Novel process for synthesis of polysubstituted pyridine derivatives

Abstract

The present invention relates to a novel method for synthesizing a polysubstituted pyridine derivative and, more specifically, to a method for synthesizing a 2,3,5-substituted pyridine derivative through a specific ring cleavage reaction. In the synthesis method of the present invention, an enamine structure is formed in situ by using beta keto ester / sulfone / phosphonic acid ester and ammonium acetate and subjected to an aldol condensation reaction with 3-formyl (aza) indole / benzofuran, a cyclization reaction, and a ring-cleavage reaction in that order to synthesize a characteristic pyridine structure having an alkyl / aryl substituent attached to the 2-position thereof, an ester / sulfone / phosphonic acid ester attached to the 3-position thereof, and ortho-aminoaryl / phenol including various substituents attached to the 5-position thereof. In particular, (aza)indole / benzofuran and beta keto ester / sulfone / phosphonic acid ester, which are reaction substrates, are substrates having very high accessibility, and enable the introduction of various substituents, thereby constructing a pyridine skeleton having high biocompatibility into which ortho-aminoaryl or phenol substituents having various substituents are introduced.

Description

A novel synthetic method for polysubstituted pyridine derivatives

[0001] The present invention relates to a novel synthetic method for a multi-substituted pyridine derivative, and more specifically, to a method for synthesizing a pyridine derivative substituted at the 2,3,5-position of pyridine through a specific ring cleavage reaction.

[0002] Pyridine is a representative privileged structure in pharmaceutical development, maximizing the potential for biological activity when incorporated into a small-molecule backbone. Pyridine is a key hexagonal aromatic ring commonly found in various natural products and pharmaceuticals. Incorporating pyridine maximizes the biological relevance of small-molecule compounds, thereby increasing the likelihood of the synthesized molecular backbone exhibiting medicinal effects.

[0003] Furthermore, pyridine is a key structural element, present in 15% of FDA-approved small-molecule pharmaceutical compounds. Incorporating pyridine into the molecular backbone maximizes the potential for biological activity. The small-molecule pharmaceutical market is expected to exceed $76 billion in 2022 and is expected to reach $164 billion by 2032. Pyridine structures are expected to account for a significant portion of this market, driving continued growth in market demand for selective pyridine synthesis technologies.

[0004] Despite the aforementioned utility of pyridine, the introduction of substituents at positions 3 and 5, which correspond to the meta position of pyridine, has been very limited. This is because the meta position of pyridine is nucleophilic but has very low electron density, resulting in low reactivity. In addition, selective carbon-hydrogen bond activation has the disadvantage of low selectivity for the ortho, meta, and para positions and the use of noble metal catalysts. Furthermore, although pyridine can be synthesized through cyclization reaction, the types of substituents introduced at positions 3 and 5 are very limited, and the synthesis of compounds with asymmetric substitution at positions 3 and 5 is even more limited. The types of functional groups that can be introduced are also very limited, and there is a limitation that the introduction of substituents at non-desired positions cannot be avoided.

[0005] Accordingly, the present invention presents an innovative methodology for synthesizing tridentate-substituted pyridines with highly biocompatible substituents at positions 2, 3, and 5 of carbons through the reactivity of specifically breaking the carbon-heteroatom bond in the skeleton of 3-formyl (aza) indole / benzofuran using beta-keto ester / sulfone / phosphonic acid ester.

[0006] The synthetic method of the present invention provides a method for producing a 2,3,5-tridentate substituted pyridine skeleton by cleaving a carbon-heteroatom bond using 3-formyl (aza) indole / benzofuran as a beta-keto ester / sulfone / phosphonic acid ester and an ammonium donor. Specifically, through the synthetic method of the present invention, a pyridine skeleton with high biocompatibility can be constructed by introducing various alkyl and aryl substituents at the 2-position, an electron-withdrawing substituent such as an ester / sulfone / phosphonic acid ester at the 3-position, and an ortho-aminoaryl or phenol substituent with various substituents at the 5-position.

