WO2024034767A1 - Method for producing nitrogen-selective chiral aldol reaction product of nitroso compound using organic chiral catalyst compound - Google Patents

Method for producing nitrogen-selective chiral aldol reaction product of nitroso compound using organic chiral catalyst compound Download PDF

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WO2024034767A1
WO2024034767A1 PCT/KR2023/003846 KR2023003846W WO2024034767A1 WO 2024034767 A1 WO2024034767 A1 WO 2024034767A1 KR 2023003846 W KR2023003846 W KR 2023003846W WO 2024034767 A1 WO2024034767 A1 WO 2024034767A1
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formula
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심재호
김현수
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고려대학교 산학협력단
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

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  • the present invention relates to a method for producing a nitrogen-selective chiral aldol reaction product of a cyclic ketone and a nitroso compound using an organic chiral catalyst compound.
  • Organic catalysts generally contain carbon, hydrogen, nitrogen, and sulfur and are structurally different from metal catalysts, which include a metal core and ligands.
  • the Aldol reaction is the main reaction that forms carbon-carbon bonds and is an important reaction used to synthesize a wide range of natural products or complex compounds that exhibit biological activity.
  • the asymmetric nitroso aldol reaction is a powerful synthetic tool that can introduce nitrogen to carbonyl groups and can be used to construct optically active ⁇ -hydroxyamino carbonyl compounds.
  • the present inventors achieved high yield by using a (R,R)-1,2-diphenylethylenediamine (DPEN)-based catalyst that can effectively catalyze the nitroso aldol reaction and control the stereochemistry of the product. And the present invention was completed by developing a method for producing a reaction product with optical purity.
  • DPEN diphenylethylenediamine
  • the purpose of the present invention is to provide a method for producing chiral nitroso derivatives through an asymmetric aldol reaction using a chiral diamine catalyst.
  • Another object of the present invention is to provide a chiral nitroso derivative prepared by the above production method.
  • the present invention includes the step of reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] to prepare a compound represented by [Formula 3], and in the reaction [
  • a method for producing a chiral nitroso derivative is provided, characterized by using a catalyst compound represented by Formula 4.
  • R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
  • R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
  • R 4 may be a C 1 -C 9 chain alkyl group or a cycloalkyl group.
  • the reaction may be an asymmetric aldol reaction.
  • the reaction involves reacting a compound represented by [Formula 1] with a catalyst compound represented by [Formula 4] to form an enamine intermediate, and then reacting with a compound represented by [Formula 2].
  • a compound represented by [Formula 3] may be produced through a nitrogen-selective aldol reaction.
  • nitroso aldol reactions use enolate as a nucleophile, pre-activate a carbonyl compound, or directly use an enamine compound and show oxygen selectivity, but the present invention forms an enamine intermediate during the reaction. By doing so, a nitrogen-selective nitroso aldol reaction can be induced.
  • the nitrogen-selective nitroso derivative represented by [Compound 3] can be used in the main reactions of various synthetic intermediates and thus can be utilized in the field of pharmaceutical organic synthesis.
  • the compound represented by [Formula 1] may be a compound represented by the following [Formula 1-1].
  • the compound represented by [Formula 2] may be a compound represented by the following [Formula 2-1].
  • the compound represented by [Formula 3] may be a compound represented by the following [Formula 3-1].
  • the compound represented by [Formula 4] may be any one or more selected from the compounds represented by [Formula 4-1] to [Formula 4-5] below.
  • the catalyst compound may be a salt form of the compound represented by [Formula 4], and preferably may be hydrochloride (HCl).
  • the reaction may be performed in a polar protic solvent, a polar aprotic solvent, or a non-polar solvent.
  • the solvent may be water, brine ( brine), dimethyl sulfoxide (DMSO), nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), ethanol (EtOH), acetone, cyclohexanone, chloroethane (EtCl 2 ), Dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), aniline, chlorobenzene, chloroform (CHCl 3 ), diethyl ether (Et 2 O), toluene, benzene, carbon tetrachloride (CCl 4 ), cyclohexane, heptane. It may be, but is not limited to this.
  • the reaction may be carried out in a polar solvent having a dielectric constant of 30 or more, more preferably water, brine, dimethyl sulfoxide (DMSO), It may be performed in one or more solvents selected from the group consisting of nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), and combinations thereof, but is not limited thereto.
  • a polar solvent having a dielectric constant of 30 or more more preferably water, brine, dimethyl sulfoxide (DMSO)
  • DMSO dimethyl sulfoxide
  • the reaction may be performed by reacting the compound represented by [Formula 1] with the compound represented by [Formula 2] at an equivalence ratio of 2:1 to 1:2, preferably 2:1.
  • the reaction may involve adding 5 to 10 mol% of a catalyst compound represented by [Formula 4].
  • benzoic acid may be added and reacted with the compound represented by [Formula 1] and the compound represented by [Formula 2].
  • the reaction may be performed in a single reactor at room temperature.
  • the reaction may be completed within 15 minutes to 24 hours.
  • the reaction may be performed at -10 to 25°C. Preferably, it may be performed at a temperature of 0 to -10°C.
  • the present invention provides a chiral nitroso derivative prepared by the above-described production method.
  • the method for producing a chiral nitroso derivative uses a diamine catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) to form a cyclic ketone and an enamine. And, the enamine reacts with the nitroso compound to produce a nitroso derivative with high yield and enantioselectivity.
  • the catalyst is an organic catalyst that can be easily synthesized and can increase electrophilicity by activating nitroso compounds through hydrogen bonding.
  • the method for producing a chiral nitroso derivative according to an embodiment of the present invention is environmentally friendly by using water or brine as a solvent, and can improve the yield of the asymmetric nitroso aldol reaction product by stabilizing the transition state.
  • the method for producing a chiral nitroso derivative according to an embodiment of the present invention induces a nitrogen-selective nitroso aldol reaction by forming a transition state in the direction of minimizing steric hindrance, thereby increasing optical purity.
  • the chiral nitroso derivative prepared according to an embodiment of the present invention has nitrogen selectivity and can be used in the main reactions of various synthetic intermediates, so it can be used in the field of pharmaceutical organic synthesis.
  • Figure 1 is a reaction scheme of a method for producing a chiral nitroso derivative according to a nitrogen-selective nitroso aldol reaction as an example of the present invention.
  • Figure 2 shows the catalytic cycle of the nitroso aldol reaction including the proposed transition state.
  • Figure 3 shows the relative free energy diagram representing the catalytic transition state of catalysts 1a and 1b (Formulas 4-1 and 4-2 ) based on the B3LYP/6-31G(d,p) method in the gas phase and aqueous phase. Calculations were performed. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, 3 is catalyst 1a , and 4 is catalyst 1b .
  • Figure 4 shows the effect of solvent on the transition state of the asymmetric nitroso aldol reaction. Calculations were performed based on the B3LYP/6-31G(d,p) method under various solvent conditions.
  • Figure 5 shows B3LYP/6-31G(d,p) calculations and relative free energies of (R,R)-1,2-diphenylethylenediamine (DPEN)-iminium salt catalyzed enantioselective nitroso aldol reaction.
  • the proposed catalytic mechanism is shown based on the diagram, and calculations were performed in the aqueous phase. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, and 3 is catalyst 1a .
  • the present inventors discovered that the enamine formed by the reaction of a catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) and a cyclic ketone is the oxygen of the nitroso compound activated through hydrogen bonding with the acid catalyst. It was confirmed that it attacks and induces a nitrogen-selective nitroso aldol reaction (Figure 1).
  • the present invention involves preparing a compound represented by [Formula 3] by reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] using a catalyst compound represented by [Formula 4]. It provides a method for producing a chiral nitroso derivative, including:
  • a nitroso aldol reaction product with a high level of enantioselectivity can be produced in excellent yield.
  • R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
  • R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
  • R 4 may be a C 1 -C 9 chain or cyclic alkyl group.
  • substitution refers to a reaction in which an atom or atomic group contained in a molecule of a compound is replaced with another atom or atomic group.
  • chain alkyl group refers to a group derived from a straight-chain or branched-chain saturated aliphatic hydrocarbon having a specified number of carbon atoms and a valency of at least one.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, etc.
  • cycloalkyl group also referred to as a cyclic alkyl group, refers to a monovalent group having one or more saturated rings in which all ring members are carbon.
  • examples of such cycloalkyl groups include, but are not limited to, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups.
  • heterocycloalkyl group typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, mono-substituted or poly-substituted, and in its structure At least one is selected from heteroatoms of N, O or S.
  • aryl group refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg, phenyl) or a plurality of condensed rings (eg, naphthyl). Examples of such aryl include, but are not limited to, phenyl, naphthyl, etc.
  • halogen group refers to elements belonging to group 17 of the periodic table and may include fluorine (F), chloride (Cl), bromine (Br), or iodine (I).
  • first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term.
  • a component is described as being “connected,” “coupled,” or “connected” to another component, that component may be directly connected or connected to that other component, but there is no need for another component between each component. It should be understood that may be “connected,” “combined,” or “connected.”
  • Optical rotation was measured using an automated digital polarimeter, and FT-IR spectra were recorded using a NICOLET 380 FT-IR spectrophotometer from Thermo Electron Corporation (Thermo Fisher Scientific Inc., Waltham, MA, USA). . using Varian Gemini 300 (300, 75 MHz) and Varian Mercury 400 (400, 100 MHz, Agilent, Santa Clara, CA, USA) with TMS (300, 75 MHz, Agilent, Santa Clara, CA, USA) as internal standard. 1 H NMR and 13 C NMR spectra were obtained.
  • the reagents and conditions are as follows: (a) 1.0 eq. Carbonyl compound, MgSO 4 , toluene (0.1 M), reflux, 48 hours. (b) Ethanol (0.1 M), NaBH 4 excess, 3 h (overall yield 81-90%).
  • a protic solvent In the case of a protic solvent, it can greatly contribute to stabilizing the transition state during a catalytic reaction by contributing to stabilizing the cation of the catalyst.
  • the reactivity of the catalyst increases in a polar solvent, and as the polarity of the catalyst increases, the binding force of the nucleophile increases and the free energy of the transition state is stabilized, showing relatively excellent yield and enantioselectivity.
  • polar aprotic solvents also showed relatively low yields because the interference of hydrogen bonding was more important than the activation of nitrosobenzene by the solvent. Therefore, from the solvent screening results in Table 1, the brine with the best yield and enantioselectivity for N-nitroso aldol reaction was determined as the reaction solvent.
  • the amount of reagent was changed to determine how the ratio of cyclic ketone (Formula 1 ) to nitroso compound (Formula 2 ) affects the nitroso aldol reaction.
  • the ratio of cyclohexanone:nitrosobenzene was 1:1 (entry 1)
  • the yield and enantioselectivity decreased compared to when the ratio was 2:1 (entry 1 in Table 2)
  • the amount of nitrosobenzene reagent was increased.
  • yield and enantioselectivity decreased (entries 6 and 7).
  • benzoic acid promotes amine catalysis and imine formation through activation of cyclohexanone.
  • the chiral diamine catalyst (Formula 4 ) reacts with cycloketone (Formula 1 ) to form an imine, which in turn forms an enamine.
  • Alkylated chiral diamine and nitroso compounds (Formula 2 ) activate the electrophile through hydrogen bonding with the acid catalyst. Afterwards, the activated electrophile and enamine react to produce a nitroso aldol reaction product (Formula 3 ).
  • the nitroso aldol reaction product forms a more stable enamine when dehydrated at room temperature.
  • process A which includes enamine synthesis through the reaction of a chiral diamine catalyst and cycloketone, proceeds slowly, resulting in a decrease in the reaction rate. Without brine, process A proceeded quickly, but after the reaction between the enamine and the nitroso compound, the hydrolysis (C) of the imine to the ⁇ -hydroxyamino compound was slow, resulting in a side reaction.
