounds

[실시예 7] 5-Phenylpyrrolidin-2-one (1)의 제조[Example 7] Preparation of 5-Phenylpyrrolidin-2-one (1)

아르곤 분위기 하에서 금속착체 Ir10 (8.1 mg, 5 mol%), sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate (NaBAr^F ₄, 8.9 mg, 5 mol%) 및 무수 TCE (1,1,2,2-tetrachloroethane) (0.4 mL)를 반응 바이알에 투입하고 교반시켰다. 다른 바이알에 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (0.2 mmol) 및 TCE (0.2 mL)를 가하고, 실온에서 5분간 교반시킨 후, 상기 반응 바이알로 옮기고, 추가로 TCE (0.2 mL × 2)를 사용하여 완전히 옮겼다. 반응혼합물을 35℃에서 24시간동안 격렬하게 교반시킨 후 감압 하에 용매를 제거하고, 플래쉬 크로마토그래피(eluent: n-Hexane/10 % methanol in EtOAc = 4:1)로 정제하여 키랄 락탐 화합물 (1)을 수득하였다.Metal complex Ir10 under argon atmosphere (8.1 mg, 5 mol%), sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate (NaBAr ^F ₄ , 8.9 mg, 5 mol%) and anhydrous TCE (1,1,2,2-tetrachloroethane) ( 0.4 mL) was added to the reaction vial and stirred. Add 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (0.2 mmol) and TCE (0.2 mL) to another vial, stir at room temperature for 5 minutes, transfer to the reaction vial, and add was completely transferred using TCE (0.2 mL × 2). The reaction mixture was stirred vigorously at 35°C for 24 hours, the solvent was removed under reduced pressure, and purified by flash chromatography (eluent: n -Hexane/10 % methanol in EtOAc = 4:1) to obtain chiral lactam compound (1). was obtained.

5-Phenylpyrrolidin-2-one (1)5-Phenylpyrrolidin-2-one (1)

흰색 고체 (31 mg, 96 %); ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.34 (m, 2H), 7.34-7.27 (m, 3H), 6.20 (br, 1H), 4.75 (t, J= 7.1 Hz, 1H), 2.63-2.52 (m, 1H), 2.52-2.35 (m, 2H), 2.04-1.92 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 178.59, 142.59, 129.06, 128.08, 125.77, 58.22, 31.54, 30.41; Specific Rotation[α]_D ²⁵ -58.2±0.2(c1.0, CHCl₃), lit.(J. Org . Chem.,　2008,　73　(17), pp 6657-6665) -51(c0.97, CH₂Cl₂); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 95:5, 1.0 mL/min, 210 nm, t_R1(major) = 9.84 min, t_R2(minor) = 11.58 min, >99:1 er.

White solid (31 mg, 96%); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.34 (m, 2H), 7.34-7.27 (m, 3H), 6.20 (br, 1H), 4.75 (t, J= 7.1 Hz, 1H), 2.63- 2.52 (m, 1H), 2.52-2.35 (m, 2H), 2.04-1.92 (m, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.59, 142.59, 129.06, 128.08, 125.77, 58.22, 31.54, 30.41; Specific Rotation[α] _D ²⁵ -58.2±0.2( c 1.0, CHCl ₃ ), lit.( J. Org . Chem. , 2008, 73 (17), pp 6657-6665) -51( c 0.97, CH ₂ Cl ₂ ); HPLC Analysis. CHIRALPAK IA-3, 32 °C, hexane: i - PrOH = 95:5, 1.0 mL/min, 210 nm, t _R1 (major) = 9.84 min, t _R2 (minor) = 11.58 min, >99:1 er.

출발물질, 반응온도, 촉매 또는 염기를 달리하여 실시예 7과 동일한 방법으로 다양한 구조의 키랄 감마-락탐 화합물을 제조하였으며, 제조된 키랄 감마-락탐 화합물의 합성데이터를 하기에 기재하였다.Chiral gamma-lactam compounds with various structures were prepared in the same manner as in Example 7 by varying the starting materials, reaction temperature, catalyst, or base, and the synthesis data of the prepared chiral gamma-lactam compounds are described below.

[실시예 8] 5-(4-Fluorophenyl)pyrrolidin-2-one (2)의 제조[Example 8] Preparation of 5-(4-Fluorophenyl)pyrrolidin-2-one (2)

흰색 고체 (30 mg, 85 %); ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23(m, 2H), 7.14-7.00 (m, 2H), 6.17 (br, 1H), 4.74 (t, J = 7.1 Hz, 1H), 2.64-2.51 (m, 1H), 2.50-2.36 (m, 1H), 2.01-1.87 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 178.5, 162.5 (d, J = 246.3 Hz), 138.3 (d, J = 3.2 Hz), 127.5 (d, J = 8.1 Hz), 116.0 (d, J = 21.6 Hz), 57.6, 31.7, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ-114.3; Specific Rotation[α]_D ²⁵ -66.2±1.7(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 23.30 min, t_R2(minor) = 36.31 min, 99:1 er.

White solid (30 mg, 85%); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30-7.23 (m, 2H), 7.14-7.00 (m, 2H), 6.17 (br, 1H), 4.74 (t, J = 7.1 Hz, 1H), 2.64- 2.51 (m, 1H), 2.50-2.36 (m, 1H), 2.01-1.87 (m, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.5, 162.5 (d, J = 246.3 Hz), 138.3 (d, J = 3.2 Hz), 127.5 (d, J = 8.1 Hz), 116.0 (d, J = 21.6 Hz), 57.6, 31.7, 30.4; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-114.3; Specific Rotation[α] _D ²⁵ -66.2±1.7(c0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 23.30 min, t _R2 (minor) = 36.31 min, 99:1 er.

[실시예 9] 5-(4-Chlorophenyl)pyrrolidin-2-one (3)의 제조[Example 9] Preparation of 5-(4-Chlorophenyl)pyrrolidin-2-one (3)

흰색 고체 (37 mg, 95 %); ¹H NMR (599 MHz, CDCl₃) δ 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.97 (br, 1H), 4.72 (t, J = 7.2 Hz, 1H), 2.62-2.50 (m, 1H), 2.49-2.33 (m, 2H), 1.95-1.84 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.90, 141.19, 133.69, 129.15, 127.11, 57.65, 31.32, 30.39; Specific Rotation[α]_D ²⁵ -52.6±1.2(c0.5, CHCl₃), lit.(J. Org . Chem.,　2013,　78　(8), pp 3647-3654) +46.0 for the (R) isomer (c0.6, CH₂Cl₂, 97% ee); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 23.12 min, t_R2(major) = 41.61 min, 99:1 er.

White solid (37 mg, 95%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.97 (br, 1H), 4.72 (t, J = 7.2 Hz) , 1H), 2.62-2.50 (m, 1H), 2.49-2.33 (m, 2H), 1.95-1.84 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.90, 141.19, 133.69, 129.15, 127.11, 57.65, 31.32, 30.39; Specific Rotation[α] _D ²⁵ -52.6±1.2( c 0.5, CHCl ₃ ), lit.( J. Org . Chem. , 2013, 78 (8), pp 3647-3654) +46.0 for the ( R ) isomer ( c 0.6, CH ₂ Cl ₂ , 97% ee); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 23.12 min, t _R2 (major) = 41.61 min, 99:1 er.

[실시예 10] 5-(4-Bromophenyl)pyrrolidin-2-one (4)의 제조[Example 10] Preparation of 5-(4-Bromophenyl)pyrrolidin-2-one (4)

흰색 고체 (47 mg, 98 %); ¹H NMR (599 MHz, CDCl₃) δ 7.49 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.31 (br, 1H), 4.72 (t, J= 7.1 Hz, 1H), 2.63-2.52(m, 1H), 2.52-2.36 (m, 2H), 1.99-1.89 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.53, 141.68, 132.21, 127.50, 121.91, 57.67, 31.43, 30.28; Specific Rotation[α]_D ²⁵ -48.5±1.2(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 25.32 min, t_R2(minor) = 48.27 min, 98:2 er.

White solid (47 mg, 98%); ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.49 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.31 (br, 1H), 4.72 (t, J = 7.1 Hz) , 1H), 2.63-2.52(m, 1H), 2.52-2.36 (m, 2H), 1.99-1.89 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.53, 141.68, 132.21, 127.50, 121.91, 57.67, 31.43, 30.28; Specific Rotation[α] _D ²⁵ -48.5±1.2( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 25.32 min, t _R2 (minor) = 48.27 min, 98:2 er.

[실시예 11] 5-(4-Iodophenyl)pyrrolidin-2-one (5)의 제조[Example 11] Preparation of 5-(4-Iodophenyl)pyrrolidin-2-one (5)

흰색 고체 (53 mg, 92 %); m.p. 187-189 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.67 (d, J = 7.9 Hz, 2H), 7.05 (br, 1H), 7.03 (d, J = 7.9 Hz, 2H), 4.68 (t, J = 7.2 Hz, 1H), 2.59-2.49 (m, 1H), 2.47-2.33 (m, 2H), 1.94-1.82 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.94, 142.41, 138.03, 127.68, 93.24, 57.77, 31.23, 30.38; IR (cm^-1) 3022, 3085, 2877, 1709, 1664, 1291, 1254, 1002, 803, 480; HRMS (EI) m/z calcd. C₁0H₁₀INO [M]⁺: 286.9807,found: 286.9809; Specific Rotation[α]_D ²⁵ -33.6±0.9(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i-PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 26.50 min, t_R2(major) =52.36 min, 99:1 er.

White solid (53 mg, 92%); mp 187-189℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.67 (d, J = 7.9 Hz, 2H), 7.05 (br, 1H), 7.03 (d, J = 7.9 Hz, 2H), 4.68 (t, J = 7.2 Hz) , 1H), 2.59-2.49 (m, 1H), 2.47-2.33 (m, 2H), 1.94-1.82 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.94, 142.41, 138.03, 127.68, 93.24, 57.77, 31.23, 30.38; IR (cm ^-1 ) 3022, 3085, 2877, 1709, 1664, 1291, 1254, 1002, 803, 480; HRMS (EI) m/z calcd. C ₁ 0H ₁₀ INO [M] ⁺ : 286.9807,found: 286.9809; Specific Rotation[α] _D ²⁵ -33.6±0.9( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i- PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 26.50 min, t _R2 (major) =52.36 min, 99:1 er.

[실시예 12] 5-{4-(Trifluoromethyl)phenyl}pyrrolidin-2-one (6)의 제조[Example 12] Preparation of 5-{4-(Trifluoromethyl)phenyl}pyrrolidin-2-one (6)

흰색 고체 (38 mg, 83 %); m.p. 139-141 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.63 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.01 (br, 1H), 4.83 (t, J = 7.1 Hz, 1H), 2.67-2.55 (m, 1H), 2.53-2.36 (m, 2H), 1.99-1.91 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.91, 146.75, 130.36 (q, J = 32.4 Hz), 126.11, 126.08 (q, J = 3.7 Hz), 124.10 (q, J = 272.0 Hz), 57.81, 31.27, 30.49; ¹⁹F NMR (564 MHz, CDCl₃) δ -62.61; IR (cm^-1) 3198, 3099, 2946, 2882, 1703, 1119, 1013, 739, 489; HRMS (EI) m/z calcd. for C₁₁H₁₀F₃NO [M]⁺: 229.0714, found: 229.0711; Specific Rotation[α]_D ²⁵ -56.2±0.4(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 12.60 min, t_R2(major) = 26.55 min, 99:1 er.

White solid (38 mg, 83%); mp 139-141℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.63 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.01 (br, 1H), 4.83 (t, J = 7.1 Hz) , 1H), 2.67-2.55 (m, 1H), 2.53-2.36 (m, 2H), 1.99-1.91 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.91, 146.75, 130.36 (q, J = 32.4 Hz), 126.11, 126.08 (q, J = 3.7 Hz), 124.10 (q, J = 272.0 Hz), 57.81, 31.27 , 30.49; ¹⁹ F NMR (564 MHz, CDCl ₃ ) δ -62.61; IR (cm ^-1 ) 3198, 3099, 2946, 2882, 1703, 1119, 1013, 739, 489; HRMS (EI) m/z calcd. for C ₁₁ H ₁₀ F ₃ NO [M] ⁺ : 229.0714, found: 229.0711; Specific Rotation[α] _D ²⁵ -56.2±0.4( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 12.60 min, t _R2 (major) = 26.55 min, 99:1 er.