[0007] To achieve the above purpose,

[0008] (S1) A step of adding and mixing a compound represented by chemical formula 1, a compound represented by chemical formula 2, and ammonium acetate (NH4OAc) into a polar organic solvent; and

[0009] (S2) A step of heating the mixture to synthesize a compound represented by the following chemical formula 3;

[0010] A method for synthesizing a multi-substituted pyridine derivative including

[0011]

[0012] [Chemical Formula 1]

[0013]

[0014] [Chemical Formula 2]

[0015]

[0016] [Chemical Formula 3]

[0017]

[0018] In the above chemical formulas 1 and 3,

[0019] X1 is C, N, O or S,

[0020] X2 is C or N,

[0021] In the above chemical formulas 1 to 3,

[0022] “*” indicates a bonding portion with another atom or functional group.

[0023] The synthetic method according to the present invention enables the synthesis of novel molecules previously unoccupied in chemical space by forming 2,3,5-tridentate substituted pyridine structures, which were previously inaccessible using existing methodologies. In particular, the substituents at each site are highly biorelevant, and the design incorporates structural elements of various bioactive molecules, including pyridines, thereby enabling the construction of a library for the discovery of diverse physiologically active molecules.

[0024] Figure 1 illustrates a synthetic strategy for substituted pyridines having various functional groups (ester / sulfone / phosphonate) according to the present invention.

[0025] Figure 2 illustrates a proposed mechanism according to the present invention. A mechanism for the synthesis of 2-alkyl / aryl 3-ester 5-aminoaryl pyridines is proposed based on an aldol-type reaction between 3-formyl (aza)indole and β-aminoacrylate produced from β-ketoester and ammonium acetate.

[0026] Figure 3 shows the substrate range according to the present invention. Reaction conditions: 1 (0.2 mmol), 2 (1.2 equivalents), NH4OAc (4.0 equivalents), TFA (1.0 equivalents) in DCE (2 mL) at 120°C for 16 hours. The yield of the isolated product (3) is indicated in parentheses (a is the reaction performed in ethanol without trifluoroacetic acid).

[0027] Figure 4 illustrates the use of various enamine sources for the synthesis of pyridyl sulfone / phosphonates according to the present invention. Reaction conditions: 1 (0.2 mmol), β-keto sulfone / phosphonate (4b-c / 5b-c, 1.2 equiv), NH4OAc (6.0 equiv), TFA (1.0 equiv) in DCE (2 mL / 1 mL) at 120°C for 16-48 h. The yields of the isolated products (6 and 7) are indicated in parentheses (a 30 h reaction time; b 48 h reaction time; c 55% crude NMR yield).

[0028] Figure 5 illustrates a reaction with a benzofuran analogue according to the present invention. Reaction conditions: 8 (0.2 mmol), β-ketoester (2a, 2d, or 2f, 1.2 equivalents), NH4OAc (4.0 equivalents), TFA (1.0 equivalent) in DCE (2 mL) at 120°C for 16 hours. The yield of the isolated product (9) was reported.

[0029] Figure 6 illustrates synthetic applications according to the present invention. a Synthesis of bio-relevant molecules containing pyridine supports. b Conjugation of ethyl 2-methyl nicotinate with drugs / natural products.

[0030] The technology described below is susceptible to various modifications and embodiments. Specific embodiments are illustrated and described in detail in the drawings. However, this does not limit the technology described below to specific embodiments, and it should be understood that all modifications, equivalents, and alternatives fall within the spirit and scope of the technology described below.

[0031]

[0032] The present invention provides a method for synthesizing a polysubstituted pyridine derivative, comprising the steps of (S1) adding a compound represented by the chemical formula 1, a compound represented by the chemical formula 2, and ammonium acetate (NH4OAc) to a polar organic solvent and mixing them; and (S2) heating the mixture to synthesize a compound represented by the chemical formula 3 below.

[0033]

[0034] [Chemical Formula 1]

[0035]

[0036] [Chemical Formula 2]

[0037]

[0038] [Chemical Formula 3]

[0039]

[0040] In the above chemical formulas 1 and 3,

[0041] X1 is C, N, O or S,

[0042] X2 is C or N,

[0043] In the above chemical formulas 1 to 3,

[0044] “*” indicates a bonding portion with another atom or functional group.

[0045]

[0046] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may be a compound represented by the following chemical formula 1a.