  • toluene was used as a solvent (entry 8 in Table 1)
  • the reaction time was short, but side reactions proceeded quickly and several by-products were produced.
  • benzoic acid was added (entry 8 in Table 3)
  • self-aldol condensation was prevented, by-products were minimized, and cycloketone was activated.
  • Density Functional Theory (DFT) calculations were intended to demonstrate the mechanisms of substrates and catalysts and were performed using Gaussian 16 and Gauss-View 6.0 programs.
  • the optimized shape was described using the Becke three-parameter Lee-Yang-Parr (B3LYP) level. Afterwards, single point calculations were performed on the optimized shape using the 6-31G(d,p) basis set. After the shapes of reactants, intermediates (IM), transition states (TS), and products are fully optimized, the thermodynamic functions and parameters (Gibbs free energy) of the reactants are determined through calculation of vibrational frequencies. was obtained. Minimum or transition state energies were obtained at the same level of theory. Enthalpy correction and temperature-dependent entropy were calculated at 298 K and 1 atm.
  • thermodynamic analysis was performed to confirm the solvent effect on the nitroso aldol reaction. To this end, based on the results confirmed in Figure 3, the thermodynamic energies of various solvents for the transition state of catalyst 1a were compared ( Figure 4).

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Abstract

The present invention relates to a method for producing a chiral nitroso derivative using an organic chiral catalyst compound based on (R,R)-1,2-diphenylethylenediamine (DPEN), and the like. According to the production method, a chiral nitroso derivative with high enantioselectivity through an asymmetric aldol reaction between a cyclic ketone and a nitroso compound can be produced with high yield. In particular, in the production method of the present invention, the catalyst compound forms a hydrogen bond with the nitroso compound to activate an electrophile and form a transition state in such a manner that steric hindrance is minimized, thereby producing a stable product. In addition, a chiral nitroso derivative produced according to the present invention can be used in the main reaction of various synthetic intermediates, and thus can be used in the field of pharmaceutical organic synthesis.

Description

유기 키랄 촉매 화합물을 이용한 나이트로소 화합물의 질소 선택적 키랄 알돌 반응 생성물의 제조방법Method for producing nitrogen-selective chiral aldol reaction products of nitroso compounds using organic chiral catalyst compounds
본 발명은 유기 키랄 촉매 화합물을 이용한 고리형 케톤과 나이트로소 화합물의 질소 선택적 키랄 알돌 반응 생성물의 제조방법 등에 관한 것이다.The present invention relates to a method for producing a nitrogen-selective chiral aldol reaction product of a cyclic ketone and a nitroso compound using an organic chiral catalyst compound.
분자의 기본적 성질을 이해함에 있어 분자 내 원자의 공간적 배열은 중요한 의미를 갖는다. 지난 수십 년 동안 유기화학자들은 화합물의 입체화학을 효율적으로 제어하기 위해 촉매를 이용한 입체 선택적 유기 반응을 개발하기 위해 많은 노력을 기울였으며, 최근까지 금속 촉매를 이용한 다양한 입체 선택적 유기 반응에 대한 연구들이 상당수 보고되고 있다.In understanding the basic properties of molecules, the spatial arrangement of atoms within a molecule is important. Over the past few decades, organic chemists have put a lot of effort into developing stereoselective organic reactions using catalysts to efficiently control the stereochemistry of compounds, and until recently, a significant number of studies have been conducted on various stereoselective organic reactions using metal catalysts. It is being reported.
금속 촉매는 높은 촉매 활성을 나타내나, 고가이며, 금속 이온에는 공기와 수분이 포함되어 있어 반응 환경에서 불안정한 경우가 많다. 또한, 금속 촉매를 사용하는 경우, 생성물에 금속이 소량 잔류할 수 있고, 사용 후 폐기로 인해 환경 오염 문제가 발생할 수 있다. 따라서 이러한 단점을 극복하기 위해 유기 촉매를 이용한 입체 선택적 합성에 대한 연구가 주목받고 있다. 유기 촉매는 일반적으로 탄소, 수소, 질소, 및 황을 포함하며 금속 코어와 리간드를 포함하는 금속 촉매와 구조적으로 상이하다.Metal catalysts exhibit high catalytic activity, but are expensive, and because metal ions contain air and moisture, they are often unstable in the reaction environment. Additionally, when a metal catalyst is used, a small amount of metal may remain in the product, and environmental pollution problems may occur due to disposal after use. Therefore, to overcome these shortcomings, research on stereoselective synthesis using organic catalysts is attracting attention. Organic catalysts generally contain carbon, hydrogen, nitrogen, and sulfur and are structurally different from metal catalysts, which include a metal core and ligands.
알돌 반응(Aldol reaction)은 탄소-탄소 결합을 형성하는 주요 반응이며, 생물학적 활성을 나타내는 광범위한 천연 생성물 또는 복합 화합물을 합성하는데 사용되는 중요한 반응이다. 비대칭 나이트로소 알돌 반응은 카보닐기에 질소를 도입할 수 있는 강력한 합성 도구로서 광학적으로 활성인 α-하이드록시아미노 카보닐 화합물을 구성하는데 사용할 수 있다. The Aldol reaction is the main reaction that forms carbon-carbon bonds and is an important reaction used to synthesize a wide range of natural products or complex compounds that exhibit biological activity. The asymmetric nitroso aldol reaction is a powerful synthetic tool that can introduce nitrogen to carbonyl groups and can be used to construct optically active α-hydroxyamino carbonyl compounds.
이런 배경 하에서, 본 발명자들은 나이트로소 알돌 반응을 효과적으로 촉매하여 생성물의 입체화학을 제어할 수 있는 (R,R)-1,2-다이페닐에틸렌다이아민(DPEN) 기반 촉매를 이용하여 높은 수율 및 광학 순도로 반응 생성물을 제조하는 방법을 개발하여 본 발명을 완성하였다.Under this background, the present inventors achieved high yield by using a (R,R)-1,2-diphenylethylenediamine (DPEN)-based catalyst that can effectively catalyze the nitroso aldol reaction and control the stereochemistry of the product. And the present invention was completed by developing a method for producing a reaction product with optical purity.
본 발명의 목적은 키랄 디아민 촉매를 이용하여 비대칭 알돌 반응을 통해 키랄 나이트로소 유도체의 제조방법을 제공하는 것이다.The purpose of the present invention is to provide a method for producing chiral nitroso derivatives through an asymmetric aldol reaction using a chiral diamine catalyst.
본 발명의 다른 목적은 상기 제조방법으로 제조된 키랄 나이트로소 유도체를 제공하는 것이다.Another object of the present invention is to provide a chiral nitroso derivative prepared by the above production method.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당해 기술분야의 통상의 기술자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.
상기 과제를 해결하기 위하여, 본 발명은 [화학식 1]로 표시되는 화합물과 [화학식 2]로 표시되는 화합물을 반응시켜 [화학식 3]로 표시되는 화합물을 제조하는 단계를 포함하고, 상기 반응에서 [화학식 4]로 표시되는 촉매 화합물을 이용하는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법을 제공한다.In order to solve the above problem, the present invention includes the step of reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] to prepare a compound represented by [Formula 3], and in the reaction [ A method for producing a chiral nitroso derivative is provided, characterized by using a catalyst compound represented by Formula 4.
[화학식 1][Formula 1]
Figure PCTKR2023003846-appb-img-000001
;
Figure PCTKR2023003846-appb-img-000001
;
[화학식 2][Formula 2]
Figure PCTKR2023003846-appb-img-000002
;
Figure PCTKR2023003846-appb-img-000002
;
[화학식 3][Formula 3]
Figure PCTKR2023003846-appb-img-000003
;
Figure PCTKR2023003846-appb-img-000003
;
[화학식 4][Formula 4]
Figure PCTKR2023003846-appb-img-000004
.
Figure PCTKR2023003846-appb-img-000004
.
상기 화학식 1 및 화학식 3에서, R1 및 R2는 이들이 부착된 탄소 및 별표(*) 표시된 탄소와 함께 C5-C8의 사이클로알킬기 또는 헤테로사이클로알킬기를 형성할 수 있고, In Formulas 1 and 3, R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
상기 화학식 2 및 화학식 3에서, R3는 할로겐기, 시아노기, 니트로기, 하이드록시기, C1-C9의 사슬형 알킬기, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상으로 치환되거나 비치환된 C5-C8의 아릴기이고, In Formula 2 and Formula 3, R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
상기 화학식 4에서, R4는 C1-C9의 사슬형 알킬기 또는 사이클로알킬기일 수 있다.In Formula 4, R 4 may be a C 1 -C 9 chain alkyl group or a cycloalkyl group.
본 발명의 일 구현예로서, 상기 반응은 비대칭 알돌 반응(asymmetric aldol reaction)일 수 있다. As an embodiment of the present invention, the reaction may be an asymmetric aldol reaction.
본 발명의 다른 구현예로서, 상기 반응은 [화학식 1]로 표시되는 화합물이 [화학식 4]로 표시되는 촉매 화합물과 반응하여 엔아민 중간체를 형성한 후, [화학식 2]로 표시되는 화합물과 반응하여 질소 선택적 알돌 반응을 통해 [화학식 3]로 표시되는 화합물을 생성하는 것일 수 있다. In another embodiment of the present invention, the reaction involves reacting a compound represented by [Formula 1] with a catalyst compound represented by [Formula 4] to form an enamine intermediate, and then reacting with a compound represented by [Formula 2]. Thus, a compound represented by [Formula 3] may be produced through a nitrogen-selective aldol reaction.
종래 나이트로소 알돌 반응은 친핵체로서 엔올레이트를 이용하거나, 카보닐 화합물을 사전 활성화하거나, 직접적으로 엔아민 화합물을 사용하며 산소 선택성을 보이는 반응이 대부분이나, 본 발명은 반응 중에 엔아민 중간체를 형성함으로써 질소 선택적 나이트로소 알돌 반응을 유도할 수 있다. [화합물 3]로 표시되는 질소 선택성 나이트로소 유도체는 다양한 합성 중간체의 주요 반응에 사용될 수 있으므로 의약품 유기합성 분야에 활용될 수 있다.Most of the conventional nitroso aldol reactions use enolate as a nucleophile, pre-activate a carbonyl compound, or directly use an enamine compound and show oxygen selectivity, but the present invention forms an enamine intermediate during the reaction. By doing so, a nitrogen-selective nitroso aldol reaction can be induced. The nitrogen-selective nitroso derivative represented by [Compound 3] can be used in the main reactions of various synthetic intermediates and thus can be utilized in the field of pharmaceutical organic synthesis.
본 발명의 다른 구현예로서, 상기 [화학식 1]로 표시되는 화합물은 하기 [화학식 1-1] 로 표시되는 화합물일 수 있다.As another embodiment of the present invention, the compound represented by [Formula 1] may be a compound represented by the following [Formula 1-1].
[화학식 1-1][Formula 1-1]
Figure PCTKR2023003846-appb-img-000005
.
Figure PCTKR2023003846-appb-img-000005
.
본 발명의 다른 구현예로서, 상기 [화학식 2]로 표시되는 화합물은 하기 [화학식 2-1] 로 표시되는 화합물일 수 있다.As another embodiment of the present invention, the compound represented by [Formula 2] may be a compound represented by the following [Formula 2-1].
[화학식 2-1][Formula 2-1]
Figure PCTKR2023003846-appb-img-000006
.
Figure PCTKR2023003846-appb-img-000006
.
본 발명의 다른 구현예로서, 상기 [화학식 3]로 표시되는 화합물은 하기 [화학식 3-1] 로 표시되는 화합물일 수 있다.As another embodiment of the present invention, the compound represented by [Formula 3] may be a compound represented by the following [Formula 3-1].
[화학식 3-1][Formula 3-1]
Figure PCTKR2023003846-appb-img-000007
.
Figure PCTKR2023003846-appb-img-000007
.