[실시예 13] 5-(4-Nitrophenyl)pyrrolidin-2-one (7)의 제조[Example 13] Preparation of 5-(4-Nitrophenyl)pyrrolidin-2-one (7)

반응온도 50 ℃, 촉매 Ir10 (10 mol%) 및 NaBAr^F ₄ (10 mol%)를 사용; 흰색 고체 (21 mg, 51 %); ¹H NMR (599 MHz, CDCl₃) δ 8.25 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 6.02 (s, 1H), 4.87 (t, J = 7.2 Hz, 1H), 2.71-2.61 (m, 1H), 2.57-2.40 (m, 1H), 2.01-1.91 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.74, 150.01, 147.79, 126.58, 124.42, 57.58, 31.20, 30.17; Specific Rotation[α]_D ²⁵ -38.3±0.3(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 254 nm, t_R1(minor) = 13.45 min, t_R2(major) = 22.5 min, 91:9 er.

Reaction temperature was 50°C, catalysts Ir10 (10 mol%) and NaBAr ^F ₄ (10 mol%) were used; White solid (21 mg, 51%); ^1H NMR (599 MHz, CDCl ₃ ) δ 8.25 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 6.02 (s, 1H), 4.87 (t, J = 7.2 Hz) , 1H), 2.71-2.61 (m, 1H), 2.57-2.40 (m, 1H), 2.01-1.91 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.74, 150.01, 147.79, 126.58, 124.42, 57.58, 31.20, 30.17; Specific Rotation[α] _D ²⁵ -38.3±0.3( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 254 nm, t _R1 (minor) = 13.45 min, t _R2 (major) = 22.5 min, 91:9 er.

[실시예 14] 5-(p-Tolyl)pyrrolidin-2-one (8)의 제조[Example 14] Preparation of 5-( p -Tolyl)pyrrolidin-2-one (8)

흰색 고체 (28 mg, 80 %); ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.09 (m, 4H), 6.27 (br, 1H), 4.71 (t, J = 7.1 Hz, 1H), 2.63-2.49 (m, 1H), 2.49-2.38 (m, 2H), 2.34 (s, 3H), 2.03-1.87 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 178.60, 139.58, 137.81, 129.67, 125.72, 58.03, 31.58, 30.51, 21.18; Specific Rotation[α]_D ²⁵ -43.0±0.2(c1.30, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 95:5, 1.0 mL/min, 210 nm, t_R1(major) = 10.25 min, t_R2(minor) =12.18 min, 97:3 er.

White solid (28 mg, 80%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.09 (m, 4H), 6.27 (br, 1H), 4.71 (t, J = 7.1 Hz, 1H), 2.63-2.49 (m, 1H), 2.49- 2.38 (m, 2H), 2.34 (s, 3H), 2.03-1.87 (m, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.60, 139.58, 137.81, 129.67, 125.72, 58.03, 31.58, 30.51, 21.18; Specific Rotation[α] _D ²⁵ -43.0±0.2( c 1.30, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 95:5, 1.0 mL/min, 210 nm, t _R1 (major) = 10.25 min, t _R2 (minor) = 12.18 min, 97:3 er.

[실시예 15] 5-{4-(tert-Butyl)phenyl}pyrrolidin-2-one (9)의 제조[Example 15] Preparation of 5-{4-( tert -Butyl)phenyl}pyrrolidin-2-one (9)

흰색 고체 (42 mg, 97 %); ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.69 (br, 1H), 4.72 (t, J = 7.1 Hz, 1H), 2.59-2.46 (m, 1H), 2.46-2.32 (m, 2H), 2.04-1.91 (m, 1H), 1.31 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 178.79, 150.95, 139.52, 125.85, 125.48, 57.96, 34.62, 31.40, 30.56; Specific Rotation[α]_D ²⁵ -43.8±0.1(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 14.27 min, t_R2(major) = 35.97 min, 99:1 er.

White solid (42 mg, 97%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.38 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.69 (br, 1H), 4.72 (t, J = 7.1 Hz) , 1H), 2.59-2.46 (m, 1H), 2.46-2.32 (m, 2H), 2.04-1.91 (m, 1H), 1.31 (s, 9H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.79, 150.95, 139.52, 125.85, 125.48, 57.96, 34.62, 31.40, 30.56; Specific Rotation[α] _D ²⁵ -43.8±0.1( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 14.27 min, t _R2 (major) = 35.97 min, 99:1 er.

[실시예 16] 5-(3-Bromophenyl)pyrrolidin-2-one (10)의 제조[Example 16] Preparation of 5-(3-Bromophenyl)pyrrolidin-2-one (10)

흰색 고체 (45 mg, 94 %); m.p. 165-167 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.51-7.39 (m, 2H), 7.21-7.19 (m, 2H), 6.40 (br, 1H), 4.83-4.65 (m, 1H), 2.66-2.54 (m, 1H), 2.54-2.36 (m, 2H), 2.02-1.89 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.64, 145.07, 131.20, 130.69, 128.97, 124.41, 123.19, 57.66, 31.37, 29.82; IR (cm^-1) 3178, 3086, 1682, 1650, 1262, 786, 764, 694, 486, 432; HRMS (EI) m/z calcd. for C₁₀H₁₀BrNO [M]⁺: 238.9946, found: 238.9941; Specific Rotation[α]_D ²⁵ -43.9±1.4(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i-PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 21.97 min, t_R2(major) = 36.78 min, 99:1 er.

White solid (45 mg, 94%); mp 165-167℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.51-7.39 (m, 2H), 7.21-7.19 (m, 2H), 6.40 (br, 1H), 4.83-4.65 (m, 1H), 2.66-2.54 (m , 1H), 2.54-2.36 (m, 2H), 2.02-1.89 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.64, 145.07, 131.20, 130.69, 128.97, 124.41, 123.19, 57.66, 31.37, 29.82; IR (cm ^-1 ) 3178, 3086, 1682, 1650, 1262, 786, 764, 694, 486, 432; HRMS (EI) m/z calcd. for C ₁₀ H ₁₀ BrNO [M] ⁺ : 238.9946, found: 238.9941; Specific Rotation[α] _D ²⁵ -43.9±1.4( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i- PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 21.97 min, t _R2 (major) = 36.78 min, 99:1 er.

[실시예 17] 5-(3,5-Dimethylphenyl)pyrrolidin-2-one (11)의 제조[Example 17] Preparation of 5-(3,5-Dimethylphenyl)pyrrolidin-2-one (11)

흰색 고체 (31 mg, 82 %); m.p. 177-179 ℃; ¹H NMR (599 MHz, CDCl₃) δ 6.93 (s, 1H), 6.90 (s, 2H), 6.10 (br, 1H), 4.67 (t, J = 7.1 Hz, 1H), 2.59-2.51 (m, 1H), 2.51-2.44 (m, 1H), 2.44-2.36 (m, 1H), 2.31 (s, 6H) 2.00-1.91 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.5, 142.6, 138.7, 129.6, 123.5, 58.1, 31.5, 30.4, 21.4; IR (cm^-1) 3167, 2945, 2885, 1685, 1656, 1334, 1261, 852, 791, 702, 485; HRMS (EI) m/z calcd. for C₁₂H₁₅NO [M]⁺: 189.1154, found: 189.1155; Specific Rotation[α]_D ²⁵ -48.0(c1.0, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 95:5, 0.5 mL/min, 210 nm, t_R1(major) = 12.69 min, t_R2(minor) = 13.73 min, 99:1 er.

White solid (31 mg, 82%); mp 177-179℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 6.93 (s, 1H), 6.90 (s, 2H), 6.10 (br, 1H), 4.67 (t, J = 7.1 Hz, 1H), 2.59-2.51 (m, 1H), 2.51-2.44 (m, 1H), 2.44-2.36 (m, 1H), 2.31 (s, 6H) 2.00-1.91 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.5, 142.6, 138.7, 129.6, 123.5, 58.1, 31.5, 30.4, 21.4; IR (cm ^-1 ) 3167, 2945, 2885, 1685, 1656, 1334, 1261, 852, 791, 702, 485; HRMS (EI) m/z calcd. for C ₁₂ H ₁₅ NO [M] ⁺ : 189.1154, found: 189.1155; Specific Rotation[α] _D ²⁵ -48.0( c 1.0, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 °C, hexane: i - PrOH = 95:5, 0.5 mL/min, 210 nm, t _R1 (major) = 12.69 min, t _R2 (minor) = 13.73 min, 99:1 er.

[실시예 18] 5-(o-Tolyl)pyrrolidin-2-one (12)의 제조[Example 18] Preparation of 5-( o -Tolyl)pyrrolidin-2-one (12)

반응온도 50 ℃, 촉매 Ir10 (10 mol%) 및 NaBAr^F ₄ (10 mol%)를 사용; 흰색 고체 (31 mg, 47 %); m.p. 93-95 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.34 (d, J = 7.6 Hz, 1H), 7.23 (appt, J = 7.2 Hz, 1H), 7.21-7.14 (m, 2H), 6.21 (br, 1H), 4.99 (t, J = 6.8 Hz, 1H), 2.68-2.57 (m, 1H), 2.49-2.36 (m, 2H), 2.34 (s, 3H), 1.91-1.84 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.74, 140.60, 134.57, 130.92, 127.63, 126.75, 124.13, 54.69, 29.99, 29.72, 19.10; IR (cm^-1) 3428, 3181, 1660, 1347, 1085, 791, 751, 448; HRMS (EI) m/z calcd. for C₁₁H₁₃NO [M]⁺: 175.0997, found: 175.0996; Specific Rotation[α]_D ²⁵ -72.4±2.4(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 5.01 min, t_R2(minor) = 5.83 min, 85:5 er.

Reaction temperature was 50°C, catalysts Ir10 (10 mol%) and NaBAr ^F ₄ (10 mol%) were used; White solid (31 mg, 47%); mp 93-95℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.34 (d, J = 7.6 Hz, 1H), 7.23 (appt, J = 7.2 Hz, 1H), 7.21-7.14 (m, 2H), 6.21 (br, 1H) , 4.99 (t, J = 6.8 Hz, 1H), 2.68-2.57 (m, 1H), 2.49-2.36 (m, 2H), 2.34 (s, 3H), 1.91-1.84 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.74, 140.60, 134.57, 130.92, 127.63, 126.75, 124.13, 54.69, 29.99, 29.72, 19.10; IR (cm ^-1 ) 3428, 3181, 1660, 1347, 1085, 791, 751, 448; HRMS (EI) m/z calcd. for C ₁₁ H ₁₃ NO [M] ⁺ : 175.0997, found: 175.0996; Specific Rotation[α] _D ²⁵ -72.4±2.4( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 5.01 min, t _R2 (minor) = 5.83 min, 85:5 er.

[실시예 19] 5-(2-Chlorophenyl)pyrrolidin-2-one (13)의 제조[Example 19] Preparation of 5-(2-Chlorophenyl)pyrrolidin-2-one (13)

반응온도 50 ℃, 촉매 Ir10 (10 mol%) 및 NaBAr^F ₄ (10 mol%)를 사용; 흰색 고체 (16 mg, 41 %); m.p. 99-101 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.39 (appt, J = 7.7 Hz, 2H), 7.30 (appt, J = 7.5 Hz, 1H), 7.28-7.21 (m, 1H), 6.13 (br, 1H), 5.21-5.13 (m, 1H), 2.77-2.68 (m, 1H), 2.50-2.35 (m, 2H), 2.01-1.89 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 178.78, 139.98, 132.43, 130.13, 129.04, 127.52, 125.90, 54.83, 29.74, 29.27; HRMS(EI) m/z calcd. for C₁₀H₁₀ClNO [M]⁺: 195.0451, found: 195.04514; Specific Rotation[α]_D ²⁵ -37.4±2.0(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 5.01 min, t_R2(minor) = 5.83 min, 80:20 er.

Reaction temperature was 50°C, catalysts Ir10 (10 mol%) and NaBAr ^F ₄ (10 mol%) were used; White solid (16 mg, 41%); mp 99-101℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.39 (appt, J = 7.7 Hz, 2H), 7.30 (appt, J = 7.5 Hz, 1H), 7.28-7.21 (m, 1H), 6.13 (br, 1H) , 5.21-5.13 (m, 1H), 2.77-2.68 (m, 1H), 2.50-2.35 (m, 2H), 2.01-1.89 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.78, 139.98, 132.43, 130.13, 129.04, 127.52, 125.90, 54.83, 29.74, 29.27; HRMS(EI) m/z calcd. for C ₁₀ H ₁₀ ClNO [M] ⁺ : 195.0451, found: 195.04514; Specific Rotation[α] _D ²⁵ -37.4±2.0( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 5.01 min, t _R2 (minor) = 5.83 min, 80:20 er.

[실시예 20] 5-(Naphthalen-2-yl)pyrrolidin-2-one (14)의 제조[Example 20] Preparation of 5-(Naphthalen-2-yl)pyrrolidin-2-one (14)

흰색 고체 (32 mg, 76 %); ¹H NMR (599 MHz, CDCl₃) δ 7.89-7.80 (m, 3H), 7.73 (s, 1H), 7.53-7.45 (m, 2H), 7.40 (dd, J = 8.5, 1.8 Hz, 1H), 6.51 (br, 1H), 4.90 (t, J = 7.1 Hz, 1H), 2.71-2.57 (m, 1H), 2.55-2.39 (m, 2H), 2.12-1.98 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.74, 139.93, 133.39, 133.14, 129.10, 127.95, 127.83, 126.65, 126.27, 124.42, 123.72, 58.28, 31.24, 30.35; Specific Rotation[α]_D ²⁵ -28.5±1.8(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 7.48 min, t_R2(major) =64.16 min, 93:7 er.