[0047]

[0048] [Chemical Formula 1a]

[0049]

[0050] In the above chemical formula 1a,

[0051] X1 is C, NR1, O or S,

[0052] X2 is C or N,

[0053] R1 is hydrogen, C 1-20 Linear or branched alkyl; R a Benzyl substituted or unsubstituted; R a Heteroaryl substituted or unsubstituted with R; phenyl group is R b Phenylsulfonyl substituted or unsubstituted; R b substituted or unsubstituted phenyl; pyridine; or pyrimidine; and

[0054] The above R a and R b are each independently a halogen; C 1-10 Linear or branched alkoxy; C 1-10 linear or branched alkyl; amino; or acetyl; and

[0055] The above R2 is halogen; C 1-10 Linear or branched alkyl; halogen; hydroxy; C 1-10 Linear or branched alkoxy; or nitro;

[0056]

[0057] According to one embodiment of the present invention, the compound represented by the chemical formula 2 may be a compound represented by the following chemical formula 2a.

[0058]

[0059] [Chemical Formula 2a]

[0060]

[0061] In the above chemical formula 2a,

[0062] R3 is C 1-20 Linear, branched or cyclic alkyl; R c Phenyl substituted or unsubstituted with R; or R c is a substituted or unsubstituted heteroaryl,

[0063] The above R c is a halogen;

[0064] R4 is R d substituted or unsubstituted ester, R d is a substituted or unsubstituted sulfonyl or phosphonic acid ester,

[0065] The above R d is C 1-10 Linear or branched alkoxy; phenyl; benzyl;

[0066]

[0067] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may be any one selected from the group consisting of compounds represented by the following chemical formulas 1b to 1n.

[0068]

[0069] [Chemical Formula 1b]

[0070]

[0071] [Chemical Formula 1c]

[0072]

[0073] [Chemical Formula 1d]

[0074]

[0075] [Chemical Formula 1e]

[0076]

[0077] [Chemical formula 1f]

[0078]

[0079] [Chemical formula 1g]

[0080]

[0081] [Chemical formula 1h]

[0082]

[0083] [Chemical Formula 1i]

[0084]

[0085] [Chemical formula 1j]

[0086]

[0087] [Chemical formula 1k]

[0088]

[0089] [Chemical formula 1l]

[0090]

[0091] [Chemical formula 1m]

[0092]

[0093] [chemical formula 1n]

[0094]

[0095] In the above chemical formulas 1b to 1n,

[0096] X2 is C or N,

[0097] Z1 and Z2 are C or N,

[0098] R e Inland R h is C 1-20 linear or branched alkyl; halogen; nitro; or alkoxy;

[0099]

[0100] According to one embodiment of the present invention, the compound represented by the chemical formula 2 may be any one selected from the group consisting of compounds represented by the following chemical formulas 2b to 2q.

[0101]

[0102] [Chemical Formula 2b]

[0103]

[0104] [Chemical Formula 2c]

[0105]

[0106] [Chemical formula 2d]

[0107]

[0108] [Chemical Formula 2e]

[0109]

[0110] [Chemical formula 2f]

[0111]

[0112] [Chemical formula 2g]

[0113]

[0114] [Chemical formula 2h]

[0115]

[0116] [Chemical formula 2i]

[0117]

[0118] [Chemical formula 2j]

[0119]

[0120] [Chemical formula 2k]

[0121]

[0122] [Chemical formula 2l]

[0123]

[0124] [Chemical formula 2m]

[0125]

[0126] [chemical formula 2n]

[0127]

[0128] [Chemical formula 2o]

[0129]

[0130] [Chemical formula 2p]

[0131]

[0132] [Chemical formula 2q]

[0133]

[0134]

[0135] According to one embodiment of the present invention, the polysubstitution may be a tridentate substitution at the ortho and meta sites of pyridine.

[0136] According to one embodiment of the present invention, the compound represented by the chemical formula 3 can be synthesized by breaking a bond between a carbon-heteroatom in the compound represented by the chemical formula 1.

[0137] According to one embodiment of the present invention, the polar organic solvent may be dichloroethane (DCE).

[0138] According to one embodiment of the present invention, the compound represented by the above chemical formula 2 may be added in an amount of 1 to 1.5 equivalents, preferably 1.1 to 1.4 equivalents, more preferably 1.1 to 1.3 equivalents, and most preferably 1.2 equivalents.