본 발명의 다른 구현예로서, 상기 [화학식 4]로 표시되는 화합물은 하기 [화학식 4-1] 내지 [화학식 4-5]로 표시되는 화합물들로부터 선택되는 어느 하나 이상일 수 있다.As another embodiment of the present invention, the compound represented by [Formula 4] may be any one or more selected from the compounds represented by [Formula 4-1] to [Formula 4-5] below.
[화학식 4-1][Formula 4-1]
Figure PCTKR2023003846-appb-img-000008
;
Figure PCTKR2023003846-appb-img-000008
;
[화학식 4-2][Formula 4-2]
Figure PCTKR2023003846-appb-img-000009
;
Figure PCTKR2023003846-appb-img-000009
;
[화학식 4-3][Formula 4-3]
Figure PCTKR2023003846-appb-img-000010
;
Figure PCTKR2023003846-appb-img-000010
;
[화학식 4-4][Formula 4-4]
Figure PCTKR2023003846-appb-img-000011
; 및
Figure PCTKR2023003846-appb-img-000011
; and
[화학식 4-5][Formula 4-5]
Figure PCTKR2023003846-appb-img-000012
.
Figure PCTKR2023003846-appb-img-000012
.
본 발명의 다른 구현예로서, 상기 촉매 화합물은 [화학식 4]로 표시되는 화합물의 염 형태일 수 있으며, 바람직하게는 염산염(HCl)일 수 있다.As another embodiment of the present invention, the catalyst compound may be a salt form of the compound represented by [Formula 4], and preferably may be hydrochloride (HCl).
본 발명의 다른 구현예로서, 상기 반응은 극성 양성자성 용매, 극성 비양성자성 용매, 또는 무극성 용매에서 수행될 수 있으며, 상기 용매의 비제한적인 예로서, 상기 용매는 물(water), 염수(brine), 디메틸설폭사이드(DMSO), 니트로메탄(CH3NO2), 아세토니트릴(CH3CN), 메탄올(MeOH), 에탄올(EtOH), 아세톤, 사이클로헥사논, 클로로에탄(EtCl2), 디클로로메탄(CH2Cl2), 테트라하이드로퓨란(THF), 아닐린, 클로로벤젠, 클로로포름(CHCl3), 디에틸에테르(Et2O), 톨루엔, 벤젠, 사염화탄소(CCl4), 사이클로헥산, 헵탄 등일 수 있으나, 이에 제한되는 것은 아니다. As another embodiment of the present invention, the reaction may be performed in a polar protic solvent, a polar aprotic solvent, or a non-polar solvent. As a non-limiting example of the solvent, the solvent may be water, brine ( brine), dimethyl sulfoxide (DMSO), nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), ethanol (EtOH), acetone, cyclohexanone, chloroethane (EtCl 2 ), Dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), aniline, chlorobenzene, chloroform (CHCl 3 ), diethyl ether (Et 2 O), toluene, benzene, carbon tetrachloride (CCl 4 ), cyclohexane, heptane. It may be, but is not limited to this.
바람직하게는, 상기 반응은 유전상수(dielectric constant)가 30 이상인 극성 용매(polar solvent)에서 수행되는 것일 수 있으며, 더욱 바람직하게는 물(water), 염수(brine), 디메틸설폭사이드(DMSO), 니트로메탄(CH3NO2), 아세토니트릴(CH3CN), 메탄올(MeOH), 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상의 용매에서 수행되는 것일 수 있으나, 이에 제한되는 것은 아니다.본 발명의 다른 구현예로서, 상기 반응은 [화학식 1]로 표시되는 화합물과 [화학식 2]로 표시되는 화합물를 2:1 내지 1:2의 당량비, 바람직하게는 2:1로 반응시키는 것일 수 있다.Preferably, the reaction may be carried out in a polar solvent having a dielectric constant of 30 or more, more preferably water, brine, dimethyl sulfoxide (DMSO), It may be performed in one or more solvents selected from the group consisting of nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), and combinations thereof, but is not limited thereto. As another embodiment of the invention, the reaction may be performed by reacting the compound represented by [Formula 1] with the compound represented by [Formula 2] at an equivalence ratio of 2:1 to 1:2, preferably 2:1.
본 발명의 다른 구현예로서, 상기 반응은 [화학식 4]로 표시되는 촉매 화합물을 5 ~ 10 mol%를 첨가하는 것일 수 있다.As another embodiment of the present invention, the reaction may involve adding 5 to 10 mol% of a catalyst compound represented by [Formula 4].
본 발명의 다른 구현예로서, 상기 [화학식 1]로 표시되는 화합물, [화학식 2]로 표시되는 화합물과 함께 추가적으로 벤조산을 첨가하여 반응시키는 것일 수 있다.As another embodiment of the present invention, benzoic acid may be added and reacted with the compound represented by [Formula 1] and the compound represented by [Formula 2].
본 발명의 다른 구현예로서, 상기 반응은 상온에서 하나의 반응기 내에서 수행되는 것일 수 있다.As another embodiment of the present invention, the reaction may be performed in a single reactor at room temperature.
본 발명의 다른 구현예로서, 상기 반응은 15분 ~ 24시간 내에 완료되는 것일 수 있다.As another embodiment of the present invention, the reaction may be completed within 15 minutes to 24 hours.
본 발명의 다른 구현예로서, 상기 반응은 -10 ~ 25℃에서 수행되는 것일 수 있다. 바람직하게는 0 ~ -10 ℃의 온도에서 수행되는 것일 수 있다.As another embodiment of the present invention, the reaction may be performed at -10 to 25°C. Preferably, it may be performed at a temperature of 0 to -10°C.
또한, 본 발명은 상술한 제조방법으로 제조된 키랄 나이트로소 유도체를 제공한다.Additionally, the present invention provides a chiral nitroso derivative prepared by the above-described production method.
본 발명의 일 실시예에 따른 키랄 나이트로소 유도체의 제조방법은 (R,R)-1,2-다이페닐에틸렌다이아민(DPEN) 기반의 디아민 촉매를 이용하여 고리형 케톤과 엔아민을 형성하고, 상기 엔아민이 나이트로소 화합물과 반응하여 높은 수율과 거울상선택성을 가지는 나이트로소 유도체를 제조할 수 있다. 특히, 상기 촉매는 쉽게 합성이 가능한 유기 촉매로서 수소결합을 통해 나이트로소 화합물을 활성화시켜 친전자성을 높일 수 있다.The method for producing a chiral nitroso derivative according to an embodiment of the present invention uses a diamine catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) to form a cyclic ketone and an enamine. And, the enamine reacts with the nitroso compound to produce a nitroso derivative with high yield and enantioselectivity. In particular, the catalyst is an organic catalyst that can be easily synthesized and can increase electrophilicity by activating nitroso compounds through hydrogen bonding.
본 발명의 일 실시예에 따른 키랄 나이트로소 유도체의 제조방법은 용매로 물 또는 염수를 사용하여 친환경적이며, 전이상태를 안정화시키므로 비대칭 나이트로소 알돌 반응 생성물의 수율을 향상시킬 수 있다.The method for producing a chiral nitroso derivative according to an embodiment of the present invention is environmentally friendly by using water or brine as a solvent, and can improve the yield of the asymmetric nitroso aldol reaction product by stabilizing the transition state.
본 발명의 일 실시예에 따른 키랄 나이트로소 유도체의 제조방법은 입체장애를 최소화하는 방향으로 전이상태를 형성함으로써 질소 선택적 나이트로소 알돌 반응을 유도하므로 광학순도를 증가시킬 수 있다.The method for producing a chiral nitroso derivative according to an embodiment of the present invention induces a nitrogen-selective nitroso aldol reaction by forming a transition state in the direction of minimizing steric hindrance, thereby increasing optical purity.
본 발명의 일 실시예에 따라 제조된 키랄 나이트로소 유도체는 질소 선택성을 가지며 다양한 합성 중간체의 주요 반응에 사용될 수 있으므로 의약품 유기합성 분야에 활용될 수 있다.The chiral nitroso derivative prepared according to an embodiment of the present invention has nitrogen selectivity and can be used in the main reactions of various synthetic intermediates, so it can be used in the field of pharmaceutical organic synthesis.
본 발명의 일 실시예에 따른 키랄 나이트로소 유도체 및 이의 제조방법의 효과는 이상에서 언급된 것들에 한정되지 않으며, 언급되지 아니한 다른 효과들은 아래의 기재로부터 통상의 기술자에게 명확하게 이해될 수 있을 것이다.The effects of the chiral nitroso derivative and its preparation method according to an embodiment of the present invention are not limited to those mentioned above, and other effects not mentioned can be clearly understood by those skilled in the art from the description below. will be.
도 1은 본 발명의 일 실시예로서 질소 선택적 나이트로소 알돌 반응에 따른 키랄 나이트로소 유도체의 제조방법의 반응식이다.Figure 1 is a reaction scheme of a method for producing a chiral nitroso derivative according to a nitrogen-selective nitroso aldol reaction as an example of the present invention.
도 2는 제안된 전이상태를 포함하는 나이트로소 알돌 반응의 촉매 사이클을 나타낸 것이다.Figure 2 shows the catalytic cycle of the nitroso aldol reaction including the proposed transition state.
도 3은 B3LYP/6-31G(d,p) 방법을 기반으로 촉매 1a 및 1b(화학식 4-1 및 4-2)의 촉매화 전이 상태를 나타내는 상대 자유 에너지 다이어그램을 나타낸 것으로서, 기상 및 수상에서 계산을 수행하였다. 이 때, 1은 사이클로헥사논, 2는 나이트로소벤젠, 3은 촉매 1a, 4는 촉매 1b이다.Figure 3 shows the relative free energy diagram representing the catalytic transition state of catalysts 1a and 1b (Formulas 4-1 and 4-2 ) based on the B3LYP/6-31G(d,p) method in the gas phase and aqueous phase. Calculations were performed. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, 3 is catalyst 1a , and 4 is catalyst 1b .
도 4는 비대칭 나이트로소 알돌 반응의 전이상태에 대한 용매 효과를 나타낸 것이다. 다양한 용매 조건에서 B3LYP/6-31G(d,p) 방법을 기반으로 계산을 수행하였다.Figure 4 shows the effect of solvent on the transition state of the asymmetric nitroso aldol reaction. Calculations were performed based on the B3LYP/6-31G(d,p) method under various solvent conditions.
도 5는 B3LYP/6-31G(d,p) 계산과 (R,R)-1,2-다이페닐에틸렌다이아민(DPEN)-이미늄염 촉매화된 거울상선택성 나이트로소 알돌 반응의 상대 자유 에너지 다이어그램을 기반으로 제안된 촉매 메커니즘을 나타낸 것으로서, 수상에서 계산을 수행하였다. 이 때, 1은 사이클로헥사논, 2는 나이트로소벤젠, 3은 촉매 1a이다.Figure 5 shows B3LYP/6-31G(d,p) calculations and relative free energies of (R,R)-1,2-diphenylethylenediamine (DPEN)-iminium salt catalyzed enantioselective nitroso aldol reaction. The proposed catalytic mechanism is shown based on the diagram, and calculations were performed in the aqueous phase. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, and 3 is catalyst 1a .
본 발명자들은 (R,R)-1,2-다이페닐에틸렌다이아민(DPEN) 기반 촉매와 고리형 케톤이 반응하여 형성된 엔아민이 산 촉매와의 수소 결합을 통해 활성화된 나이트로소 화합물의 산소를 공격하여 질소 선택적 나이트로소 알돌 반응을 유도한다는 점을 확인하였다(도 1). The present inventors discovered that the enamine formed by the reaction of a catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) and a cyclic ketone is the oxygen of the nitroso compound activated through hydrogen bonding with the acid catalyst. It was confirmed that it attacks and induces a nitrogen-selective nitroso aldol reaction (Figure 1).