White solid (32 mg, 76%); ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.89-7.80 (m, 3H), 7.73 (s, 1H), 7.53-7.45 (m, 2H), 7.40 (dd, J = 8.5, 1.8 Hz, 1H), 6.51 (br, 1H), 4.90 (t, J = 7.1 Hz, 1H), 2.71-2.57 (m, 1H), 2.55-2.39 (m, 2H), 2.12-1.98 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.74, 139.93, 133.39, 133.14, 129.10, 127.95, 127.83, 126.65, 126.27, 124.42, 123.72, 58.28, 31.24, 30.35; Specific Rotation[α] _D ²⁵ -28.5±1.8( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 7.48 min, t _R2 (major) =64.16 min, 93:7 er.

[실시예 21] 5-(Cyclohexylmethyl)pyrrolidin-2-one (15)의 제조[Example 21] Preparation of 5-(Cyclohexylmethyl)pyrrolidin-2-one (15)

흰색 고체 (22 mg, 61 %); m.p. 97-99 ℃; ¹H NMR (599 MHz, CDCl₃) δ 6.14 (br, 1H), 3.73 (p, J = 6.7 Hz, 1H), 2.39-2.19 (m, 3H), 1.74-1.61 (m, 6H), 1.46-1.40 (m, 1H), 1.36-1.10 (m, 5H), 0.96-0.86 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 178.21, 52.15, 44.68, 34.98, 33.73, 33.31, 30.27, 28.04, 26.52, 26.28, 26.25; IR (cm^-1) 3348, 3174, 3089, 2973, 2849, 1686, 1461, 1288, 797, 652, 523; HRMS (EI) m/z calcd. for C₁₁H₁₉NO [M]⁺: 181.1467, found: 181.1464; Specific Rotation[α]_D ²⁵ +10.7±1.1(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 85:15, 1.0 mL/min, 210 nm, t_R1(minor) = 16.56 min, t_R2(major) = 30.02 min, 96:4 er.

White solid (22 mg, 61%); mp 97-99℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 6.14 (br, 1H), 3.73 (p, J = 6.7 Hz, 1H), 2.39-2.19 (m, 3H), 1.74-1.61 (m, 6H), 1.46- 1.40 (m, 1H), 1.36-1.10 (m, 5H), 0.96-0.86 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.21, 52.15, 44.68, 34.98, 33.73, 33.31, 30.27, 28.04, 26.52, 26.28, 26.25; IR (cm ^-1 ) 3348, 3174, 3089, 2973, 2849, 1686, 1461, 1288, 797, 652, 523; HRMS (EI) m/z calcd. for C ₁₁ H ₁₉ NO [M] ⁺ : 181.1467, found: 181.1464; Specific Rotation[α] _D ²⁵ +10.7±1.1( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 85:15, 1.0 mL/min, 210 nm, t _R1 (minor) = 16.56 min, t _R2 (major) = 30.02 min, 96:4 er.

[실시예 22] 5-Phenethylpyrrolidin-2-one (16)의 제조[Example 22] Preparation of 5-Phenethylpyrrolidin-2-one (16)

흰색 고체 (28 mg, 73 %); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (appt, J = 7.3 Hz, 2H), 7.23-7.11 (m, 3H), 6.84 (br, 1H), 3.86-3.54 (m, 1H), 2.67 (t, J = 7.6 Hz, 2H), 2.40-2.22 (m, 3H), 1.94-1.70 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 178.65, 141.10, 128.69, 128.45, 126.29, 54.17, 38.57, 32.47, 30.64, 27.46; Specific Rotation[α]_D ²⁵ +20.5±1.2(c1.0, CHCl₃), lit.(J. Am. Chem. Soc .,　2013,　135　(18), pp 6814-6817) -22.2 for the (S) isomer (c1.35, CHCl₃, 82% ee); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 95:5, 0.5 mL/min, 210 nm, t_R1(major) = 18.59 min, t_R2(minor) = 21.32 min, 95:5 er.

White solid (28 mg, 73%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.29 (appt, J = 7.3 Hz, 2H), 7.23-7.11 (m, 3H), 6.84 (br, 1H), 3.86-3.54 (m, 1H), 2.67 ( t, J = 7.6 Hz, 2H), 2.40-2.22 (m, 3H), 1.94-1.70 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.65, 141.10, 128.69, 128.45, 126.29, 54.17, 38.57, 32.47, 30.64, 27.46; Specific Rotation[α] _D ²⁵ +20.5±1.2( c 1.0, CHCl ₃ ), lit.( J. Am. Chem. Soc . , 2013, 135 (18), pp 6814-6817) -22.2 for the ( S ) isomer ( c 1.35, CHCl ₃ , 82% ee); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 95:5, 0.5 mL/min, 210 nm, t _R1 (major) = 18.59 min, t _R2 (minor) = 21.32 min, 95:5 er.

[실시예 23] 2-{2-(5-Oxopyrrolidin-2-yl)ethyl}isoindoline-1,3-dione (17)의 제조[Example 23] Preparation of 2-{2-(5-Oxopyrrolidin-2-yl)ethyl}isoindoline-1,3-dione (17)

촉매 Ir10 (10 mol%)를 사용; 흰색 고체 (39 mg, 75 %); m.p. 119-121 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.86-7.81 (m, 2H), 7.74-7.70 (m, 2H), 6.58 (br, 1H), 3.82-3.70 (m, 2H), 3.58 (p, J = 5.7 Hz, 1H), 2.42-2.34 (m, 1H), 2.34-2.24 (m, 2H), 1.93-1.85 (m, 1H), 1.85-1.70 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 178.09, 168.56, 134.30, 132.00, 123.53, 51.54, 35.66, 34.81, 29.88, 27.12; IR (cm^-1) 3197, 3090, 2919, 2851, 1707, 1685, 1438, 1257, 1071, 797, 721; HRMS (EI) m/z calcd. for C₁₄H₁₄N₂O₃ [M]⁺: 258.1004, found: 258.1006; Specific Rotation[α]_D ²⁵ +71.4±0.4(c0.5, CHCl₃); HPLC Analysis. CHIRALCEL OJ-H, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 42.21 min, t_R2(major) = 46.83 min, 97:3 er.

using catalyst Ir10 (10 mol%); White solid (39 mg, 75%); mp 119-121℃; ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.86-7.81 (m, 2H), 7.74-7.70 (m, 2H), 6.58 (br, 1H), 3.82-3.70 (m, 2H), 3.58 (p, J = 5.7 Hz, 1H), 2.42-2.34 (m, 1H), 2.34-2.24 (m, 2H), 1.93-1.85 (m, 1H), 1.85-1.70 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.09, 168.56, 134.30, 132.00, 123.53, 51.54, 35.66, 34.81, 29.88, 27.12; IR (cm ^-1 ) 3197, 3090, 2919, 2851, 1707, 1685, 1438, 1257, 1071, 797, 721; HRMS (EI) m/z calcd. for C ₁₄ H ₁₄ N ₂ O ₃ [M] ⁺ : 258.1004, found: 258.1006; Specific Rotation[α] _D ²⁵ +71.4±0.4( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALCEL OJ-H, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 42.21 min, t _R2 (major) = 46.83 min, 97:3 er.

[실시예 24] 5-Benzylpyrrolidin-2-one (18)의 제조[Example 24] Preparation of 5-Benzylpyrrolidin-2-one (18)

촉매 Ir10 (10 mol%)를 사용; Cololess resin (30 mg, 86 %); ¹H NMR (599 MHz, CDCl₃) δ 7.31 (t, J = 7.5 Hz, 2H), 7.24 (appt, J = 7.4 Hz, 1H), 7.17 (d, J = 7.3 Hz, 2H), 6.02 (br, 1H), 3.88 (p, J = 6.5 Hz, 1H), 2.83 (dd, J = 13.4, 5.7 Hz, 1H), 2.73 (dd, J = 13.5, 8.0 Hz, 1H), 2.36-2.27 (m, 2H), 2.29-2.20 (m, 1H), 1.89-1.79 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 177.99, 137.63, 129.13, 128.90, 126.96, 55.79, 43.11, 30.19, 27.03; IR (cm^-1) 3219, 2925, 1681, 1603, 1261, 699; HRMS (EI) m/z calcd. for C₁₁H₁₃NO [M]⁺: 175.0997, found: 175.0999; Specific Rotation[α]_D ²⁵ +60.9±0.6(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 36.14 min, t_R2(major) = 44.16 min, 96:4 er.

using catalyst Ir10 (10 mol%); Colorless resin (30 mg, 86%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.31 (t, J = 7.5 Hz, 2H), 7.24 (appt, J = 7.4 Hz, 1H), 7.17 (d, J = 7.3 Hz, 2H), 6.02 (br , 1H), 3.88 (p, J = 6.5 Hz, 1H), 2.83 (dd, J = 13.4, 5.7 Hz, 1H), 2.73 (dd, J = 13.5, 8.0 Hz, 1H), 2.36-2.27 (m, 2H), 2.29-2.20 (m, 1H), 1.89-1.79 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 177.99, 137.63, 129.13, 128.90, 126.96, 55.79, 43.11, 30.19, 27.03; IR (cm ^-1 ) 3219, 2925, 1681, 1603, 1261, 699; HRMS (EI) m/z calcd. for C ₁₁ H ₁₃ NO [M] ⁺ : 175.0997, found: 175.0999; Specific Rotation[α] _D ²⁵ +60.9±0.6( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 36.14 min, t _R2 (major) = 44.16 min, 96:4 er.

[실시예 25] 5-Isopropylpyrrolidin-2-one (19)의 제조[Example 25] Preparation of 5-Isopropylpyrrolidin-2-one (19)

촉매 Ir10 (10 mol%)를 사용; 흰색 고체 (20 mg, 79 %); ¹H NMR (599 MHz, CDCl₃) δ 6.38 (br, 1H), 3.38 (q, J = 6.9 Hz, 1H), 2.37-2.26 (m, 2H), 2.22-2.13 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.58 (m, 1H), 0.94 (d, J =6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 178.61, 60.66, 33.65, 30.66, 24.86, 18.90, 18.20; Specific Rotation[α]_D ²⁵ -11.7±0.8(c0.5, CHCl₃) lit.(Org . Lett .,　2007,　9　(6), pp 1001-1004) -16.5 (c2.0, CH₂Cl₂); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 85:15, 1.0 mL/min, 210 nm, t_R1(minor) = 12.17 min, t_R2(major) = 15.94 min, 97:3 er.

using catalyst Ir10 (10 mol%); White solid (20 mg, 79%); ^1H NMR (599 MHz, CDCl ₃ ) δ 6.38 (br, 1H), 3.38 (q, J = 6.9 Hz, 1H), 2.37-2.26 (m, 2H), 2.22-2.13 (m, 1H), 1.81- 1.72 (m, 1H), 1.69-1.58 (m, 1H), 0.94 (d, J =6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.61, 60.66, 33.65, 30.66, 24.86, 18.90, 18.20; Specific Rotation[α] _D ²⁵ -11.7±0.8 ( c 0.5, CHCl ₃ ) lit. ( Org . Lett . , 2007, 9 (6), pp 1001-1004) -16.5 ( c 2.0, CH ₂ Cl ₂ ); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 85:15, 1.0 mL/min, 210 nm, t _R1 (minor) = 12.17 min, t _R2 (major) = 15.94 min, 97:3 er.

[실시예 26] Octahydro-3a,7:5,9-dimethanocycloocta[b]pyrrol-2(3H)-one (20)의 제조[Example 26] Preparation of Octahydro-3a,7:5,9-dimethanocycloocta[b]pyrrol-2( 3H )-one (20)

흰색 고체 (20 mg, 52 %); ¹H NMR (599 MHz, CDCl₃) δ 6.21 (br, 1H), 3.45(s, 1H), 2.10-1.98 (m, 3H), 1.92-1.76 (m, 6H), 1.75-1.67 (m, 3H), 1.65 (d, J = 12.0 Hz, 1H), 1.58 (d, J = 12.8 Hz, 1H), 1.39 (d, J = 11.9 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 179.38, 64.17, 46.44, 40.15, 38.69, 37.28, 37.17, 37.06, 36.86, 29.61, 29.09, 27.46; Specific Rotation[α]_D ²⁵ +4.1±0.4(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 5.17 min, t_R2(minor) = 5.86 min, 83:17 er.

