WO2004037808A1 - 2 - substituted heterocyclic compounds and antitumor composition comprising the same - Google Patents

2 - substituted heterocyclic compounds and antitumor composition comprising the same Download PDF

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WO2004037808A1
WO2004037808A1 PCT/KR2003/002258 KR0302258W WO2004037808A1 WO 2004037808 A1 WO2004037808 A1 WO 2004037808A1 KR 0302258 W KR0302258 W KR 0302258W WO 2004037808 A1 WO2004037808 A1 WO 2004037808A1
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mmol
compound
nmr
cdc1
300mhz
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PCT/KR2003/002258
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French (fr)
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Sang Sup Jew
Hyeung Geun Park
Boon Saeng Park
Doo Yeon Lim
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2004037808A1 publication Critical patent/WO2004037808A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid

Definitions

  • the present invention relates to 2-substituted heterocyclic compounds and antitumor composition comprising the same.
  • telomere is located at the terminal end of chromosome in eukaryotic cell, and has a structure of uniquely repeated bases (guanine-rich sequence), and in case of vertebrate, hundreds to thousands of base sequence of telomere, 'TTAGGG', are serially connected, and this guarantees stability of chromosome and allows completion of DNA replication.
  • telomere nucleotides are lost to lead to shorter length, and when the length of the telomere becomes shorter than certain level, this functions as sign for no more cell division, causing instability of DNA and aging, resulting in cell death.
  • Enzyme involved in the replication of telomere is telomerase and it is directly responsible for endless multiplication of tumor cell.
  • telomere Since telomerase was discovered by Dr. Blackburn (Berkeley University) in 1984, studies have been intensively conducted.
  • the enzyme is reverse transcription enzyme, ribonucleoprotein complex consisting of RNA template and protein component and allows synthesis and maintenance of repeated structure of telomere, thereby enabling the length of telomere which is to be gradually reduced according to cell division to be maintained at a constant level, leading to infinite cell division, that is, multiplication of cancer cell.
  • Geron company discovered the existence of telomerase activity in 90 of 101 kinds of human carcinoma cell, and conformed by experiments that when telomerase in mouse was artificially destroyed, no more differentiation of cell was possible and aging was stimulated. Considering all the available results obtained until 1997, it was conformed that regardless of the kind of carcinoma, telomearse activity exists in at least 85 to 90%> of the carcinoma and no normal cell except germ cell showed the activity (Table 1).
  • telomere-telomerase is tumor-specific and selective
  • the antitumor agent using such mechanism can improve and resolve the side effects (nausea, vomiting, depilation and bleeding) due to absence of selectivity between normal cell and tumor cell.
  • cross resistance to the conventional drugs can be overcome.
  • Object of the present invention lies in providing novel compounds exhibiting telomerase- inhibitory activity based on novel tumor-selective telomere-telomerase action mechanism and antitumor agent comprising the same, to resolve the problems of conventional antitumor agent, i.e. side effects and cross resistance between related mechanisms on using chemotherapeutics.
  • the present invention provides novel compounds of the following formula I:
  • M means H, CN, NO 2 , OH, OR a , OC(O)R b , F, CI, Br, I, NH 2 , NHR C , NHC(O)R d or R e substituted at 3,4 or 5 position in case X is pyridine, at 3 or 4 position in case X is thiophene or furan, and R a ⁇ R e define C 1-4 alkyl;
  • Y means CO or CH 2 substituted at 2 or 6 position in case X is pyridine, or at 2 or 5 position in case X is thiophene or furan;
  • Z defines O, NH or S;
  • L is wherein, R t means that 2, 3, 4, 5 and 6 position of phenyl are independently substituted with hydrogen, methyl, methoxy, halogen, trihalogenmethyl, nitro, t-butyl or acetamido group;
  • N is substituted at 2 or 6 position, in case X is pyridine, or at 2 or 5 position, in case X is thiophene or furan, and selected among the following groups:
  • R f defines phenyl or C 1-4 alkyl.
  • L can be specifically exemplified as follows:
  • Said compounds according to the present invention are novel derivatives of small molecule, 6-substituted pyridine, 5 -substituted furan and 5-substituted thiophene exhibiting telomerase inhibition activity based on novel tumor selective telomere- telomerase mechanism.
  • in-vitro telomerase activity assay Telomeric Repeat Amplification protocol was conducted, and several kinds among the compounds showing superior activity were selected and subjected to in-vitro cytotoxicity test and in-vivo telomerase activity assay using nude mouse, thereby deriving antitumor candidate substance based on novel mechanism.
  • the compounds represented by the formula I can be synthesized according to the following reaction schemes 1 to 15.
  • 2,6-pyridinedicarboxylic acid commercial material
  • the compound 2 is subjected to partial reduction with NaBH 4 to convert the position 2 to hydroxymethyl group (compound 3), and subjected to partial oxidation and hydrolysis to lead to compound 5, which is basic parent nucleus necessary for the synthesis of telomerase inhibitor.
  • the compound 5 is subjected to esterfication with various benzenethiols to form compound 6 group included in the scope of the formula I.
  • R1 2,5-CH 3
  • R1 2,4,6-CI 1
  • R1 2,4 1 6-CI 41
  • R1 s p ⁇ nta-F m .R1 3,4-F 4m;R1 ⁇ 3,4-F n
  • R1 2-CI 4n
  • R1 4-CF 3 o
  • R1 3"CI 4o
  • 4-CI p R1 2,5-CI 4p
  • R1 2-Cl,4-F q
  • R1 2,6-CI *q
  • R1 3,5-CI 4r;
  • R1 2,4- F 4s; R1 -2,4-F t ;
  • R1 ⁇ e ⁇ ta-F 4t;
  • R1 2,4.0CH 3 4u;
  • 5-formylfuran-2-carboxylic acid (compound 12) is reacted with trimethyl orthoformate to convert position 5 to acetal group, subjected to condensation with various anilines to form compound 16, and the acetal protecting group is converted to formyl group by using p-toluenesulfonic acid thereby to form compound 17 group included in the scope of the formula I.
  • Compound 19 was obtained from 5-hydroxymethylfurfural (compound 18), commercial product, by introducing alkyl halide into the position 5 thereof. Alkylation of the compound 19 with various benzenetliiols forms compound 20 group included in the scope of the formula I, and alkylation of the compound 19 with various phenols according to the same method forms compound 21 group included in the scope of the formula I.
  • Compound 23 is obtained from 2,5-thiophene dicarboxylic acid (compound 22), commercial product, by introducing ester group to 2 and 5 positions thereof using thionyl chloride.
  • the compound 23 is subjected to partial reduction with NaBH 4 to convert the position 5 to hydroxymethyl group thereby to form compound 24, the compound 24 is subjected to partial oxidation to form compound 25, and the compound 25 is subjected to hydrolysis to yield compound 26 which is basic parent nucleus necessary for the synthesis of telomerase inhibitor.
  • Esterfication of the compound 26 with various phenols forms compound 27 group included in the scope of the formula I
  • esterfication of the compound 26 with various benzenetliiols forms compound 29 group included in the scope of the formula I. [Reaction scheme 7]
  • Alkyl halide is introduced to position 2 of the compound 24 synthesized according to the reaction scheme 6, and alkylation is conducted with various phenols to form compound 31.
  • the compound 31 is subjected to partial reduction using DIBAL- H(diisobutylaluminum hydride) and partial oxidation to form compound 33 group included in the scope of the formula I.
  • Alkylation of the compound 30 with various benzenethiols according to the same method leads to the formation of compound 34 group, and the compound 34 is subjected to partial reduction and partial oxidation to form compound 36 group included in the scope of the formula I.
  • Benzylic alcohol moiety of the compound 3 obtained in the reaction scheme 1 is protected with THP to form compound 37, and via hydrolysis, compound 38 is obtained.
  • the compound 38 is subjected to condensation with 3,4-dichlorobenzenethiol, commercial product, deprotection and acylation to form compounds 40 and 41 included in the scope of the formula I.
  • the compound 2 obtained in the reaction scheme 1 is used as the starting material and condensation is carried out with 3,4-dichlorobenzenethiol, commercial product, to form compound 44 included in the scope of the formula I.
  • the compound 50 of the reaction scheme 12 is reacted with TMS- diazomethane, methyl chloroformate, p-toluenesulfonyl chloride, acetic anhydride and methanesulfonyl chloride to form, respectively, compound 51, compound 52, compound 53, compound 54 and compound 55 which are included in the scope of the formula I.
  • the compound 6j of the reaction scheme 1 is oxidized with sodium chlorite to form compound 56 included in the scope of the formula I.
  • the compound 13r of the reaction scheme 3 is subjected to oxidation with sodium chlorite to form compounds 57, 58, 59 and 60 included in the scope of the formula I.
  • Compound 61 commercial product, is subjected to oxidation and methyl esterification of alcohol moiety on position 2 thereof to form compound 63.
  • the compound 63 is subjected to methylation of phenolic alcohol moiety at position 3, oxidation of nitrogen on pyridine ring and conversion of methyl group on position 6 to acetal via aldehyde thereby to form compound 69.
  • the compound 69 is subjected to condensation with thiophenol to form thioester (compounds 70 and 71), and subjected to deacetalization under an acid catalyst to form compounds 72 and 73 included in the scope of the formula I.
  • Another embodiment of the present invention is to provide telomerase inhibitor comprising the compound of the formula I.
  • Another embodiment of the present invention is to provide antitumor composition comprising the compound of the formula I as active component.
  • the antitumor composition comprising the compound of the formula I as active component can be used for parenteral or oral administration, e.g. liquid preparation such as syrup or emulsion, solid preparation such as tablets, capsules, granules or powder, and external preparation such as ointment, via mixing with proper vehicle.
  • liquid preparation such as syrup or emulsion
  • solid preparation such as tablets, capsules, granules or powder
  • external preparation such as ointment
  • Fig. 1 represents tumor volume change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ⁇ ; Example 10, 20 mg/kg J& ; Example 48, 5 mg/kg ⁇ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
  • Fig. 2 represents body weight change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ⁇ ; Example 10, 20 mg/kg . ; Example 48, 5 mg/kg ⁇ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
  • Example 12 6-formylpyridine-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (61) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
  • Example 32-1 6- dimethoxymethyl-pyridine-2-carboxylic acid methyl ester (8)
  • the compound 4 (5 g, 30.22 mmol) of the reaction scheme 1 and p-TsOH of a catalytic amount were dissolved in anhydrous methanol (100 ml). After an excess of trimethyl orthoformate (100 ml) was added thereto, the mixture was reacted at room temperature for 1 hour and methanol was removed under reduced pressure. Water (100 ml) was added to the residue solution and then an extraction process was conducted with ethylacetate (100 x 2).
  • Example 32-3 6-dimethoxymethyl-pyridine-2-carboxylic acid-(o-tolyl)amide
  • Dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et 3 N (91.9 ⁇ l, 0.65 mmol), followed by stirring for 5 min.
  • o-Toluidine (69.5 mg, 0.65 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2).
  • the obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 8:1 to 5:1) to obtain the compound 10a (103.6 mg, yield 71%).
  • Example 32-6 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-fluoropheny) amide (lOd)
  • Example 32-8 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-bromophenyl) amide (lOf)
  • Example 32-13 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2,3,4- trifluorophenyl)amide (10k)
  • dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et 3 N (91.9 ⁇ l, 0.65 mmol), followed by stirring for 5 min.
  • 2,3,4-Trifluoroaniline (95.6 mg, 0.65 mmol) was added thereto to obtain the compound 10k (109.8 mg, yield 66%).
  • Example 32 6-formyl-pyridine-2-carboxylic acid-(o-tolyf)amide (11a) p-TsOH mono-hydrate (106 mg, 0.56 mmol) was put to the already obtained compound 10a (90 mg, 0.37 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 12hours. After confirming the completion of the reaction with TLC, NaHCO 3 (10 ml aqueous solution) was added thereto to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • Example 36 6-formyl-pyridine-2-carboxylic acid-(4-chlorophenyl)amide (lie) p-TsOH monohydrate (83.7 mg, 0.44 mmol) was added to the compound lOe
  • Example 37 6-formyl-pyridine-2-carboxylic acid-(4-bromophenyl)amide (llf) p-TsOH monohydrate (72.2 mg, 0.38 mmol) was added to the compound lOf (90 mg, 0.25 mmol) according to the same method as in Example 32, to obtain the final compound (46.5 mg, yield 61%).
  • Example 38 6-formyl-pyridine-2-carboxylic acid-(3,4-dichlorophenyf)amide (llg) p-TsOH monohydrate (75.3 mg, 0.40 mmol) was added to the compound lOg (90 mg, 0.26 mmol) according to the same method as in Example 32, to obtain the final compound (38.4 mg, yield 50%).
  • Example 39 6-formyl-pyridine-2-carboxylic acid-(2,5-dimethylphenyl)amide (llh) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOh (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (55.6 mg, yield 73%).
  • Example 40 6-formyl-pyridine-2-carboxylic acid-(3,4-dimethylpheny ⁇ )amide (Hi) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOi (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (57 mg, yield 75%).
  • Example 42 6-formyl-pyridine-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (Ilk) p-TsOH monohydrate (78.7 mg, 0.41 mmol) was added to the compound 10k (90 mg, 0.28 mmol) according to the same method as in Example 32, to obtain the final compound (61.9 mg, yield 79%).
  • Dichloromethane (2 ml) was added to the compound 12 (50 mg, 0.35 mmol) of the reaction scheme 3, HOBT (24 mg, 0.18 mmol), EDC (75 mg,0.39 mmol) and triethylamine (50 ⁇ l , 0.33 mmol), followed by stirring for 5 min.
  • 2-Methylbenzenethiol 58.12 mg, 0.46 mmol was added thereto, followed by stirring for 30min to conduct esterification.
  • Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anliydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (64 mg, yield 63%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 3-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (80.8 mg, yield 70%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-methoxy benzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (66.5 mg, yield 65%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-fluorobenzenethiol (58.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-chlorobenzenethiol (66.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorobenzenethiol (82.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (79.1 mg, yield 73%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 2, 5 -dimethyl benzenethiol (49.2 mg, 0.33 mmol) according to the same method as in Example 44, to obtain the final compound (57.4 mg, yield 53%).
  • Example 55 5-formyl-furan-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (131)
  • the compound 12 50 mg, 0.39 mmol
  • 2,4,6- trichlorobenzenethiol 49.2 mg, 0.33 mmol
  • Example 58 5-formyl-furan-2-carbothionic acid-S-3-chlorophenyl ester (13o) The compound 12 (50 mg, 0.39 mmol) was used with 3-chlorobenzenethiol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2,6-dichlorobenzenethiol (81.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71 %) .
  • Example 61 5-formyl-furan-2-carbothionic acid-S-3,5-dichlorophenyl ester (13r)
  • the compound 12 50 mg, 0.39 mmol
  • 3,5-dichloro benzenethiol 81.8 mg, 0.46 mmol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2,4-difluoro benzenethiol (67.2 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (70.4 mg, yield 73%).
  • the compound 12 (50 mg, 0.39 mmol) was used with pentafluorobenzenethiol (92.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.7 mg, yield 53%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.8 mg, yield 63%).
  • Example 68 5-formyl-furan-2-carboxylic acid-O-4-methoxyphenyl ester (14e) The compound 12 (50 mg, 0.39 mmol) was used with 4-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (62.9 mg, yield 71%).
  • Example 69 5-formyl-furan-2-carboxylic acid-O-4-fluorophenyl ester (14f)
  • the compound 12 50 mg, 0.39 mmol
  • 4-fluorophenol 51.6 mg, 0.46 mmol
  • Example 71 5-formyl-furan-2-carboxylic acid-O-4-bromophenyl ester (14h)
  • the compound 12 50 mg, 0.39 mmol
  • 4-bromophenol 79.5 mg, 0.46 mmol
  • the compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorophenol (74.9 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.9 mg, yield 76%).
  • Example 78 5-formyl-furan-2-carboxylic acid-O-2,3 5 4-trichlorophenyl ester (14o) The compound 12 (50 mg, 0.39 mmol) was used with 2,3,4-trichloro phenol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-chloro-4-fluorophenol (67.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (78.3 mg, yield 81%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-t-butylphenol (69.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.4 mg, yield 79%).
  • the compound 12 (50 mg, 0.39 mmol) was used with phenol (43.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (52.1 mg, yield 67%).
  • Example 85 5-formyl-furan-2-carboxylic acid pyridin-2-yl ester (14v)
  • the compound 12 50 mg, 0.39 mmol
  • 2-hydroxy ⁇ yridine 43.7 mg, 0.46 mmol
  • Example 44 The compound 12 (50 mg, 0.39 mmol) was used with 2-hydroxy ⁇ yridine (43.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (46.9 mg, yield 60%).
  • Example 86-3 5-dimethoxymethyl-furan-2-carboxylic acid-(m- tolyl)amide (16b) m-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16b (107.1 mg, yield 72%).
  • Example 86-4 5-dimethoxymethyl-furan-2-carboxylic acid-(p-tolyl)amide (16c) p-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16c (115.9 mg, yield 78%).
  • Example 86-5 5-dimethoxymethyI-furan-2-carboxyIic acid-(2-methoxyphenyl) amide (16d) o-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16d (102.2 mg, yield 65%).
  • Example 86-6 5-dimethoxymethyl-furan-2-carboxylic acid-(4-methoxyphenyl) amide (16e) p-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg,
  • Example 86 5- formyl-furan-2-carboxylic acid-(2-methylphenyl)amide (17a)
  • p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the obtained compound 16a (90 mg, 0.32 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours.
  • NaHCO 3 (aq 10 ml) was added to stop the reaction.
  • the mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 6:1) to obtain the final compound (52.1 mg, yield 71%).
  • Example 88 5-formyl-furan-2-carboxylic acid-(4-methylphenyl)amide (17c) p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the compound 16c (90 mg, 0.32 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 92 5-formyl-furan-2-carboxylic acid-(2,5-dimethylphenyl)amide (17g) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16g (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • Example 93 5-formyl-furan-2-carboxylic acid-(3,4-dimethylphenyl)amide (17h) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16h (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 6:1) to obtain the final compound (49.0 mg, yield 65%).
  • Example 94 5-formyl-furan-2-carboxylic acid-(4-trif ⁇ uoromethanepheny ⁇ )amide (17i)
  • p-TsOH monohydrate (77.9 mg, 0.41 mmol) was added to the compound 16i (90 mg, 0.27 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 95 5-formyl-furan-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (17j)
  • p-TsOH monohydrate (81.5 mg, 0.43 mmol) was added to the compound 16j (90 mg, 0.29 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours.
  • NaHCO 3 (aq 10 ml) was added to stop the reaction.
  • the mixture was extracted with dichloromethane (10 ml x 2).
  • Example 97 5-(m-torylsulfanylmethyl)-furan-2-carbaldehyde (20b)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and m-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (50.5 mg, 63%).
  • Example 98 5-(p-tolylsulfanylmethyf)-furan-2-carbaldehyde (20c)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and p-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (60 mg, 63%).
  • Example 99 5-(2-methoxy-phenylsulfanylmethyl-furan-2-carbaldehyde (20d)
  • the compound 19 50 mg, 0.34 mmol
  • anhydrous potassium carbonate 60 mg
  • 2-methoxybenzenethiol 57.4 mg, 0.41 mmol
  • Example 109 5-(4-methoxy-phenoxymethyl)-furan-2-carbaldehyde (21b)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-methoxyphenol (50.8 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (56.0 mg, 71%).
  • Example 110 5-(4-chloro-phenoxymethyf)-furan-2-carbaldehyde (21c)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-chlorophenol (52.7 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (70.8 mg, 88%).
  • Example 117 5-(2,3 ? 4,5,6-pentafluoro-phenoxymethyl)-furan-2-carbaldehyde (21j)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with pentafluorophenol
  • Example 125-1 2,5-thiophene dicarboxylate (23) 2,5-Thiophenedicarboxylic acid (5 g, 29 mmol), which is compound 22 and commercial, was dissolved in methanol (300 ml) and thionyl chloride (SOCl 2 ) was slowly added dropwise thereto at 0 ° C. The reaction vessel was warmed up to room temperature, followed by reflux for 3hours. After confirming the disappearance of the starting material using TLC, methanol was removed under reduced pressure. The residue was dissolved in 200 ml of chloroform and the solution was slowly added to 300ml of chloroform saturated with NH 3.
  • SOCl 2 thionyl chloride
  • the water layer was titrated with IN HC1 solution in pH 1-2 and then extracted with ethyl acetate (200 ml x 5) to obtain the desirable compound 25 (1.2 g, yield 59%).
  • Example 131 5-formyl-thiophene-2-carboxylic acid-3,4-dichlorophenyl ester (27g) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et 3 N (58.5 ⁇ l, 0.42 mmol), followed by stirring for 5 min and then 3,4-dichlorophenol (61.9 mg, 0.38 mmol) was added thereto to obtain the final compound (65.5 mg, yield 68%).
  • Example 132 5-formyl-thiophene-2-carboxylic acid-2,5-dimethylphenyl ester (27h) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
  • Example 138 5-formyl-thiophene-2-carboxylic acid-2,4-difluorophenyl ester (27n) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et 3 N (58.5 ⁇ l, 0.42 mmol), followed by stirring for 5 min and then 2,4-difluorophenol (47.2 mg, 0.38 mmol) was used thereto to obtain the final compound (52.4 mg, yield 61%).
  • the comound 24 (5 g, 29.0 mmol) was dissolved in anhydrous methylene chloride (200 ml).
  • Et N (8 ml, 58 mmol) and methanesulfonyl chloride (2.78 ml, 43.8 mmol) were sequently added dropwise at 0 ° C and then the mixture was reacted at room temperature for 3 hours, H O (100 ml) was added thereto to stop the reaction.
  • An extracting process was conducted with methylene chloride (10 ml x 2). The obtained organic solution was washed with brine (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 144-3 5-(m-tolyloxymethy ⁇ )thiophene-2-carboxylic acid methyl ester (31b) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then m-methylphenol (68.1 mg, 0.63 mmol) was added thereto to obtain the compound 31b (118.2 mg, yield 85%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then m- methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 31c (118.0 mg, yield 80%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K CO 3 (86.8 mg, 0.63 mmol) and then p-methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 Id (123.9 mg, yield 84%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-fluorophenol (70.5 mg, 0.63 mmol) was added thereto to obtain the compound 31e (124.1 mg, yield 88%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-bromophenol (142.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 If (118.0 mg, yield 82%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 3,4-dichlorophenol (102.9 mg, 0.63 mmol) was added thereto to obtain the compound 31g (142.0 mg, yield 85%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 2,5-dimethylphenol (76.9 mg, 0.63 mmol) was added thereto to obtain the compound 3 lh (127.0 mg, yield 87%).
  • anliydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then pentafluorophenol (115.9 mg, 0.63 mmol) was added thereto to obtain the compound 31i (143.4 mg, yield 80%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-trifluoromethanephenol (102.2 mg, 0.63 mmol) was added thereto to obtain the compound 31 k ( 134 mg, yield 81%).
  • Example 144-13 5-(4-t-butylphenoxymethyl)thiophene-2-carboxylic acid methyl ester (311)
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 4-t-butyl-phenol (94.6 mg, 0.63 mmol) was added thereto to obtain the compound 31k (134.7 mg, yield 88%).
  • Example 144-14 5-(2-chloro-4-methoxyphenoxymethyl)thiophene-2-carboxylic acid methyl ester (31m) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 2-chloro-4-methoxyphenol (92.2 mg, 0.63 mmol) was added thereto to obtain the compound 31m (148 mg, yield 90%>).
  • Example 144 5-(o-tolyloxymethyl)thiophene-carbaIdehyde (33a)
  • the compound 31a (100 mg, 0.38 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 ° C and DIBA1-H (1.0 M solution in toluene, 0.4 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 ° C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dicliloromethane (5 ml x 2).
  • the obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue.
  • the residue was dried under vacuum, crude compound was dissolved in acetone (50 ml) without the more separation process and an oxidation was conducted with an excess of MnO 2 .
  • the resultant was filtered under reduced pressure with Celite545 and the filtrate was dried under reduced pressure to obtain residue.
  • the compound 31e (100 mg, 0.37 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (50.5 mg, yield of two steps: 57%).
  • the compound 31h (100 mg, 0.36 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (56.1 mg, yield of two steps: 63%).
  • the compound 31 j (100 mg, 0.35 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (43.8 mg, yield of two steps: 49%).
  • DIBAl-H 1.0 M solution in toluene, 0.4 ml
  • Example 154 5-(4-trifluoromethanephenoxymethyl)thiophene-2-carbaldehyde (33k) According to the same method as in Example 144, the compound 31k (100 mg,
  • Example 155 5-(t-butylphenoxymethyl)thiophene-2-carbaldehyde (331) According to the same method as in Example 144, the compound 311 (100 mg,
  • reaction scheme 7 0.35 mmol of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (48.3 mg, yield of two steps: 51%).
  • DIBAl-H 1.0 M solution in toluene, 0.4 ml
  • the compound 34a (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 ° C and DIBAl-H (1.0M solution in toluene, 0.35 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 ° C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue.
  • the compound 34b (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO to obtain the final compound (42.1 mg, yield of two steps: 53%).
  • the compound 34d (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO 2 to obtain the final compound (53.2 mg, yield of two steps: 66%).
  • Example 164 6-acetoxymethylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (41)
  • the compound 40 (8.4 mg, 0.027 mmol) was dissolved in pyridine (0.5 ml) and acetic anhydride (25 ⁇ 1, 0.27 mmol) was added thereto, followed by stirring at room temperature. After 8 hours, water was added to the reaction solution and then an extraction process was conducted with ethyl acetate.
  • Example 165 pyridine-2-carbothionic acid-S-(3,4-dichlorophenyl)ester (43)

Abstract

The present invention relates with 2-substituted heterocyclic compounds and antitumor composition comprising the same. The compound according to the present invention exhibits superior effect as telomerase inhibitor based on new mechanism (terlomere-terlomerase) which can resolve the problems occurring at the time of using chemotherapeutics, i.e side effects and cross resistance between related mechanism on using chemotherapeutics. In addition, the antitumor composition comprising the compound of the present invention exhibits superior effect in inhibiting the growth of cancer cell.

Description

2-Substituted Heterocyclic Compounds and Antitumor Composition Comprising the Same
Technical Field
The present invention relates to 2-substituted heterocyclic compounds and antitumor composition comprising the same.
Background Art The latest trend and situation in the development of antitumor agent has been moved toward development of drugs based on a new mechanism and having high selectivity to tumor cell because of problems revealed from previous studies on the conventional chemotherapeutics, i.e. side effects and cross resistance between related mechanisms. That is, studies have been made to improve and resolve side effects due to the lack of selectivity between normal somatic cell and carcinoma cell, e.g. nausea, vomiting, depilation and dysenteric bleeding, and studies have been conducted in an attempt to develop a tumor-specific, -selective mechanism. As comprehensive example, since 1990, studies have been intensively carried out to develop a novel antitumor agent such as (1) inhibitor (camptothecin series) against topoisomerase-I, which enzyme is primarily abundant in solid carcinoma, (2) angiogenesis inhibitor (clinical trial stage) which inhibits the formation of blood vessel at the time of development tumor and (3) inhibitor of telomerase, an endless multiplication-related enzyme, which exists only in carcinoma. Meeting such needs of the times, the inventors of the present invention have conducted development, as antitumor agent based on a novel mechanism as mentioned above, of inhibitor (3) against telomerase, which enzyme is infinite survival-related enzyme and exists only in carcinoma.
First of all, action mechanism based on which telomerase inhibitor exhibits antitumor efficacy and its development situation is as described below. Telomere is located at the terminal end of chromosome in eukaryotic cell, and has a structure of uniquely repeated bases (guanine-rich sequence), and in case of vertebrate, hundreds to thousands of base sequence of telomere, 'TTAGGG', are serially connected, and this guarantees stability of chromosome and allows completion of DNA replication. When normal cell divides, 50 to 100 telomere nucleotides are lost to lead to shorter length, and when the length of the telomere becomes shorter than certain level, this functions as sign for no more cell division, causing instability of DNA and aging, resulting in cell death. Enzyme involved in the replication of telomere is telomerase and it is directly responsible for endless multiplication of tumor cell.
Since telomerase was discovered by Dr. Blackburn (Berkeley University) in 1984, studies have been intensively conducted. The enzyme is reverse transcription enzyme, ribonucleoprotein complex consisting of RNA template and protein component and allows synthesis and maintenance of repeated structure of telomere, thereby enabling the length of telomere which is to be gradually reduced according to cell division to be maintained at a constant level, leading to infinite cell division, that is, multiplication of cancer cell. In 1994, Geron company discovered the existence of telomerase activity in 90 of 101 kinds of human carcinoma cell, and conformed by experiments that when telomerase in mouse was artificially destroyed, no more differentiation of cell was possible and aging was stimulated. Considering all the available results obtained until 1997, it was conformed that regardless of the kind of carcinoma, telomearse activity exists in at least 85 to 90%> of the carcinoma and no normal cell except germ cell showed the activity (Table 1).