특히, 메탄올(MeOH), 아세토니트릴(CH3CN), DMSO, 염수(brine)와 같은 극성 용매를 사용하거나, 온도를 낮추거나, 촉매량을 늘리거나, 벤조산을 첨가하거나, 고리형 케톤과 나이트로소 화합물의 당량비가 2:1인 경우 최적으로 진행된다는 점을 확인하였다.In particular, using polar solvents such as methanol (MeOH), acetonitrile (CH 3 CN), DMSO, or brine, lowering the temperature, increasing the amount of catalyst, adding benzoic acid, or using cyclic ketones and nitro It was confirmed that optimal progress was made when the equivalence ratio of the small compounds was 2:1.
따라서, 본 발명은 [화학식 4]로 표시되는 촉매 화합물을 이용하여 [화학식 1]로 표시되는 화합물과 [화학식 2]로 표시되는 화합물을 반응시켜 [화학식 3]로 표시되는 화합물을 제조하는 단계를 포함하는, 키랄 나이트로소 유도체의 제조방법을 제공한다.Therefore, the present invention involves preparing a compound represented by [Formula 3] by reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] using a catalyst compound represented by [Formula 4]. It provides a method for producing a chiral nitroso derivative, including:
상기 제조방법에 따르면 높은 수준의 거울상선택성을 가진 나이트로소 알돌 반응 생성물을 우수한 수율로 제조할 수 있다.According to the above production method, a nitroso aldol reaction product with a high level of enantioselectivity can be produced in excellent yield.
[화학식 1][Formula 1]
Figure PCTKR2023003846-appb-img-000013
;
Figure PCTKR2023003846-appb-img-000013
;
[화학식 2][Formula 2]
Figure PCTKR2023003846-appb-img-000014
;
Figure PCTKR2023003846-appb-img-000014
;
[화학식 3][Formula 3]
Figure PCTKR2023003846-appb-img-000015
;
Figure PCTKR2023003846-appb-img-000015
;
[화학식 4][Formula 4]
Figure PCTKR2023003846-appb-img-000016
.
Figure PCTKR2023003846-appb-img-000016
.
상기 화학식 1 및 화학식 3에서, R1 및 R2는 이들이 부착된 탄소 및 별표(*) 표시된 탄소와 함께 C5-C8의 사이클로알킬기 또는 헤테로사이클로알킬기를 형성할 수 있고, In Formulas 1 and 3, R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
상기 화학식 2 및 화학식 3에서, R3는 할로겐기, 시아노기, 니트로기, 하이드록시기, C1-C9의 사슬형 알킬기, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상으로 치환되거나 비치환된 C5-C8의 아릴기이고, In Formula 2 and Formula 3, R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
상기 화학식 4에서, R4는 C1-C9의 사슬형 또는 고리형 알킬기일 수 있다.In Formula 4, R 4 may be a C 1 -C 9 chain or cyclic alkyl group.
본 발명에서, 용어 “치환”은 화합물의 분자 중에 포함되는 원자 또는 원자단을 다른 원자 또는 원자단으로 바꾸어 놓는 반응이다.In the present invention, the term “substitution” refers to a reaction in which an atom or atomic group contained in a molecule of a compound is replaced with another atom or atomic group.
본 발명에서, 용어 “사슬형 알킬기”는 특정된 수의 탄소 원자를 가지며 적어도 하나의 원자가를 갖는 직쇄 또는 분지쇄 포화 지방족 탄화수소로부터 유래된 기를 지칭한다. 이러한 알킬기의 예로는 메틸, 에틸, 프로필, 아이소프로필, 부틸, 아이소부틸, 2-부틸, 3-부틸, 펜틸, n-헥실 등을 포함하나 이에 제한되지 않는다.In the present invention, the term “chain alkyl group” refers to a group derived from a straight-chain or branched-chain saturated aliphatic hydrocarbon having a specified number of carbon atoms and a valency of at least one. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, etc.
본 발명에서, 용어 “사이클로알킬기”는 고리형 알킬기라고도 하며, 모든 고리 구성원이 탄소인 하나 이상의 포화 고리를 갖는 1가 기를 지칭한다. 이러한 사이클로알킬기의 예로는 사이클로부틸기, 사이클로펜틸기, 사이클로헥실기 등을 포함하나 이에 제한되지 않는다.In the present invention, the term “cycloalkyl group”, also referred to as a cyclic alkyl group, refers to a monovalent group having one or more saturated rings in which all ring members are carbon. Examples of such cycloalkyl groups include, but are not limited to, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups.
본 발명에서, 용어 "헤테로사이클로알킬기"는 통상적으로 포화 또는 불포화(그러나 방향족은 아님) 사이클로탄화수소 (Cyclohydrocarbon)를 지칭하고, 이는 선택적으로 비치환, 단일 치환 또는 다중 치환된 것일 수 있으며, 이의 구조에서 적어도 하나는 N, O 또는 S의 헤테로 원자로부터 선택된다.In the present invention, the term "heterocycloalkyl group" typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, mono-substituted or poly-substituted, and in its structure At least one is selected from heteroatoms of N, O or S.
본 발명에서, 용어 "아릴기"는 단일링(예를 들면 페닐) 또는 복수의 축합링(예를 들면 나프틸)을 갖는 탄소원자수 6 내지 20의 불포화 방향족 고리화합물을 의미한다. 이러한 아릴의 예로는 페닐, 나프틸 등을 포함하나 이에 제한되지 않는다.In the present invention, the term “aryl group” refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg, phenyl) or a plurality of condensed rings (eg, naphthyl). Examples of such aryl include, but are not limited to, phenyl, naphthyl, etc.
본 발명에서, 용어 “할로겐기”는 주기율표의 17족에 속하는 원소들로, 플루오린 (F), 클로라이드 (Cl), 브로민 (Br), 또는 아이오딘 (I) 등일 수 있다.In the present invention, the term “halogen group” refers to elements belonging to group 17 of the periodic table and may include fluorine (F), chloride (Cl), bromine (Br), or iodine (I).
실시예에서 사용한 용어는 단지 설명을 목적으로 사용된 것으로, 한정하려는 의도로 해석되어서는 안 된다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 명세서에서, "포함하다" 또는 "가지다" 등의 용어는 명세서 상에 기재된 특징, 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terms used in the examples are for descriptive purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features. It should be understood that this does not exclude in advance the possibility of the existence or addition of elements, numbers, steps, operations, components, parts, or combinations thereof.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 실시예가 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the embodiments belong. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless explicitly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.
실시예의 구성 요소를 설명하는 데 있어서, 제1, 제2, A, B, (a), (b) 등의 용어를 사용할 수 있다. 이러한 용어는 그 구성 요소를 다른 구성 요소와 구별하기 위한 것일 뿐, 그 용어에 의해 해당 구성 요소의 본질이나 차례 또는 순서 등이 한정되지 않는다. 어떤 구성 요소가 다른 구성요소에 "연결", "결합" 또는 "접속"된다고 기재된 경우, 그 구성 요소는 그 다른 구성요소에 직접적으로 연결되거나 접속될 수 있지만, 각 구성 요소 사이에 또 다른 구성 요소가 "연결", "결합" 또는 "접속"될 수도 있다고 이해되어야 할 것이다.In describing the components of the embodiment, terms such as first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term. When a component is described as being "connected," "coupled," or "connected" to another component, that component may be directly connected or connected to that other component, but there is no need for another component between each component. It should be understood that may be “connected,” “combined,” or “connected.”
이하에서, 첨부된 도면을 참조하여 실시예들을 상세하게 설명한다. 그러나, 실시예들에는 다양한 변경이 가해질 수 있어서 특허출원의 권리범위가 이러한 실시예들에 의해 제한되거나 한정되는 것은 아니다. 실시예들에 대한 모든 변경, 균등물 내지 대체물이 권리 범위에 포함되는 것으로 이해되어야 한다.Hereinafter, embodiments will be described in detail with reference to the attached drawings. However, since various changes can be made to the embodiments, the scope of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents, or substitutes for the embodiments are included in the scope of rights.
또한, 첨부 도면을 참조하여 설명함에 있어, 도면 부호에 관계없이 동일한 구성 요소는 동일한 참조부호를 부여하고 이에 대한 중복되는 설명은 생략하기로 한다. 실시예를 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 실시예의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.In addition, when describing with reference to the accompanying drawings, identical components will be assigned the same reference numerals regardless of the reference numerals, and overlapping descriptions thereof will be omitted. In describing the embodiments, if it is determined that detailed descriptions of related known technologies may unnecessarily obscure the gist of the embodiments, the detailed descriptions are omitted.
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 이하 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Since the present invention can be modified in various ways and can have various embodiments, specific embodiments will be illustrated in the drawings and explained in detail in the detailed description below. However, this is not intended to limit the present invention to specific embodiments, and should be understood to include all transformations, equivalents, and substitutes included in the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a detailed description of related known technologies may obscure the gist of the present invention, the detailed description will be omitted.
실시예 1. 본 발명의 키랄 나이트로소 유도체의 합성Example 1. Synthesis of chiral nitroso derivatives of the present invention
1.1. 기기 및 시약1.1. Instruments and Reagents
자동 디지털 편광계를 사용하여 광학 회전(optical rotation)을 측정하였고, Thermo Electron Corporation(Thermo Fisher Scientific Inc., Waltham, MA, USA)의 NICOLET 380 FT-IR 분광 광도계를 사용하여 FT-IR 스펙트럼을 기록하였다. Varian Gemini 300(300, 75MHz) 및 Varian Mercury 400(400, 100MHz, Agilent, Santa Clara, CA, USA)을 사용하여 내부 표준으로 TMS(300, 75MHz, Agilent, Santa Clara, CA, USA)를 사용하여 1H NMR 및 13C NMR 스펙트럼을 수득하였다. Jasco LC-1500 Series HPLC system(JASCO, 4-21, Sennin-cho 2-chome, Hachioji, Tokyo 193-0835, Japan)을 사용하여 키랄 HPLC 분석을 수행하였다. 톨루엔(CaH2), THF(Na, benzophenone), 및 CH2Cl2(CaH2) 반응용매는 정제하여 사용하였다. 본 발명에 사용된 시약은 Aldrich(Louis, MO, USA), TCI(Tokyo, Japan)의 제품을 사용하였으며, 필요한 경우 공지된 방법으로 정제 또는 건조하였다. Merck's silica gel 60 (230-400 mech)을 컬럼 크로마토그래피의 고정상으로 사용하였다.Optical rotation was measured using an automated digital polarimeter, and FT-IR spectra were recorded using a NICOLET 380 FT-IR spectrophotometer from Thermo Electron Corporation (Thermo Fisher Scientific Inc., Waltham, MA, USA). . using Varian Gemini 300 (300, 75 MHz) and Varian Mercury 400 (400, 100 MHz, Agilent, Santa Clara, CA, USA) with TMS (300, 75 MHz, Agilent, Santa Clara, CA, USA) as internal standard. 1 H NMR and 13 C NMR spectra were obtained. Chiral HPLC analysis was performed using a Jasco LC-1500 Series HPLC system (JASCO, 4-21, Sennin-cho 2-chome, Hachioji, Tokyo 193-0835, Japan). Toluene (CaH 2 ), THF (Na, benzophenone), and CH 2 Cl 2 (CaH 2 ) reaction solvents were purified and used. The reagents used in the present invention were products from Aldrich (Louis, MO, USA) and TCI (Tokyo, Japan), and, if necessary, were purified or dried by known methods. Merck's silica gel 60 (230-400 mech) was used as a stationary phase for column chromatography.