White solid (20 mg, 52%); ¹ H NMR (599 MHz, CDCl ₃ ) δ 6.21 (br, 1H), 3.45 (s, 1H), 2.10-1.98 (m, 3H), 1.92-1.76 (m, 6H), 1.75-1.67 (m, 3H) ), 1.65 (d, J = 12.0 Hz, 1H), 1.58 (d, J = 12.8 Hz, 1H), 1.39 (d, J = 11.9 Hz, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 179.38, 64.17, 46.44, 40.15, 38.69, 37.28, 37.17, 37.06, 36.86, 29.61, 29.09, 27.46; Specific Rotation[α] _D ²⁵ +4.1±0.4( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 5.17 min, t _R2 (minor) = 5.86 min, 83:17 er.

[실시예 27] 5-Decylpyrrolidin-2-one (21)의 제조[Example 27] Preparation of 5-Decylpyrrolidin-2-one (21)

흰색 고체 (28 mg, 62 %); m.p. 65-67 ℃; ¹H NMR (599 MHz, CDCl₃) δ 6.20 (br, 1H), 3.62 (p, J = 6.6 Hz, 1H), 2.39-2.27 (m, 2H), 2.27-2.19 (m, 1H), 1.74-1.66 (m, 1H), 1.56-1.48 (m, 1H), 1.49-1.40 (m, 1H), 1.32-1.21 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃, one carbon merged to others) δ 178.43, 54.80, 36.89, 32.01, 30.51, 29.68, 29.66, 29.61, 29.42, 27.44, 25.97, 22.78, 14.21; IR (cm^-1) 3176, 3089, 2955, 2916, 2850, 1704, 1654, 1469, 798, 455; HRMS(EI) m/z calcd. for C₁₄H₂₇NO [M]⁺: 225.2093, found: 225.2094; Specific Rotation[α]_D ²⁵ -6.9±0.3(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 5.68 min, t_R2(minor) = 6.68 min, 94:6 er.

White solid (28 mg, 62%); mp 65-67℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 6.20 (br, 1H), 3.62 (p, J = 6.6 Hz, 1H), 2.39-2.27 (m, 2H), 2.27-2.19 (m, 1H), 1.74- 1.66 (m, 1H), 1.56-1.48 (m, 1H), 1.49-1.40 (m, 1H), 1.32-1.21 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCl ₃ , one carbon merged to others) δ 178.43, 54.80, 36.89, 32.01, 30.51, 29.68, 29.66, 29.61, 29.42, 27.44, 25.97, 22.78, 14.21; IR (cm ^-1 ) 3176, 3089, 2955, 2916, 2850, 1704, 1654, 1469, 798, 455; HRMS(EI) m/z calcd. for C ₁₄ H ₂₇ NO [M] ⁺ : 225.2093, found: 225.2094; Specific Rotation[α] _D ²⁵ -6.9±0.3( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 5.68 min, t _R2 (minor) = 6.68 min, 94:6 er.

[실시예 28] (Z)-5-(Tetradec-5-en-1-yl)pyrrolidin-2-one (22)의 제조[Example 28] Preparation of ( Z )-5-(Tetradec-5-en-1-yl)pyrrolidin-2-one (22)

반응온도 50 ℃, 촉매 Ir10 (10 mol%)를 사용; 무색의 액체 (39 mg, 70 %); ¹H NMR (599 MHz, CDCl₃) δ 6.59 (br, 1H), 5.39-5.27 (m, 2H), 3.61 (p, J = 6.6 Hz, 1H), 2.41-2.27 (m, 2H), 2.27-2.18 (m, 1H), 2.08-1.94 (m, 4H), 1.73-1.63 (m, 1H), 1.59-1.48 (m, 1H), 1.49-1.40 (m, 1H), 1.35-1.22(m, 16H), 0.86 (t, J = 6.9 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 178.41, 130.53, 129.29, 54.72, 36.76, 32.01, 30.38, 29.85, 29.67, 29.63, 29.44, 29.42, 27.40, 27.36, 27.10, 25.56, 22.78, 14.21; IR (cm^-1) 3198, 3003, 2921, 2852, 1693, 1460, 722; HRMS (EI) m/z calcd. for C₁₈H₃₃NO [M]⁺: 279.2562, found: 279.2561; Specific Rotation[α]_D ²⁵ +6.1±0.3(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 95:5, 1.0 mL/min, 216 nm, t_R1(major) = 4.17 min, t_R2(minor) = 4.63 min, 95:5 er.

Reaction temperature: 50°C, catalyst Ir10 (10 mol%) used; Colorless liquid (39 mg, 70%); ^1H NMR (599 MHz, CDCl ₃ ) δ 6.59 (br, 1H), 5.39-5.27 (m, 2H), 3.61 (p, J = 6.6 Hz, 1H), 2.41-2.27 (m, 2H), 2.27- 2.18 (m, 1H), 2.08-1.94 (m, 4H), 1.73-1.63 (m, 1H), 1.59-1.48 (m, 1H), 1.49-1.40 (m, 1H), 1.35-1.22(m, 16H) ), 0.86 (t, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.41, 130.53, 129.29, 54.72, 36.76, 32.01, 30.38, 29.85, 29.67, 29.63, 29.44, 29.42, 27.40, 27.36, 27.10, 25.56, 22.78, 14.21; IR (cm ^-1 ) 3198, 3003, 2921, 2852, 1693, 1460, 722; HRMS (EI) m/z calcd. for C ₁₈ H ₃₃ NO [M] ⁺ : 279.2562, found: 279.2561; Specific Rotation[α] _D ²⁵ +6.1±0.3( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 95:5, 1.0 mL/min, 216 nm, t _R1 (major) = 4.17 min, t _R2 (minor) = 4.63 min, 95:5 er.

[실시예 29] (E)-5-(Tetradec-5-en-1-yl)pyrrolidin-2-one (23)의 제조[Example 29] Preparation of ( E )-5-(Tetradec-5-en-1-yl)pyrrolidin-2-one (23)

반응온도 50 ℃, 촉매 Ir10 (10 mol%)를 사용; Colorless resin (31 mg, 55 %); ¹H NMR (599 MHz, CDCl₃) δ 6.12 (s, 1H), 5.47-5.27 (m, 2H), 3.61 (p, J = 6.6 Hz, 1H), 2.38-2.27 (m, 2H), 2.28-2.18 (m, 1H), 2.01-1.93 (m, 4H), 1.74-1.65 (m, 1H), 1.57-1.48 (m, 1H), 1.50-1.41 (m, 1H), 1.37-1.23 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 178.25, 131.12, 129.75, 54.67, 36.73, 32.72, 32.48, 32.03, 30.31, 29.75, 29.61, 29.53, 29.45, 29.32, 27.46, 25.42, 22.81, 14.24; IR (cm^-1) 3445, 3185, 3089, 2957, 2918, 2849, 1677, 1463, 963, 777, 656; HRMS (EI) m/z calcd. for C₁₈H₃₃NO [M]⁺: 279.2562, found: 279.2565; Specific Rotation[α]_D ²⁵ -9.3±0.7(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i-PrOH = 95:5, 1.0 mL/min, 220 nm, t_R1(major) = 4.33 min, t_R2(minor) = 4.94 min, 92:8 er.

Reaction temperature: 50°C, catalyst Ir10 (10 mol%) used; Colorless resin (31 mg, 55%); ^1H NMR (599 MHz, CDCl ₃ ) δ 6.12 (s, 1H), 5.47-5.27 (m, 2H), 3.61 (p, J = 6.6 Hz, 1H), 2.38-2.27 (m, 2H), 2.28- 2.18 (m, 1H), 2.01-1.93 (m, 4H), 1.74-1.65 (m, 1H), 1.57-1.48 (m, 1H), 1.50-1.41 (m, 1H), 1.37-1.23 (m, 16H) ), 0.87 (t, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.25, 131.12, 129.75, 54.67, 36.73, 32.72, 32.48, 32.03, 30.31, 29.75, 29.61, 29.53, 29.45, 29.32, 27.46, 25.42, 22.81, 14.24; IR (cm ^-1 ) 3445, 3185, 3089, 2957, 2918, 2849, 1677, 1463, 963, 777, 656; HRMS (EI) m/z calcd. for C ₁₈ H ₃₃ NO [M] ⁺ : 279.2562, found: 279.2565; Specific Rotation[α] _D ²⁵ -9.3±0.7( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i- PrOH = 95:5, 1.0 mL/min, 220 nm, t _R1 (major) = 4.33 min, t _R2 (minor) = 4.94 min, 92:8 er.

[실시예 30] 5-(Phenylethynyl)pyrrolidin-2-one (24)의 제조[Example 30] Preparation of 5-(Phenylethynyl)pyrrolidin-2-one (24)

흰색 고체 (25 mg, 67 %); ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.37 (m, 2H), 7.37-7.27 (m, 3H), 6.39 (br, 1H), 4.62 (s, 1H), 2.58-2.44 (m, 2H), 2.41-2.23 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 178.00, 131.79, 128.72, 128.45, 122.31, 88.08, 84.11, 45.47, 30.04, 29.29; Specific Rotation[α]_D ²⁵ +10.4±0.1(c0.1, CHCl₃); HPLCAnalysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 21.01 min, t_R2(minor) = 32.31 min, 86:14 er.

White solid (25 mg, 67%); ^1H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.37 (m, 2H), 7.37-7.27 (m, 3H), 6.39 (br, 1H), 4.62 (s, 1H), 2.58-2.44 (m, 2H) ), 2.41-2.23 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.00, 131.79, 128.72, 128.45, 122.31, 88.08, 84.11, 45.47, 30.04, 29.29; Specific Rotation[α] _D ²⁵ +10.4±0.1( c 0.1, CHCl ₃ ); HPLCAnalysis. CHIRALPAK IC-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 21.01 min, t _R2 (minor) = 32.31 min, 86:14 er.

[실시예 31] (E)-5-Styrylpyrrolidin-2-one (25)의 제조[Example 31] Preparation of ( E )-5-Styrylpyrrolidin-2-one (25)

반응온도 50 ℃, 촉매 Ir10 (10 mol%) 및 NaBAr^F ₄ (10 mol%)를 사용; 흰색 고체 (15 mg, 40 %); ¹H NMR (599 MHz, CDCl₃) δ 7.37 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.29-7.26 (m, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.13 (dd, J = 15.8, 7.4 Hz, 1H), 5.63 (br, 1H), 4.34 (q, J = 7.4,1H), 2.50-2.33 (m, 3H), 2.01-1.90 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 178.11, 136.09, 131.44, 129.93, 128.86, 128.25, 126.65, 56.56, 30.01, 28.70; Specific Rotation[α]_D ²⁵ +3.1±5.0(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i-PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 35.7 min, t_R2(major) = 106.19 min, 87:13 er.

Reaction temperature was 50°C, catalysts Ir10 (10 mol%) and NaBAr ^F ₄ (10 mol%) were used; White solid (15 mg, 40%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.37 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.29-7.26 (m, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.13 (dd, J = 15.8, 7.4 Hz, 1H), 5.63 (br, 1H), 4.34 (q, J = 7.4,1H), 2.50-2.33 (m, 3H), 2.01-1.90 (m, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.11, 136.09, 131.44, 129.93, 128.86, 128.25, 126.65, 56.56, 30.01, 28.70; Specific Rotation[α] _D ²⁵ +3.1±5.0( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane: i- PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 35.7 min, t _R2 (major) = 106.19 min, 87:13 er.

[실시예 32] anti-4-Benzyl-5-phenylpyrrolidin-2-one (26)의 제조[Example 32] Preparation of anti- 4-Benzyl-5-phenylpyrrolidin-2-one (26)

흰색 고체 (45 mg, 90 %); m.p. 114-116 ℃; ¹H NMR(400 MHz, CDCl₃) δ 7.26-7.15 (m, 5H), 7.16-7.06 (m, 3H), 7.01 (d, J = 7.0 Hz, 2H), 6.63 (s, 1H), 4.31 (d, J = 5.3 Hz, 1H), 2.82 (dd, J= 13.6, 6.0 Hz, 1H), 2.63 (dd, J = 13.6, 8.2 Hz, 1H), 2.51-2.34 (m, 2H), 2.07 (dd, J =16.2, 6.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 177.59, 141.54, 138.98, 128.98, 128.89, 128.63, 128.01,126.59, 126.09, 63.31, 46.55, 39.56, 36.31; IR (cm^-1) 3248, 2955, 2913, 1691, 1285, 1023, 698, 475; HRMS (EI) m/z calcd. for C₁₇H₁₇NO [M]⁺: 251.1310, found: 251.1313; Specific Rotation[α]_D ²⁵ -4.0±0.5(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 6.01 min, t_R2(minor) = 7.04 min, 97:3 er.