[0139] According to one embodiment of the present invention, the ammonium acetate may be added in an amount of 3.0 to 6.0 equivalents, preferably 3.5 to 5.5 equivalents, more preferably 3.8 to 5.2 equivalents, and most preferably 4 to 5 equivalents.

[0140] According to one embodiment of the present invention, the heating may be performed at 80 to 150°C, preferably 85 to 140°C, more preferably 90 to 130°C, and most preferably 100 to 120°C.

[0141] In the present invention, “the compound represented by the chemical formula 1” means a compound that includes a skeletal structure represented by the chemical formula 1 as a part of the compound, and in which the skeletal structure part acts as a reaction nucleus and in which a synthetic reaction according to the present invention occurs.

[0142] In the present invention, “the compound represented by the chemical formula 2” means a compound that includes a skeletal structure represented by the chemical formula 2 as a part of the compound, and in which the skeletal structure part acts as a reaction nucleus and in which a synthetic reaction according to the present invention occurs.

[0143] In the present invention, “the compound represented by the chemical formula 3” means a compound that includes a skeletal structure represented by the chemical formula 3 as a part of the compound, and in which the skeletal structure part acts as a reaction nucleus and in which a synthetic reaction according to the present invention occurs.

[0144] In the present invention, "C 1-20 "Linear or branched alkyl" means a saturated hydrocarbon group having 1 to 20 carbon atoms, which may be linear or branched. Examples thereof include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, iso-propyl, sec-butyl, tert-butyl, neo-pentyl, sec-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0145] In the present invention, "C 1-10 "Linear or branched alkyl" means a saturated hydrocarbon group having 1 to 10 carbon atoms, which is linear or branched. Examples thereof include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, iso-propyl, sec-butyl, tert-butyl, neo-pentyl, sec-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0146] In the present invention, "C 1-20 "Linear or branched alkoxy" is defined as R is C as above.1-20 An alkyl group is an OR group. Examples of such groups include, but are not limited to, methoxy, pentoxy, or heptoxy.

[0147] In the present invention, "C 1-10 "Linear or branched alkoxy" is defined as R is C as above. 1-10 An alkyl group is an OR group. Examples of such groups include, but are not limited to, methoxy, pentoxy, or heptoxy.

[0148] In the present invention, "substituted benzyl" refers to a group in which at least one hydrogen atom on an aromatic ring is replaced with another functional group. Examples thereof include, but are not limited to, 2-methylbenzyl, 4-ethyl-2-methylbenzyl, 2-bromo-3-methylbenzyl, 4-methoxybenzyl, and the like.

[0149] In the present invention, “heteroaryl” means a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from O, N and S, for example, 1 to 4 heteroatoms.

[0150]

[0151] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[0152]

[0153] Example 1: General reaction procedure for N-substituted 3-formyl(aza)indoles and various β-keto esters (2a-2f)

[0154]

[0155] To a 4 mL vial equipped with a magnetic stir bar and a Teflon-lined screw cap was added 1 (0.2 mmol) dissolved in dichloroethane (DCE, 2.0 mL), β-keto esters (2a-2f, 1.2 equiv), trifluoroacetic acid (TFA, 22.80 mg, 14.86 μL, 1.0 equiv), and NH4OAc (61.66 mg, 4.0 equiv). The vial was then sealed and heated at 120 °C for 16 h. After completion of the reaction was confirmed by LC-MS and TLC analysis, the reaction mixture was diluted with dichloromethane (DCM), quenched with saturated aqueous NaHCO3 solution, and extracted with DCM (3 × 10 mL). The mixed organic fractions were washed with brine (10 mL), dried over anhydrous Na2SO4(s), filtered, and concentrated under reduced pressure. The concentrated mixture was purified by silica gel flash column chromatography to obtain the target product.

[0156]

[0157] Example 2: General reaction procedure for N-substituted 3-formyl(aza)indoles and β-keto sulfones (4b-c) / β-ketophosphonates (5b-c)

[0158]

[0159] A 4 mL vial equipped with a magnetic stir bar and a Teflon-lined screw cap was added 1 (0.2 mmol) in DCE (1.0 mL (4b-c) / 2.0 mL (5b-c)), β-keto sulfone / phosphonate (4b-c / 5b-c, 1.2 equiv), TFA (22.80 mg, 14.86 μL, 1.0 equiv), and NH4OAc (92.50 mg, 6.0 equiv). The vial was then sealed and heated at 120 °C for 16 to 48 h. After completion of the reaction was confirmed by LC-MS and TLC analysis, the reaction mixture was diluted with DCM, quenched with saturated aqueous NaHCO3 solution, and extracted with DCM (3 × 10 mL). The mixed organic fractions were washed with brine (10 mL), dried over anhydrous Na2SO4(s), filtered, and concentrated under reduced pressure. The concentrated mixture was purified by silica gel flash column chromatography to obtain the target product containing 3-pyridylsulfone (6) / 3-pyridyl phosphonate (7).

[0160]

[0161] Example 3: General reaction procedure for benzofuran-3-carboxaldehyde and β-keto ester

[0162]

[0163] A 4 mL vial equipped with a magnetic stir bar and a Teflon-lined screw cap was added 8 (0.2 mmol) in DCE (2.0 mL), β-keto ester (2a, 2d, or 2f, 1.2 equiv), TFA (22.80 mg, 14.86 μL, 1.0 equiv), and NH4OAc (61.66 mg, 4.0 equiv). The vial was then sealed and heated at 120 °C for 16 h. After completion of the reaction was confirmed by LC-MS and TLC analysis, the reaction mixture was diluted with DCM, quenched with saturated aqueous NaHCO3 solution, and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine (10 mL), dried over anhydrous Na2SO4(s), filtered, and concentrated under reduced pressure. The concentrated mixture was purified by silica gel flash column chromatography to obtain the target phenol conjugate product (9).

[0164]

[0165] Example 4: Mechanism Study

[0166]

[0167] The synthesis of m-aminopyridyl-o-methyl substituted ethyl nicotinates (3aa) was investigated via a proposed ring cleavage reaction of N-phenylsulfonyl 3-formyl 7-azaindole (1a) and ethyl acetoacetate (2a). Ammonium acetate served as the nitrogen source for the substituted enamine, a key intermediate in the (aza)indole ring cleavage reaction (Figure 2). The substituted β-amino acrylate intermediate (II) is formed from the β-keto ester (I) and ammonium acetate. Subsequently, an aldol-type condensation between the β-amino acrylate intermediate and 3-formyl (aza)indole (III) yields intermediate (V) by dehydration of (IV). Sequential intramolecular cyclization (VI) and C-N bond cleavage yield the target m-aminopyridyl-o-methyl substituted ethyl nicotinates (VII).

[0168]

[0169] Meanwhile, the mechanism for synthesizing substituted pyridines through ring cleavage of (aza)indole and benzofuran is summarized as follows.

[0170]

[0171] [Reaction Formula 1]

[0172]

[0173]

[0174]

[0175] Example 5: Reaction Optimization and Substrate Scope

[0176]

[0177] The present inventors have identified optimal reaction conditions and substrate ranges. Figure 1 comprehensively illustrates the synthetic experiments of substituted pyridines with various functional groups (ester / sulfone / phosphonate) according to the present example.

[0178]

[0179] The starting materials, β-keto ester / sulfone / phosphonate and product materials used in the present invention are as follows.

[0180]

[0181] Starting material

[0182]

[0183]

[0184]

[0185]

[0186] β-keto ester / sulfone / phosphonate

[0187]

[0188]

[0189] generated substance

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] [Reaction Formula 2]

[0197]

[0198]

[0199] N-Phenylsulfonyl 7-azaindole 3-carboxaldehyde (1a) and ethyl acetoacetate (2a) were heated in dichloroethane (DCE) under NH4OAc and trifluoroacetic acid (TFA) at 120°C for 16 h to obtain the desired m-aminoaryl-o-methyl nicotinate 3aa in 70% yield.

[0200]

[0201]

[0202]

[0203] The optimal substrate range was investigated using N-phenylsulfonyl 3-formyl 7-azaindole (1a) and indole (1a') to give various β-keto esters (2b-2f) such as alkyl and aryl β-keto esters (Fig. 3). Ring cleavage of 3-formyl(aza)indole (1a and 1a') with n-propyl β-keto ester (2b) gave m-aminoaryl-o-propyl ethyl nicotinates (3ab and 3a'b) in good yields.

[0204]

[0205]

[0206]

[0207] Isopropyl (2c) and cyclopropyl (2d) β-keto esters also produced the desired substituted nicotinates (3ac-3a'd) in suitable yields according to the above method.