1.2. 아민 촉매(화학식 4)의 합성1.2. Synthesis of amine catalyst (Formula 4)
디클로로메탄에서 (R,R)-1,2-디페닐에틸렌디아민(DPEN, 300 mg, 1.41 mmol)의 용액에 카보닐 화합물(1.41 mmol) 및 MgSO4 141 mL를 첨가하였다. 혼합물을 48시간 동안 환류시켰다. 이후 셀라이트 필터(celite filter)를 통해 MgSO4를 제거하고 진공에서 농축하였다. NaBH4(4.0 당량) 및 에탄올 14 mL를 첨가하고, 혼합물을 실온에서 3시간 동안 교반하고, 1 N NaOH 용액으로 퀜칭하고, 에틸 아세테이트 20 mL로 3회 추출하였다. 합한 유기 추출물을 염수(brine)로 세척하고, MgSO4를 건조시키고 진공에서 농축시켰다. 생성물을 실리카겔 칼럼 크로마토그래피(메탄올/염화메틸렌 1:20)로 정제하여 거품상 고체로서 순수한 아미드 생성물(정량적 수율)을 수득하였다(반응식 1).To a solution of (R,R)-1,2-diphenylethylenediamine (DPEN, 300 mg, 1.41 mmol) in dichloromethane was added the carbonyl compound (1.41 mmol) and 141 mL of MgSO 4 . The mixture was refluxed for 48 hours. Afterwards, MgSO 4 was removed through a celite filter and concentrated in vacuum. NaBH 4 (4.0 equiv) and 14 mL of ethanol were added, and the mixture was stirred at room temperature for 3 hours, quenched with 1 N NaOH solution, and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated in vacuo. The product was purified by silica gel column chromatography (methanol/methylene chloride 1:20) to obtain the pure amide product (quantitative yield) as a foamy solid (Scheme 1).
[반응식 1][Scheme 1]
Figure PCTKR2023003846-appb-img-000017
Figure PCTKR2023003846-appb-img-000017
이 때, 시약 및 조건은 다음과 같다: (a) 1.0 eq. 카보닐 화합물, MgSO4, 톨루엔(0.1 M), 환류, 48시간. (b) 에탄올(0.1 M), NaBH4 과량, 3시간(전반적인 수율 81-90%).At this time, the reagents and conditions are as follows: (a) 1.0 eq. Carbonyl compound, MgSO 4 , toluene (0.1 M), reflux, 48 hours. (b) Ethanol (0.1 M), NaBH 4 excess, 3 h (overall yield 81-90%).
본 발명의 일 실시예에 따른 촉매의 비제한적인 예는 다음과 같다:Non-limiting examples of catalysts according to one embodiment of the present invention are as follows:
(1) (1R,2R)-N-isopropyl-1,2-diphenyl ethylenediamine(1a, 화학식 4-1)(1) (1R,2R)-N-isopropyl-1,2-diphenyl ethylenediamine ( 1a, Formula 4-1 )
[α]D 25 +24.5° (c = 5.1, CHCl3), IR (KBr): 3378, 3023, 2958, 1609, 1454, 767, 718 cm-1; 1H NMR (300 MHz, CDCl3) δ7.21 - 7.07 (m, 10H), 3.96 (d, 1H, J = 7.5 Hz), 3.79 (d, 1H, J = 7.2 Hz), 2.60 - 2.47 (m, 1H), 1.74 (s, 3H), 0.95 (d, 3H, J = 2.7 Hz), 0.93 (d, 3H, J = 2.7 Hz); 13C NMR (75 MHz, CDCl3) δ141.9, 127.7 (2C), 127.7 (2C), 127.5 (2C), 126.9 (2C), 126.6, 126.5, 66.8, 61.8, 45.6, 24.3, 21.7, HRMS (FAB+) for C17H23N2 [M+H] +, Calcd: 255.1861, Found: 255.1863 [α] D 25 +24.5° (c = 5.1, CHCl 3 ), IR (KBr): 3378, 3023, 2958, 1609, 1454, 767, 718 cm -1 ; 1H NMR (300 MHz, CDCl 3 ) δ7.21 - 7.07 (m, 10H), 3.96 (d, 1H, J = 7.5 Hz), 3.79 (d, 1H, J = 7.2 Hz), 2.60 - 2.47 (m , 1H), 1.74 (s, 3H), 0.95 (d, 3H, J = 2.7 Hz), 0.93 (d, 3H, J = 2.7 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ141.9, 127.7 (2C), 127.7 (2C), 127.5 (2C), 126.9 (2C), 126.6, 126.5, 66.8, 61.8, 45.6, 24.3, 21.7, HRMS ( FAB+) for C 17 H 23 N 2 [M+H] + , Calcd: 255.1861, Found: 255.1863
(2) (1R,2R)-N-(3-pentyl)-1,2-diphenyl ethylenediamine(1b, 화학식 4-2)(2) (1R,2R)-N-(3-pentyl)-1,2-diphenyl ethylenediamine ( 1b, Formula 4-2 )
[α]D 25 +9.4 (c = 6.3, CHCl3), IR (KBr): 3374, 3031, 2953, 1605, 1458, 767, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ7.18 - 7.09 (m, 10H), 3.95 (d, 1H, J = 6.8 Hz), 3.77 (d, 1H, J = 6.4 Hz), 2.21 - 2.16 (m, 1H), 1.71 (s, 3H), 1.37 - 1.19 (m, 4H), 0.76 (t, 3H, J = 7.6 Hz), 0.68 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ142.1, 127.8 (2C), 127.7 (2C), 126.9 (2C), 126.6 (2C), 126.5 (2C), 66.6, 62.0, 56.1, 26.6, 24.1, 10.2, 8.2; HRMS (FAB+) for C19H27N2 [M+H] +, Calcd: 283.2174, Found: 283.2176[α] D 25 +9.4 (c = 6.3, CHCl 3 ), IR (KBr): 3374, 3031, 2953, 1605, 1458, 767, 702 cm -1 ; 1H NMR (400 MHz, CDCl 3 ) δ7.18 - 7.09 (m, 10H), 3.95 (d, 1H, J = 6.8 Hz), 3.77 (d, 1H, J = 6.4 Hz), 2.21 - 2.16 (m , 1H), 1.71 (s, 3H), 1.37 - 1.19 (m, 4H), 0.76 (t, 3H, J = 7.6 Hz), 0.68 (t, 3H, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ142.1, 127.8 (2C), 127.7 (2C), 126.9 (2C), 126.6 (2C), 126.5 (2C), 66.6, 62.0, 56.1, 26.6, 24.1, 10.2 , 8.2; HRMS (FAB+) for C 19 H 27 N 2 [M+H] + , Calcd: 283.2174, Found: 283.2176
(3) (1R,2R)-N-(4-heptyl)-1,2-diphenyl ethylenediamine(1c, 화학식 4-3)(3) (1R,2R)-N-(4-heptyl)-1,2-diphenyl ethylenediamine ( 1c, Formula 4-3 )
[α]D 25 +16.7 (c = 17.3, CHCl3), IR (KBr): 3382, 3023, 2953, 1597, 1450, 759, 710 cm-1; 1H NMR (400 MHz, CDCl3) δ7.19 - 7.10 (m, 10H), 3.95 (d, 1H, J = 7.2 Hz), 3.78 (d, 1H, J = 7.2 Hz), 2.30 - 2.24 (m, 1H), 1.69 (s, 3H), 1.33 - 1.07 (m, 8H), 0.80 (t, 3H, J = 6.8 Hz), 0.74 (t, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ142.3, 127.9 (2C), 127.8 (2C), 127.7 (2C), 126.9 (2C), 126.7, 126.6, 66.8, 62.0, 53.6, 37.2, 35.2, 18.9, 17.6, 14.4, 14.1; HRMS (FAB+) for C21H31N2 [M+H] +, Calcd: 311.2487, Found: 311.2480 [α] D 25 +16.7 (c = 17.3, CHCl 3 ), IR (KBr): 3382, 3023, 2953, 1597, 1450, 759, 710 cm -1 ; 1H NMR (400 MHz, CDCl 3 ) δ7.19 - 7.10 (m, 10H), 3.95 (d, 1H, J = 7.2 Hz), 3.78 (d, 1H, J = 7.2 Hz), 2.30 - 2.24 (m , 1H), 1.69 (s, 3H), 1.33 - 1.07 (m, 8H), 0.80 (t, 3H, J = 6.8 Hz), 0.74 (t, 3H, J = 6.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ142.3, 127.9 (2C), 127.8 (2C), 127.7 (2C), 126.9 (2C), 126.7, 126.6, 66.8, 62.0, 53.6, 37.2, 35.2, 18.9, 17.6, 14.4, 14.1; HRMS (FAB+) for C 21 H 31 N 2 [M+H] + , Calcd: 311.2487, Found: 311.2480
(4) (1R,2R)-N-(5-nonyl)-1,2-diphenyl ethylenediamine(1d, 화학식 4-4)(4) (1R,2R)-N-(5-nonyl)-1,2-diphenyl ethylenediamine ( 1d, Formula 4-4 )
[α]D 25 -4.1 (c = 8.5 , CHCl3), IR (KBr): 3370, 3031, 2925, 1601, 1458, 767, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ7.24 - 7.10 (m, 10H), 3.96 (d, 1H, J = 6.8 Hz), 3.78 (d, 1H, J = 6.8 Hz), 2.29 - 2.23 (m, 1H), 1.74 (s, 3H), 1.31 - 0.99 (m, 12H), 0.83 (t, 3H, J = 6.8 Hz), 0.80 (t, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ142.2, /126.6, 126.6, 66.6, 61.9, 53.8, 34.4, 32.2, 27.9, 26.3, 23.0, 22.7, 14.0, 13.9; HRMS (FAB+) for C23H35N2 [M+H] +, Calcd: 339.2800, Found: 339.2806 [α] D 25 -4.1 (c = 8.5, CHCl 3 ), IR (KBr): 3370, 3031, 2925, 1601, 1458, 767, 702 cm -1 ; 1H NMR (400 MHz, CDCl 3 ) δ7.24 - 7.10 (m, 10H), 3.96 (d, 1H, J = 6.8 Hz), 3.78 (d, 1H, J = 6.8 Hz), 2.29 - 2.23 (m , 1H), 1.74 (s, 3H), 1.31 - 0.99 (m, 12H), 0.83 (t, 3H, J = 6.8 Hz), 0.80 (t, 3H, J = 6.8 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ142.2, /126.6, 126.6, 66.6, 61.9, 53.8, 34.4, 32.2, 27.9, 26.3, 23.0, 22.7, 14.0, 13.9; HRMS (FAB+) for C 23 H 35 N 2 [M+H] + , Calcd: 339.2800, Found: 339.2806
(5) (1R,2R)-N-(cyclohexyl)-1,2-diphenyl ethylenediamine(1e, 화학식 4-5)(5) (1R,2R)-N-(cyclohexyl)-1,2-diphenyl ethylenediamine ( 1e, Formula 4-5 )
[α]D 25 +14.8 (c = 31.8, CHCl3), IR (KBr): 3362, 3027, 2933, 2847, 1609, 1458, 751, 706 cm-1; 1H NMR (300 MHz, CDCl3) δ7.23 - 7.10 (m, 10H), 3.95 (d, 1H, J = 6.9 Hz), 3.85 (d, 1H, J =6.9 Hz), 2.23 - 2.16 (m, 1H), 1.69 (s, 3H), 1.88 - 1.47 (m, 5H), 1.10 - 0.90 (m, 5H); 13C NMR (100 MHz, CDCl3) δ142.2, 127.8 (2C), 127.7 (2C), 127.5 (2C), 126.9 (2C), 126.6, 126.5, 66.1, 61.9, 53.3, 34.7, 32.4, 26.0, 24.9, 24.4; HRMS (FAB+) for C20H27N2 [M+H] +, Calcd: 295.2174, Found: 295.2178[α] D 25 +14.8 (c = 31.8, CHCl 3 ), IR (KBr): 3362, 3027, 2933, 2847, 1609, 1458, 751, 706 cm -1 ; 1H NMR (300 MHz, CDCl 3 ) δ7.23 - 7.10 (m, 10H), 3.95 (d, 1H, J = 6.9 Hz), 3.85 (d, 1H, J = 6.9 Hz), 2.23 - 2.16 (m , 1H), 1.69 (s, 3H), 1.88 - 1.47 (m, 5H), 1.10 - 0.90 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) δ142.2, 127.8 (2C), 127.7 (2C), 127.5 (2C), 126.9 (2C), 126.6, 126.5, 66.1, 61.9, 53.3, 34.7, 32.4, 26.0, 24.9, 24.4; HRMS (FAB+) for C 20 H 27 N 2 [M+H] + , Calcd: 295.2174, Found: 295.2178
1.3. 고리형 케톤(화학식 1)과 나이트로소 화합물(화학식 2)의 비대칭 알돌 반응1.3. Asymmetric aldol reaction of a cyclic ketone (Formula 1) and a nitroso compound (Formula 2)
실온에서 2 mL의 반응 용매(Brine:1 N HCl = 1:1)에 아민 촉매(화학식 4, 0.023 mmol)를 용해하고 고리형 케톤(화학식 1, 0.92 mmol)을 첨가하였다. 약 10분 동안 교반한 후, 나이트로소 화합물(화학식 2, 0.46 mmol)을 첨가하였다. 6시간 동안 교반한 후 염수로 세척하고 디에틸에테르로 3회 추출하였다. 유기층을 NaHCO3로 중화하고 무수 MgSO4로 건조하고, 진공 농축 후 실리카겔 컬럼(EA:Hex = 1:10) 크로마토그래피로 반응 생성물(화학식 3)을 수득하였다.The amine catalyst (Formula 4 , 0.023 mmol) was dissolved in 2 mL of reaction solvent (Brine: 1 N HCl = 1:1) at room temperature, and cyclic ketone (Formula 1 , 0.92 mmol) was added. After stirring for about 10 minutes, a nitroso compound (Formula 2 , 0.46 mmol) was added. After stirring for 6 hours, it was washed with brine and extracted three times with diethyl ether. The organic layer was neutralized with NaHCO 3 and dried with anhydrous MgSO 4 , and after vacuum concentration, the reaction product (Formula 3 ) was obtained by chromatography on a silica gel column (EA:Hex = 1:10).