White solid (45 mg, 90%); mp 114-116℃; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.15 (m, 5H), 7.16-7.06 (m, 3H), 7.01 (d, J = 7.0 Hz, 2H), 6.63 (s, 1H), 4.31 ( d, J = 5.3 Hz, 1H), 2.82 (dd, J= 13.6, 6.0 Hz, 1H), 2.63 (dd, J = 13.6, 8.2 Hz, 1H), 2.51-2.34 (m, 2H), 2.07 (dd , J =16.2, 6.7 Hz, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 177.59, 141.54, 138.98, 128.98, 128.89, 128.63, 128.01,126.59, 126.09, 63.31, 46.55, 39.56, 36.31; IR (cm ^-1 ) 3248, 2955, 2913, 1691, 1285, 1023, 698, 475; HRMS (EI) m/z calcd. for C ₁₇ H ₁₇ NO [M] ⁺ : 251.1310, found: 251.1313; Specific Rotation[α] _D ²⁵ -4.0±0.5( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 6.01 min, t _R2 (minor) = 7.04 min, 97:3 er.

[실시예 33] syn-3,3a,4,8b-Tetrahydroindeno[1,2-b]pyrrol-2(1H)-one (27)의 제조[Example 33] Preparation of syn -3,3a,4,8b-Tetrahydroindeno[1,2-b]pyrrol-2( 1H )-one (27)

흰색 고체 (34 mg, 98 %); ¹H NMR (599 MHz, CDCl₃) δ 7.40 (br, 1H), 7.30-7.17 (m, 4H), 5.02 (d, J = 6.7 Hz, 1H), 3.32-3.24 (m, 2H), 2.82 (q, J = 8.1 Hz, 1H), 2.70 (dd, J = 17.3, 8.8 Hz, 1H), 2.19 (dd, J = 17.5, 4.4 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 178.00, 142.49, 141.72, 128.68, 127.34, 125.38, 124.94, 63.62, 38.60, 37.77, 37.52; Specific Rotation[α]_D ²⁵ +55.1±0.3(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(major) = 7.02 min, t_R2(minor) =15.54 min, 97:3 er.

White solid (34 mg, 98%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.40 (br, 1H), 7.30-7.17 (m, 4H), 5.02 (d, J = 6.7 Hz, 1H), 3.32-3.24 (m, 2H), 2.82 ( q, J = 8.1 Hz, 1H), 2.70 (dd, J = 17.3, 8.8 Hz, 1H), 2.19 (dd, J = 17.5, 4.4 Hz, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 178.00, 142.49, 141.72, 128.68, 127.34, 125.38, 124.94, 63.62, 38.60, 37.77, 37.52; Specific Rotation[α] _D ²⁵ +55.1±0.3( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (major) = 7.02 min, t _R2 (minor) =15.54 min, 97:3 er.

[실시예 34] 2-{(2-Oxooctahydro-3aH-indol-3a-yl)methyl}isoindoline-1,3-dione (28)의 제조[Example 34] Preparation of 2-{(2-Oxooctahydro-3aH-indol-3a-yl)methyl}isoindoline-1,3-dione (28)

흰색 고체 (59 mg, 99 %); ¹H NMR (400 MHz, CDCl₃) δ (dd, J= 5.4, 3.1Hz, 2H), 7.72 (dd, J= 5.4, 3.1 Hz, 2H), 6.29 (br, 1H), 3.76 (s, 2H), 3.55 (s, 1), 2.46 (d, J= 16.4 Hz, 1H), 1.98 (d, J= 16.4Hz, 1H), 1.92-1.80 (m, 1H), 1.77-1.65 (m, 1H), 1.61-1.37 (m, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 177.04, 168.94, 134.34, 131.87, 123.58, 55.53, 43.45, 43.00, 42.48, 30.72, 26.30, 21.19, 19.91; Specific Rotation[α]_D ²⁵ -19.9±0.6(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 210 nm, t_R1(minor) = 23.28min, t_R2(major) =29.67 min, 88:12 er.

White solid (59 mg, 99%); ^1H NMR (400 MHz, CDCl ₃ ) δ (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.4, 3.1 Hz, 2H), 6.29 (br, 1H), 3.76 (s, 2H) ), 3.55 (s, 1), 2.46 (d, J = 16.4 Hz, 1H), 1.98 (d, J = 16.4Hz, 1H), 1.92-1.80 (m, 1H), 1.77-1.65 (m, 1H) , 1.61-1.37 (m, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 177.04, 168.94, 134.34, 131.87, 123.58, 55.53, 43.45, 43.00, 42.48, 30.72, 26.30, 21.19, 19.91; Specific Rotation[α] _D ²⁵ -19.9±0.6( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i - PrOH = 90:10, 1.0 mL/min, 210 nm, t _R1 (minor) = 23.28 min, t _R2 (major) = 29.67 min, 88:12 er.

[실시예 35] 2-[{syn-2-Oxohexahydrocyclopenta[b]pyrrol-3a(1H)-yl}methyl]isoindoline-1,3-dione (29)의 제조[Example 35] Preparation of 2-[{ syn -2-Oxohexahydrocyclopenta[b]pyrrol-3a( 1H )-yl}methyl]isoindoline-1,3-dione (29)

흰색 고체 (25 mg, 88 %, 0.1 mmol scale); m.p. 192-194 ℃; ¹H NMR (599 MHz, CDCl₃) δ 7.89-7.80 (m, 2H), 7.79-7.69 (m, 2H), 6.28 (s, 1H), 4.05 (d, J = 5.0 Hz, 1H), 3.81 (d, J =14.0 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 2.69 (d, J = 17.8 Hz, 1H), 2.22 (d, J =17.8 Hz, 1H), 1.79-1.64 (m, 6H); ¹³C NMR (151 MHz, CDCl₃) δ 176.79, 169.17, 134.40, 131.83, 123.64, 62.53, 51.43, 45.15, 41.72, 38.39, 34.06, 23.85; IR (cm^-1) 3293, 2967, 2931, 1772, 1706, 1695, 1651, 1420, 1338, 1262, 975, 713, 530; HRMS (EI) m/z calcd. for C₁₆H₁₆N₂O₃ [M]⁺: 284.1161, found: 284.1159; Specific Rotation[α]_D ²⁵ -15.1±1.1(c0.5, CHCl₃); HPLC Analysis. CHIRALCELOJ-H, 32 ℃, hexane:i -PrOH = 95:5, 1.0 mL/min, 210 nm, t_R1(minor) = 43.07 min, t_R2(major) = 51.55 min, 96:4 er.

White solid (25 mg, 88%, 0.1 mmol scale); mp 192-194℃; ^1H NMR (599 MHz, CDCl ₃ ) δ 7.89-7.80 (m, 2H), 7.79-7.69 (m, 2H), 6.28 (s, 1H), 4.05 (d, J = 5.0 Hz, 1H), 3.81 ( d, J =14.0 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 2.69 (d, J = 17.8 Hz, 1H), 2.22 (d, J =17.8 Hz, 1H), 1.79-1.64 ( m, 6H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 176.79, 169.17, 134.40, 131.83, 123.64, 62.53, 51.43, 45.15, 41.72, 38.39, 34.06, 23.85; IR (cm ^-1 ) 3293, 2967, 2931, 1772, 1706, 1695, 1651, 1420, 1338, 1262, 975, 713, 530; HRMS (EI) m/z calcd. for C ₁₆ H ₁₆ N ₂ O ₃ [M] ⁺ : 284.1161, found: 284.1159; Specific Rotation[α] _D ²⁵ -15.1±1.1( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALCELOJ-H, 32 ℃, hexane: i - PrOH = 95:5, 1.0 mL/min, 210 nm, t _R1 (minor) = 43.07 min, t _R2 (major) = 51.55 min, 96:4 er.

[실시예 36-40 및 비교예 1-6] 키랄 감마-락탐 화합물의 제조[Examples 36-40 and Comparative Examples 1-6] Preparation of chiral gamma-lactam compounds

촉매 구조에 따른 키랄 감마-락탐 화합물의 제조 여부를 알아보기 위하여 하기와 같이 실험하였다.In order to determine whether a chiral gamma-lactam compound could be produced according to the catalyst structure, an experiment was performed as follows.

아르곤 분위기 하에서 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (20.6 mg, 0.1 mmol) 및 TCE-d ₂ (0.5 mL)를 반응 바이알에 투입하고, 이어서 하기의 촉매 (4 mol%)와 NaBAr^F ₄ (3.5 mg, 4 mol%)를 첨가하였다. 반응혼합물을 50℃에서 12시간동안 격렬하게 교반시켰다. 반응 수율은 1,1,2-트리클로로에탄을 내부표준으로 사용하여 ¹H NMR로 측정하였고, 거울상이성질체 비(e.r.)는 HPLC(High Performance　Liquid Chromatography) 분석(CHIRALPAK IA-3 column, 32℃, hexane:i -PrOH = 95:5, flow rate = 1.0mL/min, UV = 210 nm)으로 결정하였다. Under argon atmosphere, 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (20.6 mg, 0.1 mmol) and TCE- d ₂ (0.5 mL) were added to the reaction vial, followed by the following catalyst ( 4 mol%) and NaBAr ^F ₄ (3.5 mg, 4 mol%) was added. The reaction mixture was stirred vigorously at 50°C for 12 hours. The reaction yield was measured by ¹ H NMR using 1,1,2-trichloroethane as an internal standard, and the enantiomeric ratio (er) was determined by HPLC (High Performance Liquid Chromatography) analysis (CHIRALPAK IA-3 column, 32°C, hexane: i - PrOH = 95:5, flow rate = 1.0mL/min, UV = 210 nm).

동일한 반응 조건 하에서 오직 촉매만 달리한 반응 결과를 하기 표 1에 나타내었다. The reaction results under the same reaction conditions but with different catalysts are shown in Table 1 below.

촉매catalyst 키랄 감마-락탐 화합물 (1)Chiral gamma-lactam compounds (1) 화합물 A의 수율 (%)Yield of Compound A (%) 수율 (transference number ( %% )) e.r.e.r. 실시예 36Example 36 Ir10Ir10 >95>95 98:298:2 <5<5 실시예 37Example 37 Ir6Ir6 3131 98:298:2 <5<5 실시예 38Example 38 Ir9Ir9 1212 96:496:4 <5<5 실시예 39Example 39 Ir8Ir8 1919 94:694:6 <5<5 실시예 40Example 40 Ir7Ir7 2525 91:991:9 <5<5 비교예 1Comparative Example 1 Ir-DIr-D 4040 59:4159:41 3535 비교예 2Comparative Example 2 Ir-CIr-C 3939 51:4951:49 2222 비교예 3Comparative Example 3 Ir-BIr-B 2424 51:4951:49 2424 비교예 4Comparative Example 4 Ir-AIr-A 1919 53:4753:47 2828 비교예 5Comparative Example 5 Ir-EIr-E 1212 81:1981:19 1515 비교예 6Comparative Example 6 Ir-FIr-F 1212 40:6040:60 5050 NaBAr^F ₄ : sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate
TCE-d ₂ : 1,1,2,2- tetrachloroethane-d ₂

NaBAr ^F ₄ : sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate
TCE- d ₂ : 1,1,2,2- tetrachloroethane- d ₂

상기 표 1로부터, 본 발명의 금속 착체를 이용한 실시예 36 내지 40의 경우 높은 거울상이성질선택성을 가지는 키랄 감마-락탐 화합물 (1)을 생성하였을 뿐만 아니라, 부산물인 화합물 A의 형성을 현저하게 억제하였음을 알 수 있다. From Table 1, in Examples 36 to 40 using the metal complex of the present invention, not only was a chiral gamma-lactam compound (1) having high enantioselectivity produced, but the formation of Compound A, a by-product, was significantly suppressed. It can be seen that this was done.

그러나, 비교예 1 내지 4와 같이 N,O-리간드 및 D-prolinamide 리간드를 가지는 이리듐 착체를 아미드화 촉매로 사용하는 경우 키랄 감마-락탐 화합물 (1)의 거울상이성질체 비(e.r.)가 51:49 내지 59:41로, ee 값이 2% 내지 18%로, 광학 순도가 매우 낮을 뿐만 아니라, 중간체인 카보닐나이트렌이 쉽해 분해되어 부산물인 이소시아네이트 (화합물 A)로 다량 전환되는 것을 알 수 있다.However, when an iridium complex having an N,O-ligand and a D-prolinamide ligand is used as an amidation catalyst as in Comparative Examples 1 to 4, the enantiomer ratio (e.r.) of the chiral gamma-lactam compound (1) is 51:49. to 59:41, and the ee value is 2% to 18%, indicating that not only is the optical purity very low, but the intermediate carbonylnitrene is easily decomposed and converted into a large amount of isocyanate (Compound A), a by-product.