[0208]

[0209]

[0210]

[0211] The above (aza)indole cleavage reaction is also compatible with cyclohexyl (2e) and phenyl (2f) β-keto esters and generated o-cyclohexyl and o-phenyl nicotinate analogues (3ae-3a'f) from the corresponding (aza)indoles.

[0212]

[0213]

[0214]

[0215] Additionally, the substitution effect of indole substrates (1b-1k) in the ring cleavage reaction with ethyl acetoacetate (2a) was investigated, and it was confirmed that the target substituted pyridine analogues were formed in good yields regardless of the electronic effect of the substituents (Fig. 3).

[0216]

[0217] N-Phenylsulfonyl 3-formyl indoles containing bromo (1b-1d) and nitro (1e-1g) groups as electron-withdrawing groups at C-4, C-5 and C-6 positions, respectively, afforded the target substituted pyridines (3ba-3ga) in good yields at appropriate levels.

[0218]

[0219] For the electron-donating group, methoxy group (1h-1k), the target substituted pyridines (3ha-3ka) were obtained in similar yields.

[0220]

[0221]

[0222]

[0223] The optimal substrate range was investigated using positional isomeric azaindoles (1l-1n) to generate various o-aminopyridyl-linked pyridine analogues (3la-3na). Subsequently, various N-substituted (aza)indoles (1o-1x) were investigated for their compatibility and substrate range using ethyl acetoacetate (2a) in the present invention (Figure 3). 3-Formyl(aza)indoles containing N-benzyl substituents (1o-1q) successfully underwent the target reaction in excellent yields regardless of the functional groups on the benzene ring. Furthermore, the target transformations were well achieved when the benzene ring was substituted with thiophenes (1r and 1r').

[0224]

[0225] 3-Formyl(aza)indoles containing alkyl groups such as methyl (1s), cyclohexylmethyl (1t and 1t'), and 2-morpholinoethyl (1u and 1u') were also converted to the desired pyridine analogues (3sa-3u'a).

[0226]

[0227]

[0228]

[0229] N-aryl substituted 3-formyl azaindoles such as phenyl (1v), pyridyl (1w) and pyrimidyl (1x) moieties are well suited to this ring cleavage method, and N-aryl substituted aminopyridyl nicotinates (3va-3xa) were obtained in moderate to good yields.

[0230]

[0231]

[0232]

[0233]

[0234] Example 6: Use of β-keto sulfone and β-keto phosphonate

[0235]

[0236] The synthesis of pyridine analogues containing various sulfones and phosphonates was investigated (Figure 4).

[0237]

[0238] The reactivity of N-substituted 3-formyl(aza)indoles (1a and 1a') with phenyl sulfonyl acetone (4a) was investigated, but the undesired o-methylsulfonyl pyridine (6aa') was formed along with the target o-methyl-m-sulfonyl pyridine analogue (6aa) due to the regioselectivity of enamine formation. A similar reactivity pattern was observed with diethyl(2-oxopropyl)phosphonate (5a). To address this, 3,3-dimethyl phenylsulfonyl acetone (4b) was used as a source of sulfonyl enamine to successfully obtain the target o-isopropyl-m-sulfonyl pyridine (6ab) without forming regioisomers.

[0239]

[0240] Unlike the β-keto esters, the corresponding sulfones and phosphonates were not sufficiently reactive, so the reaction conditions were further optimized and it was confirmed that isopropyl (4b) and phenyl β-keto sulfone (4c) were less reactive than the phosphonate analogues (5b and 5c), indicating that higher reaction concentrations were required. The reactivity of N-phenylsulfonyl 3-formyl 7-azaindole (1a) and indole (1a') with β-keto sulfones (4b-4c) or phosphonates (5b-5c) was investigated under the optimized conditions (Fig. 4). The target m-(hetero)aryl pyridyl sulfones (6ab-6a'c) and phosphonates (7ab-7a'c) were obtained in moderate to good yields.

[0241]

[0242] [Reaction Formula 3]

[0243]

[0244]

[0245]

[0246]

[0247] [Reaction Formula 4]

[0248]

[0249]

[0250]

[0251]

[0252] For N-alkyl substituents, Np-methoxybenzyl (1q and 1q') and N-(2-morpholinoethyl)-3-formyl(aza)indole (1u and 1u') afforded the target ring cleavage products (6qb-6u'c and 7qb-7u'c) in reasonable yields. This reactivity pattern was further confirmed using N-pyrimidyl (1x and 1x'), Np-nitrophenyl (1y and 1y'), and Np-methoxyphenyl (1z and 1z') 3-formyl(aza)indoles.

[0253]

[0254] [Reaction Formula 5]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] Compared with the electron-donating Np-methoxyphenyl analogues (6zb-6z'c and 7zb-7z'c), the electron-withdrawing N-pyrimidyl and Np-nitrophenyl 3-formyl(aza)indoles provided the target pyridyl sulfones and phosphonates in better yields (6xb-6x'c and 7xb-7x'c; 6yb-6y'c and 7yb-7y'c).

[0262]

[0263] Example 7: Using benzofuran as a substrate

[0264]

[0265] To utilize o-substituted-m-phenol-conjugated nicotinates, the reactivity of representative β-keto esters with 3-formyl benzofuran was investigated (Fig. 5). Methyl (2a), cyclopropyl (2d), and phenyl (2f) β-keto esters were selected as enamine sources.

[0266]

[0267] Under optimized conditions, 3-formyl benzofuran (8a) reacted with three representative β-keto esters to give the target products containing methyl (9aa), cyclopropyl (9ad), and phenyl (9af) moieties at the C-2 position.

[0268]

[0269] [Reaction Formula 6]

[0270]

[0271]

[0272]

[0273]

[0274] Subsequently, the substrate scope of this ring cleavage reaction was investigated using various 5- and 6-substituted 3-formyl benzofurans (8b-8i), and polysubstituted nicotinate derivatives (9ba-9ia, 9bd-9id, and 9bf-9if) were obtained in good yields.

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] The target (hetero)biaryl products were generated by reaction of 3-formyl benzofuran with electron-withdrawing groups (chloro, bromo, and nitro; 8b-8e) and electron-donating groups (methyl and methoxy; 8f-8i) at the C-5 and C-6 positions.

[0283]

[0284] O-substituted nicotinate analogues (9ja, 9jd and 9jf) containing a naphthol moiety were obtained from 3-formyl naphthofuran (8j).

[0285]

[0286]

[0287]

[0288] Example 8: Synthetic Applications

[0289]

[0290] The (aza)indole ring cleavage reaction of the present invention has been applied to the synthesis of various bioactive pyridine analogues. Initially, structural units were extracted from bioactive natural products (fusaric acid and epibatidine) and drug molecules (clonixin, nicoboxylin, and vismodegib). These pyridine supports were then synthesized using the (aza)indole ring cleavage method.

[0291]

[0292] Multisubstituted pyridine analogs (10a-10e) were synthesized from N-substituted 3-formyl(aza)indoles (Figure 6a) and various β-keto esters / sulfones (2a, 2g, 2h, 2i, and 4d). For example, N-aryl 3-formyl azaindole (1aa) reacted with ethyl acetoacetate (2a) to give the nonsteroidal anti-inflammatory drug (NSAID) clonixin analog (10a) in 59% yield.

[0293]

[0294] Other bio-relevant molecules were synthesized in a single step from N-phenylsulfonyl 3-formyl indole (1a') via ring cleavage reaction with the corresponding β-keto esters (2g-2i) to give the nicoboxyl analogue (10b), fusaric acid analogue (10c) and epibatidine analogue (10d) in 78%, 60% and 62% yields, respectively.

[0295]

[0296] Ring cleavage reaction of N-phenylsulfonyl 3-formyl indole (1a') and aryl β-ketosulfone (4d) also provided the target bismodegib analog (10e).

[0297]

[0298] The later stages transformation method was applied to drug-drug or drug-natural product conjugation (Fig. 6b). Substituted 3-formyl benzofurans (8k and 8l) were reacted with ethyl acetoacetate (2a) to form sesamol-linked 2-methyl nicotinate (10 g, natural product-drug conjugate) and julolidine-nicotinate conjugate (10h) in 60% and 58% yields, respectively.

[0299]

[0300] Paracetamol-conjugated 2-methyl nicotinate (10f, drug-drug conjugate) was also obtained in 51% yield from the corresponding 3-formyl benzofuran (8m).