본 발명의 일 실시예에 따라 고리형 케톤과 나이트로소 화합물의 비대칭 알돌 반응으로 제조된 키랄 나이트로소 유도체의 비제한적인 예는 다음과 같다:Non-limiting examples of chiral nitroso derivatives prepared by an asymmetric aldol reaction of a cyclic ketone and a nitroso compound according to an embodiment of the present invention are as follows:
(1) (S)-2-(N-Phenyl hydroxyamino)-cyclohexanone(2a, 화학식 3-1)(1) (S)-2-(N-Phenyl hydroxyamino)-cyclohexanone ( 2a , Formula 3-1 )
[α]D 25 +189.2 (c = 9.8, CHCl3), IR (KBr) : 3398, 3058, 2937, 1712, 1598, 1492, 1448, 1400, 1290, 1122, 935 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.26 (t, 2H, J = 8.4 Hz, Ar-H), 7.05 (d, 2H, J =7.5 Hz, Ar-H), 6.94 (t, 1H, J = 7.2 Hz, Ar-H), 6.27 (s, 1H, OH), 4.23 (t, 1H, J = 9.6 Hz, CH), 1.63 - 2.58 (m, 8H, eight proton of CH2); 13C NMR (75 MHz, CDCl3) δ 209.7, 150.1, 128.6 (2C), 121.6, 115.9 (2C), 72.5, 42.0, 27.8, 27.2, 24.3; HRMS (FAB+) for C12H15NO2 [M] +, Calcd 205.1103, Found 205.1106; Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (97.6:2.4 hexane:2-propanol), 1.0 mL/min; major enantiomer tr = 42.5 min, minor enantiomer tr = 50.3 min.[α] D 25 +189.2 (c = 9.8, CHCl 3 ), IR (KBr): 3398, 3058, 2937, 1712, 1598, 1492, 1448, 1400, 1290, 1122, 935 cm -1 ; 1H NMR (300 MHz, CDCl 3 ) δ 7.26 (t, 2H, J = 8.4 Hz, Ar-H), 7.05 (d, 2H, J =7.5 Hz, Ar-H), 6.94 (t, 1H, J = 7.2 Hz, Ar-H), 6.27 (s, 1H, OH), 4.23 (t, 1H, J = 9.6 Hz, CH), 1.63 - 2.58 (m, 8H, eight protons of CH2); 13 C NMR (75 MHz, CDCl 3 ) δ 209.7, 150.1, 128.6 (2C), 121.6, 115.9 (2C), 72.5, 42.0, 27.8, 27.2, 24.3; HRMS (FAB+) for C 12 H 15 NO 2 [M] + , Calcd 205.1103, Found 205.1106; Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (97.6:2.4 hexane:2-propanol), 1.0 mL/min; major enantiomer tr = 42.5 min, minor enantiomer tr = 50.3 min.
실험예 1. 비대칭 나이트로소 알돌 반응Experimental Example 1. Asymmetric nitroso aldol reaction
1.1. 용매의 종류에 따른 반응1.1. Reactions depending on the type of solvent
나이트로소 알돌 반응에서 용매가 생성물의 반응성 및 입체선택성에 미치는 영향을 확인하기 위해 촉매 1b(화학식 4-2)를 사용하여 다양한 용매를 시험하였다(표 1). 대부분의 용매는 높은 질소 선택성과 상대적으로 높은 거울상선택성(81-94%)을 나타내었다. 다만, 용매의 극성에 따라 수율이 25%에서 65%로 상이했다. 실온에서 동일한 등가 촉매를 사용하여 실험을 수행했을 때 가장 높은 수율(65%)을 나타낸 용매는 염수(brine)였다., 본 발명에서 촉매는 염산염(HCl)의 형태로 반응에 참여하기 때문에, 극성 양성자성 용매의 경우, 촉매의 양이온의 안정화에 기여하여 촉매 반응 시 전이상태를 안정화하는데 크게 기여할 수 있다. 즉, 극성 용매에서 촉매의 반응성이 증가하며, 촉매의 극성이 증가함에 따라 친핵체의 결합력이 증가하고 전이상태의 자유에너지가 안정화되므로 비교적 우수한 수율 및 거울상선택성을 나타내었다. 반면, 극성 비양성자성 용매도 수소 결합의 간섭이 용매에 의한 나이트로소벤젠의 활성화보다 더 중요하기 때문에 비교적 낮은 수율을 나타내었다. 따라서, 표 1의 용매 스크리닝 결과로부터 N-나이트로소 알돌 반응의 수율 및 거울상선택성이 가장 좋은 염수를 반응 용매로 결정하였다.To determine the effect of the solvent on the reactivity and stereoselectivity of the product in the nitroso aldol reaction, various solvents were tested using Catalyst 1b (Formula 4-2 ) (Table 1). Most solvents showed high nitrogen selectivity and relatively high enantioselectivity (81-94%). However, the yield varied from 25% to 65% depending on the polarity of the solvent. When an experiment was performed using the same equivalent catalyst at room temperature, the solvent that showed the highest yield (65%) was brine. In the present invention, the catalyst participates in the reaction in the form of hydrochloride (HCl), so it is polar. In the case of a protic solvent, it can greatly contribute to stabilizing the transition state during a catalytic reaction by contributing to stabilizing the cation of the catalyst. In other words, the reactivity of the catalyst increases in a polar solvent, and as the polarity of the catalyst increases, the binding force of the nucleophile increases and the free energy of the transition state is stabilized, showing relatively excellent yield and enantioselectivity. On the other hand, polar aprotic solvents also showed relatively low yields because the interference of hydrogen bonding was more important than the activation of nitrosobenzene by the solvent. Therefore, from the solvent screening results in Table 1, the brine with the best yield and enantioselectivity for N-nitroso aldol reaction was determined as the reaction solvent.
Figure PCTKR2023003846-appb-img-000018
Figure PCTKR2023003846-appb-img-000018
EntryEntry SolventSolvent Dielectric constantDielectric constant TimeTime Yield (%)　Yield (%) aa ee (%)　ee (%) bb
1One BrineBrine 3232 1 h1 h 6565 9494
22 DMSODMSO 4747 1 h1 h 5858 9191
33 CH3CN CH3CN 3737 1 h1 h 5252 9090
44 MeOHMeOH 3333 1 h1 h 5050 9090
55 -- -- 1 h1 h 4646 9292
66 CH2Cl2 CH 2 Cl 2 9.09.0 1 h1h 4242 8181
77 THFTHF 7.67.6 1 h1h 4040 9494
88 TolueneToluene 2.42.4 15 min15min 2525 8686
a Isolated yield. b ee values were determined by chiral phase HPLC using the AD-H columns. an isolated yield. b ee values were determined by chiral phase HPLC using the AD-H columns.
1.2. 촉매의 종류에 따른 반응1.2. Reaction depending on the type of catalyst
최적화된 반응 조건에서 모노알킬 치환 키랄 아민 촉매의 효과를 조사하였다. 알킬기 치환체의 입체장애가 증가할수록 수율은 감소하였다. 특히, 촉매 1d(화학식 4-4)의 수율은 촉매 1b(화학식 4-2)의 수율보다 낮았는데, 이는 상대적으로 입체장애가 덜한 단점이 있으나 입체선택성은 약간 증가하였다. 촉매 1a(화학식 4-1)와 유사한 수준의 입체장애를 갖는 촉매 1b(화학식 4-2)의 경우, 촉매 1a에 비해 수율에서 예상외로 큰 차이를 보였다. 따라서 최고의 수율과 입체선택성을 보이는 촉매 1a를 선택하였다(표 2).The effect of monoalkyl substituted chiral amine catalyst was investigated under optimized reaction conditions. As the steric hindrance of the alkyl group substituent increased, the yield decreased. In particular, the yield of Catalyst 1d (Formula 4-4 ) was lower than that of Catalyst 1b (Formula 4-2 ), which had the disadvantage of relatively less steric hindrance, but slightly increased stereoselectivity. Catalyst 1b (Formula 4-2 ), which has a similar level of steric hindrance as Catalyst 1a (Formula 4-1 ), showed an unexpectedly large difference in yield compared to Catalyst 1a . Therefore, catalyst 1a, which showed the highest yield and stereoselectivity, was selected (Table 2).
Figure PCTKR2023003846-appb-img-000019
Figure PCTKR2023003846-appb-img-000019
EntryEntry Catcat Yield (%)　Yield (%) aa ee (%)　b ee (%) b
1One 1a1a 8282 9999
22 1b1b 6565 9494
33 1c1c 6161 9696
44 1d1d 5353 9898
55 1e1e 4949 9898
a Isolated yield. b ee values were determined by chiral phase HPLC using AD-H columns. an isolated yield. b ee values were determined by chiral phase HPLC using AD-H columns.
1.3. 다양한 온도 및 당량비에 따른 반응1.3. Reactions according to various temperatures and equivalence ratios
생성물이 불안정하고 상온에서 수율이 높지 않기 때문에 보다 낮은 온도에서 실험을 수행하였다. 영하 10℃에서 수율은 실온에서와 유사한 거울상선택성을 나타내는 대신 82%에서 95%로 증가하였다(표 3). Because the product was unstable and the yield was not high at room temperature, the experiment was performed at a lower temperature. At -10°C, the yield increased from 82% to 95% instead of showing similar enantioselectivity as at room temperature (Table 3).
Figure PCTKR2023003846-appb-img-000020
Figure PCTKR2023003846-appb-img-000020
EntryEntry Cyclohexanone:Cyclohexanone:
NitrosobenzeneNitrosobenzene 		Temp (°C)Temp (°C) Time (h)Time (h) Yield (%)　Yield (%) aa ee (%)　ee (%) bb
1One 1:11:1 rtrt 1One 5555 9292
22 2:12:1 00 1.51.5 8888 9898
33 2:12:1 -10-10 33 9595 9999
44 cc 2:12:1 -10-10 66 9595 9999
55 dd 2:12:1 -10-10 2424 5252 9999
66 1:21:2 -10-10 22 7171 8282
77 1:51:5 -10-10 22 6565 8080
88 ee 2:12:1 -10-10 66 9898 9999
a Isolated yield. b ee values were determined by chiral phase HPLC using AD-H columns. c Using 5 mol % 1a cat. d Using 1 mol % 1a cat. e Using 5 mol % benzoic acid and 1a cat. an isolated yield. b ee values were determined by chiral phase HPLC using AD-H columns. c Using 5 mol % 1a cat. d Using 1 mol % 1a cat. e Using 5 mol % benzoic acid and 1a cat.
또한, 나이트로소 화합물(화학식 2)에 대한 고리형 케톤(화학식 1)의 비율이 나이트로소 알돌 반응에 어떤 영향을 미치는지 알아보기 위해 시약의 양을 변경하였다. 사이클로헥사논:나이트로소벤젠의 비율이 1:1인 경우(entry 1), 2:1인 경우(표 2의 entry 1)보다 수율 및 거울상선택성이 감소하였으며, 나이트로소벤젠 시약의 양을 증가시키면 수율 및 거울상선택성이 감소하였다(entry 6 및 7). In addition, the amount of reagent was changed to determine how the ratio of cyclic ketone (Formula 1 ) to nitroso compound (Formula 2 ) affects the nitroso aldol reaction. When the ratio of cyclohexanone:nitrosobenzene was 1:1 (entry 1), the yield and enantioselectivity decreased compared to when the ratio was 2:1 (entry 1 in Table 2), and the amount of nitrosobenzene reagent was increased. When increased, yield and enantioselectivity decreased (entries 6 and 7).
첨가되는 촉매의 양이 1 mol%로 감소된 경우(entry 5), 수율 및 거울상선택성이 감소하였다. 촉매의 양이 5 mol%로 줄였을 때 반응시간을 6시간으로 늘리면(entry 4) 수율 95% 및 거울상선택성 99%를 나타내었다.When the amount of added catalyst was reduced to 1 mol% (entry 5), the yield and enantioselectivity decreased. When the amount of catalyst was reduced to 5 mol% and the reaction time was increased to 6 hours (entry 4), the yield was 95% and the enantioselectivity was 99%.
한편, 벤조산(5 mol%)을 첨가하면 부산물의 수율이 감소하고 수율이 향상되었다(entry 8). 이는 벤조산이 사이클로헥사논의 활성화를 통해 아민 촉매 작용 및 이민 형성을 촉진한 것이다.Meanwhile, adding benzoic acid (5 mol%) decreased the yield of by-products and improved the yield (entry 8). This means that benzoic acid promotes amine catalysis and imine formation through activation of cyclohexanone.
1.4. 예상 전이 상태를 포함하는 제안 메커니즘1.4. Proposed mechanism with expected transition states
키랄 디아민 촉매(화학식 4)는 사이클로케톤(화학식 1)과 반응하여 이민을 형성하고, 차례로 엔아민을 형성한다. 알킬화된 키랄 디아민과 나이트로소 화합물(화학식 2)은 산 촉매와의 수소 결합을 통해 친전자체를 활성화한다. 이후 활성화된 친전자체와 엔아민이 반응하여 나이트로소 알돌 반응 생성물(화학식 3)을 생성한다. 나이트로소 알돌 반응 생성물은 실온에서 탈수될 때 보다 안정적인 엔아민을 형성한다.The chiral diamine catalyst (Formula 4 ) reacts with cycloketone (Formula 1 ) to form an imine, which in turn forms an enamine. Alkylated chiral diamine and nitroso compounds (Formula 2 ) activate the electrophile through hydrogen bonding with the acid catalyst. Afterwards, the activated electrophile and enamine react to produce a nitroso aldol reaction product (Formula 3 ). The nitroso aldol reaction product forms a more stable enamine when dehydrated at room temperature.
이 때, 엔아민과 나이트로소 화합물 사이의 결합이 형성될 때 예상되는 전이상태가 존재하고, 그 결과 나이트로소 화합물이 입체장애를 최소화하는 방향으로 반응이 진행될 것으로 예상된다. 따라서 (R)-거울상 이성질체보다 (S)-거울상 이성질체를 주 생성물로 수득하였다(도 2).At this time, an expected transition state exists when the bond between the enamine and the nitroso compound is formed, and as a result, the reaction is expected to proceed in a direction that minimizes steric hindrance to the nitroso compound. Therefore, the (S)-enantiomer was obtained as the main product rather than the (R)-enantiomer (Figure 2).
한편, 케톤의 양을 줄이면 키랄 디아민 촉매와 사이클로케톤의 반응에 의한 엔아민 합성을 포함하는 공정 A가 천천히 진행되어 결과적으로 반응 속도가 감소하였다. 염수가 없으면 공정 A가 빠르게 진행되나, 엔아민과 나이트로소 화합물이 반응한 후 이민에서 α-하이드록시아미노 화합물로의 가수분해(C)가 느려서 부반응이 발생하였다. 특히 톨루엔을 용매로 사용하는 경우(표 1의 entry 8), 반응시간은 짧지만 부반응이 빠르게 진행되어 여러 부산물이 생성되었다. 소량의 벤조산을 첨가한 경우(표 3의 entry 8), 자가 알돌 축합을 방지하여 부산물을 최소화하고 사이클로케톤을 활성화하였다.On the other hand, if the amount of ketone is reduced, process A, which includes enamine synthesis through the reaction of a chiral diamine catalyst and cycloketone, proceeds slowly, resulting in a decrease in the reaction rate. Without brine, process A proceeded quickly, but after the reaction between the enamine and the nitroso compound, the hydrolysis (C) of the imine to the α-hydroxyamino compound was slow, resulting in a side reaction. In particular, when toluene was used as a solvent (entry 8 in Table 1), the reaction time was short, but side reactions proceeded quickly and several by-products were produced. When a small amount of benzoic acid was added (entry 8 in Table 3), self-aldol condensation was prevented, by-products were minimized, and cycloketone was activated.
실험예 2. 양자 계산을 통한 용매 효과 및 메커니즘의 열역학적 에너지 비교Experimental Example 2. Comparison of thermodynamic energies of solvent effects and mechanisms through quantum calculations
2.1. 밀도 함수 이론에 따른 깁스 자유 에너지 계산2.1. Calculation of Gibbs free energy according to density functional theory
밀도 함수 이론(Density Functional Theory, DFT) 계산은 기질과 촉매의 메커니즘을 보여주기 위한 것으로서, Gaussian 16 및 Gauss-View 6.0 프로그램을 사용하여 수행하였다. 최적화된 형상은 Becke three-parameter Lee-Yang-Parr (B3LYP) 레벨을 사용하여 설명하였다. 이후, 6-31G(d,p) 기본 세트를 사용하여 최적화된 형상에 대한 단일 포인트 계산을 수행하였다. 반응물, 중간체(intermediates, IM), 전이상태(transition states, TS), 및 생성물의 형상이 완전히 최적화된 후, 진동주파수 계산을 통해 반응물의 열역학적 함수 및 매개변수(깁스 자유 에너지(Gibbs free energy))를 수득하였다. 동일한 이론 수준에서 최소 또는 전이상태 에너지를 수득하였다. 엔탈피 보정 및 온도에 따른 엔트로피는 298 K 및 1기압에서 계산하였다.Density Functional Theory (DFT) calculations were intended to demonstrate the mechanisms of substrates and catalysts and were performed using Gaussian 16 and Gauss-View 6.0 programs. The optimized shape was described using the Becke three-parameter Lee-Yang-Parr (B3LYP) level. Afterwards, single point calculations were performed on the optimized shape using the 6-31G(d,p) basis set. After the shapes of reactants, intermediates (IM), transition states (TS), and products are fully optimized, the thermodynamic functions and parameters (Gibbs free energy) of the reactants are determined through calculation of vibrational frequencies. was obtained. Minimum or transition state energies were obtained at the same level of theory. Enthalpy correction and temperature-dependent entropy were calculated at 298 K and 1 atm.
2.2. 촉매 및 유형별 전환 상태의 깁스 자유 에너지 비교2.2. Comparison of Gibbs free energies of transition states by catalyst and type
각 메커니즘 단계에 대해 촉매 1a(화학식 4-1) 및 1b(화학식 4-2)의 예상 전이 상태를 기상(gas phase) 및 수상(water phase)에서 비교하여 반응성 차이를 조사하였다(표 2). 계산 결과, 기상에서 촉매 1a가 촉매 1b보다 0.424 kcal/mol만큼 더 안정적이었으나, 수상에서 촉매 1a가 촉매 1b보다 13.016 kcal/mol 낮았다(도 3).For each mechanism step, differences in reactivity were investigated by comparing the expected transition states of catalysts 1a (Formula 4-1 ) and 1b (Formula 4-2 ) in the gas phase and water phase (Table 2). As a result of the calculation, Catalyst 1a was 0.424 kcal/mol more stable than Catalyst 1b in the gas phase, but Catalyst 1a was 13.016 kcal/mol lower than Catalyst 1b in the aqueous phase (Figure 3).
표 1과 같이 나이트로소 알돌 반응에 대한 용매 효과를 확인하기 위해 열역학적 분석을 수행하였다. 이를 위해 도 3에서 확인한 결과를 바탕으로 촉매 1a의 전이상태에 대한 다양한 용매의 열역학적 에너지를 비교하였다(도 4).As shown in Table 1, thermodynamic analysis was performed to confirm the solvent effect on the nitroso aldol reaction. To this end, based on the results confirmed in Figure 3, the thermodynamic energies of various solvents for the transition state of catalyst 1a were compared (Figure 4).
실험 결과(표 1)와 양자 계산 결과를 비교한 결과 톨루엔과 같은 무극성 용매가 가장 낮은 반응성을 나타냄을 확인하였다. 또한, 테트라하이드로퓨란(THF), 디클로로메탄(CH2Cl2)를 사용하거나 용매를 사용하지 않는 경우 계산에 표시된 것과 유사한 반응성이 나타났다. 메탄올(MeOH), 아세토니트릴(CH3CN), DMSO와 같은 극성용매를 사용할 경우 반응성이 비교적 우수하여 실험결과는 계산결과와 유사하였다. 특히 이들 용매 중 물이 최고의 반응성과 입체선택성을 보였으며, DFT 계산 결과 역시 나이트로소 알돌 반응의 전이 상태가 물 용매에서 가장 안정한 것으로 확인되었다.As a result of comparing the experimental results (Table 1) and quantum calculation results, it was confirmed that non-polar solvents such as toluene showed the lowest reactivity. Additionally, reactivity similar to that shown in the calculations was observed when tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 ) or no solvent was used. When using polar solvents such as methanol (MeOH), acetonitrile (CH 3 CN), and DMSO, the reactivity was relatively excellent and the experimental results were similar to the calculated results. In particular, among these solvents, water showed the highest reactivity and stereoselectivity, and DFT calculation results also confirmed that the transition state of the nitroso aldol reaction was the most stable in water solvent.
2.3. 각 메커니즘의 깁스 자유 에너지2.3. Gibbs free energy of each mechanism
제안된 반응 주기에서 사이클로헥사논은 1차 아민과 반응하여 이민을 거쳐 엔아민을 형성하였다. 방향족 나이트로소 화합물은 알킬화된 키랄 디아민의 암모늄염과 수소 결합을 형성하여 전이 상태를 형성하였다. 상기 전이 상태에 따라 N-모노알킬기의 입체 장애가 최소화되도록 새로운 탄소-질소(C-N) 결합을 형성하였다.In the proposed reaction cycle, cyclohexanone reacted with a primary amine to form an enamine via an imine. The aromatic nitroso compound formed a hydrogen bond with the ammonium salt of the alkylated chiral diamine to form a transition state. According to the transition state, a new carbon-nitrogen (C-N) bond was formed to minimize steric hindrance of the N-monoalkyl group.