또한, 키랄 에틸렌디아민 리간드를 가지는 Ir-E 및 Ir-F의 경우 말단 질소원자에 수소 원자 대신 메틸이 결합된 구조로, 메틸의 치환 개수에 따라 부산물의 수율이 증가하며, 목적하는 키랄 감마-락탐 화합물의 거울상이성질체 비(e.r.)가 현저하게 감소됨을 알 수 있다.In addition, in the case of Ir-E and Ir-F, which have chiral ethylenediamine ligands, the terminal nitrogen atom has a structure in which methyl is bonded to the terminal nitrogen atom instead of a hydrogen atom, so the yield of by-products increases depending on the number of methyl substitutions, and the desired chiral gamma-lactam It can be seen that the enantiomeric ratio (e.r.) of the compound is significantly reduced.

이상으로부터, 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조된 키랄 감마-락탐 화합물의 거울상이성질선택성은 촉매인 금속 착체의 리간드 구조에 영향을 받음을 알 수 있다.From the above, it can be seen that the enantioselectivity of the chiral gamma-lactam compound prepared from the prochiral 1,4,2-dioxazol-5-one compound is affected by the ligand structure of the catalyst metal complex.

[실시예 41-44 및 비교예 7 내지 9] 키랄 감마-락탐 화합물의 제조[Examples 41-44 and Comparative Examples 7 to 9] Preparation of chiral gamma-lactam compounds

반응조건에 따른 키랄 감마-락탐 화합물의 제조 여부를 알아보기 위하여 하기와 같이 실험하였다.In order to determine whether a chiral gamma-lactam compound was produced according to the reaction conditions, an experiment was performed as follows.

아르곤 분위기 하에서 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (20.6 mg, 0.1 mmol) 및 용매 (0.5 mL)를 반응 바이알에 투입하고, 이어서 촉매와 염기를 첨가하였다. 반응혼합물을 35℃에서 24시간 또는 50℃에서 12시간동안 격렬하게 교반시켰다. 반응 수율은 1,1,2-트리클로로에탄을 내부표준으로 사용하여 ¹H NMR로 측정하였고, 거울상이성질체 비(enantiomeric ratio; e.r.)는 HPLC(High Performance　Liquid Chromatography) 분석(CHIRALPAK IA-3 column, 32 ℃, hexane:iPrOH = 95:5, flow rate = 1.0mL/min, UV = 210 nm)으로 결정하였다. Under argon atmosphere, 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (20.6 mg, 0.1 mmol) and solvent (0.5 mL) were added to the reaction vial, and then the catalyst and base were added. The reaction mixture was stirred vigorously at 35°C for 24 hours or at 50°C for 12 hours. The reaction yield was measured by ¹ H NMR using 1,1,2-trichloroethane as an internal standard, and the enantiomeric ratio (er) was determined by HPLC (High Performance Liquid Chromatography) analysis (CHIRALPAK IA-3 column, 32 ℃, hexane: i PrOH = 95:5, flow rate = 1.0 mL/min, UV = 210 nm).

촉매의 유무, 염기 및 용매의 종류 또는 반응온도 및 반응시간에 따른 결과를 하기 표 2에 나타내었다. The results according to the presence or absence of catalyst, type of base and solvent, reaction temperature, and reaction time are shown in Table 2 below.

촉매
(mol%)catalyst
(mol%) 염기
(mol%)base
(mol%) 용매menstruum 반응
온도
(℃)reaction
temperature
(℃) 반응
시간
(h)reaction
hour
(h) 키랄 감마-락탐 화합물 (1)Chiral gamma-lactam compounds (1) 화합물 A의 수율
(%)Yield of Compound A
(%) 수율 (transference number ( %% )) e.r.e.r. 실시예 41Example 41 Ir10
(4 mol%)Ir10
(4 mol%) NaBAr^F ₄
(4 mol%)NaBAr ^F ₄
(4 mol%) TCE-d ₂ TCE _- d2 3535 2424 >95>95 >99:1>99:1 <5<5 실시예 42Example 42 Ir10
(4 mol%)Ir10
(4 mol%) AgNTf₂
(4 mol%)AgNTf ₂
(4 mol%) TCE-d ₂ TCE _- d2 3535 2424 9090 99:199:1 <5<5 실시예 43Example 43 Ir10
(4 mol%)Ir10
(4 mol%) NaBAr^F ₄
(4 mol%)NaBAr ^F ₄
(4 mol%) DCE-d ₄ DCE _- d4 3535 2424 7878 97:397:3 <5<5 실시예 44Example 44 Ir10
(4 mol%)Ir10
(4 mol%) NaBAr^F ₄
(4 mol%)NaBAr ^F ₄
(4 mol%) TCETCE 3535 2424 >95>95 99:199:1 <5<5 비교예 7Comparative Example 7 -- NaBAr^F ₄
(4 mol%)NaBAr ^F ₄
(4 mol%) TCE-d ₂ TCE _- d2 3535 2424 <5<5 -- <5<5 비교예 8Comparative Example 8 Ir10
(4 mol%)Ir10
(4 mol%) -- TCE-d ₂ TCE _- d2 3535 2424 <5<5 -- 7373 비교예 9Comparative Example 9 Ir10
(4 mol%)Ir10
(4 mol%) -- TCE-d ₂ TCE _- d2 5050 1212 <5<5 -- 7373 NaBAr^F ₄ : sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate
AgNTf₂ : Silver bis(trifluoromethanesulfonyl)imide
TCE-d ₂ : 1,1,2,2- tetrachloroethane-d ₂
DCE-d ₄ : 1,2-dichloroethane-d ₄
TCE : 1,1,2,2- tetrachloroethane

NaBAr ^F ₄ : sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate
AgNTf ₂ : Silver bis(trifluoromethanesulfonyl)imide
TCE- d ₂ : 1,1,2,2- tetrachloroethane- d ₂
DCE- d ₄ : 1,2-dichloroethane- d ₄
TCE: 1,1,2,2- tetrachloroethane

실시예Example III : 키랄 감마-락탐 화합물을 이용한 다양한 키랄 화합물의 제조 III: Preparation of various chiral compounds using chiral gamma-lactam compounds

[실시예 45] 4-(2-Oxo-5-phenylpyrrolidin-1-yl)benzonitrile의 제조[Example 45] Preparation of 4-(2-Oxo-5-phenylpyrrolidin-1-yl)benzonitrile

5-5- PhenylpyrrolidinPhenylpyrrolidin -2-one (-2-one ( 1)의1) of 제조 manufacturing

아르곤 분위기 하에서 금속착체 Ir10 (65 mg, 4 mol%), sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate (NaBAr^F ₄, 71 mg, 4 mol%) 및 무수 TCE (10 mL)를 50 mL round-bottom flask에 투입하였다. 실온에서 5분간 교반시킨 후, 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (2.0 mmol, 410 mg)을 직접 가하고, 50℃에서 24시간동안 격렬하게 교반시켰다. 교반 완료 후, 감압 하에서 용매를 제거하고, 실리카 크로마토그래피(eluent: n-hexane/10 % methanol in EtOAc = 1:4)로 정제하여 5-Phenylpyrrolidin-2-one (1)을 수득하였다(수율 94%, 98:2 er).Under argon atmosphere, metal complex Ir10 (65 mg, 4 mol%), sodium tetrakis{3,5-bis(trifluoromethyl)phenyl}borate (NaBAr ^F ₄ , 71 mg, 4 mol%) and anhydrous TCE (10 mL) were mixed for 50 mL. It was placed in a mL round-bottom flask. After stirring at room temperature for 5 minutes, 3-(3-phenylpropyl)-1,4,2-dioxazol-5-one (2.0 mmol, 410 mg) was directly added and stirred vigorously at 50°C for 24 hours. After completion of stirring, the solvent was removed under reduced pressure and purified by silica chromatography (eluent: n -hexane/10 % methanol in EtOAc = 1:4) to obtain 5-Phenylpyrrolidin-2-one (1) (yield 94). %, 98:2 er).

4-(2-4-(2- OxoOxo -5--5- phenylpyrrolidinphenylpyrrolidin -1--One- ylyl )) benzonitrile의benzonitrile 제조 manufacturing

대기 하, Pd₂(dba)₃ (5.8 mg, 0.01 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 17.3 mg, 0.03 mmol), 5-Phenylpyrrolidin-2-one (1) (98:2 er, 39 mg, 0.24 mmol) 및 4-bromobenzonitrile (36 mg, 0.2 mmol)을 반응 바이알에 첨가하였다. 이어서, 아르곤 분위기 하에서 Cs₂CO₃ (91 mg, 0.28 mmol)과 1,4-dioxane (0.6 mL)을 첨가한 후 105 ℃로 12시간동안 가열하였다. 반응완료 후, 반응혼합물을 CH₂Cl₂ (10 mL)으로 세척하고 셀라이트 패드를 통해 여과시킨 뒤, 플래쉬 크로마토그래피(용리액: n-헥산/EtOAc)로 정제하여 4-(2-Oxo-5-phenylpyrrolidin-1-yl)benzonitrile을 수득하였다.Under air, Pd ₂ (dba) ₃ (5.8 mg, 0.01 mmol), ) (98:2 er, 39 mg, 0.24 mmol) and 4-bromobenzonitrile (36 mg, 0.2 mmol) were added to the reaction vial. Subsequently, Cs ₂ CO ₃ (91 mg, 0.28 mmol) and 1,4-dioxane (0.6 mL) were added under an argon atmosphere and heated to 105°C for 12 hours. After completion of the reaction, the reaction mixture was washed with CH ₂ Cl ₂ (10 mL), filtered through a Celite pad, and purified by flash chromatography (eluent: n-hexane/EtOAc) to produce 4-(2-Oxo-5 -phenylpyrrolidin-1-yl)benzonitrile was obtained.

Colorless resin (52 mg, 99 %); ¹H NMR (599 MHz, CDCl₃) δ 7.60 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.9 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.28-7.22(m, 1H), 7.16 (d, J = 7.3 Hz, 2H), 5.33-5.20 (m, 1H), 2.79-2.71 (m, 1H), 2.70-2.56 (m, 2H), 2.06-1.98 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 175.33, 142.26, 140.28, 132.75, 129.33, 128.17, 125.58, 121.20, 118.78, 107.36, 63.33, 31.20, 29.09; IR (cm^-1) 2223, 1700, 1601, 1506, 1370, 1298, 1281, 836, 700, 543, 493; HRMS (EI) m/z calcd. for C₁₇H₁₄N₂O [M]⁺: 262.1106, found: 262.1107; Specific Rotation[α]_D ²⁵ -7.4±0.3(c0.5, CHCl₃); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane:i-PrOH = 90:10, 1.0 mL/min, 254 nm, t_R1(minor) = 11.79 min, t_R2(major) = 13.20 min, 98:2 er.Colorless resin (52 mg, 99%); ¹ H NMR (599 MHz, CDCl ₃ ) δ 7.60 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.9 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.28-7.22 (m, 1H), 7.16 (d, J = 7.3 Hz, 2H), 5.33-5.20 (m, 1H), 2.79-2.71 (m, 1H), 2.70-2.56 (m, 2H), 2.06-1.98 (m , 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.33, 142.26, 140.28, 132.75, 129.33, 128.17, 125.58, 121.20, 118.78, 107.36, 63.33, 31.20, 29.09; IR (cm ^-1 ) 2223, 1700, 1601, 1506, 1370, 1298, 1281, 836, 700, 543, 493; HRMS (EI) m/z calcd. for C ₁₇ H ₁₄ N ₂ O [M] ⁺ : 262.1106, found: 262.1107; Specific Rotation[α] _D ²⁵ -7.4±0.3( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALPAK IA-3, 32 ℃, hexane: i- PrOH = 90:10, 1.0 mL/min, 254 nm, t _R1 (minor) = 11.79 min, t _R2 (major) = 13.20 min, 98:2 er.

[실시예 46] 5-Phenylpyrrolidine-2-thione의 제조[Example 46] Preparation of 5-Phenylpyrrolidine-2-thione

대기 하, 5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol)을 반응 바이알에 넣고, 이어서 아르곤 대기 하에서 Lawesson's reagent (20 mg, 0.05 mmol)과 무수 톨루엔 (0.5 mL)을 가하고 80℃에서 6시간동안 교반시켰다. 반응혼합물에 탈이온수를 가하고 EtOAc로 3회 추출하고, 감압 하에 건조시켰다. 잔류물을 플래쉬 크로마토그래피(용리액: n-헥산/EtOAc)로 정제하여 5-Phenylpyrrolidine-2-thione을 수득하였다.Under atmospheric air, 5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol) was added to a reaction vial, followed by Lawesson's reagent (20 mg, 0.05 mmol) and anhydrous toluene (0.5 mL) under argon atmosphere. ) was added and stirred at 80°C for 6 hours. Deionized water was added to the reaction mixture, extracted three times with EtOAc, and dried under reduced pressure. The residue was purified by flash chromatography (eluent: n-hexane/EtOAc) to obtain 5-Phenylpyrrolidine-2-thione.

