METHOD FOR PREPARING CHIRAL MALEIMIDE DERIVATIVES USING ORGANIC CHIRAL CATALYST COMPOUNDS AND ECO-FRIENDLY SOLVENTS

Abstract

Provided are a method for preparing chiral maleimide derivatives using (R,R)-1,2-diphenylethylenediamine (DPEN)-based organic chiral catalyst compounds and water as an eco-friendly solvent, and the like. It is possible to prepare chiral maleimide derivatives having high enantioselectivity even with a small amount of catalyst in an excellent yield within a short time. In particular, the preparation method of the present disclosure can stabilize a transition state through an interfacial reaction between the catalyst and water. In addition, spironolactone derivatives are synthesized using chiral maleimide derivatives prepared according to the present disclosure to be usefully used for the treatment of edema control, heart failure, liver cirrhosis, electrolyte abnormalities, hypertension, etc.

Claims

1. A method for preparing chiral maleimide derivatives comprising preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 with a compound represented by Chemical Formula 2 in water, wherein a catalyst compound represented by Chemical Formula 4 is used in the reaction: ##STR00015## in Chemical Formulas 1 and 3, R.sub.1 and R.sub.2 are the same as or different from each other, and each independently hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when both R.sub.1 and R.sub.2 are hydrogens), wherein the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and in Chemical Formulas 2 and 3, R.sub.3 is a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a nitro group, a C.sub.1-C.sub.7 alkyl group, and combinations thereof, or hydrogen, and in Chemical Formula 4, R.sub.4 is a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.

2. The method for preparing the chiral maleimide derivatives of claim 1, wherein the reaction is an asymmetric Michael addition reaction.

3. The method for preparing the chiral maleimide derivatives of claim 1, wherein the compound represented by Chemical Formula 1 is at least one selected from the group consisting of compounds represented by Chemical Formulas 1-1 and 1-2: ##STR00016##

4. The method for preparing the chiral maleimide derivatives of claim 1, wherein the compound represented by Chemical Formula 2 is at least one selected from the group consisting of compounds represented by Chemical Formulas 2-1 to 2-5: ##STR00017##

5. The method for preparing the chiral maleimide derivatives of claim 1, wherein the compound represented by Chemical Formula 3 is at least one selected from the group consisting of compounds represented by Chemical Formulas 3-1 to 3-6: ##STR00018##

6. The method for preparing the chiral maleimide derivatives of claim 1, wherein the compound represented by Chemical Formula 4 is at least one selected from the group consisting of compounds represented by Chemical Formulas 4-1 to 4-6: ##STR00019##

7. The method for preparing the chiral maleimide derivatives of claim 1, wherein trifluoroacetic acid, acetic acid, salicylic acid, or benzoic acid is further added and reacted together with the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 2.

8. The method for preparing the chiral maleimide derivatives of claim 1, wherein the reaction is performed in one reactor at room temperature.

9. The method for preparing the chiral maleimide derivatives of claim 1, wherein the reaction is completed within 1 to 15 hours.

10. The method for preparing the chiral maleimide derivatives of claim 1, wherein 0.005 to 1 mol % of the catalyst compound represented by Chemical Formula 4 is added.

11. Chiral maleimide derivatives prepared by the preparation method according to claim 1.

12. A method for preparing chiral spironolactone derivatives comprising: (1) preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 with a compound represented by Chemical Formula 2 in water using a catalyst compound represented by Chemical Formula 4; and (2) preparing a compound represented by Chemical Formula 5 below from the compound represented by Chemical Formula 3: ##STR00020## in Chemical Formulas 1, 3, and 5, R.sub.1 and R.sub.2 are the same as or different from each other, and each independently hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when both R.sub.1 and R.sub.2 are hydrogens), wherein the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and in Chemical Formulas 2, 3, and 5, R.sub.3 is a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a nitro group, a C.sub.1-C.sub.7 alkyl group, and combinations thereof, or hydrogen, and in Chemical Formula 4, R.sub.4 is a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.

13. The method for preparing the chiral spironolactone derivatives of claim 12, wherein when the R.sub.1 and R.sub.2 form a cyclohexyl group together with the carbons to which the R.sub.1 and R.sub.2 are attached and the carbons marked with asterisks (*), the compound represented by Chemical Formula 5 is a compound represented by Chemical Formula 5 below: ##STR00021##

14. The method for preparing the chiral spironolactone derivatives of claim 12, wherein the compound represented by Chemical Formula 5 is added with BH.sub.3.Math.THF and BF.sub.3.Math.Et.sub.2O.

15. Chiral spironolactone derivatives prepared by the preparation method according to claim 12.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] These and/or other aspects, features, and advantages of the invention will become apparent and more readily appreciated from the following description of embodiments, taken in conjunction with the accompanying drawings of which:

[0038] FIG. 1 illustrates Reaction Formula of a method for preparing chiral maleimide derivatives according to an embodiment of the present disclosure. Aldehyde (Chemical Formula 1) and maleimide (Chemical Formula 2) react together with a thiourea catalyst (Chemical Formula 4) in water (H.sub.2O) to prepare a chiral maleimide derivative (Chemical Formula 3);

[0039] FIG. 2 illustrates a catalytic cycle of a Michael reaction including a proposed transition state;

[0040] FIG. 3 illustrates a catalytic mechanism proposed based on B3LYP/6-31G(d,p) calculations and a relative free energy diagram of an (R,R)-1,2-diphenylethylenediamine (DPEN)-thiourea-catalyzed enantioselective Michael reaction, in which the calculations were performed using water, CH.sub.2Cl.sub.2, THF, and the like under solvent+nH.sub.2O conditions;

[0041] FIG. 4A and FIG. 4B illustrate results of nuclear magnetic resonance spectroscopy (NMR) to confirm hydrogen bonds between fluorine (F) atoms and hydrogen (H) atoms in a Michael addition reaction using an organic chiral catalyst 4-1 and water as a solvent. FIG. 4A illustrates an NMR result when there is water (D.sub.2O) and FIG. 4B illustrates an NMR result when there is no water;

[0042] FIG. 5 illustrates a catalytic mechanism proposed based on B3LYP/6-31G(d,p) calculations and a thermal energy diagram of an (R,R)-1,2-diphenylethylenediamine (DPEN)-thiourea-catalyzed enantioselective Michael reaction, in which the calculations were performed under solvent+5H.sub.2O conditions; and

[0043] FIG. 6 illustrates results of a recycling test of an asymmetric Michael addition reaction using a chiral (R,R)-1,2-diphenylethylenediamine (DPEN)-based thiourea catalyst.

DETAILED DESCRIPTION

[0044] The present inventors applied an (R,R)-1,2-diphenylethylenediamine (DPEN)-based thiourea catalyst in water to an asymmetric Michael addition reaction of aldehyde and maleimide to prepare chiral maleimide derivatives having high enantioselectivity (94 to 99% ee) in a high yield of 97% or more in a short time even with a small amount (0.01 mol %) of catalyst (FIG. 1).

[0045] The present disclosure proceeds without metals and additives, can be performed in air, has a simple synthesis method, and is eco-friendly and economical because a required amount of catalyst is small. In addition, since the present disclosure shows excellent yield and optical purity even on a gram-scale, the chiral maleimide derivatives of the present disclosure and the chiral spironolactone derivatives prepared using the same can be used in various pharmaceutical synthesizes.

[0046] Accordingly, the present disclosure provides a method for preparing chiral maleimide derivatives, including preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 and a compound represented by Chemical Formula 2 in water using a catalyst compound represented by Chemical Formula 4:

##STR00008##

[0047] In Chemical Formulas 1 and 3, R.sub.1 and R.sub.2 are the same as or different from each other, and each independently hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when both R.sub.1 and R.sub.2 are hydrogens), in which the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), [0048] in Chemical Formulas 2 and 3, R.sub.3 is a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a nitro group, a C.sub.1-C.sub.7 alkyl group, and combinations thereof, or hydrogen, and [0049] in Chemical Formula 4, R.sub.4 may be a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.

[0050] In the present disclosure, the term substitution is a reaction in which atoms or atom groups included in molecules of a compound are replaced with other atoms or atom groups.

[0051] In the present disclosure, the term acyclic alkyl group refers to a group derived from straight-chain or branched-chain saturated aliphatic hydrocarbon having a specified number of carbon atoms and having at least one valency. Examples of such an alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, and the like, but are not limited thereto.

[0052] In the present disclosure, the term cycloalkyl group is also referred to as a cyclic alkyl group, and refers to a monovalent group having at least one saturated ring in which all ring members are carbons. Examples of such a cycloalkyl group include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like, but are not limited thereto.

[0053] In the present disclosure, the term heterocycloalkyl group usually refers to saturated or unsaturated (but, not aromatic) cyclohydrocarbon, which may optionally be unsubstituted, monosubstituted or polysubstituted, and in its structure, at least one is selected from the group consisting of heteroatoms of N, O, or S.

[0054] In the present disclosure, the term aryl group refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (e.g., phenyl) or a plurality of condensed rings (e.g., naphthyl). Examples of such aryl include phenyl, naphthyl, and the like, but are not limited thereto.

[0055] In the present disclosure, the term alkoxy group refers to an atom group C.sub.nH.sub.2n+1O.sup. formed by binding oxygen atoms to an alkyl group, and examples of such an alkoxy group include methoxy, ethoxy, propoxy, phthaloxy, and the like, but are not limited thereto.

[0056] In the present disclosure, the term halogen group refers to elements belonging to Group 17 of the periodic table, and may be fluorine (F), chloride (Cl), bromine (Br), iodine (I), or the like.

[0057] In addition, since the chiral maleimide derivatives of the present disclosure may be economically prepared because expensive metal catalysts are not used unlike conventional preparing methods and use water as an eco-friendly solvent under mild reaction conditions, the chiral spironolactone derivatives prepared using the chiral maleimide derivatives may be included in pharmaceutical compositions used for the treatment or prevention of various diseases.

[0058] The type of disease is not limited, but the chiral spironolactone derivatives of the present disclosure can be used as therapeutic agents for edema control, heart failure, liver cirrhosis, electrolyte abnormality, hypertension, etc., so that the present disclosure may provide a composition for the prevention or treatment of edema control, heart failure, liver cirrhosis, electrolyte abnormality, and hypertension, including derivatives represented by Chemical Formula 5 below as an active ingredient.

##STR00009##

[0059] In Chemical Formula 5, R.sub.1 and R.sub.2 are the same as or different from each other, and each independently hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when both R.sub.1 and R.sub.2 are hydrogens), in which the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and R.sub.3 may be a C.sub.4-C.sub.10 aryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a nitro group, a C.sub.1-C.sub.7 alkyl group, and combinations thereof, or hydrogen.

[0060] The pharmaceutical composition according to the present disclosure may include a pharmaceutically acceptable carrier in addition to the active ingredients. At this time, the pharmaceutically acceptable carrier is generally used in preparation and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. Further, the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the ingredients.

[0061] The pharmaceutical composition of the present disclosure may be administered orally or parenterally (e.g., applied intravenously, subcutaneously, intraperitoneally, or topically) according to a desired method, and a dose thereof varies depending on the condition and body weight of a patient, the severity of disease, a drug form, and route and time of administration, but may be appropriately selected by those skilled in the art.

[0062] The pharmaceutical composition of the present disclosure is administered in a pharmaceutically effective dose. The pharmaceutically effective dose used herein refers to an amount enough to treat diseases at a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level may be determined according to factors including the type and severity of a disease of a patient, the activity of a drug, the sensitivity to a drug, a time of administration, a route of administration, an excretion rate, duration of treatment, and simultaneously used drugs, and other factors well-known in the medical field. The pharmaceutical composition according to the present disclosure may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to administer an amount capable of obtaining a maximum effect with a minimal amount without side effects by considering all the factors, which may be easily determined by those skilled in the art.

[0063] Specifically, the effective dose of the pharmaceutical composition of the present disclosure may vary depending on the age, sex, condition, and body weight of a patient, absorption rate, inactivity rate, and excretion rate of active ingredients in the body, a disease type, and combined drugs.

[0064] As another aspect of the present disclosure, the present disclosure provides a method for the prevention or treatment of edema control, heart failure, liver cirrhosis, electrolyte abnormality, and hypertension, including administering the pharmaceutical composition to a subject. The subject used herein refers to a subject in need of treatment or prevention for diseases, and more particularly, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle.

[0065] The terms used in the embodiments are used for the purpose of description only, and should not be construed to be limited. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present specification, it should be understood that term comprising or having indicates that a feature, a number, a step, an operation, a component, a part, or the combination thereof described in the specification is present, but does not exclude a possibility of presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof, in advance.

[0066] Unless otherwise contrarily defined, all terms used herein including technological or scientific terms have the same meanings as those generally understood by a person with ordinary skill in the art to which embodiments pertain. Terms which are defined in a generally used dictionary should be interpreted to have the same meaning as the meaning in the context of the related art, and are not interpreted as ideal or excessively formal meanings unless otherwise defined in the present application.

[0067] In describing the components of the embodiments of the present disclosure, terms including first, second, A, B, (a), (b), and the like may be used. These terms are just intended to distinguish the components from other components, and the terms do not limit the nature, sequence, or order of the components. When it is disclosed that any component is connected, coupled, or linked to other components, it should be understood that the component may be directly connected or linked to other components, but another component may be connected, coupled, or linked between the respective components.

[0068] Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. However, since various modifications may be made to the embodiments, the scope of the present disclosure is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents and substitutes for the embodiments are included in the scope of the present disclosure.

[0069] In addition, in the description with reference to the accompanying drawings, like components designate like reference numerals regardless of reference numerals and a duplicated description thereof will be omitted. In describing the embodiments, a detailed description of related known technologies will be omitted if it is determined that they unnecessarily make the gist of the embodiments unclear.

[0070] The present disclosure may have various modifications and various embodiments and specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this does not limit the present disclosure within specific embodiments, and it should be understood that the present disclosure covers all the modifications, equivalents, and replacements within the idea and technical scope of the present disclosure. In the interest of clarity, not all details of the relevant art are described in detail in the present specification in so much as such details are not necessary to obtain a complete understanding of the present disclosure.

EXAMPLE 1. Synthesis of Chiral Maleimide Derivatives of Present Disclosure

[0071] 1.1. Instruments and Reagents

[0072] Optical rotation was measured using an automatic digital polarimeter, and Fourier transform infrared (FT-IR) spectra were recorded using a Nicolet 380 FT-IR spectrophotometer (Thermo Electron Corporation). Nuclear magnetic resonance (.sup.1H NMR and .sup.13C NMR) spectra were obtained using Varian Gemini 300 (300, 75 MHz) and Bruker Avance 500 (500, 125 MHz) using tetramethylsilane as an internal standard. Low-resolution mass spectrometry profiles were obtained using JEOL the MStation JMS-700. Chiral high-performance liquid chromatography (HPLC) analysis was performed using a Jasco LC-1500 series HPLC system. Toluene (CaH.sub.2), tetrahydrofuran (THF) (Na, benzophenone), and CH.sub.2Cl.sub.2 (CaH.sub.2) reaction solvents were purified and used. Reagents used in this study were obtained from Aldrich, Acros, Alfa, Sigma, Merck, Fluka, TCI, and Lancaster, and were purified or dried by known methods, if necessary. Merck's silica gel 60 (230 to 400 mesh) was used as a stationary phase in column chromatography.

[0073] 10 1.2. Synthesis of N-mono-thiourea Catalyst

[0074] (R,R)-1.2-diphenylethylenediamine (DPEN, 0.5 g, 0.235 mmol) was dissolved in toluene (2.50 mL), and then the solution was added with isothiocyanate (0.35 mL, 0.235 mmol) and stirred at 0 C. for 1 hour, and then the reaction was terminated with distilled water. The mixture was extracted with ethyl acetate (20 mL3 times), dehydrated with MgSO.sub.4, filtrated, and concentrated under reduced pressure, and purified by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2: n-hexane=1:2) to separate a product (Chemical Formula 4) (Reaction Formula 1).

##STR00010##

[0075] Non-limiting examples of the thiourea catalyst according to an embodiment of the present disclosure were as follows:

[0076] (1) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-[3,5-bis(trifluoromethyl)phenyl]thiourea (Chemical Formula 4-1)

[0077] [].sub.D.sup.25 +13.5 (c 1.0, CH.sub.3Cl); .sup.1H-NMR (500 MHz, DMSO-d6) 8.25 (s, 2H), 7.78 (s, 1H), 7.32-7.15 (m, 13H), 5.99 (d, J=3 Hz, 1H), 4.77 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (125 MHz, DMSO-d6) 180.51, 143.26, 142.48, 130.82, 130.56, 128.51, 128.29 127.66, 127.55, 127.38, 124.78, 122.62, 121.34, 116.08, 63.66, 59.94 ppm; IR (KBr) 3305, 3032, 2963, 1652,1601, 1557, 1383, 1277, 1262, 803, 700 cm.sup.1; HRMS (FAB+) for C.sub.23H.sub.19F.sub.6N.sub.3S [M+H].sup.+ Calcd: 484.1282, Found: 484.1254;

[0078] (2) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-phenylthiourea (Chemical Formula 4-2)

[0079] [].sub.D.sup.20 =+62.0 (c=0.02, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) 7.76 (s, 1 H), 7.54-7.19 (m, 15 H), 5.54 (s, 1 H), 4.42 (d, 1 H, J=5 Hz), 1.35 (br s, 1 H); .sup.13C-NMR (100 MHz, DMSO-d6) 182.09, 134.48, 133.93, 129.89, 128.70, 128.10, 127.91, 127.15, 126.94, 126.82, 126.74, 126.23, 125.59, 125.24, 122.98, 63.07,59.09; IR (KBr) 3287.86, 3027.84, 1521.63, 1241.99, 1072.28, 939.20, 698.13 cm.sup.1; HRMS (FAB+) for C.sub.21H.sub.22N.sub.3S [M+H].sup.+ Calcd: 348.4918, Found: 348.1534.

[0080] (3) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-p-tolythiourea (Chemical Formula 4-3)

[0081] [].sub.D.sup.22 +0.27 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) 9.79 (s, 1H), 7.13-7.38 (m, 15H), 5.50 (s, 1H), 4.32 (d, J=3 Hz, 1H), 2.27 (s, 3H) ppm; .sup.13C-NMR (100 MHz, DMSOd6) 180.90, 143.72, 142.20, 137.14, 134.32, 129.86, 128.82 128.59, 127.68, 127.61, 127.46, 127.39, 123.97, 63.88, 60.00, 21.23 ppm; IR (KBr) 3301.69, 2861.98, 1889.99, 1527.42, 1342.28, 964.28, 701.99, 524.56 cm.sup.1; HRMS (FAB+) for C.sub.22H.sub.24N.sub.3S [M+H].sup.+ Calcd: 362.1691, Found: 362.2188

[0082] (4) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-methoxyphenyl)thiourea (Chemical Formula 4-4)

[0083] [].sub.D.sup.22 +0.327 (c 1.00, CH.sub.3Cl); 1H-NMR (300 MHz, DMSO-d6) 9.55 (s, 1H), 8.17 (s, 1H), 7.12-7.22 (m, 12H), 6.87 (d, J=6.0 Hz, 3H), 5.94 (s, 1H), 3.72 (s, 3H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) 180.72, 156.54, 139.70, 131.67, 128.09, 127.97, 127.19, 125.61, 113.93, 62.38, 59.81. 55.24 ppm; IR (KBr) 3303.63, 3027.84, 1733.78, 1510.06, 1297.92, 1243.92, 1029.85, 831.21, 700.07, 568.93 cm.sup.1; HRMS (FAB+) for C.sub.22H.sub.24N.sub.3OS [M+H].sup.+ Calcd: 378.1640, Found: 378.1563

[0084] (5) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-fluorophenyl)thiourea (Chemical Formula 4-5)

[0085] [].sub.D.sup.22 +0.132 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) 9.93 (s, 1H), 7.08-7.46 (m, 15H), 5.52 (s, 1H), 4.34 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) 181.28, 160.71, 143.73, 142.10, 136.32, 128.79, 128.58, 127.70, 127.59, 127.49, 127.39, 125.79, 115.94, 115.71, 63.88, 60.06 ppm; IR (KBr) 3301.69, 3029.77, 1874.56, 1527.42, 1342.27, 1218.85, 840.85, 701.99 cm.sup.1; HRMS (FAB+) for C.sub.21H.sub.21FN.sub.3S [M+H].sup.+ Calcd: 366.1440, Found: 366.1440

[0086] (6) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-cyanophenyl)thiourea (Chemical Formula 4-6)

[0087] [].sub.D.sup.22 +1.50 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) 10.50 (s, 1H), 7.07-7.88 (m, 15H), 5.56 (d, J=3 Hz, 1H), 4.39 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) 180.47, 145.05, 143.34, 141.61, 133.36, 128.83, 128.64 127.74, 127.68, 127.59, 127.50, 121.37, 119.85, 105.11, 63.74, 60.04 ppm; IR (KBr) 3263.1, 2219.7, 1646.9, 1592.9, 1361.5, 1091.5 cm.sup.1; HRMS (FAB+) for C.sub.22H.sub.20N.sub.4S [M+H].sup.+ Calcd: 372.1487, Found: 372.1400

[0088] 1.3. Asymmetric Michael Addition Reaction of Aldehyde and Maleimide

[0089] An N-mono-thiourea catalyst (Chemical Formula 4, 0.01 mol %) and maleimide (Chemical Formula 2, 2.88 mmol) were added in a reaction container at room temperature and dissolved in water (0.1 mL) under air conditions. Then, the mixture was added with aldehyde (Chemical Formula 1, 2 equiv.) and stirred for 10 to 13 hours. After completion of the reaction with distilled water, the mixture was extracted with ethyl acetate (0.3 mL3 times), dehydrated with MgSO.sub.4, filtrated and concentrated under reduced pressure, and purified with column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2: hexane=1:3) to separate a product (Chemical Formula 3).

[0090] Non-limiting examples of the chiral maleimide derivatives prepared by the asymmetric Michael addition reaction between aldehyde and maleimide according to an embodiment of the present disclosure were as follows:

[0091] (1) (R)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal (2a, Chemical Formula 3-1)

[0092] [].sub.D.sup.25 +6.2 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.51 (s, 1H), 7.26-7.50 (m, 5H), 3.14 (dd, J=6.0, 12 Hz, 1H), 2.96 (dd, J=9.0, 18 Hz, 1H), 2.60 (dd, J=6.0, 12 Hz, 1H), 1.32 (s, 3H), 1.27 (s, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 203.0, 177.1, 175.0, 132.0, 129.4, 128.9, 126.7, 48.8, 45.2, 32.1, 20.6, 19.8 ppm; LRMS (EI+) Calcd. for [C.sub.14H.sub.15NO.sub.3].sup.+: 245, found: 245; HPLC [Chiralcel OD-H, hexane/2-propanol=75/25, flow rate=0.7 mL/min, =210 nm, retention times: (major) 38.8 min, (minor) 32.3 min].

[0093] (2) (R)-2-(2,5-Dioxopyrrolidin-3-yl)-2-methylpropanal (2b, Chemical Formula 3-2)

[0094] [].sub.D.sup.21 9.00 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.49 (s, 1H), 8.57 (br. s, 1H), 3.09 (dd, J=6.0, 9.0 Hz, 1H), 2.85 (dd, J=12, 18 Hz, 1H), 2.51 (dd, J=6.0, 18 Hz, 1H), 1.26 (s, 3H), 1.24 (s, 3H) ppm; .sup.13C NMR (100 MHz, DMSO) 185.4, 183.3, 182.8, 53.3, 48.8, 38.8, 29.5, 28.4 ppm; LRMS (EI+) Calcd. for [C.sub.8H.sub.11NO.sub.3].sup.+: 169, found: 169; HPLC [Chiralcel AD-H, hexane/2-propanol=85/15, flow rate=0.7 mL/min, =210 nm, retention times: (major) 25.3 min, (minor) 33.7 min].

[0095] (3) (R)-2-(2,5-Dioxo-1-p-tolylpyrrolidin-3-yl)-2-methylpropanal (2c, Chemical Formula 3-3)

[0096] [].sub.D.sup.21 6.5 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.52 (s, 1H), 7.26 (t, 3H), 7.15 (d, J=9.0 Hz, 2H), 3.14 (dd, J=6.0, 9.0 Hz, 1H), 2.96 (dd, J=9.0, 18 Hz, 1H), 2.56-2.64 (dd, J=6.0, 18 Hz, 1H), 2.37 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 203.0, 177.2, 175.2, 139.0, 130.1, 129.3, 126.5, 48.7, 45.2, 32.0, 21.4, 20.5, 19.8 ppm; LRMS (EI+) Calcd. for [C.sub.15H.sub.17NO.sub.3].sup.+: 259, found: 259; HPLC [Chiralcel OD-H, hexane/2-propanol=75/25, flow rate=0.6 mL/min, =210 nm, retention times: (major) 37.7 min, (minor) 31.3 min].

[0097] (4) (R)-2-[1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methylpropanal (2d, Chemical Formula 3-4)

[0098] [].sub.D.sup.20 +5.7 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.48 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.19 (d, J=6.0 Hz, 2H), 3.11 (dd, J=6.0, 9.0 Hz, 1H), 2.97 (dd, J=9.0, 18 Hz, 1H), 2.60 (dd, J=6.0, 18 Hz, 1H), 1.36 (s, 3H), 1.28 (s, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 203.0, 176.8, 174.6, 132.6, 131.0, 128.3, 122.8, 48.9, 45.1, 32.2, 20.7, 20.1 ppm; LRMS (EI+) Calcd. for [C.sub.14H.sub.14BrNO.sub.3].sup.+: 323, found: 323; HPLC [Chiralcel OD-H, hexane/2-propanol=75/25, flow rate=0.6 mL/min, =210 nm, retention times: (major) 58.6 min, (minor) 31.5 min].

[0099] (5) (R)-2-[1-(4-Nitrophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methylpropanal (2e, Chemical Formula 3-5)

[0100] [].sub.D.sup.20 +2.7 (c 0.1, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.47 (s, 1H), 8.33 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 3.13 (dd, J=6.0, 12 Hz, 1H), 3.02 (dd, J=12, 18 Hz, 1H), 2.68 (dd, J=6.0, 18 Hz, 1H), 1.42 (s, 3H), 1.31 (s, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 203.0, 176.5, 174.1, 147.2, 137.6, 127.3, 124.6, 49.2, 45.2, 32.4, 21.0, 20.5 ppm; LRMS (EI+) Calcd. for [C.sub.14H.sub.14N.sub.2O.sub.5].sup.+: 290, found: 290; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=1.0 mL/min, =210 nm, retention times: (major) 72.6 min, (minor) 44.4 min].

[0101] (6) (R)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarbaldehyde (2f, Chemical Formula 3-6)

[0102] [].sub.D.sup.20 +5.2 (c 0.1, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 9.54 (s, 1H), 7.26-7.50 (m, 5H), 3.25 (dd, J=6.0, 9.0 Hz, 1H), 2.88 (dd, J=9.0, 18 Hz, 1H), 2.67 (dd, J=6.0, 18 Hz, 1H), 1.82-2.04 (m, 3H), 1.53-1.64 (m, 7H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 204.9, 177.4, 175.2, 132.3, 129.5, 129.0, 127.0, 52.6, 43.0, 31.9, 29.0, 28.5, 25.5, 21.8, 21.6 ppm; LRMS (FAB+) Calcd. for [C.sub.17H1.sub.9NO.sub.3].sup.+: 285, found: 285; HPLC [Chiralcel OD-H, hexane/2-propanol=75/25, flow rate=1.0 mL/min, =210 nm, retention times: (major) 53.2 min, (minor) 42.4 min].

[0103] 1.4. Gram-Scale Asymmetric Michael Addition Reaction of Aldehyde and Maleimide

[0104] An N-mono-thiourea catalyst (Chemical Formula 4, 0.01 mol %) and maleimide (Chemical Formula 2, 288.7 mmol) were added in a reaction container at room temperature and dissolved in water (10 mL) under air conditions. Then, the mixture was added with aldehyde (Chemical Formula 1, 2 equiv.) and stirred for 10 to 13 hours. After completion of the reaction with distilled water, the mixture was extracted with ethyl acetate (30 mL3 times), dehydrated with MgSO.sub.4, filtrated and concentrated under reduced pressure, and then purified by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2: n-hexane=1:3) to separate a product (Chemical Formula 3). Finally, the catalyst was separated by changing the column chromatography condition (SiO.sub.2, CH.sub.2Cl.sub.2: n-hexane=1:3).

EXAMPLE 2. Synthesis of Chiral Spironolactone Derivatives of Present Disclosure

[0105] An N-mono-thiourea catalyst (Chemical Formula 4, 0.01 mol %) and N-phenyl maleimide (Chemical Formula 2-1, 288.7 mmol) were added in a reaction container at room temperature and dissolved in water (10 mL) under air conditions. Then, the mixture was added with cyclohexane carboxaldehyde (Chemical Formula 1-2, 2 equiv.) and stirred for 14 hours. After completion of the reaction with distilled water, the mixture was extracted with ethyl acetate (30 mL3 times), dehydrated with MgSO.sub.4, filtrated and concentrated under reduced pressure, and then purified by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2: n-hexane=1:3) to obtain a product (Chemical Formula 3-6) in 98.6% yield (8.19 g) and 99% optical purity (ee). Finally, the catalyst was separated by changing the column chromatography condition (SiO.sub.2, CH.sub.2Cl.sub.2: n-hexane=1:3).

[0106] 8.19 g of the product (Chemical Formula 3-6) was diluted with CH.sub.2Cl.sub.2 (45 mL) and cooled to 20 C. The product was added with BH.sub.3.Math.THF (60 mL, 60 mmol), and then the reaction mixture was left while stirring and the reaction was heated to room temperature. After completion of reduction (24 to 48 hours, determined by TLC), BF.sub.3.Math.Et.sub.2O (12 mL, 100 mmol) was added at 20 C. and the reactant was stirred at room temperature for 24 hours. The reaction mixture was dried under reduced pressure and the product was purified using column chromatography with petroleum ether (40 to 60 C.)/ethyl acetate (6:4) to obtain desired spironolactone (Chemical Formula 5-1) (Reaction Formula 2).

##STR00011##

[0107] (R)-2-(3-Oxo-2-oxaspiro[4.5]decan-4-yl)-N-phenylacetamide (3a, Chemical Formula 5-1)

[0108] [].sub.D.sup.20 4.2 (c 0.1, CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, CDCl.sub.3) 8.78 (s, 1H), 7.55 (d, J=6.0, Hz, 2H), 7.32 (t, J=6.0 Hz, 2H), 7.10 (t, J=9.0 Hz, 1H), 3.85 (m, 1H), 3.54 (m, 1H), 3.06 (dd, J=3.0, 9.0 Hz, 1H), 2.59 (dd, J=9.0, 15 Hz, 1H), 2.29 (dd, J=3.0, 15 Hz, 1H), 1.60 (m, 4H), 1.39 (m, 4H), 1.25 (m, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) 180.2, 170.0, 138.9, 129.5, 124.7, 120.5, 70.3, 47.3, 46.1, 33.2, 32.0, 28.9, 25.8, 23.1, 19.9 ppm; LRMS (FAB+) Calcd. for [C.sub.17H.sub.21NO.sub.3].sup.+: 287, found: 287; HPLC [Chiralcel OD-H, hexane/2-propanol=90/10, flow rate=1.0 mL/min, =254 nm, retention times: (major) 9.9 min, (minor) 14.9 min].

[0109] Since the spironolactons are diuretics known for a potential medicinal use, the chiral spironolactone derivatives of the present disclosure may be usefully used for the treatment of edema control, heart failure, cirrhosis, electrolyte abnormalities, hypertension, and the like.

Experimental Example 1. Asymmetric Michael Addition Reaction Using Thiourea Catalyst

[0110] In order to examine an effect of the catalyst on the enantioselective Michael reaction of aldehyde and maleimide, the Michael addition reaction was performed by using DPEN as a basic backbone and a catalyst in which thiourea has replaced one of amines. At this time, the reaction was performed at room temperature using CH.sub.2Cl.sub.2 as a solvent. As a result, in the case of using a catalyst (Chemical Formula 4-1) substituted with a 3,5-bis(trifluoromethyl) group, the highest yield and stereoselectivity were exhibited.

[0111] 1.1. Optimization of Additives and Solvents

[0112] The effect of acid additives was evaluated to further enhance the catalysis (Table 1). The acid additives activated the aldehyde to promote the catalytic function and the imine formation. In particular, the reaction yield slightly increased when benzoic acid was added (entry 4), and excellent yield and stereoselectivity were exhibited when the reaction solvent was changed to THF (entry 5).

[0113] However, when water was used as a solvent, the catalyst provided the highest reactivity and enantioselectivity with optimal yield and stereoselectivity even in the absence of weak acid additives, and the reaction time (2 to 36 times) and the catalyst amount (10 to 1000 times) were also dramatically reduced. In particular, in the case of entry 8 of Table 1, excellent yield and stereoselectivity were exhibited even with a supported catalyst amount of 0.01 mol %, which was 1/1000 of other solvents.

##STR00012##

TABLE-US-00001 TABLE 1 Entry Time (h) Additive Solvent Yield (%) .sup.a ee (%) .sup.b 1 24 Trifluoro- CH.sub.2Cl.sub.2 78 98 acetic acid 2 24 Acetic acid CH.sub.2Cl.sub.2 83 94 3 24 Salicylic CH.sub.2Cl.sub.2 82 94 acid 4 24 Benzoic Toluene 78 99 acid 5 24 Benzoic THF 98 99 acid 6 .sup.c 0.67 Water 99 99 7 .sup.d 6 Water 99 99 8 .sup.e 12 Water 97 99 .sup.a Separated yield. .sup.b Enantiomeric excess (ee) values were determined by chiral-phase high-performance liquid chromatography (HPLC) using an OD-H column. Reactions were run with catalyst(1a) loading of .sup.c 1, .sup.d 0.1, .sup.e 0.01 mol %.

[0114] 1.2. Reaction Depending on Type of Maleimide

[0115] The reactions between isobutyraldehyde and various maleimides were performed according to the conditions optimized in Example 1.1. The reaction time was the shortest when the maleimide was not substituted with a phenyl group (Chemical Formula 2-2), and maleimides substituted with toluene, bromophenyl, and nitrophenyl groups (Chemical

[0116] Formulas 2-3, 2-4, and 2-5) also showed excellent yield and optical purity (Table 2).

##STR00013##

TABLE-US-00002 TABLE 2 Entry Ar Time (h) Yield (%) .sup.a ee (%) .sup.b 1 H 10 98 99 2 4-MeC.sub.6H.sub.4 12 99 99 3 4-BrC.sub.6H.sub.4 12 98 99 4 4-NO.sub.2C.sub.6H.sub.4 12 97 99 .sup.a Separated yield. .sup.b ee values were determined by chiral-phase HPLC using OD-H, AD-H, and AS-H columns.

Experimental Example 2. Reaction Mechanism Inferred Through Expected Transition State

[0117] A mechanism of the Michael addition reaction between aldehyde and maleimide using a thiourea catalyst expected according to an embodiment of the present disclosure was illustrated in FIG. 2.

[0118] In step A, the thiourea catalyst reacted with isobutyraldehyde to form imine, and the imine formed enamine later. In addition, a thiourea portion of the catalyst and a ketone portion of the maleimide activated a maleimide electrophile through a hydrogen bond. Accordingly, a transition state including an electrophile activated in step B was formed, which can minimize steric hindrance of maleimide due to Re face attack. Finally, in step C, the catalyst and the product are separated through hydrolysis. According to the mechanism, the present disclosure may prepare an (R)-enantiomer as a main product.

[0119] To more accurately predict a solvent effect of the catalyst, the relative free energy of the transition state during an interfacial reaction between fluorine atoms of a trifluoromethyl group of the thiourea catalyst (Chemical Formula 4-1) and water as a solvent was calculated as follows in an aqueous binary mixture (H.sub.2O+solvent). When water was used as the solvent, the relative free energy of the transition state was calculated to be the lowest. As illustrated in FIG. 3, fluorine (F) atoms of the 3,5-bis(trifluoromethyl)phenyl group of the catalyst (Chemical Formula 4-1) interacted with hydrogen (H) atoms of the water solvent through hydrogen bonds, and the relative free energy was decreased as the number of hydrogen bonds in water was increased. That is, when water was used as the solvent in the Michael addition reaction, it means that the reactivity increased due to the stabilization of the relative energy and a hydrophobic effect of the hydration reaction.

[0120] In addition, in order to prove through nuclear magnetic resonance spectroscopy (NMR) that the reaction proceeded through hydrogen bonds between fluorine (F) atoms and hydrogen (H) atoms in the reaction with the catalyst 4-1 when water was used as a solvent, as a result of measuring NMR by using D.sub.2O instead of water, it was confirmed that the peaks of observing fluorine (.sup.19F) in the catalyst shifted depending on the presence or absence of D.sub.2O (FIG. 4A and FIG. 4B). This suggests a possibility of forming hydrogen bonds between fluorine atoms and hydrogen atoms.

[0121] In general, hydrophobic non-polar solvents such as toluene provide excellent yield and stereoselectivity in the Michael addition reaction. However, since the solvent effect on the Michael addition reaction was confirmed in FIG. 3, a thermodynamic analysis was performed on the effect of water on the Michael addition reaction. Quantum calculations were performed to predict the relative free energy of the interfacial reaction system in the transition state of the catalyst (FIG. 5).

[0122] As a result of comparing the actual reaction results (Table 1) and quantum calculation results, toluene as a non-polar solvent showed the lowest reactivity, and tetrahydrofuran and CH.sub.2Cl.sub.2 showed similar reactivity in the calculated results. In particular, water exhibited the highest reactivity and stability beyond the results recorded for weak acids such as formic acid and dimethyl sulfoxide, and ethanol as polar hydrophilic solvents (FIG. 5).

Experimental Example 3. Gram-Scale Asymmetric Michael Addition Reaction

[0123] Recycling of the thiourea catalyst was evaluated (FIG. 6 and Reaction Formula 3). During 4 cycles of reuse, chiral maleimide derivatives produced through the Michael addition reaction maintained high yield (99.5 to 98.3%) and stereoselectivity (99%).

##STR00014##

[0124] A gram-scale reaction of adding a cyclohexyl group to aldehyde was performed using the recovered catalyst. As in Example 2, through the Michael addition reaction of cyclohexane carboxaldehyde (Chemical Formula 1-2) and N-phenylmaleimide (Chemical Formula 2-1), (R)-1-(2,5-Dioxo-1-phenylpyrrolidin-3 -yl)cyclohexanecarbaldehyde (Chemical Formula 3-6) was produced, and then added with BH.sub.3.Math.THF and BF.sub.3.Math.Et.sub.2O to produce (R)-2-(3-Oxo-2-oxaspiro[4.5]decan-4-yl)-N-phenylacetamide (Chemical Formula 5-1).

[0125] Therefore, according to an embodiment of the present disclosure, it is possible to prepare chiral maleimide derivatives with excellent yield (98.6%) and enantioselectivity (99%) even on a gram scale using an eco-friendly solvent and a recyclable catalyst. Based on this, it is possible to prepare chiral spironolactone derivatives with significant yield (84%) and enantioselectivity (99%).

[0126] As described above, although the embodiments have been described by the restricted drawings, various modifications and variations can be applied on the basis of the embodiments by those skilled in the art. For example, even if the described techniques are performed in a different order from the described method, and/or components such as a system, a structure, a device, a circuit, and the like described above are coupled or combined in a different form from the described method, or replaced or substituted by other components or equivalents, an appropriate result can be achieved.

[0127] Therefore, other implementations, other embodiments, and equivalents to the appended claims fall within the scope of the claims to be described below.