Table 1. Telomerase Activity in Human Normal Tissue and Carcinoma Cell
Figure imgf000005_0001
Figure imgf000006_0001
Because action mechanism of telomere-telomerase is tumor-specific and selective, the antitumor agent using such mechanism can improve and resolve the side effects (nausea, vomiting, depilation and bleeding) due to absence of selectivity between normal cell and tumor cell. Furthermore, because of the distinction in action mechanism, cross resistance to the conventional drugs can be overcome.
Structure and regulation of the telomerase enzyme complex has not yet been clarified, and as of 2002, Geron and Atlantic Pharmaceutical companies have been pursuing the development, yet no product is under clinical trial (Table 2). Table 2. Domestic and Overseas Development Situation of Telomerase antitumor agent
Figure imgf000007_0001
Figure imgf000008_0002
Disclosure of the Invention
Object of the present invention lies in providing novel compounds exhibiting telomerase- inhibitory activity based on novel tumor-selective telomere-telomerase action mechanism and antitumor agent comprising the same, to resolve the problems of conventional antitumor agent, i.e. side effects and cross resistance between related mechanisms on using chemotherapeutics.
The present invention provides novel compounds of the following formula I:
Figure imgf000008_0001
( I ) wherein, X defines pyridine, thiophene or furan;
M means H, CN, NO2, OH, ORa, OC(O)Rb, F, CI, Br, I, NH2, NHRC, NHC(O)Rd or Re substituted at 3,4 or 5 position in case X is pyridine, at 3 or 4 position in case X is thiophene or furan, and Ra~Re define C1-4 alkyl;
Y means CO or CH2 substituted at 2 or 6 position in case X is pyridine, or at 2 or 5 position in case X is thiophene or furan;
Z defines O, NH or S; L is
Figure imgf000009_0001
wherein, Rt means that 2, 3, 4, 5 and 6 position of phenyl are independently substituted with hydrogen, methyl, methoxy, halogen, trihalogenmethyl, nitro, t-butyl or acetamido group; and
N is substituted at 2 or 6 position, in case X is pyridine, or at 2 or 5 position, in case X is thiophene or furan, and selected among the following groups:
Figure imgf000009_0002
Figure imgf000009_0003
Figure imgf000009_0004
Figure imgf000009_0005
wherein, Rf defines phenyl or C1-4 alkyl. L can be specifically exemplified as follows:
Phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,4-dimethoxyphenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,4- dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,4,5-tri chlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl, 4-fluorophenyl, 3,4- difluorophenyl, 2,3,4-trifluorophenyl, pentafluorophenyl, 4-bromophenyl, 2-fluoro-4- clilorophenyl, 3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl, 2-chloro-4- methoxyphenyl, 2-pyridinyl, 4-t-butylphenyl, 4-nitrophenyl, 4-acetamidophenyl, 3,4- dimethylphenyl, 2,5-dimethylphenyl or 2-thiophene.
Said compounds according to the present invention are novel derivatives of small molecule, 6-substituted pyridine, 5 -substituted furan and 5-substituted thiophene exhibiting telomerase inhibition activity based on novel tumor selective telomere- telomerase mechanism. In the present invention, in-vitro telomerase activity assay (Telomeric Repeat Amplification protocol) was conducted, and several kinds among the compounds showing superior activity were selected and subjected to in-vitro cytotoxicity test and in-vivo telomerase activity assay using nude mouse, thereby deriving antitumor candidate substance based on novel mechanism.
Among the compounds represented by the formula I, more preferred compounds in the present invention are as follows:
Among the compounds represented by the formula I, a compound where M is H, Y is CO and Z is S; and
Among the compounds represented by the formula I, a compound where X is pyridine or furan, M is H, Y is CO, Z is S and N is formyl group(-COH) or carboxyl group (-COOH).
The compounds represented by the formula I can be synthesized according to the following reaction schemes 1 to 15.
[Reaction scheme 1]
Figure imgf000012_0001
7a; Rl=p-CH3 6J R1=3,4-CI
7b; Rl=p-0CH3 6k R1=2,5-CH3
7c; R1=4-F 61 R1=2,4,6-CI
7d; R1=4-CI 6m R1=3,4-F
7e; R1=3,4-CI δn R1=2-CI
7f ; R1=2,5-CH3 60: R1=3-Ci
7g; R1=3,4-F δp R1=2,5-CI
7h; R1=2(3,4-F δq; R1=2,6-CI
71 ; R1=2-CI,4-F 6r R1=3,5-Ci
7J ; R1=2,4,5-CI 6s R1=4-N02
7k; Rl=4-t-butyl 6t R1=4-NHC0CH3
2,6-pyridinedicarboxylic acid, commercial material, is subjected to esterification with thionyl chloride at the 2,6 positions thereof to form the compound 2, then the compound 2 is subjected to partial reduction with NaBH4 to convert the position 2 to hydroxymethyl group (compound 3), and subjected to partial oxidation and hydrolysis to lead to compound 5, which is basic parent nucleus necessary for the synthesis of telomerase inhibitor. The compound 5 is subjected to esterfication with various benzenethiols to form compound 6 group included in the scope of the formula I.
Esterfication of the intermediate, the compound 5, with various phenols forms compound 7 group included in the scope of the formula I.
[Reaction scheme 2]
Figure imgf000013_0001
Figure imgf000013_0002
10 11
10a; R1=o-CH3 10b; R1=m-CH3 11a; R1=o-CH3 10c; R1=O-OCH3 11b R1=rτvCH3 10d; R1=4-F 11c; R1=o-OCH3 10e; R1=4-CI 10f ; R1=4-Br 11 ; R1=4-F 10g; R1=3,4-CI 11θ R1 =4-Ct lO ; R1=2,5-CH3 11f ; R1=4-Br 101 ; R1=3,4-CH3 11g ; R1=3,4-CI 10j ; R1=-4-CF3 10k; R1=2,3,4-F 11h R1 =2,5-CH3 101 ; R1=2-CI,4-F 111 , R1 =3,4-CH3
11J R1=4-CF3
11 k R1=2,3,4-F
111 R1=2-CI,4-F
Substitution group on the position 6 of 6-formylpyridine 2-carboxylic acid methyl ester (compound 4) obtained in the reaction scheme 1 is converted to acetal group with trimethyl orthoformate to form compound 8, ester group at position 2 in the compound 8 is hydrolyzed to form compound 9, and reaction with various aniline leads to synthesis of compound 11 group included in the scope of the formula I.
[Reaction scheme 3]
Figure imgf000014_0001
13 14
R1 = 4a a; o-CH3 R1 =o-CH3 b; R1=m-CH3 4b R1 *m-CH3 c; R1 = p-CH3 4c R1 =p-CH3 d; R1*o-OCH3 4d R1 =*Q-0CH3
R1= -0CH 4* e; R1 ap-0CH3 4f f R1 = p-0CH3 R1 =4«F g R1»4-F 4g R1 ■4-CI 4h h R. -C! R1 =4-8r 1 ; R1=4-Br 41 R1 =3,4-01 1 ; R1 = 3,4-CI *J R1 *2,5-CH3
4k K; R1 = 2,5-CH3 R1 =2,4,6-CI 1 ; R1 = 2,416-CI 41 R1 spβnta-F m .R1 = 3,4-F 4m;R1 ■3,4-F n R1 = 2-CI 4n; R1 =4-CF3 o R1 = 3"CI 4o; Rl -2,3t4-CI p R1 = 2,5-CI 4p; R1 = 2-Cl,4-F q R1 = 2,6-CI *q; R1 -2.3.4-F r ; R1 = 3,5-CI 4r; R1 *4-t-Butyl s ; R1 =2,4- F 4s; R1 -2,4-F t ; R1 = ρeπta-F 4t; R1 = 2,4.0CH3 4u; R1 «H
4v; Rl =pyridin-2-yl
Commercial product, 5-formylfuran-2-carboxylic acid (compound 12) is subjected to condensation with various benzenethiols to form compound 13 group included in the scope of the formula I, and condensation with various phenols is conducted according to the same method to obtain compound 14 group included in the scope of the formula I. [Reaction scheme 4]
Figure imgf000015_0001
Commercial product, 5-formylfuran-2-carboxylic acid (compound 12) is reacted with trimethyl orthoformate to convert position 5 to acetal group, subjected to condensation with various anilines to form compound 16, and the acetal protecting group is converted to formyl group by using p-toluenesulfonic acid thereby to form compound 17 group included in the scope of the formula I.
[Reaction scheme 5]
Figure imgf000016_0001
Compound 19 was obtained from 5-hydroxymethylfurfural (compound 18), commercial product, by introducing alkyl halide into the position 5 thereof. Alkylation of the compound 19 with various benzenetliiols forms compound 20 group included in the scope of the formula I, and alkylation of the compound 19 with various phenols according to the same method forms compound 21 group included in the scope of the formula I.
[Reaction scheme 6]
Figure imgf000017_0001
Figure imgf000017_0002
Compound 23 is obtained from 2,5-thiophene dicarboxylic acid (compound 22), commercial product, by introducing ester group to 2 and 5 positions thereof using thionyl chloride. The compound 23 is subjected to partial reduction with NaBH4 to convert the position 5 to hydroxymethyl group thereby to form compound 24, the compound 24 is subjected to partial oxidation to form compound 25, and the compound 25 is subjected to hydrolysis to yield compound 26 which is basic parent nucleus necessary for the synthesis of telomerase inhibitor. Esterfication of the compound 26 with various phenols forms compound 27 group included in the scope of the formula I, and esterfication of the compound 26 with various benzenetliiols forms compound 29 group included in the scope of the formula I. [Reaction scheme 7]
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Alkyl halide is introduced to position 2 of the compound 24 synthesized according to the reaction scheme 6, and alkylation is conducted with various phenols to form compound 31. The compound 31 is subjected to partial reduction using DIBAL- H(diisobutylaluminum hydride) and partial oxidation to form compound 33 group included in the scope of the formula I. Alkylation of the compound 30 with various benzenethiols according to the same method leads to the formation of compound 34 group, and the compound 34 is subjected to partial reduction and partial oxidation to form compound 36 group included in the scope of the formula I.
[Reaction scheme 8]
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Reagents and Conditions ; (a) p-TsOH, 3,4-Di ydro-2H-pyran, CH2C!2, rt, 12h, 95% ; (b) KOH, H20, THF, rt, 10min ; (c) HOBT, EDC, Et^ , 3,4-dichlorobenzenethiol, CH2CI2, rt, 10min ; (d) p-TsOH, CH3OH, rt, 30min ; (e) Ac20, pyridine, rt, 8 , 78%
Benzylic alcohol moiety of the compound 3 obtained in the reaction scheme 1 is protected with THP to form compound 37, and via hydrolysis, compound 38 is obtained. The compound 38 is subjected to condensation with 3,4-dichlorobenzenethiol, commercial product, deprotection and acylation to form compounds 40 and 41 included in the scope of the formula I.
[Reaction scheme 9]
Figure imgf000020_0001
Reagents and Conditions ; (a) HOBT, EDC, Et3N, 3,4-dichlorobenzenethiol, CH2CI2, rt, 10min
Using the compound 42 as the starting material, condensation is carried out with 3,4-dichlorobenzenethiol, commercial product, to form the compound 43 included in the scope of the formula I.
[Reaction scheme 10]
Figure imgf000021_0001
Reagents and Conditions ; (a) AIMe3, 3,4-dichlorobenzenethiol, CH2CI2, 0°C, 10min, 50%
The compound 2 obtained in the reaction scheme 1 is used as the starting material and condensation is carried out with 3,4-dichlorobenzenethiol, commercial product, to form compound 44 included in the scope of the formula I.
[Reaction scheme 11]
Figure imgf000021_0002
Reagents and Conditions ; (a) AIMe^ 3,4-dichloro enzenet ioi, CH2Ci2, 0°C, 10min, 45%
Condensation of the compound 8 of the reaction scheme 2 with 3,4- dichlorobenzenethiol, commercial product, leads to the formation of compound 45 included in the scope of the formula I.
[Reaction scheme 12]
Figure imgf000022_0001
Figure imgf000022_0002
49 50
Reagents and Conditions ; (a) SOCI2, CH3OH, reflux, 14h, 90% ; (b) TBSCI, DMAP, Et3N, CH2CI2, rt, 18h, 79% (c) AI e3, 3,4-dichIorobenzenethiol, CH2CI2, 0°C to rt, 2h, 55% ; (d) p-TsOH, CH3OH, rt, 5min, 64% ;
Esterification of carboxylic acid moiety on the compound 46 with thionylchloride leads to the formation of compound 47, and protection of alcohol moiety with TBS produces compound 48. Condensation with commercial product, 3,4- dichlorobenzenethiol (compound 49) and deprotection leads to the formation of compound 50 included in the scope of the formula I.
[Reaction scheme 13]
Figure imgf000023_0001
Reagents and conditions ; (a) TMS-diazomethane, Benzene, CH3OH, 0°C ; (b) CH3OCOCI, Et3N, D AP, CH2CI2, rt ; (c) Et3N, TsCI, CH2CI2, 0°C ; (d) Ac20, pyridine, rt, δh, 67% ; (e) Et3N, MsCI, CH2CI2, 0°C
The compound 50 of the reaction scheme 12 is reacted with TMS- diazomethane, methyl chloroformate, p-toluenesulfonyl chloride, acetic anhydride and methanesulfonyl chloride to form, respectively, compound 51, compound 52, compound 53, compound 54 and compound 55 which are included in the scope of the formula I.
[Reaction scheme 14]
Figure imgf000024_0001
Reagents and Conditions ; (a) NaCI02, Acetone, H20, rt, 12hr
The compound 6j of the reaction scheme 1 is oxidized with sodium chlorite to form compound 56 included in the scope of the formula I.
[Reaction scheme 15]
Figure imgf000024_0002
13j; R,=3,4-CI 57; -^-CI 59; R^ -CI
13r; R.,=3,5-CI 58; R^.S-CI 60; R^.S-CI
Reagents and Conditions ; (a) NaCI02, Acetone, H20, rt, 12hr. (b) CH2N2, Et20, rt. 30 min
The compound 13r of the reaction scheme 3 is subjected to oxidation with sodium chlorite to form compounds 57, 58, 59 and 60 included in the scope of the formula I.
[Reaction scheme 16]
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0003
67 68
69
Figure imgf000025_0004
70 ; R1=3,4-CI2 72 ; R.,=3,4-CI2 71 ; R^.S-CI;. 73 ; R.|=3,5-Cl2
Reagents and Conditions ; (a) Mn02, Acetone, rt, 12h, 79% ; (b) NaCN, AcOH,Mn02, CH3OH, rt, 75% ;
(c) NaOCH3, CH3I, DMF, rt, 83% ; (d) m-CPBA, CH2CI2 , rt, 3 , 93%; (e) Ac20, reflux, 2h, 75% ;
(f) sat. NaHC03, H20, CH3OH, rt, 6h, 82% ; (g) (COCI)2> D SO, EtgN, CH2CI2 , -78°C to rt, 92% ;
(h) p-TsOH, CH(OCH3)3,CH3OH, rt, 97% ; (i) AIMe3, ArSH, CH2CI2, 0°C, 10min ; (j) p-TsOH, Acetone, rt, 1.5h
Compound 61, commercial product, is subjected to oxidation and methyl esterification of alcohol moiety on position 2 thereof to form compound 63. The compound 63 is subjected to methylation of phenolic alcohol moiety at position 3, oxidation of nitrogen on pyridine ring and conversion of methyl group on position 6 to acetal via aldehyde thereby to form compound 69. The compound 69 is subjected to condensation with thiophenol to form thioester (compounds 70 and 71), and subjected to deacetalization under an acid catalyst to form compounds 72 and 73 included in the scope of the formula I.
Another embodiment of the present invention is to provide telomerase inhibitor comprising the compound of the formula I.
In addition, another embodiment of the present invention is to provide antitumor composition comprising the compound of the formula I as active component.
The antitumor composition comprising the compound of the formula I as active component can be used for parenteral or oral administration, e.g. liquid preparation such as syrup or emulsion, solid preparation such as tablets, capsules, granules or powder, and external preparation such as ointment, via mixing with proper vehicle.
Brief Explanation of Drawings
Fig. 1 represents tumor volume change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ♦ ; Example 10, 20 mg/kg J& ; Example 48, 5 mg/kg ■ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
Fig. 2 represents body weight change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ♦ ; Example 10, 20 mg/kg . ; Example 48, 5 mg/kg ■ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
Best mode for carrying out the invention
In the below, the present invention is more specifically explained through Examples, yet the scope of the present invention is not limited by the Examples. Example
Synthesis (6a-6t and 7a-7k) of Compounds 6 and 7 according to the reaction scheme 1
Example 1: 6-formylpyridine-2-carbothionic acid-S-(o-tolyl)ester (6a)
Dichloromethane (2 ml) was added to the compound 5 (50 mg, 0.33 mmol), which is the synthesis intermediate of the reaction scheme 1, HOBT (22 mg, 0.16 mmol), EDC (63 mg, 0.33 mmol) and triethylamine (50 μl , 0.33 mmol), followed by stirring for 5 min. 2-Methylbenzenethiol (49.18 mg, 0.39 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 8:1 to 5:1) to obtain the final compound (53 mg, yield 62.4%). 1H NMR (300 MHz, CDC13) 10.15 (s, 1 H), 8.16-8.13 (dd, J= 1.44 Hz, 1 H), 8.13-8.10 (dd, J= 1.44 Hz, 2 H), 8.03-7.98 (t, J= 7.53 Hz, 1 H), 7.35-7.22(m, 4H), 2.51(s, 3 H). 13C NMR(300 MHz, CDC13 ) 192.13, 191.31, 152.09, 139.12, 138.62, 135.36, 131.85, 130.43, 129.07, 127.13, 125.18, 124.42, 21.26
Example 2: 6-formylpyridine-2-carbothionic acid-S-(m-tolyl)ester (6b)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 3-methylbenzenethiol (49.2 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (51 mg, yield 61%).
1H NMR (300 MHz, CDC13) 10.18 (s, 1 H), 8.21-8.18 (dd, J .44, 1 H), 8.17-8.14 (dd, J=1.44, 1 H), 8.09-8.04 (ddd, J=5.04, 1 H), 7.06-7.59 (d, J=2.43, 1 H), 7.52-7.48 (dd, J=8.54, 1 H), 7.40-7.36 (dd, J=8.52, 1 H), 2.52 (s, 3 H). IR 2834.85, 1716.34, 1680.66, 1585.20, 1471.42, 1351.86, 1266.04, 1202.40, 995.09, 947.84, 847.56, 816.71, 754.99, 631.57. cm"1
Example 3: 6-formylpyridine-2-carbothionic acid-S-(p-tolyϊ)ester (6c)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-methylbenzenethiol (49.2 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (59 mg, yield 70%).
1H NMR(300MHz, CDC13) 10.19(s,lH), 8.19-8.16(dd, J=1.23, IH), 8.17-8.14(dd,
J=1.23, IH), 8.07-8.02(ddd, J=7.56, IH), 7.43-7.40(d, J=8.04, IH), 7.29-7.27 (d,
J=8.2Hz, 1H), 2.41(S,1H). 13C NMR(300MHz, CDCl3) 192.13, 191.1, 152.03, 139.82, 138.61, 134.73, 130.09,
125.16, 124.43, 123.0, 21.13.
IR 2822.11, 1719.23, 1690.30, 1585.20, 1547.59, 1493.60, 1265.07, 947.84, 847.56,
808.99, 729.92, 631.57, 438.73.cin 1
Example 4: 6-fornτylpyridine-2-carbothionic acid-S-2-methoxyphenyl ester (6d)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2-methoxybenzenethiol (50.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (46.8 mg, yield 52%). 1H NMR(300MHz, CDC13) 10.15(s, IH), 8.16-8.13(dd, J=1.44, IH), 8.13-8.10(dd, J .23, IH), 8.03-7.98(t, J=7.53, IH), 7.35-7.21(m, 4H).
13C NMR(300MHz, CDC13) 912.92, 190.04, 159.81, 152.21, 152.08, 138.55, 136.92, 131.85, 125.02, 124.39, 121.15, 115.55, 111.57, 55.97.
IR 2835.66, 1716.34, 1689.34, 1583.27, 1479.13, 1270.86, 1071.26, 1022.09, 947.84, 844.67, 755.96, 631.57, 572.75, 436.80.cm"1
Example 5: 6-formylpyridine-2-carbothionic acid-S-3-methoxyphenyl ester (6e)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 3-methoxybenzenethiol (50.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (57.72 mg, yield 64%).
1H NMR(300MHz, CDC13) 10.18(s, IH), 8.19-8.17(dd, J=1.47Hz, IH), 8.17-8.14(dd,
J=1.44Hz, IH), 8.07-8.02(ddd, J-0.72Hz, IH), 7.40-7.34(t, J=7.8Hz, IH), 7.13-7.06(m,
2H), 7.01-6.97(m, IH).
13C NMR(300MHz, CDC13) 192.13(=191.51), 152.09, 139.12, 138.62, 135.36, 131.85, 130.43, 129.07, 125.18, 124.42, 21.26.
IR 2835.81, 1715.37, 1692.23, 1590.99, 1474.31, 1284.36, 1249.65, 1039.44, 949.77,
847.56, 779.10, 734.75, 688.46, 631.57.cm"1
Example 6: 6-formylpyridine-2-carbothionic acid-S-4-methoxyphenyl ester (6f) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 4-methoxybenzenethiol (50.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (64.03 mg, yield 71%). !H NMR(300MHz, CDC13) 10.20(s, IH), 8.21-8.18(dd, J=1.47Hz, IH), 8.18-8.16(dd, J=1.2Hz, IH), 8.09-8.04(ddd, J=7.8Hz, IH), 7.46-7.43(dd, J=6.6Hz, 2H), 7.03-7.00(dd, J=6.57Hz, IH), 3.86(s, 3H).
13C NMR(300MHz, CDC13) 192.21, 160.80, 151.89, 139.89, 137.47, 134.21, 128.9, 127.11, 126.11, 118.11, 115.00, 109.11, 55.01.
IR 2820.4, 1716.34, 1685.48, 1590.99, 1494.56, 1291.11, 1249.65, 1177.33, 1027.87, 947.84, 826.35, 775.24, 635.43.cm"1
Example 7: 6-formylpyridine-2-carbothionic acid-S-4-fluorophenyl ester (6g)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-fluorobenzenethiol (42.3 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (56.1 mg, yield 65%).
1H NMR(300MHz, CDC13) 10.17(s, IH), 8.21-8.18(dd, J=1.2Hz, IH), 8.17-8.14(dd,
J=1.2Hz, IH), 8.08-8.03(ddd, J=7.56Hz, IH), 7.52(d, J=4.06Hz, 2H), 7.4(d, JM4.4Hz,
2H).
13C NMR(300MHz, CDC13) 192.05, 145.00, 142.12, 152.14, 151.14, 138.74, 136.97, 136.86, 125.38, 124.52, 122.00, 116.74, 116.45.
Example 8: 6-formyIpyridine-2-carbothionic acid-S-4-chlorophenyI ester (6h)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-chlorobenzenethiol (50.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (46.8 mg, yield 52%). 1H NMR(300MHz, CDC13) 10.17(s, IH), 8.21-8.18(dd, J=1.2Hz, IH), 8.17-8.14(dd, J=1.2Hz, IH), 8.08-8.03(ddd, J=7.56Hz, IH), 7.44(s, 4H).
13C NMR(300MHz, CDC13) 192.01, 190.77, 157.13, 138.75, 136.09, 136.03, 129.55, 126.13, 125.41, 124.54. IR 2833.88, 1761.34, 1693.19, 1574.59, 1477.21, 1390.42, 1351.86, 1265.07, 1202.40, 1093.44, 1014.37, 996.05, 947.84, 902.52, 817.67, 734.75, 631.57.cm"1
Example 9: 6-formylpyridine-2-carbothionic acid-S-4-bromophenyl ester (6i) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 4-bromobenzenethiol (73.7 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (66.6 mg, yield 66%). 1H NMR(300MHz, CDC13) 10.17(s, IH), 8.21-8.18(dd, J=1.44Hz, IH), 8.17-8.14(dd, J=1.47Hz, IH), 8.08-8.03(ddd, J-7.8Hz, IH), 7.61(s, 2H), 7.56(s, 2H). IR 2822.5, 1713.44, 1679.69, 1470.46, 1380.78, 1262.18, 1068.37, 1006.66, 949.77, 848.53, 811.88, 730.89, 632.54, 573.72, 512.97.cm"1
Example 10: 6-formylpyridine-2-carbothionic acid-S-3,4-dichlorophenyl ester (6j)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 3,4-dichlorobenzenethiol (69.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (79.1 mg, yield 81%>).
1H NMR(300MHz, CDC13) 10.19(s, IH), 8.23-8.20(dd, J=1.23Hz, IH), 8.19-8.16(dd,
J=1.23Hz, IH), 8.11-8.06(dd, J-7.56Hz, IH), 7.64-7.63(d, J=1.95Hz, IH), 7.57-7.54(dd,
J=2.91Hz, IH), 7.39-7.35(dd, J=2.19Hz, IH). 13C NMR(300MHz, CDC13) 191.88, 190.25, 152.13, 151.51, 138.82, 136.30, 134.28,
133.99, 133.22, 131.01, 127.74, 125.57, 124.59.
IR 2824.24, 1717.30, 1667.16, 1455.03, 1370.18,1264.11, 1142.62, 1030.77, 953.63,
874.56, 846.60, 817.67, 732.82, 631.57.cm"1 Example 11: 6-formylpyridine-2-carbothionic acid-S-2,5-dimethylphenyl ester (6k)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2,5-dimethylbenzenethiol (53.9 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (54.7 mg, yield 65%). 1H NMR(300MHz, CDC13) 10.21(s,lH), 8.21-8.18(dd, J=1.23Hz, IH), 8.18-8.15(dd, J=1.2HZ, IH), 8.08-8.03(ddd, J-7.53Hz, IH), 7.3 l(s, IH), 7.28-7.26(d,J=7.32Hz, IH), 7.21-7.18(dd, J=7.32Hz, IH), 2.36(s, IH), 2.35(s, 3H).
13C NMR(300MHz, CDC13) 192.26, 190.75, 152.31, 152.15, 139.36, 138.58, 136.47, 136.33, 131.11, 130.66, 126.49, 125.11, 124.41, 20.73, 20.19. IR 2921.63, 1717.30, 1681.62, 1491.67, 1453.10, 1352.82, 1265.07, 1201.40, 948.81, 844.67, 815.74, 732.82, 631.57, 530.33, 408.83.cm"1
Example 12: 6-formylpyridine-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (61) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 2,4,6-trichlorobenzenethiol (50.8 mg, 0.33 mmol) according to the same method as in Example 1, to obtain the final compound (81.2 mg, yield 71%>). 1H NMR(300MHz, CDC13) 10.19(s, IH), 8.24-8.21(dd, J=1.47Hz, IH), 8.19-8.16(dd, J=1.47Hz, IH), 8.12-8.07(ddd, J=0.48Hz, IH), 7.71(s, IH), 7.69(s, IH). 13C NMR(300MHz, CDC13) 191.85, 188.65, 152.18, 158.19, 138.86, 137.95, 137.86, 135.21, 131.49, 127.52, 126.65, 124.64.
IR 2820.22, 1716.34, 1680.66, 1439.60, 1381.11,1263.15, 1060.66, 945.91, 882.27, 840.81, 730.89, 631.57.cm"1 Example 13: 6-formylpyridine-2-carbothionic acid-S-3,4-difluorophenyl ester (6m)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 3,4-difluorobenzenethiol (57 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (59.3 mg, yield 67%).
1H NMR(300MHz, CDC13) 10.18(s,lH), 8.21-8.18(dd, J=1.47Hz, IH), 8.16-8.13(dd,
J=1.44, IH), 8.08-8.03(ddd, J=7.56Hz, IH), 7.51-7.44(m, IH), 7.02-6.96(m, 2H).
13C NMR(300MHz, CDC13) 191.69, 189.37, 152.18, 151.48, 138.74, 137.7, 125.44,
124.57, 112.46, 112.20, 105.25, 104.99.
Example 14: 6-formylpyridine-2-carbothionic acid-S-2-chlorophenyl ester (6n)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 2-chlorobenzenethiol (56.4 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (60.4 mg, yield 70%). 1H NMRQOOMHz, CDC13) 10.21(s,lH), 8.23-8.20(dd, J=1.2Hz,lH), 8.19-8.16(dd,
J=1.2Hz, IH), 8.10-8.05(dd, J=7.56Hz, IH), 7.64-7.60(dd, J=1.71Hz, IH), 7.60-7.58(dd,
J=1.68Hz, IH), 7.47-7.40(ddd, J=1.71Hz, IH), 7.39-7.34(ddd, J=1.71Hz, IH).
13C NMR(300MHz, CDC13) 192.11, 189.44, 152.13, 151.74, 139.22, 138.71, 137.33,
131.34, 130.35, 127.39, 127.25, 125.37, 124.55. IR 2821.34, 1716.34, 1694.16, 1558.20, 1454.06, 1433.82, 1352.82, 1266.04, 1202.40,
1037.52, 996.05, 949.88, 840.81, 755.96, 631.57.cm"1
Example 15: 6-formylpyridine-2-carbothionic acid-S-3-chlorophenyl ester (6o)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 3-chlorobenzenethiol (56.4 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (69.1 mg, yield 82%). 1H NMR(300MHz, CDC13) 10.19(s, IH), 8.22-8.19(dd, J=1.23Hz, IH), 8.19-8.16(dd, J .2Hz, IH), 8.11-8.05(dd, J=7.56Hz, IH), 7.55(s, IH), 7.47-7.31(m, 3H). 13C NMR(300MHz, CDC13) 191.99, 190.50, 152.13, 151.72, 138.77, 134.79, 134.60, 132.98, 130.25, 129.78, 129.50, 125.45, 124.68, 124.54.
IR 2819.99, 1715.37, 1693.19, 1566.88, 1459.85, 1267.00, 1202.40, 1073.19, 995.09, 948.81, 848.53, 780.06, 733.78, 678.82, 632.54.cm"1
Example 16: 6-formylpyridine-2-carbothionic acid-S-2,5-dichlorophenyl ester (6p)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2,5-dichlorobenzenethiol (69.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (50.8 mg, yield 52%). 1H NMR(300MHz, CDC13) 10.18(s,lH), 8.21-8.18(dd, J=1.44Hz, IH), 8.17-8.14(dd, J=1.44Hz, IH), 8.09-8.04(dd, J=5.04Hz, IH), 7.60-7.59(d, J=2.43Hz, IH), 7.52-7.48(dd, J=8.54Hz, IH), 7.40-7.36(dd, J=8.52Hz, IH).
IR 2834.85, 1716.34, 1696.09, 1567.84, 1450.21, 1368.25, 1267.00, 1203.36, 1097.30, 1035.59, 996.05, 947.84, 838.99, 815.74, 735.71, 631.57, 596.86.cm"1
Example 17: 6-formylpyridine-2-carbothionic acid-S-2,6-dichlorophenyl ester (6q)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2,6-dichlorobenzenethiol (69.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (70.3 mg, yield 72%>). 1H NMR(300MHz, CDC13) 8.23-8.20(dd, J=1.47Hz, IH), 8.19-8.16(dd, J=1.2Hz, IH), 8.11-8.06(ddd, J=0.75Hz, IH), 7.53-7.52(d, J=0.99Hz, IH), 7.40(s, IH), 7.39-7.37(d, J=7.29Hz, IH), 7.36-7.34(d, J=7.32Hz, IH).
13C NMR(300MHz, CDC13) 192.08, 187.90, 152.18, 151.43, 141.21, 138.45, 131.56, 128.70, 127.52, 125.46, 124.58. IR 2834.54, 1716.34, 1697.05, 1557.24, 1427.07, 1352.82, 1266.04, 1189.86, 996.05, 945.91, 836.95.cm"1
Example 18: 6-formylpyridine-2-carbothionic acid-S-3,5-dichlorophenyl ester (6r)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 3,5-dichlorobenzenethiol (69.8 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (64.4 mg, yield 66%).
1H NMR(300MHz, CDC13) 10.18(s, IH), 8.23-8.21(dd, J=1.47Hz, IH), 8.19-8.16(dd,
J=1.47Hz, IH), 8.12-8.07(ddd, J=0.75Hz, IH), 7.47-7.46(dd, J=2.22Hz, IH), 7.45(s,
IH), 7.44-7.43(d, J-3.00Hz, IH). 13C NMR(300MHz, CDC13) 191.95, 188.83, 152.17, 151.38, 138.81, 137.52, 136.74,
132.80, 131.30, 131.12, 129.11, 125.55, 124.60.
IR 2823.11, 1717.30, 1674.87, 1561.09, 1404.89, 1265.07, 1101.15, 950.73, 852.38,
798.39, 731.85, 666.29, 631.5.cm_1
Example 19: 6-formylpyridine-2-carbothionic acid-S-4-nitrophenyl ester (6s)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-nitrobenzenethiol (60.5 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (58.8 mg, yield 60%). 1H NMRQOOMHz, CDC13) 10.20(s, IH), 8.35-8.30(ddd, J=4.41Hz, 2H), 8.26-8.23(dd, J=1.2Hz, IH), 8.21-8.18(dd, J=1.44Hz, IH), 8.14-8.09(dd, J=7.56Hz, IH), 7.77- 7.70(ddd, J=4.38Hz, IH).
13C NMR(300MHz, CDC13) 191.78, 189.48, 152.19, 151.33, 148.36, 138.92, 136.52, 135.36, 125.74, 124.69, 123.98, 111.6.
Example 20: 6-formylpyridine-2-carbothionic acid-S-4-acetamidophenyl ester (6t)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 4-acetamidobenzenethiol (65.1 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (66.8 mg, yield 52%>). 1H NMR(300MHz, CDC13) 10.20(s, IH), 8.35-8.30(ddd, J=4.41Hz, 2H), 8.26-
8.23(dd, J=1.2Hz, IH), 8.21-8.18(dd, J=1.44Hz, IH), 8.14-8.09(dd, J=7.56Hz, IH),
7.77-7.70(ddd, J=4.38Hz, IH).
13C NMR(300MHz, CDC13) 191.78, 189.48, 152.19, 151.33, 148.36, 138.92, 136.52,
135.36, 125.74, 124.69, 123.98, 111.6.
Example 21: 6-formylpyridine-2-carboxylic acid-O-p-methylphenyl ester (7a)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 4-methylphenol (42.1 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (62.2 mg, yield 88%). 1H NMR(300MHz, CDC13) 10.24(s, IH), 8.50-8.47(dd, J=0.99Hz, IH), 8.22-8.19(dd,
J=0.99Hz, IH), 8.13-8.08(t, J=7.32Hz, IH), 7.27-7.24(m, IH), 7.18-7.14(m, IH), 2,39(s,
3H).
13C NMR(300MHz, CDC13) 192.61, 163.16, 152.93, 148.45, 148.21, 138.44, 136.05,
130.08, 129.49, 124.57, 121.12, 20.88. Example 22: 6-formylpyridine-2-carboxylic acid-O-p-methoxyphenyl ester (7b)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-methoxyphenol (48.4 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (56.8 mg, yield 67%).
1H NMR(300MHz, CDC13) 10.29(s, IH), 8.54-8.52(dd, J=1.23Hz, IH), 8.27-8.24(dd, J=1.23Hz, IH), 8.18-8.13(t, J-7.56Hz, IH), 7.28-7.23(m, IH), 7.04-6.99(m, IH), 3.88(s, 3H).
13C NMR(300MHz, CDC13) 192.58, 163.30, 157.60, 152.91, 148.17, 144.12, 138.46, 129.48, 124.57, 122.23, 114.56, 55.55.
Example 23: 6-formylpyridine-2-carboxylic acid-O-4-fluorophenyl ester (7c)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-fluorophenol (43.7 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (58.3 mg, yield 72%).
1H NMR(300MHz, CDC13) 10.22(s, IH), 8.49-8.46(dd, J=0.99Hz, IH), 8.23-8.20(dd, J=1.2Hz, IH), 8.14-8.09(t, J=7.56Hz, IH), 7.27- 7.21(m, IH), 7.18-7.11(m, IH). 13C NMR(300MHz, CDC13) 192.45, 163.02, 161.74, 159.30, 152.98, 147.86, 146.47, 138.52, 129.50, 124.75, 122.99,116.41, 116.18.
Example 24: 6-formylpyridine-2-carboxylic acid-O-4-chlorophenyl ester (7d)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 4-chlorophenol (50.1 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (58.7 mg, yield 68%). 1H NMR(300MHz, CDC13) 10.23(s, IH), 8.50-8.47(dd, J=1.23Hz, IH), 8.26-8.21(dd, J=1.23Hz, IH), 8.15-8.10(t, J=7.56Hz, IH), 7.45-7.42(d, J=8.76Hz, IH), 7.26-7.23(d, J=6.6Hz, IH).
13C NMR(300MHz, CDC13) 192.41, 162.77, 152.98, 149.12, 147.75, 138.54, 131.82, 129.67, 129.56, 124.79, 122.89.
Example 25: 6-formylpyridine-2-carboxylic acid-O-3,4-dichlorophenyl ester (7e)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 3,4-dichlorophenol (63.6 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (81 mg, yield 83%)..
1H NMR(300MHz, CDC13) 10.22(s.lH), 8.49-8.46(dd, J=1.23Hz, IH), 8.25-8.22(dd,
J=1.2Hz, IH), 8.16-8.1 l(t, J=7.53Hz, IH), 7.56-7.53(d, J=8.76Hz,lH), 7.46-7.45(d,
J=2.67Hz, IH), 7.21-7.17(dd, J-2.7Hz, IH).
13C NMR(300MHz, CDC13) 192.30, 162.49, 153.02, 149.22, 147.40, 138.61, 133.2, 130.91, 130.43, 129.62, 124.95, 123.88, 121.23, 117.47, 115.22.
Example 26: 6-formylpyridine-2-carboxylic acid-O-2,5-dimethylphenyl ester (If)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2,5-dimethylphenol (47.6 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (64.0 mg, yield 76%).
1H NMR(300MHz, CDC13) 10.24(s, IH), 8.51-8.48(dd, J=1.2Hz, IH), 8.23-8.20(dd, J=l,2Hz, IH), 8.14-8.09(1, J=7.29Hz, IH), 7.20-7.17(d, J=7.53Hz, IH), 7.04-7.01(d, J=9.0,1H), 2.36(s, 3H), 2.22(s, 3H). 13C NMR(300MHz, CDC13) 192.65, 162.70, 153.00, 149.12, 148.11, 138.46, 137.09 130.97, 129.43, 127.28, 126.71, 124.55, 122.16, 20.86, 15.77.
Example 27: 6-formylpyridine-2-carboxylic acid-O-3,4-difluorophenyl ester (7g)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 3,4-difluorophenol (50.7 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (77.4 mg, yield 71%).
1H NMR(300MHz, CDC13) 10.23(s, IH), 8.49-8.46(dd, J=1.2Hz, IH), 8.25-8.22(dd,
JM1.23Hz, IH), 8.16-8.11(1, J-0.72Hz, IH), 7.28-7.24(d, J=9.75Hz, IH), 7.23-7.16(ddd,
J=2.94Hz, IH), 7.09-7.02(m, IH).
Example 28: 6-formylpyridine-2-carboxylic acid-O-2,3,4-trifluorophenyl ester (7h) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 2,3,4-trifiuorophenol (64.0 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (71.29 mg, yield 61%). 1H NMR(300MHz, CDC13) 10.23(s, IH), 8.49-8.46(dd, J-1.2Hz, IH), 8.25-8.22(dd,
J .23Hz, IH), 8.16-8.11(1, J=0.72Hz, IH), 7.28-7.24(d, J=9.75Hz, IH), 7.23-7.16(ddd,
J=2.94Hz, IH), 7.09-7.02(m, IH).
IR 2919.70, 2850.27, 1714.41, 1582.31, 1466.60, 1288.22, 1245.79, 1211.08, 1123.33,
1078.98, 1031.73, 808.99, 755.96, 637.31cm"1
Example 29: 6-formylpyridine-2-carboxylic acid-O-2-chloro-4-fluorophenyl ester
(70
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg, 0.33 mmol), was used with 2-chloro-4-fluorophenol (50.8 mg, 0.33 mmol) according to the same method as in Example 1, to obtain the final compound (75.6 mg, yield 82%). 1H NMR(300MHz, CDC13) 10.20(s, IH), 8.46-8.43(dd, J=1.2Hz, IH), 8.23-8.20(dd, J=1.2Hz, IH), 8.14-8.08(t, J=7.8Hz, IH), 7.39-7.36(dd, J=2.7Hz, IH), 7.25-7.15(m, 2H). 13C NMR(300MHz, CDC13) 192.33, 162.71, 153.01, 147.47, 146.33, 138.59, 129.59, 124.91, 123.99, 121.57, 117.11, 116.88.
Example 30: 6-formylpyridine-2-carboxylic acid-S-2,4,5-trichIorophenyl ester (7j) The synthesis intennediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 2,4,5-trichlorophenol (50.8 mg, 0.33 mmol) according to the same method as in Example 1, to obtain the final compound (70.2 mg, yield 66%).
1H NMR(300MHz, CDC13) 10.20(s, IH), 8.24-8.21(dd, J=1.47Hz, IH), 8.19-8.16(dd,
J=1.47Hz, IH), 7.71(s, IH), 7.69(s, IH).
13C NMR(300MHz, CDC13) 191.85, 188.65, 152.19, 151.19, 138.86, 135.21, 131.49,
131.41, 127.52, 125.65, 124.64.
Example 31: 6-formylpyridine-2-carboxylic acid-O-4-t-butylphenyl ester (7k)
The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
0.33 mmol), was used with 4-t-butylphenol (58.6 mg, 0.39 mmol) according to the same method as in Example 1, to obtain the final compound (64.4 mg, yield 69%). 1H NMR(300MHz, CDC13) 10.21(s, IH), 8.48-8.45(dd, J=1.2Hz, IH), 8.19-8,16(dd,
J=1.23Hz, IH), 8.10-8,05(t, J=15.33Hz, IH), 7.38-7.28(m, IH), 7.25-7.23(m, IH), 7.09-
7.05(ddd, J=1.71Hz, IH), 1.3 l(s, 9H).
13C NMR(300MHz, CDC13) 192.6, 163.07, 153.30, 152.94, 150.57, 148.25, 138.46,
129.49, 129.04, 124.57, 123.32, 118.53, 118.41 Synthesis (lla-UD of Compound 11 according to the reaction scheme 2
Example 32-1: 6- dimethoxymethyl-pyridine-2-carboxylic acid methyl ester (8) The compound 4 (5 g, 30.22 mmol) of the reaction scheme 1 and p-TsOH of a catalytic amount were dissolved in anhydrous methanol (100 ml). After an excess of trimethyl orthoformate (100 ml) was added thereto, the mixture was reacted at room temperature for 1 hour and methanol was removed under reduced pressure. Water (100 ml) was added to the residue solution and then an extraction process was conducted with ethylacetate (100 x 2). The obtained organic solution was subjected to silica gel column (hexane: ethyl acetate= 5:1) to obtain the final compound 8 (5.3 g, yield 83%). 1H NMR(300MHz, CDC13) 8.13-8.10(dd, J=1.23Hz, IH), 7.93-7.88(t, J=7.8Hz, IH), 7.79-7.79(dd, J=1.2Hz, IH), 5.46(s, IH), 4.00(s, 3H), 3.44(s, 6H).
Example 32-2: 6-dimethoxymethyl-pyridine-2-carboxylic acid (9)
THF : H2O=l :l (250 ml) was added to the compound 8 (5 g, 23.6 mmol), and then KOH (1.46 g, 26.0 mmol) was added thereto, followed by stirring for 2 hours. THF was removed under reduced pressure. The water layer was titrated with IN HC1 to control to pH 1~2 of the reaction solution, followed by extracting with ethyl acetate(100 x lO) to obtain the final compound 9 (3.33 g, yield 65%) without more purification. 1H NMR(300MHz, CDC13) 8.23-8.20(dd, J=1.2Hz, IH), 8.04-7.99(t, J=4.38Hz, IH), 7.88-7.85(dd, J=1.23Hz, IH), 5.42(s, IH), 3.43(s, 6H).
Example 32-3: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(o-tolyl)amide (10a) Dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. o-Toluidine (69.5 mg, 0.65 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate^ 8:1 to 5:1) to obtain the compound 10a (103.6 mg, yield 71%).
1H NMR(300MHz, CDC13) 10.13(s, IH), 8.30-8.27(m, 2H), 7.99-7.95(t, J=7.8Hz, IH), 7.78-7.75(dd, J=0.72Hz, IH), 7.31-7.23(m, 2H), 7.12-7.09(dd, J=0.92Hz, lh), 5.34(s, IH), 3.46(s, 6H), 2.43(s, 3H).
Example 32-4: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(m-tolyl)amide (10b)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC
(126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. m-Toluidine (69.5 mg, 0.65 mmol) was added thereto to obtain the compound 10b (100 mg, yield 69%).
1H NMR(300MHz, CDC13) 9.94(s, IH), 8.29-8.26(dd, J=0.99Hz, IH), 7.98-7.93(t, J=1.2HzlH), 7.64(s, IH), 7.59-7.57(d, JM8.04Hz, IH), 7.30-7.25(dd, J=5.5Hz, IH), 6.98-6.96(d, J=7.35Hz, IH), 5.46(s, IH), 5.44(s, 6H), 2.39(s, 3H). Example 32-5: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2-methoxyphenyι) amide (10c)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol),
EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. o-Anisidine (81.6 mg, 0.65 mmol) was added thereto to obtain the compound 10c
(114.1 mg, yield 74%).
1H NMR(300MHz, CDC13) 10.61(s, IH), 8.61-8.58(dd, J-1.95Hz, IH), 8.28-8.25(dd, J=0.99Hz, IH), 7.98-7.93(t, J=7.8Hz, IH), 7.75-7.72(dd, J=0.72hz, IH), 7.13-7.07(ddd, J=1.71Hz, IH), 7.06-7.00(ddd, J=1.47Hz, IH), 6.93-6.92(dd, J=1.47Hz, IH), 5.44(s, lH), 3.96(s, 3H), 3.51(s, 6H).
Example 32-6: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-fluoropheny) amide (lOd)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. p-Fluoroaniline (72.2 mg, 0.65 mmol) was added thereto to obtain the compound lOd (116.9 mg, yield 79%).
1H NMR(300MHz, CDC13) 9.91(s, IH), 8.27-8.24(dd, J=1.23Hz, IH), 7.97-7.92(1, J=7.8Hz, IH), 7.75-7.70(m, 3H), 7.09-7.03(ddd, J=2.19Hz, 2H), 5.43(s, IH), 3.42(s, 6H). Example 32-7: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-chlorophenyl) amide (lOe)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. p- Chloroaniline (82.9 mg, 0.65 mmol) was added thereto to obtain the compound lOe (115.7 mg, yield 74%).
1H NMR(300MHz, CDC13) 9.96(s, IH), 8.27-8.24(dd, J=0.96Hz, IH), 7.97-7.92(t, J=7.8Hz, IH), 7.76-7.70(m, 3H), 7.34-7.32(dd, J=2.19Hz, 2H), 5.43(s, IH), 3.42(s, 6H).
Example 32-8: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-bromophenyl) amide (lOf)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. p- Bromoaniline (111.8 mg, 0.65 mmol) was added thereto to obtain the compound lOf (114.6 mg, yield 64%).
1H NMR(300MHz, CDC13) 9.95(s, IH), 8.26-8.23(dd, J=0.99Hz, IH), 7.97-7.92(t, J=7.8Hz, IH), 7.76-7.73(dd, J=0.96Hz,lH), 7.69-7.66(dd, J=2.229Hz, 2H), 7.49- 7.46(dd, J=2.22Hz, 2H), 5.43(s, IH), 3.42(s, 6H).
Example 32-9: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(3,4- dichlorophenyl)amide (lOg)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. 3,4- Dichloroaniline (105.3 mg, 0.65 mmol) was added thereto to obtain the compound lOg (135.7 mg, yield 77%). 1H NMR(300MHz, CDC13) 10.00(s, IH), 8.26-8.23(d, J=7.56Hz, IH), 8.02-8.01(d, JM2.46Hz, IH), 7.98-7.93(t, J=7.8Hz, IH), 7.77-7.75(d, J=7.8Hz, IH), 7.62-7.58(dd, J=2.43Hz, IH), 7.43-7.40(d, J=8.55Hz, IH), 5.43(s, IH), 3.42(s, 6H).
Example 32-10: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2,5- dimethylphenyl)amide (lOh)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol),
EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. 2,5-Dimethylaniline (78.8 mg, 0.65 mmol) was added thereto to obtain the compound lOh (122.2 mg, yield 80%).
1H NMR(300MHz, CDC13) 9.86(s, IH), 8.26-8.23(dd, J=1.23Hz, IH), 7.94-7.88(t, J=7.8Hz, IH), 7.72-7.69(dd, J=0.99Hz, IH), 7.54(s, IH), 7.51-7.48(dd, J=2.19Hz, IH), 7.12-7.09(d, J=8.04Hz, IH), 5.42(s, 2H), 3.41(s, 6H), 2.26(s, 3H), 2.22(s, 3H).
Example 32-11: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(3,4- dimethylphenyι)amide (lOi)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. 3,4-Dimethylaniline (78.8 mg, 0.65 mmol) was added thereto to obtain the compound lOi (110.3 mg, yield 72%).
1H NMR(300MHz, CDC13) 9.85(s, IH), 8.27-8.24(dd, J=1.23Hz, IH), 7.96-7.91(t, J=7.81Hz, IH), 7.74-7.71(dd, J=0.99Hz, IH), 7.55(s, IH), 7.51-7.47(dd, J=2.46Hz, IH), 7.13-7.11(d, J=8.04Hz, IH), 5.43(s, IH), 3.43(s, 6H), 2.28(s, 3H), 2.24(s, 3H).
Example 32-12: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4- trifluoromethanephenyl)amide (10J)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC
(126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min.
4-Trifluoromethaneaniline (104.7 mg, 0.65 mmol) was added thereto to obtain the compound lOj (111.1 mg, yield 64%).
1H NMR(300MHz, CDC13) 10.09(s, IH), 8.26-8.23(dd, J=0.96Hz, IH), 8.07(s, IH), 7.97-7.92(t, J=7.8Hz, 2H), 7.77-7.74(dd, J=1.23Hz, IH), 7.49-7.44(t, J=7.8Hz, IH),
7.38-7.35(dd, J=0.48Hz, IH), 5.44(s, IH), 3.40(s, 6H).
Example 32-13: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2,3,4- trifluorophenyl)amide (10k) According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. 2,3,4-Trifluoroaniline (95.6 mg, 0.65 mmol) was added thereto to obtain the compound 10k (109.8 mg, yield 66%). 1H NMR(300MHz, CDC13) 10.20(s, IH), 8.24-8.21(dd, J=1.23Hz, 2H), 7.99- 7.92(t, J=7.8Hz, IH), 7.04-6.98(m, IH), 5.40(s, IH), 3.56(s, 6H).
Example 32-14: 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2-chloro-4- fluorophenyf)amide (101)
According to the same method as in Example 32-3, dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et3N (91.9 μl, 0.65 mmol), followed by stirring for 5 min. 2-Chloro-4-trifluoroaniline (94.6 mg, 0.65 mmol) was added thereto to obtain the compound 101 (130.8 mg, yield 79%).
1H NMR(300MHz, CDC13) 9.93(s, IH), 8.26-8.23(dd, J=1.23Hz, IH), 7.97-7.95(dd, J=2.46Hz, IH), 7.95-7.93(t, J=3.9Hz, IH), 7.77-7.74(dd, J=0.99Hz, IH), 7.61-7.56(ddd, J=3.9Hz, IH), 7.16-7.10(t, J=8.76Hz, IH), 5.42(s, IH), 3.42(s, 6H).
Example 32: 6-formyl-pyridine-2-carboxylic acid-(o-tolyf)amide (11a) p-TsOH mono-hydrate (106 mg, 0.56 mmol) was put to the already obtained compound 10a (90 mg, 0.37 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 12hours. After confirming the completion of the reaction with TLC, NaHCO3 (10 ml aqueous solution) was added thereto to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 5:1) to obtain the final compound (61.3 mg, yield 69%). 1H NMR(300MHz, CDC13) 10.12(s. IH), 9.99(s, IH), 8.55-8.52(dd, J 2.22Hz, IH), 8.25-8.22(d, J-8.76Hz, IH), 8.15-8.08(m, 2H), 7.31-7.23(m, IH), 7.13-7.08(ddd, J=1.2Hz, lh), 2.44(s,3H).
13C NMR(300MHz, CDC13) 192.00, 161, 151, 152, 139.0, 135.10, 130.54, 128.23, 127.01, 126.91, 125.41, 123.97, 121.46, 17.62.
IR 3348.78, 2933.20, 2830.99, 1692.23, 1588.09, 1532.17, 1451.17, 1343.18, 1310.39, 1138.75, 1111.72, 1138.76, 1062.59, 994.12, 826.35, 759.82, 652.79. 599.75, 457.05,cm"1
Example 33: 6-formyl-pyridine-2-carboxylic acid-(m-tolyl)amide (lib) p-TsOH monohydrate (106 mg, 0.56 mmol) was added to the compound 10b
(90 mg, 0.37 mmol) according to the same method as in Example 32, to obtain the final compound (56 mg, yield 63%).
1H NMR(300MHz, CDC13) 10.15(s, IH), 8.54-8.51(dd, J=2.43Hz, IH), 8.22-8.07(m, 2H), 7.63(s,lH), 7.59-7.56(d, J=7.8Hz, IH), 7.31-7.28(d, J=5.94Hz, IH), 7.25-7.24(d,
J=4.14Hz, IH), 7.00-6.97(d ,J=7.56Hz, IH).
IR 3346.85, 2935.13, 2831.95, 1681.62, 1591.95, 1537.95, 1492.63, 1453.10, 1344.14,
1309.43, 1195.65, 1110.80, 1057.76, 994.12, 828.28, 782.96, 692.32, 655.68,
457.05.cm"1
Example 34: 6-formyl-pyridine-2-carboxylic acid-(2-methoxyphenyl)amide (lie) p-TsOH monohydrate (85.6 mg, 0.45 mmol) was added to the compound 10c
(90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (51.2 mg, yield 67%). 1H NMR(300MHz, CDC13) 10.51(s, IH), 10.15(s, IH), 8.59-8.56(dd, J=1.71Hz, IH), 8.52-8.47(dd, J=2.19Hz, IH), 8.13-8.05(m, 2H), 7.14-7.08(ddd, J=1.71Hz, IH), 7.05- 6.99(ddd, J=1.47Hz, IH), 6.96-6.92(dd, J=l. 47Hz, IH), 3.97(s, 3H). IR 3347.82, 1685.48, 1599.66, 1530.24, 1462.74, 1250.61, 1112.73, 1068.37, 751.14, 457.05, 433.91.
Example 35: 6-formyl-pyridine-2-carboxylic acid-(4-fluorophenyl)amide (lid) p-TsOH monohydrate (88.6 mg, 0.46 mmol) was added to the compound lOd
(90 mg, 0.31 mmol) according to the same method as in Example 32, to obtain the final compound (52.9 mg, yield 70%).
1H NMRQOOMHz, CDC13) 10.14(s, IH), 9.88(s, IH), 8.53-8.50(dd, J=2.43Hz, IH),
8.15-8.07(m, 2H), 7.78-7.70(m 2H), 7.13-7.06(m, 2H).
IR 3364.85, 2936.09, 1682.59, 1592.91, 1538.92, 1455.99, 1407.78, 1211.08, 1157.08,
1110.80, 1057.76, 995.09, 834.06, 757.89, 668.21, 516.83, 470.55.cm"1
Example 36: 6-formyl-pyridine-2-carboxylic acid-(4-chlorophenyl)amide (lie) p-TsOH monohydrate (83.7 mg, 0.44 mmol) was added to the compound lOe
(90 mg, 0.29 mmol) according to the same method as in Example 32, to obtain the final compound (42.5 mg, yield 71%). 1H NMR(300MHz, CDC13) 10.14(s, IH), 9.86(s,lh), 8.49-8.46(dd, J=1.38Hz, IH),
8.10-8.04(m, 2H), 7.72-7.71(d, J=1.95Hz, IH), 7.69-7.68(d, J=2.91Hz, IH), 7.34-7.33(d,
J=2.91Hz, IH), 7.03-7.29(d, J=1.95Hz, IH).
IR 3337.21, 2933.20 1687.41, 1589.06, 1523.49, 1492.63, 1455.03, 1401.03, 1343.18,
1311.36, 1195.65, 1110.80, 1056.80, 994.12, 827.31, 758.85, 517.19, 457.05, 418.48.cm"1
Example 37: 6-formyl-pyridine-2-carboxylic acid-(4-bromophenyl)amide (llf) p-TsOH monohydrate (72.2 mg, 0.38 mmol) was added to the compound lOf (90 mg, 0.25 mmol) according to the same method as in Example 32, to obtain the final compound (46.5 mg, yield 61%).
1H NMR(300MHz, CDC13) 10.10(s, IH), 9.85(s, IH), 8.48-8.45(d, J=2.46Hz, IH), 8.11- 8.05(m, 2H), 7.66-7.65(d, J=1.95Hz, IH), 7.64-7.63(d, J=2.22Hz, IH), 7.46-7.45(d, J=2.19Hz, IH), 7.44-7.43(d, J=1.85hZ, IH). 13C NMR(300MHz, CDC13) 191.85, 160.1, 150.3 149.9, 139.8, 137.1, 131.2, 127.4, 125.1, 122.3, 117.4.
IR 3336.25, 1684.52, 1586.16, 1525.42, 1455.16, 1396.21, 1311.36, 1195.65, 1110.80, 1071.26, 995.09, 825.38, 759.82, 468.62.cm"1
Example 38: 6-formyl-pyridine-2-carboxylic acid-(3,4-dichlorophenyf)amide (llg) p-TsOH monohydrate (75.3 mg, 0.40 mmol) was added to the compound lOg (90 mg, 0.26 mmol) according to the same method as in Example 32, to obtain the final compound (38.4 mg, yield 50%).
1H NMR(300MHz, CDC13) 10.19(s, IH), 9.97(s, IH), 8.57-8.55(dd, J=1.35Hz, IH), 8.21-8.15(m, 2H), 8.09-8.08(d, J=1.80Hz, IH), 7.68-7.66(dd, J=1.80Hz, IH), 7.51- 7.49(d, J=6.54Hz, IH).
Example 39: 6-formyl-pyridine-2-carboxylic acid-(2,5-dimethylphenyl)amide (llh) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOh (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (55.6 mg, yield 73%).
1H NMR(300MHz, CDC13) 10.11(s, IH), 9.76(s, IH), 8.49-8.46(dd, J=2.43Hz, IH), 8.08-8.01(m, 2h), 7.11-7.08(d, J=8.07Hz, lh), 2.24(s, 3H), 2.20(s, 3H). 13C NMR(300MHz, CDC13) 192.07, 160.62, 150.99, 150.57, 138.96, 137.40, 134.99, 133.14, 130.10, 126.52, 123.85, 121.10, 117.30, 19.88, 19.22.
Example 40: 6-formyl-pyridine-2-carboxylic acid-(3,4-dimethylphenyι)amide (Hi) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOi (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (57 mg, yield 75%).
1H NMR(300MHz, CDC13) 10.15(s, IH), 9.80(s, IH), 8.54-8.51(dd, J=2.43Hz, IH),
8.13-8.06(m, 2H), 7.56-7.49(m, 2H), 7.16-7.13(d, J=8.04Hz, IH), 2.29(s, 3H), 2.25(s,
3H). IR 3900.32, 3564.77, 1682.59, 1524.45, 1455.99, 1109.83, 1057.76, 669.18, 468.62,
418.48.cm"1
Example 41: 6-formyl-pyridine-2-carboxylic acid-(4- trifluoromethanephenyf)amide (llj) p-TsOH monohydrate (75.5 mg, 0.40 mmol) was added to the compound lOj
(90 mg, 0.26 mmol) according to the same method as in Example 32, to obtain the final compound (58.9 mg, yield 77%).
1H NMR(300MHz, CDCI3) 10.13(s, IH), 9.97(s, IH), 8.50-8.47(dd, J-2.19Hz, IH), 8.13-8.0 l(m, 2H), 7.96-7.93(d, J=8.55Hz, IH), 7.63(m, IH), 7.50-7.36(m, 3H). Example 42: 6-formyl-pyridine-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (Ilk) p-TsOH monohydrate (78.7 mg, 0.41 mmol) was added to the compound 10k (90 mg, 0.28 mmol) according to the same method as in Example 32, to obtain the final compound (61.9 mg, yield 79%).
1H NMR(300MHz, CDC13) 10.14(s, IH), 8.51-8.48(dd, J=1.71Hz, IH), 8.29-8.21(m, IH), 8.18-8.09(m, 2H), 7.07-6.97(ddd, J=2.46Hz, IH).
IR 3339.14, 2938.02, 2833.88, 1698.98, 1618.95, 1547.59, 1514.81, 1473.35, 1447.31, 1339.32, 1233.25, 1195.65, 1112.73, 1063.55, 1040.41, 972.91, 819.60, 758.85, 680.75, 593.97, 427.47, 419.44.cm"1
Example 43: 6-formyl-pyridine-2-carboxylic acid (2-chloro-4-fluorophenyϊ)amide
(IH) p-TsOH monohydrate (79.0 mg, 0.42 mmol) was added to the compound 101
(90 mg, 0.28 mmol) according to the same method as in Example 32, to obtain the final compound (58.5 mg, yield 75%).
1H NMR(300MHz, CDC13) 10.23(s, IH), 9.97(s, IH), 8.61-8.58(dd, J=2.43Hz, IH), 8.26-8.18(m, 2H), 8.80-8.05(dd, J-2.67Hz, IH), 7.71-7.67(m, IH), 7.27-7.18(dd, J=8.52Hz, IH).
IR 3352.28, 2936.09, 1683.55, 1591.95, 1529.27, 1502.28, 1455.03, 1397.17, 1262.18, 1209.15, 1110.80, 1055.84, 995.09, 825.38, 786.82, 758.85, 692.32, 445.48, 418.48cm"1
Synthesis (13a- 13t and 14a-14v) of Compounds 13 and 14 according to the reaction scheme 3
Example 44: 5-formyl-furan -2-carbothionic acid-S-2-methylphenyl ester (13a)
Dichloromethane (2 ml) was added to the compound 12 (50 mg, 0.35 mmol) of the reaction scheme 3, HOBT (24 mg, 0.18 mmol), EDC (75 mg,0.39 mmol) and triethylamine (50 μl , 0.33 mmol), followed by stirring for 5 min. 2-Methylbenzenethiol (58.12 mg, 0.46 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anliydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 8:1 to 5:1) to obtain the final compound (53 mg, yield 62.4%). 1H NMRQOOMHz, CDC13) 9.88(s, IH), 7.48-7.45(dd, J=7.32Hz, IH), 7.40-7.39(dd, J=7.32Hz, IH), 7.3 l(s, IH), 7.30(s, IH), 7.29-7.24(ddd, J=4.79, IH), 2.39(s, IH).
13C NMR(300MHz, CDC13) 178.94, 178.78, 153.39, 152.69, 142.65, 136.19, 130.95, 130.68, 126.79, 124.66, 119.32, 116.20, 20.68.
Example 45: 5-formyl-furan-2-carbothionic acid-S-3-methylphenyl ester (13b) The compound 12 (50 mg, 0.39 mmol) was used with 3-methylbenzenethiol
(58.2 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (67 mg, yield 70%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.38-7.26(m, 4H), 7.30(s, IH), 7.29(s, IH), 2.40(s, 3H). 13C NMR(300MHz, CDC13) 179.30, 178.76, 153.38, 152.57, 139.32, 135.37, 131.86, 130.87, 129.20, 124.78, 119.29, 116.21, 21.20.
Example 46: 5-formyl-furan-2-carbothionic acid-S-4-methylphenyl ester (13c) The compound 12 (50 mg, 0.39 mmol) was used with 4-methylbenzenethiol
(58.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (71 mg, yield 74%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.39-7.36(d, J=8.04Hz, 2H), 7.30(s, IH), 7.29(s, IH), 7.29-7.26(d, J=7.56Hz, IH), 2.39(s, 3H). 13C NMR(300MHz, CDC13) 179.86, 178.80 153.39, 152.63, 140.41, 134.80, 130.25, 121.58, 119.24, 116.18, 21.23.
Example 47: 5-formyl-furan-2-carbothionic acid-S-2-methoxyphenyl ester (13d)
The compound 12 (50 mg, 0.39 mmol) was used with 2-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (64 mg, yield 63%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.50-7.44(m, 2H), 7.30(s, IH), 7.30(s, IH),
7.29(s,lH), 7.06-7.00(m. 2H), 3.85(s, 3H).
13C NMR(300MHz, CDC13) 178.87, 178.57, 159.64, 153.36, 152.75, 136.94, 132.32, 121.22, 119.18, 116.15, 113.22, 111.71, 56.00.
Example 48: 5-formyl-furan -2-carbothionic acid-S-3-methoxyphenyl ester (13e)
The compound 12 (50 mg, 0.39 mmol) was used with 3-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (80.8 mg, yield 70%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.40-7.34(t, J=8.28Hz, IH), 7.31(s, IH), 7.30(s, IH), 7.10-6.99(m, 3H), 3.81(s, 3H).
13C NMRQOOMHz, CDC13) 179.27, 178.71, 159.91, 153.35, 152.41, 130.09, 126.92, 125.98, 119.34, 116.28, 116.06, 56.29.
Example 49: 5-formyl-furan-2-carbothionic acid-S-4-methoxyphenyl ester (13f)
The compound 12 (50 mg, 0.39 mmol) was used with 4-methoxy benzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (66.5 mg, yield 65%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.42-7.40(d, J=1.95Hz, IH), 7.39-7.38(d, J-2.2Hz,lH), 7.30(s, IH), 7.29(s, IH), 7.00-6.99(d, J=1.95Hz, IH), 6.99-6.97(d, J=1.95Hz, lH), 3.84(s, 3H). 13C NMR(300MHz, CDC13) 180.36, 178.80, 161.10, 153.39, 152.63, 136.46, 119.26, 116.16, 115.57, 115.09, 55.33.
Example 50: 5-formyl-furan-2-carbothionic acid-S-4-fluorophenyl ester (13g)
The compound 12 (50 mg, 0.39 mmol) was used with 4-fluorobenzenethiol (58.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
1H NMR(300MHz, CDC13) 10.26(s, IH), 8.28-8.25(dd, J=1.23Hz, IH), 8.25-8.22(dd, J=1.23Hz, IH), 8.16-8.11(t, J-7.8Hz, IH), 7.60-7.54(m, 2H), 7.28-7.20(m, 2H). 13C NMR(300MHz, CDC13) 192.05, 145.00, 142.12, 152.14, 151.14, 138.74, 136.97, 136.86, 125.38, 124.52, 122.00, 116.74, 116.45. IR 2830.99, 1717.30, 1669.09, 1490.70, 1344.14, 1265.07, 1228.43, 948.81, 835.03, 810.92, 729.92, 632.54.cm"1
Example 51: 5-formyl-furan-2-carbothionic acid-S-4-chlorophenyl ester (13h)
The compound 12 (50 mg, 0.39 mmol) was used with 4-chlorobenzenethiol (66.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
13C NMR(300MHz, CDC13) 178.96, 178.73, 153.54, 152.25, 136.57, 136.12, 129.71, 123.65, 119.27, 116.51.
Example 52: 5-formyl-furan-2-carbothionic acid-S-4-bromophenyl ester (13i)
The compound 12 (50 mg, 0.39 mmol) was used with 4-bromobenzenethiol (86.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%). 1H NMR(300MHz, CDC13) 10.17(s, IH), 8.21-8.18(dd, J=1.44Hz, IH), 8.17-8.14(dd, J=1.47Hz, IH), 8.08-8.03(ddd, J=7.8Hz, IH), 7.61(s, 2H), 7.56(s, 2H) 13C NMR(300MHz, CDC13) 166.9, 162.3, 152.9, 152.3, 138.73, 136.97, 136.86, 125.38, 124.52, 116.74, 116.45. IR 2822.5, 1713.44, 1679.69, 1470.46, 1380.78, 1262.18, 1068.37, 1006.66, 949.77, 848.53, 811.88, 730.89, 632.54, 573.72, 512.97.cm"1
Example 53: 5-formyl-furan-2-carbothionic acid-S-3,4-dichlorophenyl ester (13j)
The compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorobenzenethiol (82.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (79.1 mg, yield 73%).
1H NMR(300MHz, CDC13) 9.84(s, IH), 7.62-7.61(d, J=2.22Hz, IH), 7.56-7.54(d, J=2.7Hz, IH), 7.36-7.35(d, J=1.95Hz, IH), 7.33-7.32(d, J=2.19Hz, IH), 7.33(s, IH). 13C NMR(300MHz, CDC13) 178.66, 178.29, 153.64, 151.93, 136.32, 134.89, 134.00, 133.43, 131.17, 125.07, 116.77.
Example 54: 5-formyl-furan-2-carbothionic acid-S-2,5-dimethylphenyl ester (13k)
The compound 12 (50 mg, 0.39 mmol) was used with 2, 5 -dimethyl benzenethiol (49.2 mg, 0.33 mmol) according to the same method as in Example 44, to obtain the final compound (57.4 mg, yield 53%).
1H NMR(300MHz, CDC13) 9.83(s, IH), 7.31-7.29(d, J=3.9Hz, IH), 7.29-7.27(d,
J=4.14Hz, IH), 7.27-7.26(d, J=2.43Hz, IH), 7.23(s, IH), 7.20-7.19(d, J=1.95Hz, IH).
13C NMR(300MHz, CDC13) 179.23, 178.86, 153.46, 152.88, 139.46, 136.63, 136.56,
131.61, 130.82, 124.27, 119.18, 116.15, 20.72, 20.22.
Example 55: 5-formyl-furan-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (131) The compound 12 (50 mg, 0.39 mmol) was used with 2,4,6- trichlorobenzenethiol (49.2 mg, 0.33 mmol) according to the same method as in
Example 44, to obtain the final compound (86.9 mg, yield 72%). 1H NMR(300MHz, CDC13) 9.84(s, IH), 7.68(s, IH), 7.67(s, IH), 7.34-7.33(d, J=3.9Hz,
IH), 7.32-7.3 l(d, J=3.66Hz, IH).
13C NMR(300MHz, CDC13) 178.68, 176.51, 153.86, 151.49, 137.96, 135.99, 131.57,
129.21, 126.00, 119.31, 117.08, 105.01. Example 56: 5-formyl-furan-2-carbothionic acid-S-3,4-difluorophenyl ester (13m)
The compound 12 (50 mg, 0.39 mmol) was used with 3,4-difluorobenzenethiol (67.2 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (58.9 mg, yield 61%). 1H NMR(300MHz, CDC13) 9.85(s, IH) 7.51-7.44(m, IH) 7.33(s, IH) 7.03-6.97(m, 2H). 13C NMR(300MHz, CDC13) 178.71, 178.21, 153.67,151.96, 138.00, 119.24, 116.74, 112.67, 105.5, 105.15.
Example 57: 5-formyl-furan-2-carbothionic acid-S-2-chlorophenyl ester (13n) The compound 12 (50 mg, 0.39 mmol) was used with 2-chlorobenzenethiol
(66.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (59.5 mg, yield 62%).
1H NMR(300MHz, CDC13) 9.85(s, IH), 7.62-7.56(dd, J=1.7Hz, IH), 7.60-7.58(dd, J=1.71Hz, IH), 7.43-7.41 (ddd, J-1.71Hz, IH), 7.39-7.36(dd, J=1.71Hz, IH), 7.33(s, IH).
13C NMR(300MHz, CDC13) 178.80, 177.61, 153.55, 152.23, 139.14, 137.42, 131.78, 130.50, 127.50, 124.84, 119.15, 116.39.
Example 58: 5-formyl-furan-2-carbothionic acid-S-3-chlorophenyl ester (13o) The compound 12 (50 mg, 0.39 mmol) was used with 3-chlorobenzenethiol
(66.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71%).
1H NMR(300MHz, CDC13) 9.86(s, IH), 7.61-7.60(m, IH), 7.52-7.49(d, J=3.39Hz, IH) 7.43-7.41(dd, J=2,43Hz, 2H) 7.36-7.33(dd, J=3.63Hz, IH). 13C NMR(300MHz, CDC13) 178.71, 176.83, 153.65, 151.86, 137.46, 136.81, 132.96,
131.77, 131.24, 126.53, 119.18, 116.89.
IR 2853.17, 1692.23, 1563.99, 1460.81, 1401.03, 1352.82, 1235.18, 1190.83, 1072.23,
996.05, 965.20, 851.42, 781.03, 750.17, 678.82.cm"1
Example 59: 5-formyl-furan-2-carbothionic acid-S-2,5-dichlorophenyl ester (13p) The compound 12 (50 mg, 0.39 mmol) was used with 2,5-dichlorobenzenethiol
(81.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71%). 1H NMR(300MHz, CDC13) 9.86(s, IH), 7.61-7.60(d, J=2.43Hz, IH), 7.52-7.49(d,
J=3.39Hz, IH), 7.43-7.39(dd, J=2.43Hz, IH), 7.36-7.33(dd, J=3.63Hz, 2H).
13C NMR(300MHz, CDC13) 178.71, 176.83, 153.67, 151.86, 137.46, 136.81, 132.96,
131.77, 131.24, 126.53, 119.18, 116.89.
IR 3190.02, 1664.27, 1558.20, 1451.17, 1350.89, 1255.43, 1186.01, 1096.33, 988.34, 843.70, 811.88, 767.53, 597.82, 566.97.cm"1
Example 60: 5-formyl-furan-2-carbothionic acid-S-2,6-dichlorophenyl ester (13q)
The compound 12 (50 mg, 0.39 mmol) was used with 2,6-dichlorobenzenethiol (81.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71 %) .
1H NMR(300MHz, CDC13) 9.86 (s, IH), 7.52-7.51(d, J=0.99Hz, IH), 7.49( s, IH), 7.40-7.37(dd, J=2.76Hz, IH), 7.36-7.33(dd, J=3.9Hz, 2H).
13C NMR(300MHz, CDC13) 178.78, 175.92, 153.64, 151.97, 141.35, 132.08, 128.81, 125.00, 119.16, 116.84. IR 3141.47, 1690.30, 1562.06, 1501.31, 1427.07, 1402.00, 1353.78, 1236.15, 1191.79, 997.02, 967.13, 848.53, 780.06, 707.75.cm"1
Example 61: 5-formyl-furan-2-carbothionic acid-S-3,5-dichlorophenyl ester (13r) The compound 12 (50 mg, 0.39 mmol) was used with 3,5-dichloro benzenethiol (81.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71%).
1H NMR(300MHz, CDC13) 9.85(s, IH), 7.48-7.47(t, J=1.95Hz, IH), 7.41(s, 2H), 7.33(s, 2H). 13C NMR(300MHz, CDC13) 178.63, 177.87, 153.69, 151.81, 135.51, 132.88, 130.28, 128.22, 119.25, 116.86.
IR 3140.51, 1689.34, 1562.06, 1403.92, 1353.78, 1235.18, 1190.83, 1101.15, 999.91, 966.16, 849.49, 801.28, 751.14, 668.21. cm"1
Example 62: 5-formyl-furan-2-carbothionic acid-S-2,4-difluorophenyl ester (13s)
The compound 12 (50 mg, 0.39 mmol) was used with 2,4-difluoro benzenethiol (67.2 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (70.4 mg, yield 73%).
1H NMR(300MHz, CDC13) 9.85(s, IH), 7.52(m, IH), 7.40(s, IH), 7.37(s, IH), 7.03- 6.97(m, 2H).
13C NMR(300MHz, CDC13) 180.71, 179.21, 154.67, 151.96, 138.00, 119.24, 116.74,
114.5, 113.9, 112.67, 105.5, 105.15.
IR 1693.19, 1642.09, 1564.95, 1495.53, 1355.71, 1262.18, 1191.79, 1096.33, 983.52,
844.67, 751.14, 468.62.cm"1 Example 63: 5-formyl-furan-2-carbothionic acid-S-2,3,4,5,6-pentafluorophenyl ester (13t)
The compound 12 (50 mg, 0.39 mmol) was used with pentafluorobenzenethiol (92.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.7 mg, yield 53%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.39-7.38(d, J=3.9Hz, IH), 7.36-7.35(d,
J=3.9Hz, IH).
13C NMR(300MHz, CDC13) 178.53, 174.54, 154.03, 150.97, 119.21, 117.61.
Example 64: 5-formyl-furan-2-carboxylic acid-O-2-methylphenyl ester (14a)
The compound 12 (50 mg, 0.39 mmol) was used with 2-methylphenol (49.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (60.5 mg, yield 70%). 1H NMR(300MHz, CDC13) 9.87(s, IH), 7.48-7.47(d, J=3,9Hz, IH), 7.36-7.34(d,
J=3.9Hz, IH), 7.29-7.04(m, IH), 2.43(s, 3H).
13C NMR(300MHz, CDC13) 179.01, 155.98, 154.34, 148.48, 146.88, 131.33, 130.03,
127.08, 126.62, 121.61, 119.84, 118.75, 16.12.
Example 65: 5-formyl-furan-2-carboxylic acid-O-3-methylphenyl ester (14b)
The compound 12 (50 mg, 0.39 mmol) was used with 3-methylphenol (49.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (60.5 mg, yield 73-%). 1H NMRQOOMHz, CDC13) 9.85(s, IH), 7.45-7.44(d, J=3.66Hz,lH), 7.34-7.33(d, J=3.66Hz, IH), 7.31-7.29(dd, J=0.96Hz, IH), 7.12-7.09(d, J=7.29Hz, IH), 7.03-7.00(m, 2H), 2.41 (s,3H).
13C NMR(300MHz, CDC13) 178.99, 156.32, 154.26, 149.83, 147.06, 139.88, 129.09, 127.22, 121.84, 119.82, 118.83, 118.22, 21.27.
Example 66: 5-formyl-furan-2-carboxylic acid-O-4-methylphenyl ester (14c)
The compound 12 (50 mg, 0.39 mmol) was used with 4- methylphenol (49.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (65.5 mg, yield 79%>). 1H NMRβOOMHz, CDC13) 9.83(s, IH), 7.45-7.44(d, J=3.66Hz, IH), 7.34-7.32(d, J-3.66Hz, IH), 7.23-7.21( m IH) 7.12-7.07(m, IH) 2.36(s, IH). 13C NMR(300MHz, CDC13) 178.98, 156.44, 154.23, 147.67, 136.15, 130.08, 120.95, 119.80, 118.94, 20.83.
Example 67: 5-formyl-furan-2-carboxylic acid-O-2-methoxyphenyl ester (14d)
The compound 12 (50 mg, 0.39 mmol) was used with 2-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.8 mg, yield 63%).
1H NMRQOOMHz, CDC13) 9.86(s, IH), 7.47-7.46(d, J=3.66Hz, IH), 7.35-7.34(d, J=3.66Hz, IH), 7.36-7.30(t, J=8.28Hz, IH), 6.87-6.77(m, 3H), 3.82(s, 3H).
13C NMR(300MHz, CDC13) 179.05, 160.56, 130.02, 119.96, 118.82, 113.44, 112.28, 107.35, 55.45.
Example 68: 5-formyl-furan-2-carboxylic acid-O-4-methoxyphenyl ester (14e) The compound 12 (50 mg, 0.39 mmol) was used with 4-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (62.9 mg, yield 71%).
1H NMR(300MHz, CDC13) 9.84(s, IH), 7.45-7.44(d, J=3.66Hz, IH), 7.34-7.33(d, J=3.66Hz, IH), 7.15-7.12(d, J=9.27Hz, 2H), 6.95-6.91(d, J=9.27Hz, 2H), 3.88(s, 3H). 13C NMR(300MHz, CDC13) 178.93, 157.84, 156.56, 154.09, 146.94, 143.19, 122.0, 119.04, 119.01, 114.46, 55.45.
Example 69: 5-formyl-furan-2-carboxylic acid-O-4-fluorophenyl ester (14f) The compound 12 (50 mg, 0.39 mmol) was used with 4-fluorophenol (51.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (62.4 mg, yield 74%).
1H NMRQOOMHz, CDC13) 9.86(s, IH), 7.48-7.46(d, J=3.66Hz, IH), 7.36-7.34(d,
J=3.66Hz, IH), 7.23-7.08(m, 4H).
Example 70: 5-formyl-furan-2-carboxylic acid-O-4-chlorophenyl ester (14g)
The compound 12 (50 mg, 0.39 mmol) was used with 4-chlorophenol (59.1 mg,
0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.5 mg, yield 76%). 1H NMR(300MHz, CDC13) 9.89(s, IH), 7.47-7.46(d, J=3.66Hz, IH), 7.42-7.40(dd,
J=1.95Hz, IH), 7.38-7.36(dd, J-1.95Hz, IH), 7.20-7.19(dd, J=1.95Hz, IH), 7.19-
7.50(dd, J=1.95Hz, IH).
Example 71: 5-formyl-furan-2-carboxylic acid-O-4-bromophenyl ester (14h) The compound 12 (50 mg, 0.39 mmol) was used with 4-bromophenol (79.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (58.4 mg, yield 55%).
1H NMR(300MHz, CDC13) 9.81(s, IH), 7.53-7.51(dd, J=2.19Hz, IH), 7.50-7.48(dd, J=2.19Hz, IH), 7.43-7.42(d, 3=3.66Hz, IH), 7.31-7.30(d, J=3.66Hz, IH), 7.11-7.09(dd, J=2.19Hz, IH), 7.08-7.06(dd, J=2.19Hz, IH).
13C NMR(300MHz, CDC13) 178.88, 155.86, 154.35, 148.87, 146.52, 132.65, 123.11, 120.22, 119.57, 119.00.
Example 72: 5-formyl-furan-2-carboxylic acid-O-3,4-dichlorophenyl ester (14i)
The compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorophenol (74.9 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.9 mg, yield 76%).
1H NMR(300MHz, CDC13) 9.82(s, IH), 7.94-7.61(d, J=8.76Hz, IH), 7.45-7.44(d, J=3.9Hz, IH), 7.37-7.36(d, J-2.7Hz, IH), 7.33-7.32(d, J=3.66Hz, IH), 7.12-7.11(d, J=2.67Hz, IH), 7.07-7.08(d, J=2.67Hz, IH).
13C NMR(300MHz, CDC13) 178.89, 155.95, 154.33, 148.31, 146.54, 131.83, 122.7, 120.19, 119.2.
Example 73: 5-formyl-furan-2-carboxylic acid-O-2,5-dimethylphenyl ester (14j)
The compound 12 (50 mg, 0.39 mmol) was used with 2,5-dimethylphenol (56.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.1 mg, yield 82%). 1H NMR(300MHz, CDC13) 9.84(s, IH), 7.46-7.45(d, J=3.66Hz, IH), 7.34-7.33(d, J=3.66Hz, IH), 7.16-7.14(d, J=7.8Hz, IH), 7.02-6.99(d, J=7.8Hz, IH), 6.95(s, IH), 2,33(s, 3H), 2.18(s, 3H).
13C NMR(300MHz, CDC13) 178.99, 156.07, 154.30, 148.29, 146.93, 137.11, 127.38, 126.71, 122.07, 119.79, 118.93, 20.81, 15.67.
Example 74: 5-formyl-furan-2-carboxylic acid-O-2,4,6-trichlorophenyl ester (14k)
The compound 12 (50 mg, 0.39 mmol) was used with 2,4,6-trichlorophenol (90.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (101.22 mg, yield 88%). 1H NMR(300MHz, CDC13) 9.92(s, IH), 7.58-7.57(d, J=3.63Hz, IH), 7.53-7.50(d, J=8.76Hz, IH), 7.40-7.39(d, J=3.9Hz, IH), 7.24-7.21(d, J=8.76Hz, IH). 13C NMR(300MHz, CDC13) 178.91, 154.71, 145.65, 133.07, 132.21, 128.39, 127.96, 121.85, 120.95, 118.58.
Example 75: 5-formyl-furan-2-carboxylic acid-O-2,3.4,5,6-pentafluorophenyl ester (141)
The compound 12 (50 mg, 0.39 mmol) was used with pentafluorophenol (84.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (59.5 mg, yield 54%). 1H NMR(300MHz, CDC13) 9.89(s,lH), 7.58-7.57(d, J=3.66Hz, IH), 7.38-7.37(d, J=3.66Hz, IH).
13C NMR(300MHz, CDC13) 179.01, 155.98, 154.33, 148.48, 146.88, 131.33, 130.03, 127.08, 126.62, 121.61, 119.84, 118.75. Example 76: 5-formyl-furan-2-carboxylic acid-O-3,4-difluorophenyl ester (14m)
The compound 12 (50 mg, 0.39 mmol) was used with 3,4-difiuorophenol (59.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (60.1 mg, yield 66%). 1H NMR(300MHz, CDC13) 9.84(s, IH), 7.48-7.47(d, J=3.63Hz, IH), 7.36-7.35(d,
J-3.6Hz, IH), 7.27-7.18(q, J-8.76Hz, IH), 7.15-7.09(ddd, J=3.9Hz, IH), 7.06-6.95(m,
IH).
13C NMR(300MHz, CDC13) 178.85, 155.57, 154.46, 148.38, 146.14, 133.19, 130.90,
130.47, 123.63, 121.00, 120.51, 118.91.
Example 77: 5-formyl-furan-2-carboxylic acid-O-4-trifluoromethylphenyl ester
(14n)
The compound 12 (50 mg, 0.39 mmol) was used with 4-trifluoromethylphenol
(74.57 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (97.5 mg, yield 88%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.74-7.73(d, J=3.6Hz, 2H), 7.67-7.66(d,
J=6.2Hz, IH), 7.34-7.32(d, J=6.9Hz, 2H), 6.97-6.96(d, J=3.6Hz, IH).
13C NMR(300MHz, CDC13) 180.04, 159.42, 155.78, 154.16, 153.16, 128.42, 127.89,
124.00, 122.67, 121.01, 117.26.
Example 78: 5-formyl-furan-2-carboxylic acid-O-2,354-trichlorophenyl ester (14o) The compound 12 (50 mg, 0.39 mmol) was used with 2,3,4-trichloro phenol
(68.11 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (95.4 mg, yield 83%). 1H NMR(300MHZ, CDCI3) 9.92(s, IH), 7.58-7.57(d, J=3.63Hz, IH), 7.53-7.50(d, J=8.76Hz, IH), 7.40-7.39(d, J=6.9Hz, IH), 7.24-7.21(d, J=8.76Hz, IH). 13C NMR(300MHz, CDC13) 178.91, 154.71, 145.65, 133.21, 128.39, 127.96, 121.85, 120.95, 118.58.
Example 79: 5-formyI-furan-2-carboxylic acid-O-2-chloro-4-fluorophenyl ester (14p)
The compound 12 (50 mg, 0.39 mmol) was used with 2-chloro-4-fluorophenol (67.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (78.3 mg, yield 81%).
1H NMR(300MHz, CDC13) 9.89(s, IH), 7.51-7.50(dd, J=0.48Hz, IH), 7.38-7.37(d,
J=3.66Hz, IH), 7.38-7.35(m, IH), 7.30-7.14(m, 2H).
13C NMR(300MHz, CDC13) 178.84, 157.46, 155.81, 154.99, 146.22, 123.79, 121.75,
121.19, 120.40, 118.56, 117.12.
Example 80: 5-formyl-furan-2-carboxylic acid-O-2,354-trifluorophenyl ester (14q)
The compound 12 (50 mg, 0.39 mmol) was used with 2,3,4-trifluoro phenol (68.11 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (95.4 mg, yield 83%). 1H NMR(300MHz, CDC13) 9.85(s, IH), 7.58(s, IH), 7.51-7.49(d, J=3.66Hz, IH), 7.41(s, IH), 7.34-7.33(d, J=3.66Hz, IH).
13C NMR(300MHz, CDC13) 178.89, 154.74, 154.58, 145.46, 144.82, 131.71, 131.33, 131.24, 126.06, 125.12, 121.03, 118.61. Example 81: 5-formyl-furan-2-carboxylic acid-O-4-t-butylphenyl ester (14r)
The compound 12 (50 mg, 0.39 mmol) was used with 4-t-butylphenol (69.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.4 mg, yield 79%).
1H NMR(300MHz, CDC13) 9.88(s,lH), 7.49-7.47(d, J=3.66Hz, IH), 7.42-7.39(d, J=8.04Hz,lH), 7.37-7.32(dd, J=1.71Hz, IH), 7.24-7.23(t, J=3.66Hz, IH), 7.09-7.08(dd, J=1.71Hz, IH), 7.07-7.06(dd, J=1.71Hz, IH), 1.36(s, IH).
13C NMR(300MHz, CDC13) 178.98, 156.38, 154.24, 153.36, 149.78, 147.15, 129.07, 123.43, 119.79, 118.85, 118.30, 118.27, 34.81, 31.17.
Example 82: 5-formyl-furan-2-carboxylic acid-O-2, 4-difluorophenyl ester (14s)
The compound 12 (50 mg, 0.39 mmol) was used with 2,4-difiuorophenol (59.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (69.8 mg, yield 71%). 1H NMR(300MHz, CDC13) 9.88(s, IH), 7.66-7.65(d, J=3.6Hz, 2H), 7.39-7.37(m, IH), 7.20-7.18(m, 2H), 7.13-1. ll(m, IH) 6.58-6.57(d, J=3.6Hz, IH). 13C NMR(300MHz, CDC13) 180.04, 162.7, 155.85, 154.16, 153.74, 153.16, 140.38, 123.43, 121.01, 115.26, 113.14, 106.31.
Example 83: 5-formyl-furan-2-carboxylic acid-O-2, 4-dimethoxyphenyl ester (14t)
The compound 12 (50 mg, 0.39 mmol) was used with 2,4-dimethoxyphenol (70.9 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (76.5 mg, yield 77%). 1H NMR(300MHz, CDC13) 9.82(s, IH), 7.42-7.41(d, J=3.66Hz, IH), 7.31-7.29(dd, J=3.66Hz, IH), 6.36(s, 3H), 3.76( s, 6H).
13C NMR(300MHz, CDC13) 178.98, 161.20, 156.03, 154.27, 151.31, 146.90, 119.92,
118.80, 99.93, 98.71, 55.48.
Example 84: 5-formyl-furan-2-carboxylic acid-O-phenyl ester (14u)
The compound 12 (50 mg, 0.39 mmol) was used with phenol (43.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (52.1 mg, yield 67%).
1H NMR(300MHz, CDC13) 9.84(s, IH), 7.47-7.45(d, J=3.66Hz, IH), 7.44-7.40(m, 2H), 7.35-7.33(d, J=3.66Hz, IH), 7.32-7.21(m, 3H).
13C NMR(300MHz, CDC13) 178.98, 156.24, 154.26, 149.88, 146.95, 129.61, 126.42, 121.30, 119.93, 118.99.
Example 85: 5-formyl-furan-2-carboxylic acid pyridin-2-yl ester (14v) The compound 12 (50 mg, 0.39 mmol) was used with 2-hydroxyρyridine (43.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (46.9 mg, yield 60%).
1H NMR(300MHz, CDC13) 9.84(s, IH), 8.59-8.58(d, J=2.67Hz, IH), 8.56-8.54(dd, J=1.2Hz, IH), 7.7-.7.66(ddd, J=1.47Hz, IH), 7.49-7.48(d, J=3.66Hz, IH), 7.46-7.42(dd, J=4.86Hz, IH) 7.34-7.33(d, J-3.66Hz, IH).
13C NMR(300MHz, CDC13) 178.83, 155.53, 154.56, 146.89, 146.70, 145.94, 142.37, 129.88, 124.39, 120.73, 118.84. Synthesis (17a-17j) of Compound 17 according to the reaction scheme 4
General synthesis method of the precursor 16a-16j to synthesize 17a-17j
Example 86-1: 5-dimethoxymethyI-furan-2-carboxylic acid (15)
The compound 12 (5 g, 35.6 mmol) and p-TsOH of a catalytic amount were dissolved in anhydrous methanol (100 ml). After an excess of trimethyl orthoformate (100 ml) was added thereto, the mixture was reacted at room temperature for 3 hours and methanol was removed under reduced pressure. Water (100 ml) was added to the residue and then an extraction process was conducted with ethylacetate (100 ml x 2). The obtained organic solution was subjected to silica gel column (hexane: ethyl acetate= 7:1) to obtain the final compound 15 (5.4 g, yield 81%). 1H NMR(300MHz, CDC13) 6.39-6.38(d, J=3.15Hz, IH), 6.31-6.29(d, J=3.18Hz, IH), 5.24(s, IH), 3.35(s, 6H).
Example 86-2: 5-dimethoxymethyl-furan-2-carboxylic acid-(o-tolyl)amide (16a)
Dichloromethane (2 ml) was added to the compound 15 (100 mg, 0.54 mmol), HOBT (36.3 mg, 0.27 mmol), EDC (133.9 mg, 0.69 mmol) and Et3N (97.3 μl, 0.69 mmol), followed by stirring for 5 min. o-Toluidine (73.9 mg, 0.69 mmol) was added thereto, followed by stirring for 30min to conduct condensation. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate^ 6:1) to the compound 16a (111.5 mg, yield 75%).
1H NMR(300MHz, CDC13) 7.930 IH), 7.25-7.19(m, 4H), 7.11-7.09(d, J=6.12Hz, IH), 6.58-6.57(d, J=3.8Hz, IH), 5.47(s, IH), 3.38(s, 6H), 2.33(s, 3H).
Example 86-3: 5-dimethoxymethyl-furan-2-carboxylic acid-(m- tolyl)amide (16b) m-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16b (107.1 mg, yield 72%).
1H NMR(300MHz, CDC13) 8.00(s, IH), 7.49(s, IH), 7.44-7.42(d, J=7.8Hz, IH), 7.25- 7.23(t, J=3.18Hz, IH), 7.19-7.18(4 J=3.66Hz, IH), 6.59-6.93(4 J=7.05Hz, IH), 6.57- 6.56(d, J=3.66Hz, IH), 5.46(s, IH), 3.37(s, 6H), 2.35(s, 3H).
Example 86-4: 5-dimethoxymethyl-furan-2-carboxylic acid-(p-tolyl)amide (16c) p-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16c (115.9 mg, yield 78%).
1H NMR(300MHz, CDC13) 8.00(s, IH), 7.53-7.51(4 J=8.31Hz, 2H), 7.18-7.17(4 J=3.42Hz, IH), 7.16-7.13(4 J=8.28Hz, 2H), 6.65-6.56(4 J=3.18Hz,' lH). 545(s, IH), 3.37(s, 6H), 2.32(s, 3H).
Example 86-5: 5-dimethoxymethyI-furan-2-carboxyIic acid-(2-methoxyphenyl) amide (16d) o-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16d (102.2 mg, yield 65%).
1H NMR(300MHz, CDC13) 8.68(s, IH), 8.45-8.42(dd, J=1.95Hz, IH), 7.18-7.17(4 J=3.39Hz, IH), 7.07-7.03(dd, J=1.71Hz, IH), 7.00-6.97(dd, J=1.71Hz, IH), 6.91-
6.88(dd, J=1.71, IH), 6.57-6.56(4 J=3.42Hz, IH), 5.50(s, IH), 3.92(s, 3H), 3.38(s, 6H).
Example 86-6: 5-dimethoxymethyl-furan-2-carboxylic acid-(4-methoxyphenyl) amide (16e) p-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg,
0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16f (133.6 mg, yield 85%).
1H NMR(300MHz, CDC13) 7.98(s, IH), 7.57-7.52(dd, J=3.42Hz, 2H), 7.17-7.16(4 J=3.42Hz, IH), 6.90-6.85(dd, J=3.66Hz, 2H), 6.56-6.55(4 J=3.18Hz, IH), 5.45(s, IH), 3.79(s, 3H), 3.37(s, 6H).
Example 86-7: 5-dimethoxymethyl-furan-2-carboxylic acid-(3-chlorophenyl) amide (16f)
3-Chloroaniline (88.0 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16g (103.8 mg, yield 65%).
1H NMR(300MHz, CDC13) 8.07(s, IH), 7.78-7.77(t, J=1.95Hz, IH), 7.24(s, IH), 7.21- 7.20(d, J=3.42Hz, IH), 7.11-7.09(dd, JM1.95Hz, IH), 6.58-6.57(4 t=3.66Hz, IH), 5.45(s, lH), 3.37(s, 6H). Example 86-8: 5-dimethoxymethyl-furan-2-carboxylic acid-(3,4-dimethylphenyl) amide (16h)
3,4-dimethylaniline (83.6 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16h (123.4 mg, yield 79%).
1H NMR(300MHz, CDC13) 7.98(s, IH), 7.43-7.42(4 J=2.19Hz, IH), 7.38-7.34(dd, J=2.19Hz, IH), 6.56-6.55(4 J=3.42Hz, IH), 5.45(s, IH), 3.37(s, 6H), 2.25(s, 3H), 2.22(s, 3H).
Example 86-9: 5-dimethoxymethyl-furan-2-carboxylic acid-(4- trifluoromethanephenyl)amide (16i)
4-Trifluoroaniline (111.8 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16i (115.5 mg, yield 65%).
1H NMR(300MHz, CDC13) 8.38(s, IH), 7.58-7.52(dd, J=5.61Hz, 2H), 7.28(s, 2H), 6.89-6.84(dd, J=5.58Hz, 2H), 3.45(s, 6H).
Example 86-10: 5-dimethoxymethyl-furan-2-carboxylic acid-(2,3>4- trifluorophenyl)amide (16j)
2,3,4-trifluoroaniline (102.2 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16j (129.3 mg, yield 76%). 1H NMR(300MHz, CDC13) 8.06(s, IH), 7.90-7.89(4 J=2.46Hz, IH), 7.47-7.46(4 J=2.46Hz, IH), 7.22-7.21(d, J=3.66Hz, IH), 6.59-6.58(4 J=3.66Hz, IH). 3.37(s, 6H).
Example 86: 5- formyl-furan-2-carboxylic acid-(2-methylphenyl)amide (17a) p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the obtained compound 16a (90 mg, 0.32 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate^ 6:1) to obtain the final compound (52.1 mg, yield 71%).
1H NMR(300MHz, CDC13) 9.74(s, IH), 8.13(s, IH), 7.87-7.86(4 J=7.56Hz, IH), 7.35- 7.31(dd, J=3.66Hz, 2H), 7.24-7.22(4 J=6.81Hz, 2H), 7.16-7.10(ddd, J=1.47Hz, IH), 2.35(s, 3H).
13C NMR(300MHz, CDC13) 177.84, 155.14, 152.34, 151.20, 134.34, 130.67, 129.67, 126.87, 125.99, 123.16, 122.11, 116.25, 17.69.
IR 3300.57, 2934.16, 1668.12, 1588.09, 1538.92, 1455.03, 1383.67, 1309.43, 1204.33, 1109.83, 1057.76, 991.23, 808.03, 754.99, 423.30, 409.80.cm"1
Example 87: 5-formyl-furan-2-carboxylic acid-(3-methylphenyϊ)amide (17b) p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the compound 16b (90 mg, 0.32 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6: 1) to obtain the final compound (49.9 mg, yield 68%).
1H NMR(300MHz, CDC13) 9.73(s, IH), 8.21(s, IH), 7.45(s, IH), 7.42-7.39(4 J=8.04Hz, IH), 7.29-7.26(dd, J=3.9Hz, 2H), 7.22-7.17(dd, J=7.8Hz, IH), 6.94-6.92(4 J=7.56Hz, IH), 2.30(s, 3H). 13C NMR(300MHz, CDC13) 177.87, 154.95, 152.27, 151.23, 139.13, 136.50, 128.97, 125.98, 122.53, 120.81, 117.28, 116.23, 21.44.
IR 3302.50, 1668.12, 1614.13, 1556.27, 1488.78, 1313.29, 1205.29, 1108.87, 1058.73, 779.10, 680.39, 480.19.cm"1
Example 88: 5-formyl-furan-2-carboxylic acid-(4-methylphenyl)amide (17c) p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the compound 16c (90 mg, 0.32 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (55.0 mg, yield 75%). 1H NMR(300MHz, CDC13) 9.79(s, IH), 8.42(s, IH), 7.63-7.59(ddd, J=4.38Hz, 2H), 7.39-7.37(dd, J=3.87Hz, 2H), 7.24-7.21(4 J=8.28Hz, 2H), 2.39(s, 3H). 13C NMR(300MHz, CDC13) 177.95, 154.95, 152.25, 151.31, 134.90, 134.16, 129.63, 122.58, 120.26, 116.12, 20.87. IR 3301.54, 2919.70, 1667.16, 1604.48, 1515.77, 1404.89, 1321.00, 1300.75, 1245.79, 1206.26, 1107.90, 1056.80, 812.85, 754.03, 509.12, 427.16, 410.76.cm"1
Example 89: 5-formyl-furan-2-carboxylic acid-(2-methoxyphenyl)amide (17d) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16d (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (47.8 mg, yield 63%).
1H NMR(300MHz, CDC13) 9.75(s, IH), 8.87(s, IH), 8.43-8.39(dd, J=1.44Hz, 2H), 7.3 l(s, 2H), 7.13-7.07(ddd, J=1.71Hz, IH), 7.01-6.95(ddd, J=1.47Hz, IH), 6.93-6.90(dd, J=1.20Hz, IH), 3.93(s, 3H).
13C NMR(300MHz, CDC13) 178.07, 152.43, 151.43, 148.33, 126.50, 124.76, 121.65, 121.05, 120.19, 116.09, 110.08, 55.84.
IR 3409.53, 2937.05, 2834.85, 1679.69, 1606.41, 1547.59, 1520.60, 1481.06, 1460.81, 1434.78,1384.64, 1336.43, 1292.07, 1252.54, 1202.40, 1105.98, 1056.80, 1024.98, 991.23, 951.70, 870.70, 808.03, 750.17, 668.21.cm"1
Example 90: 5-formyl-furan-2-carboxylic acid-(4-methoxyphenyϊ)amide (17e) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16e (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (47.1 mg, yield 62%).
1H NMR(300MHz, CDC13) 9.69(s, IH), 8.38(s, IH), 7.58-7.52(dd, J-5.61Hz, 2H),
7.28(s, 2H), 6.89-6.84(dd, J=5.58Hz, 2H), 3.77(s, 3H). 13C NMR(300MHz, CDC13) 177.96, 154.92, 151.32, 129.77, 122.64, 121.97, 115.99,
114.23, 55.40. .
IR 3302.50, 2936.09, 2835.81, 1667.16, 1604.48, 1547.59, 1513.85, 1463.71, 1414.53,
1318.11, 1301.72, 1245.79, 1179.26, 1108.87, 1031.73, 966.16, 876.49, 824.42, 771.39,
754.03, 551.54, 521.65, 431.01, 411.73.cm"1
Example 91: 5-formyl-furan-2-carboxylic acid-(3-chlorophenyl)amide (17f) p-TsOH monohydrate (86.8 mg, 0.45 mmol) was added to the compound 16f
(90 mg, 0.30 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (52.4 mg, yield 70%).
1H NMR(300MHz, CDC13) 9.66(s, IH), 8.36(s, IH), 7.74(s, IH), 7.44-7.41(4 J=7.8Hz, IH), 7.27-7.26(4 J+4.14Hz, 2H), 7.21-7.18(4 J=8.55Hz, IH), 7.07-7.05(4 J=6.84Hz, IH). 13C NMR(300MHz, CDC13) 177.92, 152.15, 138, 135.00, 130.00, 124, 122, 120.34, 118.16, 116.66.
IR 3302.50, 2936.09, 2835.81, 1667.16, 1604.48, 1547.59, 1513.85, 1463.71, 1414.53, 1318.11, 1301.72, 1245.79, 1179.26, 1108.87, 1031.73, 966.16, 876.49, 824.42, 771.39, 754.03, 551.54, 521.65, 431.01, 411.73.cm"1
Example 92: 5-formyl-furan-2-carboxylic acid-(2,5-dimethylphenyl)amide (17g) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16g (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (58.8 mg, yield 78%).
1H NMR(300MHz, CDC13) 9.72(s, IH), 8.14(s, IH), 7.67(s, IH), 7.32-7.31(4 J=4.14Hz,
IH), 7.31-7.30(4 J=3.9Hz, IH), 7.11-7.08(4 J=7.8Hz, IH), 6.95-6.92(4 J=7.8Hz, IH),
2.3 l(s, 3H), 2.28(s, 3H).
13C NMR(300MHz, CDC13) 177.90, 155.16, 152.31, 151.26, 136.58, 134.07, 130.42,
126.78, 123.80, 122.08, 116.15, 21.03, 17.21.
Example 93: 5-formyl-furan-2-carboxylic acid-(3,4-dimethylphenyl)amide (17h) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16h (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate^ 6:1) to obtain the final compound (49.0 mg, yield 65%).
1H NMR(300MHz, CDC13) 9.70(s, IH), 8.31(s, IH), 7.43-7.42(4 J=1.95Hz, IH), 7.40- 7.36(dd, J-2.46Hz, IH), 7.31-7.30(4 J=3.9Hz, IH), 7.30-7.28(4 J 3.9Hz, IH), 7.10- 7.08(d, J=8.04Hz, IH), 2.24(s, 3H), 2.21(s, 3H).
13C NMR(300MHz, CDC13) 177.94, 154.92, 151.39, 137.42, 134.41, 133.62, 130.08, 122.54, 121.52, 117.74, 116.04, 19.84, 19.19.
Example 94: 5-formyl-furan-2-carboxylic acid-(4-trifϊuoromethanephenyϊ)amide (17i) p-TsOH monohydrate (77.9 mg, 0.41 mmol) was added to the compound 16i (90 mg, 0.27 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (54.3 mg, yield 71%).
1H NMR(300MHz, CDC13) 9.69(s, IH), 8.38(s, IH), 7.58-7.52(dd, J=5.61Hz, 2H),
7.28(s, 2H), 6.89-6.84(dd, J=5.58Hz, 2H).
13C NMR(300MHz, CDC13) 177.96, 154.92, 151.32, 129.77, 122.64, 121.97, 115.99,
114.23. IR 3318.89, 1669.09, 1607.38, 1551.45, 1500.35, 1396.21, 1316.18, 1263.15, 1212.04, 1108.87, 1056.80, 813.81, 751.14, 668.21, 432.94, 412.69.cm"1
Example 95: 5-formyl-furan-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (17j) p-TsOH monohydrate (81.5 mg, 0.43 mmol) was added to the compound 16j (90 mg, 0.29 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 6:1) to obtain the final compound (67.6 mg, yield 74%).
1H NMR(300MHz, CDC13) 9.81(s, IH), 8.73(s, IH), 8.05-8.04(4 J=2.92Hz, IH), 7.41-7.40(4 JM3.34Hz, IH), 7.37-7.36(4 J=3.34Hz, IH), 7.07-7.01(dd, J-7.64Hz, IH).
Synthesis (20a-201 and 21a-21q) of Compounds 20 and 21 according to the reaction scheme 5
Example 96: 5-o-tolylsulfanylmethyl-furan-2-carbaldehyde (20a)
For the reaction vessel filled with the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol), a replacing process was conducted with argon. Anhydrous dimethylformamide (2 ml) was added thereto and then o-methylbenzenethiol (50.1 mg, 0.41 mmol) was added thereto, followed by stirring for 3hours. After the completion of the reaction, dimethylformamide was removed with a vacuum concentrator. Water (10 ml) was added to the resultant, followed by extracting with dichloromethane (10 ml x 2). The organic layer was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration. The obtained residue was subjected to the separation method of silica gel column chromatography (hexane: ethyl acetate= 5:1) to obtain the final compound (57 mg, 71%).
1H NMR(300MHz, CDC13) 9.55(s, IH), 7.26-7.24(4 J=8.04Hz, 2H), 7.13-7.12(4 J=3.66Hz, IH), 7.11-7.09(4 J=8.04Hz, 2H), 4.08(s, 2H), 2.33(s, 3H). 13C NMR(300MHz, CDC13) 177.18, 158.53, 152.14, 137.69, 130.46, 129.75, 121.2, 110.62, 32.26, 20.97.
Example 97: 5-(m-torylsulfanylmethyl)-furan-2-carbaldehyde (20b) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and m-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (50.5 mg, 63%).
1H NMR(300MHz, CDC13) 9.52(s, IH), 7.19-7.00(m, 5H), 6.28-6.27(4 J=3.42Hz, IH), 4.09(s, IH), 2.28(s, 3H).
13C NMR(300MHz, CDC13) 177.26, 159.4, 152.1, 138.87, 132.2, 131.51, 128.86, 128.18, 127.81, 110.68, 101.11, 31.61, 21.20.
Example 98: 5-(p-tolylsulfanylmethyf)-furan-2-carbaldehyde (20c) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and p-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (60 mg, 63%). 1H NMR(300MHz, CDC13) 9.55(s, IH), 7.26-7.24(4 J=8.04Hz, 2H), 7.13-7.12(4 J=3.66Hz, IH), 7.11-7.09(4 J=8.04Hz, 2H), 4.08(s, 2H), 2.33(s, 3H).
13C NMR(300MHz, CDC13) 177.18, 158.53, 152.14, 137.69, 130.46, 129.75, 121.2, 110.62, 32.26, 20.97.
Example 99: 5-(2-methoxy-phenylsulfanylmethyl-furan-2-carbaldehyde (20d) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and 2-methoxybenzenethiol (57.4 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound
(58.2 mg, 69%). 1H NMR(300MHz, CDC13) 9.54(s, IH), 7.27-7.21(t, J=8.04Hz, IH), 7.18-7.17(4
J-3.66Hz, IH), 6.97-6.95(4 J=7.8Hz, IH), 6.93-6.92(t, J=2.19Hz, IH), 6.84-6.80(dd,
J .95Hz, IH), 4.18(s, 2H), 3.81(s, 3H).
13C NMR(300MHz, CDC13) 177.24, 164.1, 160.2, 158.34, 152.9, 136.1, 129.85, 122.67,
115.87, 113.08, 110.74, 55.24, 31.43.
Example 100: 5-(3-methoxy-phenylsulfanyImethyf)-furan-2-carbaldehyde (20e)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg) were used with 3-methoxybenzenethiol (57.4 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (51.4 mg, 61%).
1H NMR(300MHz, CDC13) 9.44(s, IH), 7.20-7.19(4 J=1.47Hz, IH), 7.17-7.15(dd,
J=1.68Hz, IH), 7.02-7.00(4 J=3.66Hz, IH), 6.85-6.78(4 J=8.04Hz, 2H), 6.18-6.17(4
J=3.66Hz, IH), 4.04(s, 2H), 3.81(s, 3H).
13C NMR(300MHz, CDC13) 177.20, 169.8, 169.1, 152.1, 148.9, 132.65, 129.15, 121.3, 120.91, 110.75, 55.74, 29.76.
Example 101: 5-(4-methoxy-phenylsulfanyImethyι)-furan-2-carbaldehyde (20f)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and 4-methoxybenzenethiol (57.4 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (63.2 mg, 75%).
1H NMR(300MHz, CDC13) 9.54(s, IH), 7.27-7.24(dd, J=2.19Hz, 2H), 7.08-7.07(4 J=3.66Hz, IH), 6.79-6.76(dd, J-2.19Hz, 2H), 3.95(s, 2H), 3.74(s, 3H). 13C NMR(300MHz, CDC13) 177.15, 159.66, 158.59, 152.14, 134.76, 124.11, 122.9, 114.49, 110.59, 55.13, 33.37.
Example 102: 5-(4-fluoro-phenylsuIfanylmethyϊ)-furan-2-carbaldehyde (20g)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and 4-fluorobenzenethiol (52.3 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (57 mg,
71%).
1H NMR(300MHz, CDC13) 9.55(s, IH), 7.37-7.30(m, IH), 7.13-71.2(4 J=3.66Hz, IH),
7.03-6.95(m, 2H), 6.24-6.23(4 J=3.42Hz, IH), 4.05(s, 2H). 13C NMR(300MHz, CDC13) 177.2, 165.9, 164.21, 158.07, 152.01, 134.46, 134.35,
116.29, 116.00, 110.74, 32.82.
Example 103: 5-(4-chloro-phenylsulfanylmethyϊ)-furan-2-carbaldehyde (20h)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 4-chlorobenzenethiol (58.4 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (61.8 mg, 72%).
1H NMR(300MHz, CDC13) 9.54(s,lH), 8.46-8.43(m, IH), 7.53-7.47(ddd, J=1.95Hz, IH), 7.19-7.16(4 J=8.04Hz, IH), 7.04-7.00(dd, J=4.89Hz, IH), 6.48-6.47(4 J=3.63Hz, IH), 4.52(s, 2H).
13C NMR(300MHz, CDC13) 177.16, 160.00, 158, 152, 149.29, 136.12, 122.22, 119.93,
110.70, 26.02.
Example 104: 5-(4-bromo-phenyIsulfanylmethyf)-furan-2-carbaldehyde (20i)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 4-bromobenzenethiol (77.4 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (76.7 mg, 76%). 1H NMR(300MHz, CDC13) 9.55(s, IH), 7.42(s, IH), 7.39(s, IH), 7.21(s, IH), 7.18(s, IH), 7.14-7.13(4 J=3.42Hz, IH), 4.11(s, 2H).
3C NMR(300MHz, CDC13) 177.21, 157.76, 152.29, 133.39, 132.49, 132.09, 122.51, 121.51, 110.81, 31.64.
Example 105: 5-(2-pyridine— henylsu!fanylmethyl)-furan-2-carbaldehyde (20j)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 2-mercaptopyridine (45.5 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (41 mg, 55%). 1H NMR(300MHz, CDC13) 9.57(s, IH), 7.42-7.41(4 J=2.19Hz, IH), 7.37-7.34(4 J=8.31Hz, IH), 7.17-7.14(m, 3H), 6.34-6.33(4 J=3.66Hz, IH), 4.13( s, 2H). 13C NMR(300MHz, CDC13) 177.23, 157.23, 151.11, 134.46, 132.94, 132.19, 131.65, 130.72, 129.92, 110.99, 31.56. Example 106: 5-(3,4-dichIoro-phenylsuIfanyImethyl)-furan-2-carbaIdehyde (20k)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 3,4-dichlorobenzenethiol (72.5 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (77.1 mg, 79%).
1H NMR(300MHz, CDC13) 9.56(s, IH), 7.26(s, 3H), 7.14-7.12(4 J=3.39Hz, IH) 6.29- 6.28(d, J=3.66Hz, IH), 4.15(s, IH).
13C NMR(300MHz, CDC13) 177.22, 157.83, 151.12, 131.43, 132.47, 129.18, 110.81, 31.87.
Example 107: 5-(2,5-dimethyl-phenylsulfanylmethyl)-furan-2-carbaldehyde (201)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 2,5-dimethylbenzenethiol (56.7 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (51.9 mg, 62%) .
1H NMR(300MHz, CDC13) 9.46(s, IH), 7.29-7.21(ddd, J=8.52Hz, IH), 7.03-7.02(4 J=3.66Hz, IH), 6.81-6.69(m, IH), 6.16-6.15(4 J=3.39Hz, IH), 3.98(s,2H), 2.5(s,3H), 2.48(s, 3H). 13C NMR(300MHz, CDC13) 183.04, 156.86, 150.60, 140.24, 134.51, 131.79, 131.61, 131.16, 115.93, 114.18, 31.95, 21.24, 20.13.
Example 108: 5-(4-methyl-phenoxymethyf)-furan-2-carbaldehyde (21a)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg, 0.45 mmol) and 4-methylphenol (44.4 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (60.2 mg, 82%).
1H NMR(300MHz, CDC13) 9.63(s, IH), 7.23-7.21(4 J=3.66Hz, IH), 7.11-7.08(4 J-8.76Hz, 2H), 6.86-6.82(4 J=l 1.7Hz, 2H), 6.60-6.59(4 J=3.42Hz, IH), 5.06(s, 2H), 2.29(s, 3H).
13C NMR(300MHz, CDC13) 177.65, 157.01, 155.77, 152.62, 131.03, 130.00, 121.00, 114.66, 111.47, 62.68, 20.43.
Example 109: 5-(4-methoxy-phenoxymethyl)-furan-2-carbaldehyde (21b) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-methoxyphenol (50.8 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (56.0 mg, 71%). 1H NMR(300MHz, CDC13) 9.63(s, IH), 7.23-7.22(4 J=3.66Hz, IH), 6.92-6.81(m, 4H), 6.60-6.59(4 J=3.63Hz, IH), 5.04(s, 2H), 3.77(s, 3H).
13C NMR(300MHz, CDC13) 177.66, 157.04, 154.53, 152.62, 151.97, 121.85, 116.03, 114.68, 114.49, 63.40, 55.62.
Example 110: 5-(4-chloro-phenoxymethyf)-furan-2-carbaldehyde (21c) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-chlorophenol (52.7 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (70.8 mg, 88%). 1H NMR(300MHz, CDC13) 9.64(s, IH), 7.28-7.23(m, IH), 6,90-6.89(4 J-2.43Hz, IH), 6.88-6.87(4 J=2.43Hz, IH), 6.62-6.60(4 J=3.63Hz, IH), 5.07(s, 1H).
13C NMR(300MHz, CDC13) 177.63, 156.43, 156.12, 152.73, 129.47, 126.65, 121.83,
119.09, 111.77, 62.70.
Example 111: 5-(4-bromo-phenoxymethyϊ)-furan-2-carbaldehyde (2 Id)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-bromophenol (70.9 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (72.6 mg, 76%). 1H NMR(300MHz, CDC13) 9.64(s, IH), 7.42-7.38(d. J=9.03Hz, IH), 7.25-7.24(d. J=3.66Hz, IH), 6.86-6.83(4 J=9.00Hz, IH), 6.63-6.61(4 J=3.63Hz, IH), 5.07(s, 2H). 13C NMR(300MHz, CDC13) 177.73, 156.92, 156,17, 152.69, 132.42, 117.23, 116.58, 113.99, 112.32, 62.62.
Example 112: 5-(2-pyridine-phenoxymethyl)-furan-2-carbaldehyde (21e)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with hydroxypyridine (38.9 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (43.5 mg, 63%). 1H NMR(300MHz, CDCI3) 9.63(s, IH), 7.34-7.28(m, 2H), 7.23-7.22(4 J=3.66Hz, IH), 7.03-6.94(m, 3H), 6.62-6.61(4 J=3.66Hz, IH), 5.09(s, 2H).
13C NMR(300MHz, CDC13) 177.67, 157.82, 156.75, 151.00, 129.58, 121.69, 114.72, 111.56, 62.42. Example 113: 5-(3,4-dichloro-phenoxymethyl)-furan-2-carbaldehyde (21f)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 3,4-dichlorophenol (66.8 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (65.4 mg, 71%).
1H NMR(300MHz, CDC13) 9.68(s, IH), 7.35-7.32(4 J=8.76Hz, IH), 7.25-7.24(4 J=3,42Hz, IH), 7.05-7.04(4 J=2.94Hz, IH), 6.83-6.79(dd, J=2.91Hz, IH), 6.63-6.62(4 J=3.42Hz, IH), 5.05(s, 2H).
13C NMR(300MHz, CDC13) 177.79, 156.74, 155.57, 152.74, 132.98, 130.80, 130.66, 116.80, 115.35, 114.57, 112.07, 62.76.
Example 114: 5-(2,5-dimethyl-phenoxymethyl)-furan-2-carbaldehyde (21g)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 2,5-dimethylphenol (50.0 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (69.1 mg, 71%).
1H NMR(300MHz, CDC13) 9.68(s, IH), 7.24-7.23(4 J=3.42Hz, IH), 7.04-7.02(4 J=7.53Hz, IH), 6.74-6.71(4 J=7.56Hz, IH), 6.68(s, IH), 6.60-6.59(4 J=3.6Hz, IH), 5.08(s, 2H), 2.3 l(s, 3H), 2.19(s, 3H). 13C NMR(300MHz, CDC13) 177.61, 157.40, 155.90, 151.00, 136.63, 130.66, 124.99, 121.99, 112.51, 111.09, 62.81, 21.29, 15.70.
Example 115: 5-(phenoxymethyl)-furan-2-carbaldehyde (21h)
According to the same method as in Example 96, the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were dissolved in DMF, and then phenol (38.5 mg, 0.41 mmol) was added thereto to obtain the final compound (45.4 mg, 66%).
1H NMR(300MHz, CDC13) 9.64(s, IH), 8.17-8.15(dd, J=1.2Hz, IH), 7.64-7.58(ddd, J=1.95Hz, IH), 7.23-7.22(4 J=3.42Hz, IH), 6.95-6.90(ddd, J=0.96Hz, IH), 6.82-6.79(4 J=9.24Hz, IH), 6.63-6.62(4 J=3.66Hz, IH).
Example 116: 5-(3,5-dimethoxy-phenoxymethyl)-furan-2-carbaldehyde (21i)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 3,5- dimethoxyphenol (63.1 mg, 0.41 mmol) according to the same method as in Example
96, to obtain the final compound (59.2 mg, 67%).
1H NMRβOOMHz, CDC13) 9.65(s, IH), 7.24-7.23(4 J=3.66Hz, IH), 6.63-6.62(4
J=3.42Hz, IH), 6.14(s, 2H), 5.06(s, 2H), 6.37(s, 2H), 3.5(s, 3H), 3.4(s, 3H).
Example 117: 5-(2,3?4,5,6-pentafluoro-phenoxymethyl)-furan-2-carbaldehyde (21j) The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with pentafluorophenol
(75.4 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (yield 67%).
1H NMR(300MHz, CDC13) 9.66(s, IH), 7.24-7.23(4 J=3.66Hz, IH), 6.67-6.66(4
J=3.66Hz, IH), 5.21(s, 2H).
13C NMR(300MHz, CDC13) 177.88, 154.48, 153.24, 121.16, 113.21, 67.94. Example 118: 5-(3,4-difluoro-phenoxymethyf)-furan-2-carbaldehyde (21k)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 3,4-difluorophenol (59.9 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (53.5 mg, 66%).
1H NMR(300MHz, CDC13) 9.64(s, IH), 7.52-7.24(4 J=3.00Hz, IH), 7.13- 7.04(q, J=9Hz, IH), 6.83-6.76(ddd, J=3.18Hz, IH), 6.70-6.64(m IH), 6,63-6.62(4 J=3.39Hz, IH).
13C NMR(300MHz, CDC13) 177.68, 155.72, 152.78, 121.85, 117.47, 117.23, 117.20, 111.94, 110.17, 104.92, 63.13.
Example 119: 5-(4-trifIuoromethane-phenoxymethyl)-furan-2-carbaldehyde (211)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-trifluoromethanephenol (61.6 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (58.8 mg, 67%).
1H NMR(300MHz, CDC13) 9.66(s, IH), 7.59-7.56(4 J=8.76Hz, IH), 7.25-7.24(4 J-3.66Hz, IH), 7.05-7.02(4 J=8.79Hz, IH), 6.65-6.63(4 J=3.39Hz, IH), 5.03( s, 2H). 13C NMR(300MHz, CDC13) 177.65, 160.18, 155.64, 152.82, 127.09, 114.69, 111.94, 62.43.
Example 120: 5-(2,3j4-trifluoro-phenoxymethyl)-furan-2-carbaldehyde (21m)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anliydrous potassium carbonate (62 mg, 0.45 mmol) were used with 2,3,4-trifluorophenol (60.71 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (63.5 mg, 73%).
1H NMR(300MHz, CDC13) 9.64(s, IH), 7.25-7.24(4 J=3,42, IH), 6.94-6.84( m IH), 6.80- 6.73( m IH), 6.66-6.65(4 J=3.66Hz, IH), 5.14(s, 2H).
Example 121: 5-(3-chloro-4-fluoro-phenoxymethyl)-furan-2-carbaldehyde (21n)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 3-chloro-4-fluorophenol (60.1 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (66.7 mg, 77%).
1H NMR(300MHz, CDC13) 9.64(s, HI), 7.52-7.24(4 J=θ.66Hz, IH), 7.09-7.01(q, J=8.76Hz, IH), 7.01-6.98(q, J=2.91Hz, IH), 6.84-6.79(s, J=3.42Hz, IH), 6.62-6.61(4 3.66Hz, lH), 5.04(s, 2H).
Example 122: 5-(2,3,4-trichloro-phenoxymethyl)-furan-2-carbaldehyde (21o)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 2,3,4- trichlorophenol (80.9 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (70.6 mg, 68%). 1H NMR(300MHz, CDC13) 9.65(s, IH), 7.63-7.55(4 J=8.76Hz, IH), 7.25-7.24(4 J=3.66Hz, IH), 6.91-6.88(4 J=9.03Hz, IH), 6.68-6.66(4 J=3.66Hz, IH), 5.06(s, 2H). 13C NMR(300MHz, CDC13) 177.64, 155.20, 153.25, 152.81, 132.80, 127.95, 126.76, 124.33, 121.85, 112.65, 112.17, 64.1. Example 123: 5-(4-t-butyl-phenoxymethyι)-furan-2-carbaldehyde (21p)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-t-butylphenol
(61.5 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (71.1 mg, 81 %) .
1H NMR(300MHz, CDC13) 9.64(s, IH), 7.27-7.22(m, 2H), 7.06-7.00(m, 2H), 6.79-
6.75(ddd, J-0.72Hz, IH), 6.63-6.62(4 J=3.19Hz, IH), 5.11(s, 2H), 1.31(s, 9H).
13C NMR(300MHz, CDC13) 177.68, 159, 156,8, 153.24, 152, 129.05, 121.00, 118.88,
111.55, 110.81, 62.50, 34.75, 31.23.
Example 124: 5-(2,4,6-trichloro-phenoxymethyf)-furan-2-carbaldehyde (21q)
The compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 2,4,6- trichlorophenol (80.9 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (65.5 mg, 63%).
1H NMR(300MHz, CDC13) 9.66(s, IH), 7.47(s, IH), 7.25-7.24(4 J=3.18Hz, IH), 7.09(s,
IH), 6.68-6.67(4 J=3.66Hz, IH), 5.04(s, 2H).
13C NMR(300MHz, CDC13) 177.88, 154.79, 152.93, 152.49, 131.53, 131.20, 125.63,
122.77, 121.58, 115.91, 112.28, 64.07.
Synthesis (27a-27o and 29a- 29d of Compounds 27 and 29 accordmg to the reaction scheme 6
Example 125-1: 2,5-thiophene dicarboxylate (23) 2,5-Thiophenedicarboxylic acid (5 g, 29 mmol), which is compound 22 and commercial, was dissolved in methanol (300 ml) and thionyl chloride (SOCl2) was slowly added dropwise thereto at 0°C. The reaction vessel was warmed up to room temperature, followed by reflux for 3hours. After confirming the disappearance of the starting material using TLC, methanol was removed under reduced pressure. The residue was dissolved in 200 ml of chloroform and the solution was slowly added to 300ml of chloroform saturated with NH3. The formed white solid was filtered and then recrystallized in methanol to obtain the desirable compound 23 (5.75 g, 99.9%). 1H NMR(300MHz, CDC13) 7.71(s, 2H), 3.89(s, 6H). 13C NMR(300MHz, CDC13) 161.96, 133.99, 130.84, 51.96.
Example 125-2: 5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (24)
The compound 23 (5.6 g, 27.9 mmol) was dissolved in methanol (300 ml). After NaBH4 (1.9 g, 56 mmol) was intermittently added thereto, the mixture was reacted at room temperature for 4 hours and methanol was removed under reduced pressure. H O (200 ml) was added to the residue solution and then an extraction process was conducted with CH2C12 (2000 ml x 2). The obtained organic solution was washed with brine (100 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 1 :2) to obtain the compound 24 (3.1 g, yield 65%).
1H NMR(300MHz, CDC13) 7.69-7.68(4 J=3.9Hz, IH), 6.99-6.98(4 J=2.91Hz, IH), 4.87-4.85(4 J=6.09Hz, 2H), 3.88(s, 3H). 13C MR(300MHz, CDC13) 61.48, 139.75, 136.55, 133.01, 124.29, 64.43, 51.96. Example 125-3: 5-formyl-thiophene-2-carboxylic acid methyl ester (25)
The compound 24 (3 g, 17.4 mmol) was dissolved in acetone and an excess of MnO2 was added thereto. After 2days of the reaction time, the reaction solution was filtered under reduced pressure with Celite545 and then an exraction process was conducted with acetone sufficiently. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate^ 2:1) to obtain the compound 25 (2.2 g, yield 75%) 1H NMR(300MHz, CDC13) 9.98(s, IH), 7.85-7.84(4 J=3.9Hz, IH), 7.76-7.75(4 J=3.9Hz, IH).
13C NMR(300MHz, CDCI3) 183.02, 160.99, 139.75, 136.36, 135.09, 132.28, 51.96.
Example 125-4: 5-formyl-thiophene-2-carboxylic acid (26)
The compound 25 (2 g, 12.8 mmol) was dissolved in 200 ml of mixture solvent (THF:H2O=l:l) and hydrolyzation was conducted by adding KOH (1.1 g, 19.2 mmol). After the completion of the reaction, THF was removed under reduced pressure.
The water layer was titrated with IN HC1 solution in pH 1-2 and then extracted with ethyl acetate (200 ml x 5) to obtain the desirable compound 25 (1.2 g, yield 59%).
1H NMR(300MHz, CDCI3) 10.00(s, IH), 7.93-7.92(4 J=3.92Hz, IH), 7.78-7.77(4 J=3.9Hz, IH).
13C NMR(300MHz, CDC13) 182.2, 163.70, 141.57, 139.70, 133.79, 132.79.
Example 125: 5-formyl-thiophene-2-carboxylic acid-2-methylphenyl ester (27a)
Dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min. 2-Methylphenol (41.1 mg, 0.38 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 8:1 to 5:1) to obtain the final compound (53.6 mg, yield 68%). 1H NMR(300MHz, CDC13) 10.03(s, IH), 8.03-8.02(4 J=3.9Hz, IH), 7.82-7.80(4 J=3.9Hz, IH), 7.30-7.15(m, 4H), 2.25(s, 3H).
13C NMR(300MHz, CDC13) 183.20, 159.57, 148.38, 148.44, 139.98, 134.99, 134.37, 131.28, 130.04, 127.01, 126.52, 121.65, 16.13. IR 2924.52, 1730.80, 1678.73, 1524.45, 1489.74, 1321.96, 1242.90, 1201.43, 1171.54, 1109.83, 1068.37, 1023.05, 826.35, 744.39, 672.07, 430.05, 409.80.cm"1
Example 126: 5-formyl-thiophene-2-carboxylic acid-3-methylphenyl ester (27b)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 3-methylphenol (41.1 mg, 0.38 mmol) was added thereto to obtain the final compound (60.6 mg, yield 77%).
1H NMR(300MHz, CDC13) 10.02(s, IH), 8.01-7.99(4 J=3.9Hz, IH), 7.80-7.79(4 J=3.9Hz, IH), 7.34-7.29(t, J=7.8Hz, IH), 7.26(s, IH), 7.12-7.09(4 J-7.56Hz, IH), 7.04-7.01(m, 2H), 2.39(s, 3H).
IR 2923.56, 1730.80, 1678.73, 1524.45, 1486.85, 1321.96, 1238.08, 1199.51, 1142.62,
1070.30, 1031.73, 826.35, 682.28, 444.51.cm"1
Example 127: 5-formyl-thiophene-2-carboxylic acid-4-methylphenyl ester (27c)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
(79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-methylphenol (41.1 mg, 0.38 mmol) was added thereto to obtain the final compound (56.6 mg, yield 70%).
1H NMR(300MHz, CDCI3) 10.03(s, IH), 8.02-8.00(4 J=3.9Hz, IH), 7.81-7.80(4
J=4.38Hz, IH), 7.26-7.09(m, 4H) 2.58(s, 3H).
13C NMR(300MHz, CDCI3) 183.19, 161.75, 159.94, 148.66, 146.07, 139.79, 134.95,
134.57, 122.90, 116.42, 116.18, 16.2. IR 2924.52, 1722.12, 1675.84, 1508.06, 1453.10, 1240.00, 1205.29, 1077.05, 1024.02,
859.13, 805.13, 738.60, 675.93, 446.44, 408.83.cm"1
Example 128: 5-formyl-thiophene-2-carboxylic acid-4-fluorophenyl ester (27d)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-fluorophenol (42.5 mg, 0.38mmol) was added thereto to obtain the final compound (54.5 mg, yield 68%). 1H NMR(300MHz, CDCI3) 10.03(s, IH), 8.02-8.00(4 J=3.9Hz, IH), 7.81-7.80(4 J=4.38Hz, IH), 7.26-7.09(m, 4H).
13C NMR(300MHz, CDC13) 183.19, 161.75, 159.94, 148.66, 146.07, 139.79, 134.95, 134.57, 122.90, 116.42, 116.18.
IR 2922.59, 1723.09, 1665.23, 1510.95, 1453.10, 1280.50, 1250.61, 1191.79, 1028.84, 862.02, 812.85, 737.64, 441.62.cm"1
Example 129: 5-formyl-thiophene-2-carboxylic acid-4-chlorophenyl ester (27e)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-chlorophenol (48.8 mg, 0.38 mmol) was added thereto to obtain the final compound (60.6 mg, yield 71%).
1H NMR(300MHz, CDC13) 10.06(s, IH), 8.05-8.04(4 J=4.14Hz, IH), 7.85-7.83(4
J=3.9Hz, IH), 7.47-7.42(ddd, J=3.18Hz, 2H), 7.25-7.20(ddd, J=3.18Hz, 2H). 13C NMR(300MHz, CDC13) 183.13, 159.63, 148.69, 148.66, 139.59, 134.91, 134.61,
131.80, 129.63, 122.73.
IR 1737.55, 1665.23, 1484.92, 1325.82, 1251.57, 1205.84, 1074.16, 1028.84, 859.13,
803.21, 735.71.cm"1
Example 130: 5-formyl-thiophene-2-carboxylic acid-4-bromophenyl ester (27f)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-bromophenol (65.8 mg, 0.38 mmol) was added thereto to obtain the final compound (68.7 mg, yield 69%).
1H NMRβOOMHz, CDC13) 10.02(s, IH), 8.01-8.00(4 J=3.9Hz, IH), 7.81-7.79(4 J=3.9Hz, IH), 7.57-7.74(4 J=8.55Hz, 2H), 7.16-7.12(4 J=8.76Hz, IH). IR 1736.58, 1666.20, 1527.35, 1481.08, 1326.79, 1252.54, 1206.26, 1068.37, 1009.55, 860.10, 798.39, 736.67, 675.93, 503.33.cm"1
Example 131: 5-formyl-thiophene-2-carboxylic acid-3,4-dichlorophenyl ester (27g) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 3,4-dichlorophenol (61.9 mg, 0.38 mmol) was added thereto to obtain the final compound (65.5 mg, yield 68%).
1H NMR(300MHz, CDC13) 10.00(s, IH), 7.99-7.98(4 J=3.9Hz, IH), 7.79-7.78(4
J-3.9Hz, IH), 7.50-7.47(4 J=8.76Hz, IH), 7.37-7.38(4 J=2.7Hz, IH), 7.13-7.09(dd, J=2.67Hz, IH).
13C NMR(300MHz, CDCI3) 183.06, 159.29, 148.93, 148.73, 139.03, 134.87, 133.20,
130.87, 130.41, 123.71, 121.03.
IR 1735.62, 1663.30, 1524.45, 1468.53, 1324.86, 1240.97, 1200.47, 1122.37, 1068.37,
1024.98, 828.28, 736.67, 443.56.cm"1
Example 132: 5-formyl-thiophene-2-carboxylic acid-2,5-dimethylphenyl ester (27h) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
(79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 2,5-dimethylphenol (46.4 mg, 0.38 mmol) was added thereto to obtain the final compound (64.2 mg, yield 77%>).
1H NMR(300MHz, CDC13) 9.99(s, IH), 7.99-7.98(4 J=3.9Hz, IH), 7.79-7.77(4
J=3.9Hz, IH), 7.15-7.12(4 J=7.56Hz, IH), 7.00-6.98(4 J=7.8Hz, IH), 6.96(s, IH), 2.32(s, 3H), 2.17(s, 3H).
13C NMR(300MHz, CDC13) 183.24, 160.1, 148.64, 148.39, 137.07, 135.04, 134.31,
130.97, 127.29, 126.71, 122.13, 20.85, 15.7.
IR 2923.56, 1731.76, 1678.73, 1510.95, 1454.06, 1321.96, 1267.00, 1240.97, 1198.54,
1109.83, 1069.33, 1031.73, 811.88, 741.50, 672.07.cm"1
Example 133: 5-formyl-thiophene-2-carboxylic acid-4-trifluoromethylphenyl ester
(27i)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-trifluoromethylphenol (61.6 mg, 0.38 mmol) was added thereto to obtain the final compound (74.9 mg, yield 78%>).
1H NMR(300MHz, CDC13) 10.00(s, IH), 8.01-8.00(4 J=3.9Hz, IH), 7.79-7.78(4
J=4.2Hz, IH), 7.70-7.68(4 J=8.55Hz, 2H), 7.37-7.34(4 J=8.79Hz, 2H). 13C NMR(300MHz, CDC13) 183.13, 159.35, 152.63, 148.89, 139.23, 134.94, 134.84,
128.80, 126.99, 126.88, 125.05, 122.35, 121.91.
IR 1728.87, 1671.02, 1513.85, 1333.53, 1204.33, 1168.65, 1133.94, 1063.55, 1021.12,
871.67, 815.74, 738.60, 676.89.cm"1 Example 134: 5-formyl-thiophene-2-carboxylic acid-2,4,6-trichlorophenyl ester
(27j)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 2,4,6-trichlorophenol (75 mg, 0.38 mmol) was added thereto to obtain the final compound (94.5 mg, yield 83%).
1H NMR(300MHz, CDC13) 9.96(s, IH), 7.99-7.97(4 J=3.9Hz, IH), 7.75-7.74(4 J=3.87Hz, IH), 7.54(s, IH), 7.40(s, IH). 13C NMR(300MHz, CDC13) 183.03, 158.41, 149.26, 145.16, 136.06, 135.32, 134.85, 131.64, 131.18, 126.09, 125.18.
IR 1742.37, 1680.66, 1525.42, 1445.39, 1376.93, 1325.82, 1241.93, 1201.43, 1069.33, 1030.77, 826.35, 732.82.64, 131.18, 126.09, 125.18cm"1
Example 135: 5-formyI-thiophene-2-carboxylic acid-2-chloro-4-fluorophenyl ester
(27k)
The compound 26 (50 mg, 0.32 mmol) was used with 2-chloro-4-fluorophenol (47.2 mg, 0.38 mmol) according to the same method as in Example 125, to obtain the final compound (65.6 mg, yield 72%). 1H NMR(300MHz, CDC13) 10.05(s, IH), 8.05-8.03(4 J=4.14Hz, IH), 7.85-7.84(4 J=3.9Hz, IH), 7.39-7.36(dd, J=2.67Hz, IH), 7.24-7.21(4 J=8.28Hz, IH), 7.18-7.14(ddd, J=2.67Hz, IH).
13C NMR(300MHz, CDC13) 183.13, 159.52, 157.41, 154.95, 148.86, 139.10, 134.96, 134.81, 123.85, 121.23, 117.06, 116.83. IR 1752.01, 1676.80, 1494.56, 1321.32, 1258.32, 1200.47, 1064.51, 1024.98, 886.13,
839.85, 741.50, 670.14, 416.55.cm"
Example 136: 5-formyl-thiophene-2-carboxylic acid-2,3,4-trifluorophenyl ester (271)
The compound 26 (50 mg, 0.32 mmol) was used with 2,3,4-trifluorophenol
(47.2 mg, 0.38 mmol) according to the same method as in Example 125, to obtain the final compound (68.7 mg, yield 75%).
1H NMR(300MHz, CDC13) 10.01(s, IH), 8.03-8.02(4 J=3.9Hz, IH), 7.81-7.80(4 J=4.17Hz, IH), 7.05-7.96(m, 2H).
13C NMR(300MHz, CDC13) 183.13, 158.57, 149.18, 138.03, 135.31, 134.92, 117.37,
117.29, 111.38, 111.20, 111.16, 111.07.
IR 1743.33, 1681.62, 1504.20, 1324.86, 1269.90, 1238.08, 1195.65, 1158.04, 1068.37,
1017.27, 969.05, 795.49, 736.67, 672.07, 469.58.cm"1
Example 137: 5-formyl-thiophene-2-carboxylic acid-4-t-butylphenyl ester (27m)
The compound 26 (50 mg, 0.32 mmol) was used with 4-t-butylphenol (57 mg,
0.38 mmol) according to the same method as in Example 125, to obtain the final compound (74.7 mg, yield 81%). 1H NMR(300MHz, CDC13) 10.08(s, IH), 8.02-8.01(4 J=4.14Hz, IH), 7.81-7.80(4
J-3.9Hz, IH), 7.41-7.32(m, 2H), 7.25-7.23(t, J=1.71Hz, IH), 7.07-7.05(ddd, J=1.95Hz,
IH), 1.36(s, 9H).
13C NMR(300MHz, CDC13) 183.26, 160.23, 153.32, 150.16, 148.40, 135.04, 134.31,
129.06, 123.38, 118.34, 31.20. IR 2963.09, 1731.76, 1679.69, 1524.45, 1485.88, 1321.96, 1071.26, 1029.80, 826.35, 740.53, 698.10.cm"1
Example 138: 5-formyl-thiophene-2-carboxylic acid-2,4-difluorophenyl ester (27n) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 2,4-difluorophenol (47.2 mg, 0.38 mmol) was used thereto to obtain the final compound (52.4 mg, yield 61%). 1H NMRQOOMHz, CDC13) 10.01(s, IH), 8.01-7.99(4 J=4.14Hz, IH), 7.81-7.80(4 J=4.14Hz, IH), 7.24-7.20(4 J=9.75Hz, IH), 7.18-7.10(ddd, J=2.7Hz, IH), 7.02-6.70(m, IH).
13C NMR(300MHz, CDC13) 183.17, 159.51, 151.41, 151.27, 149.86, 149.73, 147.39, 147.27, 139.15, 134.97, 134.81, 111.66, 111.46. IR 3095.19, 1736.58, 1716.34, 1674.87, 1457.92, 1348.00, 1279.54, 1199.51, 1124.30, 1086.69, 1030.77, 878.42, 832.13, 734.75, 673.03.cm"1
Example 139: 5-formyl-thiophene-2-carboxylic acid-2,4-dimethoxyphenyl ester
(27o) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 2,4-dimethoxyphenol (55.6 mg, 0.38 mmol) was used thereto to obtain the final compound (64.7 mg, yield 71%). 1H NMR(300MHz, CDC13) 10.08(s, IH), 8.10-8.09(4 J=3.9Hz, IH), 7.87-7.86(4 J=3.9Hz, IH), 7.27-7.24(4 J=9.03Hz, IH), 7.08-7.07(4 J=2.91Hz, IH), 6.94-6.90(dd, J=2.91Hz, 2H), 3.88(s, 6H).
13C NMR(300MHz, CDC13) 183.19, 159.37, 158.1, 148.68, 139.1, 134.96, 134.74, 127.15, 123.76, 113.88, 113.44, 55.78.
IR 1730.80, 1674.87, 1514.81, 1249.65, 1200.47, 1147.44, 1027.87, 950.73, 881.31, 804.17, 737.64, 676.89.cm"1
Example 140: 5-formyl-thiophene-2-carbothionic acid-S-(4-fluorophenyl)ester (29a)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
(79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-fluorobenzenethiol (48.7 mg, 0.38 mmol) was used thereto to obtain the final compound (55.3 mg, yield 65%).
!H NMR(300MHz, CDC13) 10.07(s, IH), 7.99-7.97(4 J=4.14Hz, IH), 7.86-7.85(4
J=3.9Hz, IH), 7.59-7.58(dd, J=5.1Hz, 2H), 7.26-7.21(dd, J=6.81Hz, 2H).
13C NMR(300MHz, CDC13) 183.11, 184.01, 165.10, 147.88, 147.56, 137.02, 136.94,
134.92, 131.12, 121.18, 116.85, 116.63.
Example 141: 5-formyl-thiophene-2-carbothionic acid-S-(4-chlorophenyl)ester
(29b)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 4-chlorobenzenethiol (54.9 mg, 0.38 mmol) was used thereto to obtain the final compound (53.4 mg, yield 59%).
1H NMR(300MHz, CDC13) 9.94(s, IH), 7.85-7.84(4 J=3.9Hz, IH), 7.72-7.71(4 J=3.9Hz, IH), 7.54-7.52(4 J-10.56Hz, 2H), 7.32-7.29(4 J-8.76Hz, IH).
13C NMR(300MHz, CDCI3) 183.07, 181.85, 147.96, 147.48, 136.23, 134.89, 132.65, 131.19, 125.01, 124.85.
Example 142: 5-formyl-thiophene-2-carbothionic acid-S-(2,5-dimethylphenyϊ)ester (29c)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
(79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then 2,5-dimethylbenzenethiol (47.2 mg, 0.38 mmol) was used thereto to obtain the final compound (68.1 mg, yield 77%).
1H NMR(300MHz, CDC13) 9.99(s, IH), 7.93-7.92(4 J=3.9Hz, IH), 7.79-7.77(4
J=3.9Hz, IH), 7.30(s, IH), 7.27-7.24(4 J=7.8Hz, IH),. 7.21-7.18(4 J=7.8Hz, IH).
13C NMR(300MHz, CDC13) 183.16, 182.29, 148.24, 147.57, 139.31, 136.54, 136.51,
134.94, 131.57, 130.94, 130.77, 124.98, 20.67, 20.21.
Example 143: 5-formyl-thiophene-2-carbothionic acid-S-(2,6-dichlorophenyl)ester
(29d)
According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et3N (58.5 μl, 0.42 mmol), followed by stirring for 5 min and then dichlorobenzenethiol (68.6 mg, 0.38 mmol) was used thereto to obtain the final compound (59.8 mg, yield 59%>).
1H NMR(300MHz, CDC13) 9.99(s, IH), 7.96-7.95(4 J=3.9Hz, IH), 7.79-7.78(4 J=3.9Hz, IH), 7.31-7.26(dd, J=6.33Hz, IH), 7.21-7.18(4 J=7.56Hz, 2H), 2.41(s, 2H).
Synthesis (33a-33m and 36a-33f) of Compounds 33 and 36 according to the reaction scheme 7
Example 144-1: 5-chloromethyl-thiophene-2-carboxylic acid methyl ester (30)
The comound 24 (5 g, 29.0 mmol) was dissolved in anhydrous methylene chloride (200 ml). Et N (8 ml, 58 mmol) and methanesulfonyl chloride (2.78 ml, 43.8 mmol) were sequently added dropwise at 0 °C and then the mixture was reacted at room temperature for 3 hours, H O (100 ml) was added thereto to stop the reaction. An extracting process was conducted with methylene chloride (10 ml x 2). The obtained organic solution was washed with brine (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 7:1) to obtain the compound 30 (3.8 g, yield 69%). 1H NMR(300MHz, CDC13) 7.66-7.65(4 J=3.66Hz, IH), 7.08-7.07(4 J=3.9Hz, IH), 4.76(s, 2H), 3.89(s, 3H).
Example 144-2: 5-(o-tolyloxymethyl)thiophene-2-carboxylic acid methyl ester (31a)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and o-methylphenol (68.1mg, 0.63 mmol) was added thereto, followed by stirring at room temperature. After confirming the completion of the reaction using TLC, DMF was removed under vacuum decompression to obtain residue. H2O (10 ml) was added to the residue and then an extraction process was conducted with methylene chloride (10 ml x 2). The obtained organic solution was washed with brine (20 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 9:1) to obtain the compound 31a (112.6 mg, yield 81%). 1H NMR(300MHz, CDC13) 7.71-7.69(4 J=3.66Hz, IH), 7.18-7.11(m, 2H), 7.07-7.06(4 J=3.66Hz, IH), 6.93-6.82(m, 2H), 4.75(s, 2H), 3.88(s, 3H), 2.28(s, 3H).
Example 144-3: 5-(m-tolyloxymethyι)thiophene-2-carboxylic acid methyl ester (31b) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then m-methylphenol (68.1 mg, 0.63 mmol) was added thereto to obtain the compound 31b (118.2 mg, yield 85%). 1H NMR(300MHz, CDC13) 7.70-7.69(4 J=3.9Hz, IH), 7.07-7.06(4 J=3.66Hz, IH), 6.82-6.76(m, 4H), 4.76(s, 2H), 3.89(s, 3H), 2.33(s, 3H).
Example 144-4: 5-(3-methoxyphenoxymethyϊ)thiophene-2-carboxylic acid methyl ester (31c)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then m- methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 31c (118.0 mg, yield 80%).
1H NMR(300MHz, CDC13) 7.70-7.69(4 J=3.66Hz, IH), 7.25(s, IH), 7.08-7.07(4 J=3.9Hz,lH), 5.20(s, 2H), 3.88(s, 3H), 3.78(s, 3H).
Example 144-5: 5-(4-methoxyphenoxymethyl)thiophene-2-carboxylic acid methyl ester (3 Id)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K CO3 (86.8 mg, 0.63 mmol) and then p-methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 Id (123.9 mg, yield 84%).
1H NMR(300MHz, CDC13) 7.69-7.68(4 J=3.66Hz, IH), 7.05-7.04(4 J=3.9Hz, IH),
6.92-6.89(4 J=9.24Hz, 2H), 6.85-6.82(4 J=9.24Hz, 2H), 5.17(s, 2H), 3.88(s, 3H), 3.77(s, 3H).
Example 144-6: 5-(4-fluorophenoxymethyl)thiophene-2-carboxylic acid methyl ester (31e)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then p-fluorophenol (70.5 mg, 0.63 mmol) was added thereto to obtain the compound 31e (124.1 mg, yield 88%).
1H NMR(300MHz, CDC13) 7.70-7.69(4 J=3.66Hz, IH), 7.06-7.05(4 J=3.66Hz, IH), 7.01-6.88(m, 4H), 5.19(s, 2H), 3.88(s, 3H). Example 144-7: 5-(4-bromophenoxymethyl)thiophene-2-carboxylic acid methyl ester (31f)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then p-bromophenol (142.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 If (118.0 mg, yield 82%).
1H NMR(300MHz, CDC13) 7.70-7.69(4 J=3.9Hz, IH), 7.41-7.38(4 J=9.27Hz, 2H), 7.07-7.06(4 J=3.63Hz, IH), 6.86-6.85(4 J=9.0Hz, 2H), 5.19(s, 2H), 3.88(s, 3H).
Example 144-8: 5-(3,4-dichlorophenoxymethyl)thiophene-2-carboxylic acid methyl ester (31g)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then 3,4-dichlorophenol (102.9 mg, 0.63 mmol) was added thereto to obtain the compound 31g (142.0 mg, yield 85%).
1H NMR(300MHz, CDC13) 7.71-7.69(4 J=3.9Hz, IH), 7.36-7.33(4 J=8.79Hz, IH),
7.08-7.07(4 J=0.99Hz, IH), 7.07-7.06(4 J=2.91Hz, IH), 6.84-6.80(dd, J=2.91Hz, IH),
5.20(s,2H), 3.88(s, 2H).
Example 144-9: 5-(2,5-dimethylphenoxymethyl)thiophene-2-carboxylic acid methyl ester (31h)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then 2,5-dimethylphenol (76.9 mg, 0.63 mmol) was added thereto to obtain the compound 3 lh (127.0 mg, yield 87%).
1H NMR(300MHz, CDC13) 7.71-7.70(4 J=3.9Hz, IH), 7.07-7.03(m, 3H), 6.74-6.70(m, 2H), 3.89(s, 3H), 2.32(s, 3H), 2.23(s, 3H).
Example 144-10: 5-(pentafluorophenoxymethyl)thiophene-2-carboxylic acid methyl ester (31i)
According to the same method as in Example 144-2, anliydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then pentafluorophenol (115.9 mg, 0.63 mmol) was added thereto to obtain the compound 31i (143.4 mg, yield 80%).
1H NMR(300MHz, CDC13) 7.69-7.67(4 J=3.9Hz, IH), 7.08-7.07(4 J=2.67Hz, IH), 5.34(s, 2H), 3.89(s, 3H).
Example 144-11: 5-(3,4-difluorophenoxymethyϊ)thiophene-2-carboxylic acid methyl ester (31j)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then 3,4-difluorophenol (81.9 mg, 0.63 mmol) was added thereto to obtain the compound 3 lj (124.9 mg, yield 83%).
1H NMR(300MHz, CDC13) 7.70-7.69(4 J=3.9Hz, IH), 7.12-7.03(m. 2H), 6.81- 6.75(ddd, J=3.28Hz, IH), 6.72-6.64(m. IH), 5.17(s, 2H), 3.88(s, 3H).
Example 144-12: 5-(4-trifluoromethanephenoxymethyl)thiophene-2-carboxylic acid methyl ester (31k)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then p-trifluoromethanephenol (102.2 mg, 0.63 mmol) was added thereto to obtain the compound 31 k ( 134 mg, yield 81%).
1H NMR(300MHz, CDC13) 7.71-7.70(4 J=3.66Hz, IH), 7.58-7.55(4 J=8.28Hz, 2H), 7.10-7.08(4 J=3.9Hz, IH), 7.04-7.02(4 J=8.52Hz, 2H), 5.27(s, 2H), 3.89(s, 3H).
Example 144-13: 5-(4-t-butylphenoxymethyl)thiophene-2-carboxylic acid methyl ester (311)
According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then 4-t-butyl-phenol (94.6 mg, 0.63 mmol) was added thereto to obtain the compound 31k (134.7 mg, yield 88%). 1H NMR(300MHz, CDCl3)7.71-7.70(d, J=3.66Hz, IH), 7.24-7.21(4 J=8.04Hz, IH), 7.09-7.00(m, 4H), 6.79-6.76(ddd, J=0.99Hz, IH), 5.22(s, 2H), 3.88(s, 3H), 1.31(s, 9H).
Example 144-14: 5-(2-chloro-4-methoxyphenoxymethyl)thiophene-2-carboxylic acid methyl ester (31m) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol) and then 2-chloro-4-methoxyphenol (92.2 mg, 0.63 mmol) was added thereto to obtain the compound 31m (148 mg, yield 90%>). 1H NMR(300MHz, CDC13) 7.70-7.68(4 J=3.66Hz, IH), 7.07-7.06(4 J=3.9Hz, IH), 6.96-6.95(4 J=2.91Hz, IH), 6.93-6.90(4 J=8.78Hz, IH), 6.75-6.71(dd, J=2.91Hz, IH), 5.22(s, 2H), 3.88(s, 3H), 3.77(s, 3H).
Example 144: 5-(o-tolyloxymethyl)thiophene-carbaIdehyde (33a) The compound 31a (100 mg, 0.38 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 °C and DIBA1-H (1.0 M solution in toluene, 0.4 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 °C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dicliloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue. The residue was dried under vacuum, crude compound was dissolved in acetone (50 ml) without the more separation process and an oxidation was conducted with an excess of MnO2. After the completion of the reaction, the resultant was filtered under reduced pressure with Celite545 and the filtrate was dried under reduced pressure to obtain residue. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate=5:l) to obtain the final compound (51.2 mg, yield of two steps: 58%).
1H NMR(300MHz, CDC13) 9.88(s, IH), 7.68-7.67(4 J=3.9Hz, IH), 6.93-6.88(t, J=7.8Hz, IH), 6.85-6.83(4 J=8.04Hz, IH), 5.26(s, 2H), 2.27(s, 3H).
13C NMR(300MHz, CDC13) 182.53, 162.53, 141.93, 140.20, 137.67, 129.89, 125.97,
111.79, 69.49, 16.1.
IR 2923.56, 1666.20, 1590.02, 1494.56, 1461.78, 1372.10, 1240.44, 1050.05, 810.92,
751.14, 438.73.cm"1 Example 145: 5-(m-tolyloxymethyϊ)thiophene-2-carbaldehyde (33b)
According to the same method as in Example 144, the compound 31b (100 mg,
0.38 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (44.1 mg, yield of two steps: 50%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.67-7.66(4 J=3.9Hz, IH), 7.21-7.14(m, 2H), 6.82-6.74(m, 3H), 5.23(s, 2H), 2.32(s, 3H).
13C NMR(300MHz, CDC13) 182.53, 161.85, 141.92, 140.20, 139.78, 127.74, 126.45,
121.46, 116.07, 69.09, 21.31.
IR 2921.63, 1667.16, 1588.09, 1489.74, 1463.71, 1374.03, 1258.32, 1157.08, 1043.30,
812.85, 776.21, 688.46, 431.01.cm"1
Example 146: 5-(m-methoxyphenoxymethyl)thiophene-2-carbaldehyde (33c)
According to the same method as. in Example 144, the compound 31c (100 mg,
0.36 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (49.0 mg, yield of two steps: 55%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.67-7.65(4 J=3.9Hz, IH), 7.18-7.17(4
J=1.71Hz, IH), 7.16-7.15(4 JM2.43Hz, IH), 6.56-6.55(4 J=2.46Hz, IH), 6.53-6.50(dd, J=2.19Hz, 2H), 5.23(s, 2H), 3.77(s, 3H).
13C NMR(300MHz, CDC13) 182.53, 166.25, 158.65, 141.92, 140.20, 137.67, 126.45, 121.70, 107.91, 106.35, 101.42, 69.09, 55.20.
IR 2834.85, 1667.16, 1597.73, 1491.67, 1464.67, 1374.03, 1285.32, 1200.47, 1150.33, 1046.19, 814.78, 763.67, 684.61, 414.62.cm"1
Example 147: 5-(m-methoxyphenoxymethyl)thiophene-2-carbaldehyde (33d)
According to the same method as in Example 144, the compound 3 Id (100 mg,
0.36 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (44.5 mg, yield of two steps: 50%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.67-7.66(4 J=3.66Hz, IH), 7.03-7.02(dd, J=0.51Hz, IH), 6.90-6.87(dd, J=2.43Hz, 2H), 6.83-6.80(dd, J=2.76Hz, 2H), 5.15(s, 2H),
3.75(s, 3H).
13C NMR(300MHz, CDC13) 182.53, 157.46, 154.80, 141.92, 140.20, 137.67, 126.45,
115.72, 69.90, 55.65.
IR 1715.37, 1540.84, 1509.03, 1454.06, 1377.89, 1335.06, 1272.79, 1236.15, 1095.37, 1031.73, 824.42, 747.28, 437.76.cm"1
Example 148: 5-(4-fluorophenoxymethyι)thiophene-2-carbaldehyde (33e)
According to the same method as in Example 144, the compound 31e (100 mg, 0.37 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (50.5 mg, yield of two steps: 57%). 1H NMR(300MHz, CDC13) 9.95(s, IH), 7.75-7.34(4 J=4.08Hz, IH), 7.27-7.23(dd, J=0.72Hz, IH), 7.08-7.02(dd, J=9.27Hz, 2H), 6.98-6.94(dd, J=4.38Hz, 2H), 5.29(s, 2H). 13C NMR(300MHz, CDC13) 182.53, 160.19, 160.00, 159.93, 153.69, 141.92, 140.20, 137.67, 126.45, 117.58, 117.41, 115.93, 115.22, 69.09.
IR 2922.59, 2862.81, 1653.66, 1503.24, 1382.71, 1205.29, 1094.40, 1050.05, 1022.09, 841.78, 810.92, 784.89, 647.00, 522.61.cm"1
Example 149: 5-(4-bromophenoxymethyl)thiophene-2-carbaldehyde (33f)
According to the same method as in Example 144, the compound 3 If (100 mg,
0.31 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO2 to obtain the final compound (53.5 mg, yield of two steps: 59%). lH NMR(300MHz, CDC13) 9.95(s, IH), 7.75-7.34(4 J=4.08Hz, IH), 7.27-7.23(dd, J=0.72Hz, IH), 7.08-7.02(dd, J=9.27Hz, 2H), 6.98-6.94(dd, J=4.38Hz, 2H), 5.29(s, 2H).
13C NMRβOOMHz, CDC13) 182.53, 160.47, 141.92, 140.20, 132.57, 126.45, 119.07,
113.05, 69.05.
IR 2924.52, 2853.17, 1714.41, 1583.27, 1485.88, 1377.89, 1287.25, 1234.22, 1096.33,
1005.70, 821.53, 750.17, 409.80.cm"1 Example 150: 5-(3,4-dichlorophenoxymethyϊ)thiophene-2-carbaldehyde (33g)
According to the same method as in Example 144, the compound 31g (100 mg,
0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO to obtain the final compound (55.2 mg, yield of two steps: 61%).
1H NMR(300MHz, CDC13) 9.82(s, IH), 7.62-7.61(4 J=3.66Hz, IH), 7.29-7.26(4 J=9.03Hz, IH), 7.12-7.02(4 J=7.56Hz, IH), 7.00-6.99(4 J=2.46Hz, IH), 6.77-6.73(dd,
J=2.7Hz, lH), 5.16(s, 2H).
13C NMR(300MHz, CDC13) 182.53, 161.47, 141.92, 140.20, 137.16, 130.16, 130.04,
126.45, 125.92, 116.51, 114.59, 69.09.
IR 1663.30, 1590.99, 1473.35, 1377.89, 1283.39, 1226.50, 1123.33, 1027.87, 853.35, 808.50, 409.80.cm"1
Example 151: 5-(2,5-dimethylphenoxymethyl)thiophene-2-carbaldehyde (33h)
According to the same method as in Example 144, the compound 31h (100 mg, 0.36 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (56.1 mg, yield of two steps: 63%). 1H NMR(300MHz, CDC13) 9.86(s, IH), 7.68-7.67(4 J=3.9Hz, IH), 7.16-7.15(4 J=3.66Hz, IH), 7.05-7.02(4 J=7.56Hz, IH), 6.73-6.70(4 J=7.56Hz, IH), 6.67(s, IH), 5.24(s, 2H), 2.30(s, 3H), 2.22(s, 3H).
13C NMR(300MHz, CDC13) 182.53, 161.47, 141.92, 140.20, 137.67, 128.89, 126.65, 116.49, 69.49, 21.41, 15.97. IR 2921.63, 1666.20, 1584.24, 1508.06, 1467.56, 1373.07, 1261.22, 1226.50, 1155.15, 1129.12, 1033.66, 808.03.cm"1
Example 152: 5-(pentafluorophenoxymethyϊ)thiophene-2-carbaldehyde (33i)
According to the same method as in Example 144, the compound 3 li (100 mg, 0.29 mmol) of the reaction scheme 7 was dissolved in anliydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.3 ml) and oxidation was carried out with MnO to obtain the final compound (48.2 mg, yield of two steps: 53%). 1H NMR(300MHz, CDC13) 9.86(s, IH), 7.65-7.63(4 J=5.37Hz, IH), 7.06-7.05(4
J=3.66Hz, IH), 5.31(s, 2H).
13C NMR(300MHz, CDC13) 182.53, 146.10, 146.03, 145.93, 141.92, 140.20, 138.72,
136.67, 132.43, 119.40, 72.79.
IR 2956.34, 1717.30, 1515.77, 1467.56, 1376.93, 1290.14, 1187.94, 1097.30, 1026.91, 999.91, 824.42, 751.14.cm"1
Example 153: 5-(3,4-difluorophenoxymethyf)thiophene-2-carbaldehyde (33j)
According to the same method as in Example 144, the compound 31 j (100 mg, 0.35 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (43.8 mg, yield of two steps: 49%). 1H NMR(300MHz, CDC13) 9.87(s, IH), 7.67-7.66(4 J=3.9Hz, IH), 7.17-7.15(dd, J=0.72Hz, IH), 7.11-7.02(q, J=9.27Hz, IH), 6.81-6.74(ddd, J=2.91Hz, IH), 6.68- 6.63(ddd, J=1.95Hz, IH), 5.19(s, 2H).
13C NMR(300MHz, CDC13) 182.53, 161.60, 156.90, 150.40, 141.92, 140.20, 137.67, 126.45, 115.85, 119.95, 69.09. IR 2923.56, 1673.91, 1513.85, 1463.71, 1376.93, 1261.22, 1209.15, 1158.04, 1113.69, 1021.12, 785.85, 672.07.cm"1
Example 154: 5-(4-trifluoromethanephenoxymethyl)thiophene-2-carbaldehyde (33k) According to the same method as in Example 144, the compound 31k (100 mg,
0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO to obtain the final compound (42.5 mg, yield of two steps: 47%).
1H NMR(300MHz, CDC13) 9.83(s, IH), 7.63-7.61(4 J=3.9Hz, IH), 7.51-7.48(4 J=8.55Hz, 2H), 7.14-7.13(4 J=3.9Hz, IH), 6.98-6.95(4 J=8.76Hz, 2H), 4.99(s, 2H). 13C NMR(300MHz, CDC13) 182.53, 167.41, 141.92, 140.20, 137.67, 134.70, 127.56, 126.00, 125.46, 124.25, 117.51, 113.3, 69.09. IR 2924.52, 1671.02, 1651.09, 1571.70, 1464.67, 1376.93, 1328.71, 1252.54, 1161.90, 1113.69, 1068.37, 1010.52, 836.95, 674.00, 606.50.cm"1
Example 155: 5-(t-butylphenoxymethyl)thiophene-2-carbaldehyde (331) According to the same method as in Example 144, the compound 311 (100 mg,
0.35 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO2 to obtain the final compound (48.3 mg, yield of two steps: 51%).
1H NMR(300MHz, CDC13) 9.87(s, IH), 7.67-7.66(4 J=3.66Hz, IH), 7.22-7.16(m, 2H),
7.03-6.98(m, 2H), 6.77-6.73(dd, J=2.43Hz, IH), 5.24(s, 2H).
13C NMR(300MHz, CDC13) 182.53, 161.65, 146.14, 137.67, 126.45, 125.40, 114.87,
69.09, 34.10, 32.26. IR 2961.16, 1671.02, 1580.38, 1464.67, 1370.18, 1272.79, 1219.76, 1038.48, 810.92, 775.24, 700.03.cm"1
Example 156: 5-(2-chloro-4-methoxyphenoxymethyl)thiophene-2-carbaldehyde
(33m) According to the same method as in Example 144, the compound 3 lm (100 mg,
0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO2 to obtain the final compound (51.4 mg, yield of two steps: 57%).
1H NMR(300MHz, CDC13) 9.70(s, IH), 7.46-7.45(4 J=3.5Hz, IH), 6.92-6.91(4 J-3.5Hz, IH), 6.8(s, IH), 6.71-6.70(m, 2H), 4.99(s, 2H), 3.75(s, 3H). 13C NMR(300MHz, CDC13) 182.53, 153.91, 141.92, 140.20, 137.67, 126.42, 123.41, 115.41, 114.09, 112.88, 69.29, 55.70.
Example 157-1: 5-(o-tolylsulfanylmethyf)thiophene-2-carboxylic acid methyl ester (34a)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K CO3 (86.8 mg, 0.63 mmol), and o-methylbenzenethiol (78.2 mg, 0.63 mmol) was added thereto, followed by stirring at room temperature. After confirming the completion of the reaction using TLC, DMF was removed under vacuum decompression to obtain residue. H O (10 ml) was added to the residue and then an extraction process was conducted with methylene chloride (10 ml 2). The obtained organic solution was washed with brine (20ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 9:1) to obtain the compound 34a (102.1 mg, yield 70%).
1H NMR(300MHz, CDC13) 7.58-7.57(4 J=3.9Hz, IH), 7.19-7.11(m, 4H), 6.83-6.82(4 J=3.9Hz, IH), 4.23(s, 2H), 3.86(s, 3H), 2.36(s, 3H).
Example 157-2: 5-(m-tolylsulfanylmethyl)thiophene-2-carboxylic acid methyl ester (34b)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and m-methylbenzenethiol (78.2 mg, 0.63 mmol) was added thereto. According to the same method as in Example 157-1, the compound 34b (94.8 mg, yield 65%) was obtained.
1H NMR(300MHz, CDC13) 7.59-7.58(4 J=3.9Hz, 7.19-7.12(m, 2H), 7.04-7.02(m, IH), 6.85-6.84(4 J=3.66Hz, IH), 4.25(s, 2H), 3.85(s, 3H), 2.3 l(s, 3H).
Example 157-3: 5-(p-tolylsulfanylmethyl)thiophene-2-carboxylic acid methyl ester (34c)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and p-methylbenzenethiol (78.2 mg, 0.63 mmol) was added thereto. According to the same method as in Example 157-1, the compound 34c (105 mg, yield 75%) was obtained.
1H NMR(300MHz, CDCI3) 7.57-7.56(4 J=3.66Hz, IH), 7.25-7.23(4 J-8.04Hz, 2H),
7.09-7.07(4 J=8.04Hz, 2H), 6.80-6.79(4 J=3.66Hz, IH), 4.21(s, 2H), 3.86(s, 3H), 2.32(s, 3H).
Example 157-4: 5-(4-fluorophenylsulfanylmethyϊ)thiophene-2-carboxylic acid methyl ester (34d)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and 4-fluorobenzenethiol (80.6 mg, 0.63 mmol) was added thereto. According to the same method as in Example 157-1, the compound 34d (106.1 mg, yield 71%) was obtained.
1H NMR(300MHz, CDC13) 7.57-7.55(4 J=3.66Hz, IH), 7.36-7.29(dd, J=5.13Hz, 2H), 7.00-6.93(dd, J=8.55Hz, 2H), 6.76-6.75(4 J=3.66Hz, IH), 4.26(s, 2H), 3.86(s, 3H). Example 157-5: 5-(4-chlorophenylsulfanylmethyl)thiophene-2-carboxylic acid methyl ester (34e)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and 4-chlorobenzenethiol (90.7 mg, 0.63 mmol) was added thereto. According to the same method as in Example 157-1, the compound 34e (121.6 mg, yield 77%) was obtained. lH NMR(300MHz, CDC13) 7.58-7.59(4 J=3.66Hz, IH), 7.25(s, 4H), 6.82-6.81(4 J-3.9Hz, IH), 4.23(s, 2H), 3.86(s. 3H).
Example 157-6: 5-(4-bromophenylsulfanylmethyl)thiophene-2-carboxylic acid methyl ester (34f)
Anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K2CO3 (86.8 mg, 0.63 mmol), and 4-bromobenzenethiol (118.4 mg, 0.63 mmol) was added thereto. According to the same method as in Example 157-1, the compound 34f (118.2 mg, yield 65%) was obtained.
1H NMR(300MHz, CDC13) 7.58-7.57(4 J=3.9Hz, IH), 7.40-7.37(dd, J=1.95Hz, 2H), 7.19-7.16(dd, J=1.95Hz, 2H), 6.83-6.82(4 J=3.9Hz, IH), 4.23(s, 2H), 3.85(s, 3H).
Example 157: 5-(o-methylphenylsulfanylmethyl)thiophene-2-carbaldehyde (36a)
The compound 34a (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 °C and DIBAl-H (1.0M solution in toluene, 0.35 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 °C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue. The residue was dried under vacuum, the obtained crude compound was dissolved in acetone (50 ml) without the more separation process and an oxidation was conducted with an excess of MnO2. After the completion of the reaction, the resultant was filtered under reduced pressure with Celite545 and the filtrate was dried under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate=5:l) to obtain the final compound (41.3 mg, yield of two steps: 52%).
1H NMR(300MHz, CDC13) 9.95(s, IH), 7.53-7.52(4 J=3.9Hz, IH), 7.24-7.22(dd, J=2.67Hz, IH), 7.17-7.06(m, 3H), 6.92-6.91(4 J=3.66Hz, IH), 4.22(s, 2H), 2.34(s, 3H). 13C NMR(300MHz, CDC13) 182.70, 152.60, 148.10, 139.21, 136.44, 133.44, 130.30, 127.30, 120.21, 126.54, 33.37, 20.35. IR 3445.21, 1667.16, 1455.03, 1220.72, 1044.26, 744.39, 577.58, 444.51.cm"1
Example 158: 5-(m-methylphenylsulfanylmethyl)thiophene-2-carbaldehyde (36b)
According to the same method as in Example 157, the compound 34b (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO to obtain the final compound (42.1 mg, yield of two steps: 53%). 1H NMR(300MHz, CDC13) 9.86(s, IH), 7.54-7.53(4 J=3.9Hz, IH), 7.15-7.13(m, 3H), 7.03-7.01(m, IH), 6.94-6.93(4 J=3.9Hz, IH), 4.26(s, 2H), 2.28(s, 3H).
13C NMR(300MHz, CDC13) 182.60, 152.70, 139.31, 134.6, 134.10, 132.90, 131.81,
129.40, 127.74
IR 3444.24, 1661.37, 1455.03, 1038.48, 670.14, 456.08., 127.30, 34.25, 28.25. cm"1
Example 159: 5-(p-methylphenylsulfanylmethyl)thiophene-2-carbaldehyde (36c)
According to the same method as in Example 157, the compound 34c (90 mg,
0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO2 to obtain the final compound (48.5 mg, yield of two steps: 61%).
1H NMR(300MHz, CDC13) 9.85(s, IH), 7.83-7.82(4 J=3.66Hz, IH), 7.26-7.24(4
J=8.16Hz, 2H), 7.10-7.01(4 J=8.04Hz, 2H), 6.93-6.92(4 J=3.66Hz, IH), 4.23(s, 2H), 3.23(s, 3H).
13C NMR(300MHz, CDC13) 182.76, 152.97, 142.73, 137.21, 136.47, 131.71, 130.51,
129.86, 127.26, 34.95, 21.08.
IR 3445.21, 1660.41, 1455.03, 1219.76, 1040.41, 802.24, 445.48.cm"1
Example 160: 5-(4-fluorophenylsulfanylmethyl)thiophene-2-carbaldehyde (36d)
According to the same method as in Example 157, the compound 34d (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO2 to obtain the final compound (53.2 mg, yield of two steps: 66%).
1H NMR(300MHz, CDC13) 9.76(s, IH), 7.58-7.53(4 J=3.66Hz, IH), 7.34-7.29(m, 2H), 6.98-6.93(m, 2H), 6.85-6.84(4 J=3.66Hz, IH), 4.26(s, 2H). 13C NMR(300MHz, CDC13) 186.02, 164.88, 158.38, 142.45, 135.31, 132.91, 129.75, 115.94, 41.76.
Example 161: 5-(4-bromophenylsuIfanylmethyϊ)thiophene-2-carbaIdehyde (36e)
According to the same method as in Example 157, the compound 34e (90 mg, 0.30 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO2 to obtain the final compound (44.5 mg, yield of two steps: 53%). 1H NMRβOOMHz, CDC13) 9.79(s, IH), 7.54-7.53(4 J=3.66Hz, IH), 7.20(s, 4H), 6.91-
6.90(d, J=3.66Hz, IH), 4.28(s, 2H).
13C NMR(300MHz, CDC13) 182.74, 143.10, 136.21, 134.9, 132.9, 132.47, 129.27,
127.45, 34.57.
IR 3444.24, 1661.37, 1558.20, 1474.31, 1455.99, 1094.40, 809.96, 465.72, 401.12.cm"1
Example 162: 5-(4-chIorophenyIsulfanylmethyϊ)thiophene-2-carbaldehyde (36f)
According to the same method as in Example 157, the compound 34f (90 mg,
0.26 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 °C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.3 ml) and oxidation was carried out with MnO2 to obtain the final compound (43.5 mg, yield of two steps: 53%).
1H NMR(300MHz, CDC13) 9.82(s, IH), 7.54-7.53(4 J=3.9Hz, IH), 7.39-7.36(4 J=8.28Hz, 2H), 7.21-7.16(4 J=8.29Hz, 2H), 6.92-6.91(4 J=3.9Hz, IH), 4.27(s, 2H). 13C NMR(300MHz, CDC13) 186.02, 142.45, 137.19, 132.91, 131.93, 130.96, 130.53, 118.76, 41.76.
Example 163: 6-hydroxymethylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (40)
The compound 39 (300 mg, 0.75 mmol) and p-toluenesulfonic acid (28 mg,
0.15 mmol) were dissolved in methanol (5ml), followed by stirring at room temperature.
After 30 min, the reaction solution was concentrated under reduced pressure, followed dissolving with ethyl acetate. The resultant was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO ), followed by purification under separation by flash chromatography (hexane: ethyl acetate= 3:1) to obtain the desirable compound
(170 mg, 72%) as a white solid.
1H NMR (300 MHz, CDC13) δ 7.91-7.84 (m, 2H), 7.60 (s, IH), 7.56-7.50 (m, 2H),
7.33 (dd, J=2.0Hz, 8.2Hz, IH), 4.88 (s, 2H) 13C NMR (125 MHz, CDC13) δ 190.82, 159.82, 150.21, 138.35, 136.51, 134.25,
134.23, 133.31, 131.12, 128.48, 125.49, 119.73, 64.20
IR(neat) : 3738, 1688, 1543, 1454, 1365, 1207, 1067, 945, 811, 615 cm"1
LRMS(EI):me313(M+)
HRMS (EI) : calcd. for C13H9Cl2NO2S, 312.9731; found, 312.9738 mp : 126 °C
Example 164: 6-acetoxymethylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (41) The compound 40 (8.4 mg, 0.027 mmol) was dissolved in pyridine (0.5 ml) and acetic anhydride (25 μ 1, 0.27 mmol) was added thereto, followed by stirring at room temperature. After 8 hours, water was added to the reaction solution and then an extraction process was conducted with ethyl acetate. The obtained organic solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4), followed by purification under separation by flash chromatography (hexane: ethyl acetate= 3:1) to obtain the desirable compound (7.4 mg, 78%) as a white solid. 1H NMR (300 MHz, CDC13) δ 7.87 (d, J=6.8Hz, 2H), 7.60-7.59 (m, 2H), 7.50 (d, J=8.4Hz, IH), 7.32 (dd, J-1.9Hz, 8.3Hz, IH), 5.34 (s, 2H), 2.21 (s, 3H) 13C NMR (125 MHz, CDC13) δ 191.15, 170.76, 156.29, 150.84, 138.42, 136.58, 134.31, 134.21, 133.30, 131.13, 128.79, 126.28, 120.02, 66.11, 21.13
IR(neat) : 1746, 1692, 1541, 1456, 1370, 1223, 1035, 947, 814, 615 cm"1
LRMS (EI) : m/e 355 (M+)
HRMS (EI) : calcd. for C15HnCl2NO3S, 354.9837; found, 354.9842 mp : 116~117°C
Example 165: pyridine-2-carbothionic acid-S-(3,4-dichlorophenyl)ester (43)
According to the same method as in the synthesis method of the compound 39, the desirable compound (46 mg, 20%) as a white solid was obtaind from the compound 42 (100 mg, 0.81 mmol). 1H NMR (300 MHz, CDC13) δ 8.74-8.72 (m, IH), 7.96-7.85 (m, 2H), 7.61 (d, J=1.8Hz, IH), 7.58-7.44 (m, IH), 7.51 (d, J=8.3Hz, IH), 7.34 (dd, J=2.0Hz, 8.3Hz, IH)
13C NMR (125 MHz, CDCI3) δ 191.25, 151.30, 149.46, 137.73, 136.59, 134.32, 134.24, 133.31, 131.14, 128.67, 121.14, 104.82
IR (neat) : 1684, 1431, 1366, 1265, 1219, 1025, 911, 824, 707 cm"1 LRMS (EI) : m/e 283 (M ) mp : 160 °C
Example 166: 6-methoxycarbonylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (44)
2.0 M solution (0.62 ml, 1.23 mmol) of trimethylaluminum in heptane and 3,4-dichlorobenzenethiol (0.13 ml, 1.03 mmol) were added to dichloromethane (7 ml) at 0°C, followed by stirring at 0°C for 15 min. The compound 2 (400 mg, 2.05 mmol), which was dissolved in dichloromethane (3 ml), was added thereto and the temperature was warmed up to room temperature, followed by stirring. After 1 hour, the reaction solution was diluted with ether and lN-hydrochloric acid (1N-HC1) was added dropwise thereto to form the precipitate. The precipitate was filtered. The filtrate was washed with 5% sodium hydroxide (5% NaOH) solution, saturated-ammonium chloride (sat- NH CI), water and brine, and dried with anhydrous magnesium sulfate (MgSO ), followed by purification with flash chromatography (hexane: ethyl acetate= 5:1) to obtain the desirable compound (174 mg, 50%) as a white solid.
1H NMR (300 MHz, CDC13) δ 8.36 (d, J=7.3Hz, IH), 8.11-8.01 (m, 2H), 7.61 (d, J=2.0Hz, IH), 7.52 (d, J=8.4Hz, IH), 7.34 (dd, J=2.0Hz, 8.3Hz, IH), 4.06 (s, 3H) 13C NMR (125 MHz, CDC13) δ 190.75, 164.76, 151.32, 147.97, 138.98, 136.49, 134.38, 134.19, 133.36, 131.18, 129.53, 128.26, 123.78, 53.45 IR (neat) : 1727, 1691, 1456, 1321, 1218, 1140, 934, 838, 771, 742, 615 cm"1 LRMS (EI) : m/e 341 (M+) HRMS (EI) : calcd. for C14H9Cl2NO3S, 340.9680; found, 340.9685 mp : 138-139 °C
Example 167: 6-dimethoxymethylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (45) According to the same method as in the synthesis method of the compound 44, the white solid of 64 mg (yield 23%) was obtaind from the compound 8 (165 mg, 0.782 mmol) and the compound 8 (37 mg) was recovered, (recovery yield 45%) 1H NMR (300 MHz, CDC13) δ 7.91-7.85 (m, 2H), 7.82-7.79 (m, IH), 7.60 (d, J=2.0Hz, IH), 7.50 (d, J=8.2Hz, IH), 7.33 (dd, J=2.0Hz, 8.2Hz, IH), 5.42 (s, IH), 3.49 (s, 6H)
IR (neat) : 2936, 1688, 1588, 1455, 1208, 1114, 1066, 994, 876, 815, 616 cm"1
LRMS (EI) : m/e 357 (M+)
HRMS (EI) : calcd. for Cι5Hι3Cl2NO3S, 356.9993; found, 356.9996 mp : 120 °C
Example 168: 6-hydroxypyridine-2-carbothionic acid-S-3,4-(dichlorophenyl)ester
(50)
The compound 49 (205 mg, 0.495 mmol) and p-toluenesulfonic acid (9.44 mg, 0.05 mmol) were dissolved in methanol (5ml), followed by stirring at room temperature. After 10 min, the reaction solution was concentrated under reduced pressure, followed dissolving with ethyl acetate. The resultant was washed with water and brine, and dried with anliydrous magnesium sulfate (MgSO4) to obtain the desirable compound (90 mg, 64%>) as a white solid. 1H NMR (300 MHz, CDC13) δ 7.58-7.52 (m, 3H), 7.30 (dd, J=2.1Hz, 8.3Hz, IH), 7.16 (d, J=7.1Hz, IH), 6.89 (d, J=9.2Hz, IH)
13C NMR (125 MHz, CDC13) δ 184.52, 161.91, 139.87, 139.74, 136.58, 135.45, 134.27, 133.86, 131.55, 126.73, 125.09, 109.96 IR (neat) : 3739, 1648, 1603, 1542, 1456, 1196, 1032, 973, 815 cm"1 LRMS (EI) : m/e 299 (M+)
HRMS (EI) : calcd. for C12H7Cl2NO2S, 298.9575; found, 298.9574 mp : 181-182 °C
Example 169: 6-methoxypyridine-2-carbothionic acid-S-(3,4-dichlorophenyl)ester (51)
The compound 50 (15.7 mg, 0.055 mmol) was dissolved in benzene (0.5 ml) and methanol (0.5 ml), and 2.0M solution (0.14 ml, 0.28 mmol) of TMS-diazomethane in hexane was added thereto, followed by stirring at 0°C. After 30 min, acetic acid was added to the reaction solution to stop the reaction. The resultant was concentrated under reduced pressure, followed by diluting with ethyl acetate. The resultant was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4) to obtain the desirable compound (15.6 mg, 90%) as a white solid.
1H NMR (300 MHz, CDCI3) δ 7.74-7.69 (m, IH), 7.59 (d, J=2.0Hz, IH), 7.54-7.49 (m, 2H), 7.32 (dd, J=2.0Hz, 8.3Hz, IH), 7.00 (dd, J=0.8Hz, 8.3Hz, IH), 4.06 (s, 3H) 13C NMR (125 MHz, CDC13) δ 191.03, 163.68, 148.56, 139.73, 136.56, 134.27, 134.07, 133.26, 131.08, 129.16, 117.08, 114.23, 54.23
IR (neat) : 2924, 1692, 1596, 1471, 1277, 1218, 1031, 963, 847, 811, 616 cm"1 LRMS (EI) : m e 313 (M+) HRMS (EI) : calcd. for C13H9Cl2NO2S, 312.9731 ; found, 312.9732 mp : 122-124 °C
Example 170: 6-(methylcarbonate)pyridine-2-carbothionic acid-S-(3,4- dichlorophenyϊ)ester (52) The compound 50 (20 mg, 0.07 mmol) was dissolved in dichloromethane (0.7 ml), and triethylamine (13 μ 1, 0.09mmol) was added thereto. Methyl chloroformate (6.5 μ 1, 0.08 mmol) was added thereto at 0°C, followed by stirring at 0°C. After 1 hour, the reaction solution was diluted with ethyl acetate. The diluted solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO ). The resultant was subjedcted to flash chromatography (100%) hexane) to obtain the desirable compound (2 mg, 8%o) as a white solid.
1H NMR (300 MHz, CDC13) δ 7.57 (d, J=2.0Hz, IH), 7.41 (d, J=8.3Hz, IH), 7.31-7.27 (m, IH), 7.19 (s, 3H), 3.80 (s, 3H)
Example 171: 6-(p-toluenesulfonylpyridine)-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (53)
The compound 50 (23 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 ml), and triethylamine (17 μ 1, 0.12 mmol) was added thereto, p-toluenesulfonyl chloride (18.5 mg, 0.10 mmol) was added thereto at 0°C, followed by stirring at 0°C. After 1 hour, the reaction solution was diluted with ethyl acetate. The diluted solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4). The resultant was subjedcted to flash chromatography (hexane : ethyl acetate = 5 : 1) to obtain the desirable compound (14 mg, 38%>) as a white solid. 1H NMR (300 MHz, CDC13) δ 8.03 (d, J=8.4Hz, 2H), 7.95 (t, J=7.8Hz, IH), 7.83 (dd, J=0.9Hz, 7.5Hz, IH), 7.53-7.50 (m, 2H), 7.40-7.36 (m, 3H), 7.27 (dd, J=2.0Hz, 8.4Hz, IH), 2.44 (s, 3H)
13C NMR (75 MHz, CDC13) δ 189.58, 156.34, 149.57, 145.59, 141.60, 136.23, 134.28, 133.91, 133.59, 133.23, 131.03, 129.86, 128.84, 127.85, 120.95, 119.36, 21.77 IR (neat) : 3745, 1687, 1444, 1376, 1178, 1092, 980, 866, 818, 764 cm"1 LRMS (EI) : m/e 453 (M+)
HRMS (EI) : calcd. for C19H13Cl2NO4S2, 452.9663; found, 452.9666 mp : 120 °C
Example 172: 6-acetoxypyridine-2-carbothionic acid-S-(3,4-dichlorophenyl)ester (54)
The compound 50 (16 mg, 0.06 mmol) was dissolved in pyridine (0.6 ml), and acetic anhydride (53 μ 1, 0.56 mmol) was added thereto, followed by stirring at room temperature. After 5 hours, the reaction solution was diluted with ethyl acetate. The • diluted solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4). The resultant was subjected to flash chromatography (hexane : ethyl acetate = 3 : 1) to obtain the desirable compound (13 mg, 67%>) as a white solid. 1H NMR (300 MHz, CDC13) δ 7.97 (t, J=7.8Hz, IH), 7.88-7.86 (m, IH), 7.59 (d, J=2.0Hz, IH), 7.51 (d, J=8.3Hz, IH), 7.38-7.35 (m, IH), 7.31 (dd, J=2.0Hz, 8.4Hz, IH), 2.40 (s, 3H)
13C NMR (125 MHz, CDC13) δ 190.12, 168.81, 157.19, 150.38, 141.02, 136.53, 134.39, 134.23, 133.39, 131.19, 128.21, 122.03, 119.25, 21.49 IR (neat) : 3736, 1769, 1685, 1649, 1540, 1455, 1368, 1184, 898, 781, 615 cm"1 LRMS (EI) : m/e 341 (M+)
HRMS (EI) : calcd. for C14H9Cl2NO3S, 340.9680; found, 340.9676 mp : 132°C
Example 173: 6-(methanesulfonyl)pyridine-2-carbothionic acid-S-(3,4- dichlorophenyϊ)ester (55)
The compound 50 (22 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 ml), and triethylamine (16 μ 1, 0.10 mmol) was added thereto. Methanesulfonyl chloride (9 μ 1, 0.09mmol) was added thereto at 0°C, followed by stirring at 0°C. After
1 hour, the reaction solution was diluted with ethyl acetate. The diluted solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4).
The resultant was subjedcted to flash chromatography (hexane : ethyl acetate = 3 : 1) to obtain the desirable compound (18 mg, 61%) as a white solid.
1H NMR (300 MHz, CDC13) δ 8.02 (t, J=7.8Hz, IH), 7.91 (dd, J=0.9Hz, 7.5Hz, IH),
7.58 (d, J-2.0Hz, IH), 7.52 (d, J=8.3Hz, IH), 7.37 (dd, J=0.9Hz, 7.9Hz, IH), 7.31 (dd, J=2.1Hz, 8.3Hz, IH), 3.71 (s, 3H)
13C NMR (75 MHz, CDC13) δ 189.04, 156.74, 149.27, 142.15, 136.30, 134.48,
133.99, 133.32, 131.09, 127.26, 120.56, 119.46, 41.18
IR (neat) : 1689, 1577, 1444, 1372, 1214, 1175, 1034, 984, 866, 797, 740 cm"1
LRMS (EI) : m/e 377 (M+) HRMS (EI) : calcd. for C13H9Cl2NO4S2, 376.9350; found, 376.9354 mp : 112-113 °C
Example 174: 6-(hydroxycarbonyl)pyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (56)
The compound 6j (14 mg, 0.045 mmol), sodium chlorite (8.2 mg, 0.072 mmol) and sulfamic acid (11.2 mg, 0.13 mmol) were added to the mixture solution of acetone (1 ml) and water (1 ml), followed by stirring at room temperature. After 12 hours, acetone was removed under reduced pressure and then an extracting process was conducted with ethyl acetate. The obtained organic solution was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4) to obtain the desirable compound (12.6 mg, 85%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J=6.6Hz, IH), 8.25 (t, J=7.68, IH), 8.12 (d, J=6.4Hz, IH), 7.86 (d, J=2.0Hz, IH), 7.78 (d, J=8.4Hz, IH), 7.54 (dd, J=2.1Hz, 8.3Hz, IH)
13C NMR (75 MHz, CDC13) δ 162.72, 150.01, 145.93, 140.30, 136.31, 133.96, 131.20, 130.97, 129.22, 128.35, 126.88, 126.81, 124.78 IR (neat) : 3739, 1710, 1680, 1545, 1458, 1368, 1279, 1034, 950, 814, 615 cm"1 LRMS (EI) : m/e 327 (M+) HRMS (EI) : calcd. for C13H7Cl2NO3S, 326.9524; found, 326.9531 mp : 190-193 °C
Example 175: 5-(hydroxycarbonyl)furan-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (57) The compound 13j (150 mg, 0.498 mmol), sodium chlorite (68 mg, 0.598 mmol) and sulfamic acid (127 mg, 1.195 mmol) were added to the mixture solution of acetone (3 ml) and water (3 ml), followed by stirring at room temperature. After 30 min, acetone was removed under reduced pressure, followed by filtering under reduced pressure and drying under reduced pressure to obtain the desirable compound (157.9 mg, 100%)) as a white solid.
1H NMR (300 MHz, acetone) δ 7.82-7.81(4 J=2.22Hz, IH), 7.76-7.74(4 J=2.7Hz, IH), 7.56-7.55(4 J=1.95Hz, IH), 7.53-7.52(4 J=2.19Hz, IH), 7.53(s, IH).
Example 176: 5-(hydroxycarbonyf)furan-2-carbothionic acid-S-(3,5- dichlorophenyl)ester (58)
The compound 13r (150 mg, 0.498 mmol), sodium chlorite (68 mg, 0.598 mmol) and sulfamic acid (127 mg, 1.195 mmol) were added to the mixture solution of acetone (3 ml) and water (3 ml), followed by stirring at room temperature. After 30 min, acetone was removed under reduced pressure, followed by filtering under reduced pressure and drying under reduced pressure to obtain the desirable compound (157.9 mg,
100%)) as a white solid.
1H NMR (300 MHz, acetone) δ 7.66 (t, J=l .8Hz, IH), 7.61 (d, J=l .8Hz, 2H), 7.49 (d,
J=3.9Hz, IH), 7.41 (d, J=3.7Hz, IH)
Example 177: 5-(carbomethoxy)furan-2-carbothionic acid-S-(3,4-dichlorophenyl) ester (59)
The compound 57 (100 mg, 0.316 mmol) was dissolved in ether (2 ml), and the ether (2 ml), in which an excess of diazomethane was dissolved, was added thereto, followed by stirring at 0°C for 30 min. And then the mixture was distilled under reduced pressure to obtain the desirable compoxmd (105 mg, 100%) as a white solid. 1H NMR (300 MHz, acetone) δ 7.82-7.81(4 J=2.22Hz, IH), 7.76-7.74(4 J=2.7Hz, IH), 7.56-7.55(4 J=1.95Hz, IH), 7.53-7.52(4 J=2.19Hz, IH), 7.53(s, IH) 3.95 ( s, 3H).
Example 178: 5-(carbomethoxy)furan-2-carbothionic acid-S-(3,5-dichlorophenyl) ester (60)
The compound 58 (100 mg, 0.316 mmol) was dissolved in ether (2 ml) and the ether (2 ml), in which an excess of diazomethane was dissolved, was added thereto, followed by stirring at 0°C for 30 min. And then the mixture was distilled under reduced pressure to obtain the desirable compound (105 mg, 100%) as a white solid. 1H NMR (300 MHz, acetone) δ 7.66 (t, J=\ .8Hz, IH), 7.61 (d, J=l .8Hz, 2H), 7.49 (d, J=3.9Hz, IH), 7.41 (d, J=3.7Hz, IH), 3.95 ( s, 3H)
Example 179: 6-formyl-3-methoxypyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (72)
The compound 70 (3mg, 0.09mmol), which is the reaction intermediate of the reaction scheme 16, and p-toluenesulfonic acid (51.8 mg, 0.27 mmol) were dissolved in acetone (3.75 ml), followed by stirring at room temperature. After 30 min, the reaction solution was concentrated under reduced pressure, followed by dissolving with ethyl acetate. The resultant was washed with water and brine, and dried with anhydrous magnesium sulfate (MgSO4) to obtain the desirable compound (22 mg, 70%) as a white solid.
1H NMR (300 MHz, CDC13) d 10.06 (s, IH), 8.20 (d, J=8.8Hz, IH), 7.60 (d, J=2.0Hz, IH), 7.55-7.49 (m, 2H), 7.33 (dd, J=2.1Hz, 8.3Hz, IH), 4.01 (s, 3H) 13C NMR (125 MHz, CDC13) d 190.96, 188.07, 157.92, 144.59, 139.56, 136.79, 134.48, 134.17, 133.24, 131.07, 129.03, 127.47, 121.31, 56.68
IR (neat) : 1702, 1573, 1463, 1365, 1283, 1172, 1126, 1008, 944, 839, 726, 613 cm"1 LRMS (EI) : m/e 341 (M+)
HRMS (EI) : calcd. for C14H9Cl2NO3S, 340.9680; found, 340.9677 mp : 175-176 °C
Example 180: 6-formyl-3-methoxypyridine-2-carbothionic acid-S-(3,5- dichlorophenyf)ester (73)
According to the same method as in the above, the white solid of 8.4 mg
(yield 62%>) was obtained from the compound 71 (14.7 mg, 0.04 mmol).
1H NMR (300 MHz, CDC13) d 10.06 (s, IH), 8.20 (d, J=8.8Hz, IH), 7.54 (d, J=8.8Hz,
IH), 7.42-7.40 (m, 3H), 4.02 (s, 3H) 13C NMR (125 MHz, CDC13) d 190.93, 187.73, 157.97, 144.62, 139.39, 135.37, 133.36,
132.22, 129.73, 127.54, 121.35, 56.89
IR (neat) : 2925, 1704, 1569, 1469, 1406, 1283, 1172, 1008, 944, 839, 798, 725, 613 cm"1
LRMS (EI) : m/e 341 (M+) HRMS (EI) : calcd. for C14H9Cl2NO3S, 340.9680; found, 340.9688 mp : 140-142 °C
Experimental Example 1: In-vitro telomerase- inhibitory activity assay
To determine telomerase- inhibitory activity of the compounds accordmg to the present invention, a modified TRAP (telomeric repeat amplification protocol) using PicoGreen fluorescent dye was conducted. As a cancer cell, HeLa cell (cervical cancer cell line) was used. Under such analysis system, SMOl of the following formula II was used as a standard substance, and IC 50 value of SMOl was determined to be 77 μM, approximately 10 times higher than the value determined by Geron Company, 7.0 μM.
Formula II
Figure imgf000138_0001
As can be seen from the test result, Table 3, when telomerase inhibitory activity of the derivatives of the present invention was evaluated, activity tendency of the parent nucleus was in the order of furan >pyridine>thiophene ring, and introduction of thioester to position 2 on the heterocycle showed much stronger telomerase inhibitory activity than other functional group did. Taken together, derivatives having thioester functional group while having furan and pyridine parent nucleus the compound 6 group and compound 13 group of the present invention) exhibited superior telomerase inhibition activity over the standard substance (SMOl of Geron)
Table 3. Telomerase Inhibition Activity of Synthesized Derivatives Example
Figure imgf000138_0002
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Experimental example 2: In-vitro cytotoxicity assay To determine in-vivo antitumor activity on the basis of the in-vitro telomerase inliibitory activity determined in Experimental Example 1, first, in-vitro cytotoxicity assay was conducted against several kinds of cancer cell. As can be seen in Table 4, all the compounds tested showed almost no cytotoxicity.
Table 4. In-vitro cytotoxicity assay
Figure imgf000142_0001
When compared with camptothecin, which is topoisomerase inl ibitor used as positive control, both SMOl and the test compounds were evaluated as being almost nontoxic, and as the tested compounds were all sharing common structure except the parent nucleus, it is considered that no cytotoxicity difference occurs due to difference in parent nucleus.
Experimental Example 3: Study on in-vivo antitumor activity.
Among the compound 6 group and compound 13 group, which have showed superior in-vitro telomerase inhibitory activity according to the previous studies (in- vitro telomerase inhibitory activity assay), the compounds of Example 10 and Example 48, which exhibited specially superior efficacy, were subjected to in-vivo telomerase inhibitory activity assay by using nude mice bearing cell tissue culture of human carcinoma (Fig. 1, Fig. 2 and Table 5).
Table 5. In-vivo antitumor activity of the compoxmds of Example 10 and Example 48
Figure imgf000143_0001
As can be seen in Figs. 1 and 2, as a result of the test, while the compoxmd of
Example 10 exhibited relatively weak antitumor activity, the compoxmd of Example 48 showed antitumor activity of approximately 52% inhibition at 20 mg/kg dose, and weight loss was almost not observed in the group administered with the compound of
Example 48.
Said results were consistent with that of in-vitro cytotoxicity assay, almost no toxicity.
Industrial Applicability
The 2-substituted heterocyclic compounds and antitumor agent comprising the same according to the present invention can resolve the problems of the conventional antitumor agent, that is, the problems of side effects and cross resistance between related mechanisms on using chemotherapeutics, and exhibit superior antitumor activity. In particular, the compounds of the present invention were subjected to test to determine in-vitro activity, in-vitro cytotoxicity and in-vivo telomerase antitumor activity in nude mice, and based on the results, novel mechanism-based antitumor candidates were derived.

Claims

1. A compound represented with the following formula I:
Figure imgf000145_0001
(D herein, X defines pyridine, thiophene or furan;
M means H, CN, NO2, OH, ORa, OC(O)Rb, F, CI, Br, I, NH2, NHRC, NHC(O)Rd or Re substituted at 3,4 or 5 position in case X is pyridine, or at 3 or 4 position in case X is thiophene or furan, and Ra~Re define C1-4 alkyl;
Y means CO or CH2 substituted at 2 or 6 position in case X is pyridine, or at 2 or 5 position in case X is thiophene or furan;
Z is O, NH or S;
L defines
Figure imgf000145_0002
wherein, Ri means that 2, 3, 4, 5 and 6 position of phenyl are independently substituted with hydrogen, methyl, methoxy, halogen, trihalogenmethyl, nitro, t-butyl or acetamido group; and
N is substituted at 2 or 6 position in case X is pyridine, or at 2 or 5 position in case X is thiophene or furan, and selected among the following groups:
Figure imgf000146_0001
Figure imgf000146_0002
Figure imgf000146_0003
Figure imgf000146_0004
wherein, Rf defines phenyl or C1-4 alkyl.
2. The compound in Claim 1, wherein L is phenyl, o-methylphenyl, m- methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,4-dimethoxyphenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5- dichlorophenyl, 2,5-dichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4- trichlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4-trifluorophenyl, pentafluorophenyl, 4-bromophenyl, 2-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, 2-pyridinyl, 4-t-butylphenyl, 4- nitrophenyl, 4-acetamidophenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl or 2- thiophene.
3. The compound in Claim 1 or 2, wherein M is H, Y is CO and Z is S.
4. The compound in Claim 1 or 2 where X is pyridine or furan, M is H, Y is CO, Z is S and N is formyl group (-COH) or carboxyl group (-COOH).
5. Telomerase inhibitor comprising the compound of Claim 1.
6. Antitumor composition comprising the compound of Claim 1
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