흰색 고체(17 mg, 96 %); ¹H NMR (599 MHz, CDCl₃) δ 8.20 (s, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.34-7.30 (m, 1H), 7.25 (d, J = 7.0 Hz, 2H), 4.99 (t, J = 7.4 Hz, 1H), 3.12-3.03 (m, 1H), 3.01-2.89 (m, 1H), 2.70-2.60 (m, 1H), 2.16-2.02 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 206.35, 140.33, 129.22, 128.59, 126.05, 65.85, 43.27, 33.57; Specific Rotation[α]_D ²⁵ -90.9±0.5(c0.5, CHCl₃), lit.(J. Am. Chem . Soc .,　2012,　134　(42), pp 17605-17612) -25.2°(c0.25, CH₂Cl₂, 80% ee); HPLC Analysis. CHIRALPAK IC-3, 32 ℃, hexane:i -PrOH = 90:10, 1.0 mL/min, 254 nm, t_R1(minor) = 11.07 min, t_R2(major) = 21.09 min, 99:1 er.White solid (17 mg, 96 %); ^1H NMR (599 MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.34-7.30 (m, 1H), 7.25 (d, J = 7.0 Hz, 2H) , 4.99 (t, J = 7.4 Hz, 1H), 3.12-3.03 (m, 1H), 3.01-2.89 (m, 1H), 2.70-2.60 (m, 1H), 2.16-2.02 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 206.35, 140.33, 129.22, 128.59, 126.05, 65.85, 43.27, 33.57; Specific Rotation[α] _D ²⁵ -90.9±0.5( c 0.5, CHCl ₃ ), lit.( J. Am. Chem . Soc . , 2012, 134 (42), pp 17605-17612) -25.2°( c 0.25, CH ₂ Cl ₂ , 80% ee); HPLC Analysis. CHIRALPAK IC-3, 32 °C, hexane: i - PrOH = 90:10, 1.0 mL/min, 254 nm, t _R1 (minor) = 11.07 min, t _R2 (major) = 21.09 min, 99:1 er.

[실시예 47] N-Benzyl-2-phenylpyrrolidine 의 제조[Example 47] Preparation of N -Benzyl-2-phenylpyrrolidine

N-Benzyl-5-N-Benzyl-5- phenylpyrrolidinphenylpyrrolidin -2-one의 제조 -Manufacture of 2-one

대기 하, 5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol)을 반응 바이알에 넣고, 이어서 아르곤 대기 하에서 무수 THF (0.5 mL)을 가하고, -30℃로 냉각시키고, NaH (4 mg, 0.15 mmol)를 첨가하였다. 이어서, THF (0.5 mL) 중의 벤질 브로마이드 (21 mg, 0.12 mmol)를 상기 반응혼합물에 투입하고, 실온에서 24시간동안 교반시켰다. 교반이 완료되면, 포화 NaHCO₃ 수용액을 붓고, Et₂O로 3회 추출하고, 유기층을 감압 하에 건조시켰다. 잔류물을 플래쉬 크로마토그래피(용리액: n-헥산/EtOAc)로 정제하여 N-Benzyl-5-phenylpyrrolidin-2-one을 수득하였다.Under air, 5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol) was added to the reaction vial, then anhydrous THF (0.5 mL) was added under argon atmosphere, and cooled to -30°C. , NaH (4 mg, 0.15 mmol) was added. Next, benzyl bromide (21 mg, 0.12 mmol) in THF (0.5 mL) was added to the reaction mixture and stirred at room temperature for 24 hours. When stirring was completed, saturated aqueous NaHCO ₃ solution was poured, extracted three times with Et ₂ O, and the organic layer was dried under reduced pressure. The residue was purified by flash chromatography (eluent: n-hexane/EtOAc) to obtain N-Benzyl-5-phenylpyrrolidin-2-one.

흰색 고체(25 mg, 99 %); ¹H NMR (599 MHz, CDCl₃) δ 7.37 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.29-7.22 (m, 3H), 7.13 (d, J = 7.4 Hz, 2H), 7.07 (d, J = 6.9 Hz, 2H), 5.11 (d, J = 14.6 Hz, 1H), 4.40 (dd, J = 8.2, 5.5 Hz, 1H), 3.47 (d, J = 14.6 Hz, 1H), 2.64 (ddd, J = 16.3, 9.8, 6.0 Hz, 1H), 2.49 (ddd, J = 16.9, 9.9, 6.6 Hz, 1H), 2.45-2.34 (m, 1H), 1.94-1.84 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 175.55, 140.93, 136.47, 129.15, 128.68, 128.65, 128.24, 127.64, 126.86, 61.43, 44.47, 30.42, 28.37; Specific Rotation[α]_D ²⁵ +37.2±0.8(c0.5, CHCl₃).White solid (25 mg, 99 %); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.37 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.29-7.22 (m, 3H), 7.13 (d, J = 7.4 Hz, 2H), 7.07 (d, J = 6.9 Hz, 2H), 5.11 (d, J = 14.6 Hz, 1H), 4.40 (dd, J = 8.2, 5.5 Hz, 1H), 3.47 (d, J = 14.6 Hz, 1H), 2.64 (ddd, J = 16.3, 9.8, 6.0 Hz, 1H), 2.49 (ddd, J = 16.9, 9.9, 6.6 Hz, 1H), 2.45-2.34 (m, 1H), 1.94-1.84 (m, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.55, 140.93, 136.47, 129.15, 128.68, 128.65, 128.24, 127.64, 126.86, 61.43, 44.47, 30.42, 28.37; Specific Rotation[α] _D ²⁵ +37.2±0.8( c 0.5, CHCl ₃ ).

NN -Benzyl-2--Benzyl-2- phenylpyrrolidinephenylpyrrolidine 의 제조 manufacture of

대기 하, N-Benzyl-5-phenylpyrrolidin-2-one (25 mg, 0.1 mmol)을 반응 바이알에 넣고, 이어서 아르곤 대기 하에서 LiAlH₄ (16 mg, 0.5 mmol) 및 무수 THF (0.5 mL)을 가하고, 실온에서 6시간동안 교반시켰다. 교반 완료 후, 반응혼합물을 EtOAc로 세척하고, 3방울의 탈이온수를 첨가하여 켄칭시켰다. 물을 MgSO₄로 제거하고, 셀라이트 패드를 통해 여과시킨 뒤, 용매를 감압 하에 제거하여 N-Benzyl-2-phenylpyrrolidine을 수득하였다.Wait, N-Benzyl-5-phenylpyrrolidin-2-one (25 mg, 0.1 mmol) was placed in a reaction vial, then LiAlH ₄ (16 mg, 0.5 mmol) and anhydrous THF (0.5 mL) were added under argon atmosphere, and stirred at room temperature for 6 hours. After stirring was complete, the reaction mixture was washed with EtOAc and quenched by adding 3 drops of deionized water. Water was removed with MgSO ₄ , filtered through a Celite pad, and the solvent was removed under reduced pressure to obtain N -Benzyl-2-phenylpyrrolidine.

흰색 고체 (24 mg, 99%); ¹H NMR (599 MHz, CDCl₃) δ 7.49 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.34-7.20 (m, 6H), 3.87 (d, J = 13.1 Hz, 1H), 3.38 (t, J = 8.2 Hz, 1H), 3.11 (t, J = 8.7 Hz, 1H), 3.05 (d, J = 13.1 Hz, 1H), 2.27-2.16 (m, 2H), 1.95-1.84 (m, 1H), 1.84-1.71 (m, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 144.03, 139.89, 128.81, 128.55, 128.21, 127.69, 127.11, 126.79, 69.76, 58.25, 53.47, 35.36, 22.46; Specific Rotation[α]_D ²⁵ -96.9±0.7(c0.5, CHCl₃); HPLC Analysis. CHIRALCEL OJ-H, 32 ℃, hexane:i -PrOH = 95:5, 1.0 mL/min, 210 nm, t_R1(minor) = 5.56 min, t_R2(major) = 7.98 min, 97:3 er.White solid (24 mg, 99%); ^1H NMR (599 MHz, CDCl ₃ ) δ 7.49 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.34-7.20 (m, 6H), 3.87 (d, J = 13.1 Hz, 1H), 3.38 (t, J = 8.2 Hz, 1H), 3.11 (t, J = 8.7 Hz, 1H), 3.05 (d, J = 13.1 Hz, 1H), 2.27-2.16 (m, 2H) , 1.95-1.84 (m, 1H), 1.84-1.71 (m, 2H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 144.03, 139.89, 128.81, 128.55, 128.21, 127.69, 127.11, 126.79, 69.76, 58.25, 53.47, 35.36, 22.46; Specific Rotation[α] _D ²⁵ -96.9±0.7( c 0.5, CHCl ₃ ); HPLC Analysis. CHIRALCEL OJ-H, 32 ℃, hexane: i - PrOH = 95:5, 1.0 mL/min, 210 nm, t _R1 (minor) = 5.56 min, t _R2 (major) = 7.98 min, 97:3 er.

[실시예 48] 4-Amino-4-phenylbutanoic acid hydrochloride의 제조[Example 48] Preparation of 4-Amino-4-phenylbutanoic acid hydrochloride

5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol)을 6N 염산(0.6 mL)에 혼합한 후 100℃에서 12시간동안 가열하였다. 실온으로 냉각시킨 후, 용매를 감압 하에 제거하였다. EtOAc (1 mL)를 첨가한 후, 반응혼합물을 초음파 처리에 의해 현탁시키고, 실온에서 1시간동안 교반시켰다. 고체 생성물을 MeOH로 세척하면서 여과하여 4-Amino-4-phenylbutanoic acid hydrochloride을 수득하였다.5-Phenylpyrrolidin-2-one (1) (98:2 er, 16 mg, 0.1 mmol) was mixed with 6N hydrochloric acid (0.6 mL) and heated at 100°C for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure. After adding EtOAc (1 mL), the reaction mixture was suspended by sonication and stirred at room temperature for 1 hour. The solid product was filtered and washed with MeOH to obtain 4-Amino-4-phenylbutanoic acid hydrochloride.

흰색 고체 (21 mg, 97 %); ¹H NMR (599 MHz, CD₃OD) δ 7.49-7.41 (m, 5H), 4.35 (dd, J = 9.4, 5.4 Hz, 1H), 2.36-2.29 (m, 1H), 2.24-2.13 (m, 3H); ¹³C NMR (151 MHz, CD₃OD) δ 175.56, 137.45, 130.58, 130.49, 128.46, 56.11, 30.84, 30.55; Specific Rotation[α]_D ²⁵ +21.3±0.2(c0.5, H₂O), lit.(Org . Lett.,　2008,　10　(4), pp 537-540) -39.4 for the (R) isomer (c0.2, CD₃OD); HPLC Analysis. CROWNPAK CR-I(+), HClO₄(aq, pH =1.5):MeCN = 80:20, 0.5 mL/min, 210 nm, t_R1(major) = 3.21 min, t_R2(minor) = 5.13 min, 99:1 er.White solid (21 mg, 97%); ¹ H NMR (599 MHz, CD ₃ OD) δ 7.49-7.41 (m, 5H), 4.35 (dd, J = 9.4, 5.4 Hz, 1H), 2.36-2.29 (m, 1H), 2.24-2.13 (m, 3H); ¹³ C NMR (151 MHz, CD ₃ OD) δ 175.56, 137.45, 130.58, 130.49, 128.46, 56.11, 30.84, 30.55; Specific Rotation[α] _D ²⁵ +21.3±0.2( c 0.5, H ₂ O), lit.( Org . Lett. , 2008, 10 (4), pp 537-540) -39.4 for the ( R ) isomer ( c 0.2, CD ₃ OD); HPLC Analysis. CROWNPAK CR-I(+), HClO ₄ (aq, pH = 1.5):MeCN = 80:20, 0.5 mL/min, 210 nm, t _R1 (major) = 3.21 min, t _R2 (minor) = 5.13 min, 99:1 er.

상기 실시예 45 내지 48로부터, 본 발명의 금속 착체를 촉매로 이용하여 프로키랄 1,4,2-디옥사졸-5-온 화합물로부터 제조된 키랄 감마-락탐 화합물은 광학순도의 저하 없이 키랄 N-아릴화 락탐, 티오아미드, 키랄 피롤리딘 및 비천연 감마-아미노산과 같은 의약 및 천연물 등의 합성의 중간체 및 원료물질의 제조에 매우 유용하게 사용될 수 있음을 알 수 있다.From Examples 45 to 48, the chiral gamma-lactam compound prepared from the prochiral 1,4,2-dioxazol-5-one compound using the metal complex of the present invention as a catalyst has chiral N without lowering optical purity. -It can be seen that it can be very useful in the production of intermediates and raw materials for the synthesis of medicines and natural products such as arylated lactams, thioamides, chiral pyrrolidines, and non-natural gamma-amino acids.

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 [0341] 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustrative purposes, and those skilled in the art will recognize that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. You will understand. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.