[0301]

[0302] These examples suggest that the proposed ring cleavage reaction may be helpful in the synthesis of polysubstituted pyridines with polysubstituents introduced by the late-stage skeletal transformation of (aza)indoles and benzofurans.

[0303]

[0304]

[0305]

[0306] While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. (S1) A step of adding and mixing a compound represented by chemical formula 1, a compound represented by chemical formula 2, and ammonium acetate (NH4OAc) into a polar organic solvent; and (S2) A step of heating the mixture to synthesize a compound represented by the following chemical formula 3; A method for synthesizing a polysubstituted pyridine derivative comprising: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] In the above chemical formulas 1 and 3, X1 is C, N, O or S, X2 is C or N, In the above chemical formulas 1 to 3, “*” indicates a bonding portion with another atom or functional group.

2. In paragraph 1, A method for synthesizing a polysubstituted pyridine derivative, characterized in that the compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 1a. [Chemical Formula 1a] In the above chemical formula 1a, X1 is C, NR1, O or S, X2 is C or N, R1 is hydrogen, C 1-20 Linear or branched alkyl; R a Benzyl substituted or unsubstituted; R a Heteroaryl substituted or unsubstituted with R; phenyl group is R b Phenylsulfonyl substituted or unsubstituted; R b substituted or unsubstituted phenyl; pyridine; or pyrimidine; and The above R a and R b are each independently a halogen; C 1-10 Linear or branched alkoxy; C 1-10 linear or branched alkyl; amino; or acetyl; and The above R2 is halogen; C 1-10 Linear or branched alkyl; halogen; hydroxy; C 1-10 Linear or branched alkoxy; or nitro; 3. In paragraph 1, A method for synthesizing a polysubstituted pyridine derivative, characterized in that the compound represented by the above chemical formula 2 is a compound represented by the following chemical formula 2a. [Chemical Formula 2a] In the above chemical formula 2a, R3 is C 1-20 Linear, branched or cyclic alkyl; R c Phenyl substituted or unsubstituted with R; or R c is a substituted or unsubstituted heteroaryl, The above R c is a halogen; R4 is R d substituted or unsubstituted ester, R d is a substituted or unsubstituted sulfonyl or phosphonic acid ester, The above R d is C 1-10 Linear or branched alkoxy; phenyl; benzyl; 4. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the compound represented by the above chemical formula 1 is any one selected from the group consisting of compounds represented by the following chemical formulas 1b to 1n. [Chemical Formula 1b] [Chemical Formula 1c] [Chemical Formula 1d] [Chemical Formula 1e] [Chemical formula 1f] [Chemical formula 1g] [Chemical formula 1h] [Chemical Formula 1i] [Chemical formula 1j] [Chemical formula 1k] [Chemical formula 1l] [Chemical formula 1m] [chemical formula 1n] In the above chemical formulas 1b to 1n, X2 is C or N, Z1 and Z2 are C or N, R e Inland R h is C 1-20 linear or branched alkyl; halogen; nitro; or alkoxy; 5. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the compound represented by the above chemical formula 2 is any one selected from the group consisting of compounds represented by the following chemical formulas 2b to 2q. [Chemical Formula 2b] [Chemical Formula 2c] [Chemical formula 2d] [Chemical Formula 2e] [Chemical formula 2f] [Chemical formula 2g] [Chemical formula 2h] [Chemical formula 2i] [Chemical formula 2j] [Chemical formula 2k] [Chemical formula 2l] [Chemical formula 2m] [chemical formula 2n] [Chemical formula 2o] [Chemical formula 2p] [Chemical formula 2q] 6. In paragraph 1, A method for synthesizing a polysubstituted pyridine derivative, characterized in that the polysubstitution is a three-site substitution at the ortho and meta positions of pyridine.

7. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the compound represented by the above chemical formula 3 is formed through breaking of a bond between a carbon-heteroatom in the compound represented by the chemical formula 1.

8. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the polar organic solvent is dichloroethane (DCE).

9. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the compound represented by the above chemical formula 2 is added in an amount of 1 to 1.5 equivalents.

10. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the ammonium acetate is added in an amount of 3.0 to 6.0 equivalents.

11. In paragraph 1, A method for synthesizing a multi-substituted pyridine derivative, characterized in that the heating is performed at 80 to 150°C.

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