마지막으로 도 2 및 도 5에 도시한 바와 같이 이미늄의 가수분해를 통해 나이트로소 알돌 생성물을 생성하며, 생성물의 깁스 자유에너지가 가장 낮음, 즉 가장 안정하다는 점을 확인하였다.Finally, as shown in Figures 2 and 5, the nitroso aldol product was produced through hydrolysis of iminium, and it was confirmed that the product had the lowest Gibbs free energy, that is, the most stable.
이상과 같이 실시예들이 비록 한정된 도면에 의해 설명되었으나, 해당 기술분야에서 통상의 지식을 가진 자라면 상기를 기초로 다양한 기술적 수정 및 변형을 적용할 수 있다. 예를 들어, 설명된 기술들이 설명된 방법과 다른 순서로 수행되거나, 및/또는 설명된 시스템, 구조, 장치, 회로 등의 구성요소들이 설명된 방법과 다른 형태로 결합 또는 조합되거나, 다른 구성요소 또는 균등물에 의하여 대치되거나 치환되더라도 적절한 결과가 달성될 수 있다. Although the embodiments have been described with limited drawings as described above, those skilled in the art can apply various technical modifications and variations based on the above. For example, the described techniques are performed in a different order than the described method, and/or components of the described system, structure, device, circuit, etc. are combined or combined in a different form than the described method, or other components are used. Alternatively, appropriate results may be achieved even if substituted or substituted by an equivalent.
그러므로, 다른 구현들, 다른 실시예들 및 특허청구범위와 균등한 것들도 후술하는 청구범위의 범위에 속한다.Therefore, other implementations, other embodiments, and equivalents of the claims also fall within the scope of the following claims.

Claims (16)

  1. [화학식 1]로 표시되는 화합물과 [화학식 2]로 표시되는 화합물을 반응시켜 [화학식 3]로 표시되는 화합물을 제조하는 단계를 포함하고,Comprising the step of reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] to prepare a compound represented by [Formula 3],
    상기 반응에서 [화학식 4]로 표시되는 촉매 화합물을 이용하는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법:Method for producing a chiral nitroso derivative, characterized in that the catalyst compound represented by [Formula 4] is used in the above reaction:
    [화학식 1][Formula 1]
    Figure PCTKR2023003846-appb-img-000021
    ;
    Figure PCTKR2023003846-appb-img-000021
    ;
    [화학식 2][Formula 2]
    Figure PCTKR2023003846-appb-img-000022
    ;
    Figure PCTKR2023003846-appb-img-000022
    ;
    [화학식 3][Formula 3]
    Figure PCTKR2023003846-appb-img-000023
    ;
    Figure PCTKR2023003846-appb-img-000023
    ;
    [화학식 4][Formula 4]
    Figure PCTKR2023003846-appb-img-000024
    .
    Figure PCTKR2023003846-appb-img-000024
    .
    상기 화학식 1 및 화학식 3에서,In Formula 1 and Formula 3,
    R1 및 R2는 이들이 부착된 탄소 및 별표(*) 표시된 탄소와 함께 C5-C8의 사이클로알킬기 또는 헤테로사이클로알킬기를 형성할 수 있고,R 1 and R 2 together with the carbon to which they are attached and the carbon marked with an asterisk (*) may form a cycloalkyl group or heterocycloalkyl group of C 5 -C 8 ;
    상기 화학식 2 및 화학식 3에서,In Formula 2 and Formula 3,
    R3는 할로겐기, 시아노기, 니트로기, 하이드록시기, C1-C9의 사슬형 알킬기, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상으로 치환되거나 비치환된 C5-C8의 아릴기이고,R 3 is C 5 -C 8 unsubstituted or substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an aryl group of,
    상기 화학식 4에서,In Formula 4 above,
    R4는 C1-C9의 사슬형 또는 고리형 알킬기임.R 4 is a chain or cyclic alkyl group of C 1 -C 9 .
  2. 제1항에 있어서,According to paragraph 1,
    상기 반응은 비대칭 알돌 반응(asymmetric aldol reaction)인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the reaction is an asymmetric aldol reaction.
  3. 제1항에 있어서,According to paragraph 1,
    상기 반응은 [화학식 1]로 표시되는 화합물이 [화학식 4]로 표시되는 촉매 화합물과 반응하여 엔아민 중간체를 형성한 후, [화학식 2]로 표시되는 화합물과 반응하는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.The reaction is characterized in that the compound represented by [Formula 1] reacts with the catalyst compound represented by [Formula 4] to form an enamine intermediate, and then reacts with the compound represented by [Formula 2]. Method for producing rosso derivatives.
  4. 제1항에 있어서,According to paragraph 1,
    상기 [화학식 1]로 표시되는 화합물은 하기 [화학식 1-1]로 표시되는 화합물인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the compound represented by [Formula 1] is a compound represented by the following [Formula 1-1].
    [화학식 1-1][Formula 1-1]
    Figure PCTKR2023003846-appb-img-000025
    .
    Figure PCTKR2023003846-appb-img-000025
    .
  5. 제1항에 있어서,According to paragraph 1,
    상기 [화학식 2]로 표시되는 화합물은 하기 [화학식 2-1]로 표시되는 화합물인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the compound represented by [Formula 2] is a compound represented by the following [Formula 2-1].
    [화학식 2-1][Formula 2-1]
    Figure PCTKR2023003846-appb-img-000026
    .
    Figure PCTKR2023003846-appb-img-000026
    .
  6. 제1항에 있어서,According to paragraph 1,
    상기 [화학식 3]로 표시되는 화합물은 하기 [화학식 3-1]로 표시되는 화합물인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the compound represented by [Formula 3] is a compound represented by the following [Formula 3-1].
    [화학식 3-1][Formula 3-1]
    Figure PCTKR2023003846-appb-img-000027
    .
    Figure PCTKR2023003846-appb-img-000027
    .
  7. 제1항에 있어서,According to paragraph 1,
    상기 [화학식 4]로 표시되는 화합물은 하기 [화학식 4-1] 내지 [화학식 4-5]로 표시되는 화합물들로부터 선택되는 어느 하나 이상인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, wherein the compound represented by [Formula 4] is one or more selected from the compounds represented by [Formula 4-1] to [Formula 4-5] below.
    [화학식 4-1][Formula 4-1]
    Figure PCTKR2023003846-appb-img-000028
    ;
    Figure PCTKR2023003846-appb-img-000028
    ;
    [화학식 4-2][Formula 4-2]
    Figure PCTKR2023003846-appb-img-000029
    ;
    Figure PCTKR2023003846-appb-img-000029
    ;
    [화학식 4-3][Formula 4-3]
    Figure PCTKR2023003846-appb-img-000030
    ;
    Figure PCTKR2023003846-appb-img-000030
    ;
    [화학식 4-4][Formula 4-4]
    Figure PCTKR2023003846-appb-img-000031
    ; 및
    Figure PCTKR2023003846-appb-img-000031
    ; and
    [화학식 4-5][Formula 4-5]
    Figure PCTKR2023003846-appb-img-000032
    .
    Figure PCTKR2023003846-appb-img-000032
    .
  8. 제1항에 있어서,According to paragraph 1,
    상기 반응은 유전상수(dielectric constant)가 30 이상인 극성 용매에서 수행되는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the reaction is carried out in a polar solvent having a dielectric constant of 30 or more.
  9. 제8항에 있어서,According to clause 8,
    상기 용매는 물(water), 염수(brine), 디메틸설폭사이드(DMSO), 니트로메탄(CH3NO2), 아세토니트릴(CH3CN), 메탄올(MeOH) 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.The solvent is selected from the group consisting of water, brine, dimethyl sulfoxide (DMSO), nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), and combinations thereof. A method for producing a chiral nitroso derivative, characterized in that one or more of the following.
  10. 제1항에 있어서,According to paragraph 1,
    상기 반응은 [화학식 1]로 표시되는 화합물과 [화학식 2]로 표시되는 화합물를 2:1 내지 1:2의 당량비로 반응시키는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.The reaction is a method for producing a chiral nitroso derivative, characterized in that the compound represented by [Formula 1] and the compound represented by [Formula 2] are reacted at an equivalence ratio of 2:1 to 1:2.
  11. 제1항에 있어서,According to paragraph 1,
    상기 반응은 [화학식 4]로 표시되는 촉매 화합물을 5 ~ 10 mol%를 첨가하는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.The reaction is a method for producing a chiral nitroso derivative, characterized in that 5 to 10 mol% of the catalyst compound represented by [Formula 4] is added.
  12. 제1항에 있어서,According to paragraph 1,
    상기 [화학식 1]로 표시되는 화합물, [화학식 2]로 표시되는 화합물과 함께 추가적으로 벤조산을 첨가하여 반응시키는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that benzoic acid is additionally added and reacted with the compound represented by [Formula 1] and the compound represented by [Formula 2].
  13. 제1항에 있어서,According to paragraph 1,
    상기 반응은 하나의 반응기 내에서 수행되는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the reaction is performed in one reactor.
  14. 제1항에 있어서,According to paragraph 1,
    상기 반응은 15분 ~ 24시간 내에 완료되는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the reaction is completed within 15 minutes to 24 hours.
  15. 제1항에 있어서,According to paragraph 1,
    상기 반응은 -10 ~ 25℃에서 수행되는 것을 특징으로 하는, 키랄 나이트로소 유도체의 제조방법.A method for producing a chiral nitroso derivative, characterized in that the reaction is carried out at -10 to 25°C.
  16. 제1항 내지 제15항 중 어느 한 항에 따른 제조방법으로 제조된 키랄 나이트로소 유도체.A chiral nitroso derivative prepared by the production method according to any one of claims 1 to 15.
PCT/KR2023/003846 2022-08-11 2023-03-23 Method for producing nitrogen-selective chiral aldol reaction product of nitroso compound using organic chiral catalyst compound WO2024034767A1 (en)

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CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof

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CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof

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Title
MOMIYAMA NORIE, YAMAMOTO HISASHI: "Brønsted Acid Catalysis of Achiral Enamine for Regio- and Enantioselective Nitroso Aldol Synthesis", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 127, no. 4, 1 February 2005 (2005-02-01), pages 1080 - 1081, XP093139954, ISSN: 0002-7863, DOI: 10.1021/ja0444637 *
MOMIYAMA NORIE, YAMAMOTO HISASHI: "Enantioselective O - and N -Nitroso Aldol Synthesis of Tin Enolates. Isolation of Three BINAP−Silver Complexes and Their Role in Regio- and Enantioselectivity", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 126, no. 17, 1 May 2004 (2004-05-01), pages 5360 - 5361, XP093139955, ISSN: 0002-7863, DOI: 10.1021/ja039103i *
N. MOMIYAMA ET AL.: "o-nitroso aldol synthesis:catalytic enantioselective route to alfa-aminooxy carbonyl compounds via enamine intermediate", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 101, no. 15, 13 April 2004 (2004-04-13), pages 5374 - 5378, XP002449131, ISSN: 0027-8424, DOI: 10.1073/pnas.0307785101 *
SHIM JAE HO, LEE JI YEON, KIM HYEON SOO, HA DEOK-CHAN: "Protonated Chiral 1,2-Diamine Organocatalysts for N-Selective Nitroso Aldol Reaction", CATALYSTS, M D P I AG, CH, vol. 12, no. 4, CH , pages 435, XP093139958, ISSN: 2073-4344, DOI: 10.3390/catal12040435 *
SHIM JAE HO; KIM MIN-JOON; LEE JI YEON; KIM KYOUNG HOON; HA DEOK-CHAN: "Organocatalytic asymmetric aldol reaction using protonated chiral 1,2-diamines", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 61, no. 36, 27 July 2020 (2020-07-27), Amsterdam , NL , XP086250432, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2020.152295 *

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