Claims

하기 화학식 1-1로 표시되는 금속 착체 및 염기의 존재 하에 하기 화학식 2로 표시되는 프로키랄(prochiral) 1,4,2-디옥사졸-5-온 화합물을 아미드화하여 하기 화학식 3으로 표시되는 키랄(chiral) 감마-락탐 화합물을 제조하는 방법.
[화학식 1-1]

(상기 화학식 1-1에서,
X₁는 할로겐이며;
R₁ 내지 R₅는 각각 독립적으로 C1-C20알킬이며;
R₉는 C1-C20알킬 또는 C6-C20아릴이며, 상기 R₉의 아릴은 C1-C20알킬, 할로겐, C1-C20알콕시 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며;
R₇ 및 R₈은 각각 독립적으로 C6-C20아릴이거나, 상기 R₇과 R₈은 C3-C7알킬렌으로 서로 연결되어 지환족 고리를 형성할 수 있으며, 상기 R₇ 및 R₈의 아릴은 C1-C20알킬 및 할로C1-C20알킬로부터 선택되는 하나 이상으로 더 치환될 수 있다.)
[화학식 2]

[화학식 3]

(상기 화학식 2 및 3에서,
R₂₁은 C1-C20알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬은 C3-C20시클로알킬, C6-C20아릴 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며, 상기 R₂₁의 아릴은 C1-C20알킬, 할로겐, 할로C1-C20알킬 및 니트로로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며, 상기 R₂₁의 알케닐 또는 알키닐은 C1-C20알킬 및 C6-C20아릴로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며;
R₂₂는 수소이고; R₂₃은 수소 또는 C1-C20알킬이고, 상기 R₂₃의 알킬은 C6-C20아릴 또는 프탈이미도로 더 치환될 수 있고;
상기 R₂₁ 내지 R₂₃은 인접한 치환기와 연결되어 고리를 형성할 수 있다.)
A prochiral 1,4,2-dioxazol-5-one compound represented by Formula 2 is amidated in the presence of a metal complex represented by Formula 1-1 and a base to obtain a compound represented by Formula 3 below. Method for preparing chiral gamma-lactam compounds.
[Formula 1-1]

(In Formula 1-1 above,
X ₁ is halogen;
R ₁ to R ₅ are each independently C1-C20 alkyl;
R ₉ is C1-C20 alkyl or C6-C20 aryl, and the aryl of R ₉ may be further substituted with one or more selected from C1-C20 alkyl, halogen, C1-C20 alkoxy, and haloC1-C20 alkyl;
R ₇ and R ₈ are each independently C6-C20 aryl, or R ₇ and R ₈ may be linked to each other by C3-C7 alkylene to form an alicyclic ring, and the aryl of R ₇ and R ₈ is C1 It may be further substituted with one or more selected from -C20 alkyl and haloC1-C20 alkyl.)
[Formula 2]

[Formula 3]

(In Formulas 2 and 3 above,
R ₂₁ is C1-C20 alkyl, C6-C20 aryl, C2-C20 alkenyl or C2-C20 alkynyl, and the alkyl of R ₂₁ is any one selected from C3-C20 cycloalkyl, C6-C20 aryl and phthalimido. It may be further substituted by the above, and the aryl of R ₂₁ may be further substituted with any one or more selected from C1-C20 alkyl, halogen, haloC1-C20 alkyl, and nitro, and the alkenyl or alkynyl of R ₂₁ may be further substituted with any one or more selected from C1-C20 alkyl and C6-C20 aryl;
R ₂₂ is hydrogen; R ₂₃ is hydrogen or C1-C20 alkyl, and the alkyl of R ₂₃ may be further substituted with C6-C20 aryl or phthalimido;
R ₂₁ to R ₂₃ may be connected to adjacent substituents to form a ring.)

삭제delete

제 1항에 있어서,
상기 금속 착체는 하기 화학식 1-2로 표시되는 금속 착체인, 키랄 감마-락탐 화합물의 제조방법:
[화학식 1-2]

(상기 화학식 1-2에서,
X₁는 할로겐이며;
R₁ 내지 R₅는 각각 독립적으로 C1-C10알킬이며;
R₉는 C1-C10알킬 또는 C6-C12아릴이며, 상기 R₉의 아릴은 C1-C10알킬, 할로겐, C1-C10알콕시 및 할로C1-C10알킬로부터 선택되는 하나 이상으로 더 치환될 수 있으며;
R₁₀ 및 R₁₁는 각각 독립적으로 C1-C10알킬이며;
c 및 d는 각각 독립적으로 0 내지 5의 정수이다.)According to clause 1,
Method for producing a chiral gamma-lactam compound, wherein the metal complex is a metal complex represented by the following formula 1-2:
[Formula 1-2]

(In Formula 1-2 above,
X ₁ is halogen;
R ₁ to R ₅ are each independently C1-C10 alkyl;
R ₉ is C1-C10 alkyl or C6-C12 aryl, and the aryl of R ₉ may be further substituted with one or more selected from C1-C10 alkyl, halogen, C1-C10 alkoxy, and haloC1-C10 alkyl;
R ₁₀ and R ₁₁ are each independently C1-C10 alkyl;
c and d are each independently integers from 0 to 5.)

제 1항에 있어서,
상기 금속 착체는 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰로 사용되는 것인, 키랄 감마-락탐 화합물의 제조방법.According to clause 1,
A method for producing a chiral gamma-lactam compound, wherein the metal complex is used in an amount of 0.01 to 0.1 mol based on 1 mol of the prochiral 1,4,2-dioxazol-5-one compound.

제 1항에 있어서,
상기 염기는 상기 프로키랄 1,4,2-디옥사졸-5-온 화합물 1몰에 대하여 0.01 내지 0.1몰로 사용되는 것인, 키랄 감마-락탐 화합물의 제조방법.According to clause 1,
A method for producing a chiral gamma-lactam compound, wherein the base is used in an amount of 0.01 to 0.1 mol per mole of the prochiral 1,4,2-dioxazol-5-one compound.

제 6항에 있어서,
상기 염기는 NaBAr^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF₆ (Silver hexafluoroantimonate(V)), AgNTf₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF₄ (Silver tetrafluoroborate), AgPF₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate) 및 AgOAc (Silver acetate) 에서 선택되는 하나 또는 둘 이상인, 키랄 감마-락탐 화합물의 제조방법.According to clause 6,
The bases are NaBAr ^F ₄ (Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), AgSbF ₆ (Silver hexafluoroantimonate(V)), AgNTf ₂ (Silver bis(trifluoromethanesulfonyl)imide), AgBF ₄ (Silver tetrafluoroborate) , AgPF ₆ (Silver hexafluorophosphate), AgOTf Silver trifluoromethanesulfonate), and AgOAc (Silver acetate). A method for producing one or more chiral gamma-lactam compounds.

제 1항에 있어서,
상기 아미드화는 20 내지 60℃에서 수행되는 것인, 키랄 감마-락탐 화합물의 제조방법.According to clause 1,
A method for producing a chiral gamma-lactam compound, wherein the amidation is performed at 20 to 60°C.

제 1항에 있어서,
상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-1의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-1의 키랄 감마-락탐 화합물인, 키랄 감마-락탐 화합물의 제조방법:
[화학식 2-1]

[화학식 3-1]

(상기 화학식 2-1 및 3-1에서,
R₂₁은 C1-C20알킬, C6-C20아릴, C2-C20알케닐 또는 C2-C20알키닐이고, 상기 R₂₁의 알킬은 C3-C20시클로알킬, C6-C20아릴 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며, 상기 R₂₁의 아릴은 C1-C20알킬, 할로겐, 할로C1-C20알킬 및 니트로로부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며, 상기 R₂₁의 알케닐 또는 알키닐은 C1-C20알킬 및 프탈이미도로부터 선택되는 어느 하나 이상으로 더 치환될 수 있다.)According to clause 1,
The prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-1, and the chiral gamma-lactam compound is Method for producing a chiral gamma-lactam compound, which is a chiral gamma-lactam compound of Formula 3-1:
[Formula 2-1]

[Formula 3-1]

(In Formulas 2-1 and 3-1 above,
R ₂₁ is C1-C20 alkyl, C6-C20 aryl, C2-C20 alkenyl or C2-C20 alkynyl, and the alkyl of R ₂₁ is any one selected from C3-C20 cycloalkyl, C6-C20 aryl and phthalimido. It may be further substituted by the above, and the aryl of R ₂₁ may be further substituted with any one or more selected from C1-C20 alkyl, halogen, haloC1-C20 alkyl, and nitro, and the alkenyl or alkynyl of R ₂₁ may be further substituted with any one or more selected from C1-C20 alkyl and phthalimido.)

제 1항에 있어서,
상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-2의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-2의 키랄 감마-락탐 화합물인, 키랄 감마-락탐 화합물의 제조방법:
[화학식 2-2]

[화학식 3-2]
According to clause 1,
The prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the formula 2-2, and the chiral gamma-lactam compound is Method for producing a chiral gamma-lactam compound, which is a chiral gamma-lactam compound of Formula 3-2:
[Formula 2-2]

[Formula 3-2]

제 1항에 있어서,
상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-3의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-3의 키랄 감마-락탐 화합물인, 키랄 감마-락탐 화합물의 제조방법:
[화학식 2-3]

[화학식 3-3]

(상기 화학식 2-3 및 3-3에서,
R₂₁은 C6-C20아릴이고;
R_22a은 C6-C20아릴이다.)According to clause 1,
The prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the formula 2-3, and the chiral gamma-lactam compound is Method for producing a chiral gamma-lactam compound, which is a chiral gamma-lactam compound of formula 3-3:
[Formula 2-3]

[Formula 3-3]

(In Formulas 2-3 and 3-3,
R ₂₁ is C6-C20 aryl;
R _22a is C6-C20 aryl.)

제 1항에 있어서,
상기 프로키랄 1,4,2-디옥사졸-5-온 화합물은 하기 화학식 2-4의 프로키랄 1,4,2-디옥사졸-5-온 화합물이고, 상기 키랄 감마-락탐 화합물은 하기 화학식 3-4의 키랄 감마-락탐 화합물인, 키랄 감마-락탐 화합물의 제조방법:
[화학식 2-4]

[화학식 3-4]

(상기 화학식 2-4 및 3-4에서,
L₁은 , , 또는 이고;
R₂₃은 수소 또는 C1-C20알킬이고, 상기 R₂₃의 알킬은 C6-C20아릴 또는 프탈이미도로 더 치환될 수 있다.)According to clause 1,
The prochiral 1,4,2-dioxazol-5-one compound is a prochiral 1,4,2-dioxazol-5-one compound of the following formula 2-4, and the chiral gamma-lactam compound is Method for producing chiral gamma-lactam compounds, which are chiral gamma-lactam compounds of formula 3-4:
[Formula 2-4]

[Formula 3-4]

(In Formulas 2-4 and 3-4 above,
L ₁ is , , or ego;
R ₂₃ is hydrogen or C1-C20 alkyl, and the alkyl of R ₂₃ may be further substituted with C6-C20 aryl or phthalimido.)

하기 화학식 4-1로 표시되는 금속 착체:
[화학식 4-1]

(상기 화학식 4-1에서,
X₂는 할로겐이며;
R₃₁ 내지 R₃₅는 각각 독립적으로 C1-C10알킬이며;
R₃₆는 C1-C10알콕시로 치환된 C6-C12아릴 또는 할로겐으로 치환된 C6-C12아릴이다.)Metal complex represented by the following formula 4-1:
[Formula 4-1]

(In Formula 4-1 above,
X ₂ is halogen;
R ₃₁ to R ₃₅ are each independently C1-C10 alkyl;
R ₃₆ is C6-C12 aryl substituted with C1-C10 alkoxy or C6-C12 aryl substituted with halogen.)

제 13항에 있어서,
상기 금속 착체는 하기 구조에서 선택되는 금속 착체:

According to clause 13,
The metal complex is a metal complex selected from the following structures:

하기 화학식 4-2로 표시되는 금속 착체:
[화학식 4-2]

(상기 화학식 4-2에서,
X₂는 할로겐이며;
R₃₁ 내지 R₃₅는 각각 독립적으로 C1-C10알킬이며;
R₃₆는 C1-C10알킬로 치환된 C6-C12아릴이며;
R₃₉ 및 R₄₀는 각각 독립적으로 C1-C10알킬이며;
e 및 f는 각각 독립적으로 1 내지 3의 정수이다.)Metal complex represented by the following formula 4-2:
[Formula 4-2]

(In Formula 4-2 above,
X ₂ is halogen;
R ₃₁ to R ₃₅ are each independently C1-C10 alkyl;
R ₃₆ is C6-C12aryl substituted with C1-C10alkyl;
R ₃₉ and R ₄₀ are each independently C1-C10 alkyl;
e and f are each independently integers from 1 to 3.)

제 15항에 있어서,
상기 금속 착체는 하기 구조로 표시되는 것인 금속 착체:

According to clause 15,
The metal complex is represented by the following structure: