WO2022149618A1 - 酸性官能基のアルキル化方法 - Google Patents

酸性官能基のアルキル化方法 Download PDF

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WO2022149618A1
WO2022149618A1 PCT/JP2022/003468 JP2022003468W WO2022149618A1 WO 2022149618 A1 WO2022149618 A1 WO 2022149618A1 JP 2022003468 W JP2022003468 W JP 2022003468W WO 2022149618 A1 WO2022149618 A1 WO 2022149618A1
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compound
reaction
substituted
aryl
mmol
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French (fr)
Japanese (ja)
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忠克 早瀬
智史 土屋
研一 野村
岳 江村
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Priority to CN202280009097.5A priority Critical patent/CN116829524A/zh
Priority to EP22736786.9A priority patent/EP4279476A4/en
Priority to KR1020237025719A priority patent/KR102800659B1/ko
Priority to JP2022548060A priority patent/JP7236598B2/ja
Priority to US18/270,793 priority patent/US20240132431A1/en
Publication of WO2022149618A1 publication Critical patent/WO2022149618A1/ja
Priority to JP2023027927A priority patent/JP2023065526A/ja
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Definitions

  • the present invention relates to a method for alkylating an acidic functional group. Further, the present invention relates to a method for producing a compound, which comprises a step of alkylating an acidic functional group.
  • Alkylation of acidic functional groups is a widely used reaction in compound synthesis.
  • an acidic functional group for example, in the case of alkylating a phenolic hydroxyl group, a method of using iodomethane as an alkylating agent and potassium carbonate as a base is known (Non-Patent Document 1), but the alkyl of the desired phenolic hydroxyl group is known.
  • the tertiary amine is alkylated as a side reaction (Non-Patent Document 2).
  • a method using a less reactive alkylating agent for example, a trialkyl phosphate ester as an alkylating agent, or a method using a tetraalkylammonium salt as an alkylating agent is available.
  • a less reactive alkylating agent for example, a trialkyl phosphate ester as an alkylating agent, or a method using a tetraalkylammonium salt as an alkylating agent.
  • inorganic bases such as potassium carbonate (Patent Document 1) and potassium hydroxide (Patent Document 2) are used as bases.
  • Non-Patent Document 3 a method using iodomethane as an alkylating agent and potassium carbonate as a base is known.
  • the reaction conditions are such that the tertiary amine is alkylated, similar to the alkylation of the phenolic hydroxyl group (Non-Patent Document 2).
  • Non-Patent Documents 4 and 5 As an alkylating agent having a lower reactivity, a method of using a trialkyl phosphate ester as an alkylating agent can be mentioned.
  • sodium salts of carboxylic acids are first prepared and reacted (Non-Patent Documents 4 and 5).
  • reagents and impurities generated from the reagents can be removed from the target compound library by a simple method (liquid-liquid extraction, vacuum distillation, or a method using a solid phase reagent).
  • the substrate compound may contain an alkylable functional group other than the target acidic functional group, for example, an alcoholic hydroxyl group and a nitrogen-containing structure (amide, tertiary amine, pyridine, pyridazine, etc.).
  • an alkylable functional group other than the target acidic functional group for example, an alcoholic hydroxyl group and a nitrogen-containing structure (amide, tertiary amine, pyridine, pyridazine, etc.).
  • an alcoholic hydroxyl group and a nitrogen-containing structure amide, tertiary amine, pyridine, pyridazine, etc.
  • One of the objects of the present invention is to provide a novel alkylation method, and in particular, to provide an alkylation method having a high yield and high regioselectivity. Furthermore, one of the objects of the present invention is to provide a method for alkylating an acidic functional group which has a wide range of substrate adaptation and can be used as a substrate in a mixture containing a plurality of compounds, particularly in compound library synthesis.
  • the present inventors have found an alkylation method having favorable reactivity, and have completed the present invention.
  • the present inventors have found that the method is applicable to a mixture containing a plurality of compounds as a substrate, for example, in the production of a compound library, a selective alkyl of an acidic functional group generated when excised from a solid phase. It was confirmed that it is applicable to the conversion.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,. Alternatively, it may be substituted with one or more substituents independently selected from C 1-4 alkoxy;
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy.
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • the compound comprises reacting the compound with an alkylating agent selected from the compounds represented by the above to alkylate the acidic functional group, wherein the base is an organic having a pKa of the conjugate acid in acetonitrile 23-34.
  • the base is selected from the group consisting of a base and an inorganic base having a pKa of the conjugate acid in water of 9 to 20.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,. Alternatively, it may be substituted with one or more substituents independently selected from C 1-4 alkoxy;
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy.
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • the method comprising reacting the compound with an alkylating agent selected from the compounds represented by to alkylate the hydroxyl group substituted with an aromatic ring, wherein the base is selected from phosphazenes.
  • a method for producing an ester compound wherein a compound containing a carboxy group is subjected to a formula A, a formula B, or a formula C: in the presence of a base.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,.
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy. May be;
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • the method comprising reacting the compound with an alkylating agent selected from the compounds represented by to alkylate the carboxy group, wherein the base is selected from phosphazenes.
  • the base is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazene) (P2Et), 1-tert-butyl-2,2.
  • Alkylation C or Alkylation D is an alkyl of a nitrogen atom contained in a nitrogen-containing structure selected from diallylamine, alkylarylamine, aniline, tertiary amine, amide, sulfonamide, acylsulfonamide, and pyridine.
  • the method for producing a compound constituting a compound library which comprises producing an alkylated compound by the method according to any one of [1] to [16].
  • [18] The method according to any one of [1] to [17], which is produced as a mixture containing 10 or more compounds.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,. Alternatively, it may be substituted with one or more substituents independently selected from C 1-4 alkoxy;
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy.
  • R 3 is selected independently of C 1-6 Alkoxy, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl. And C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • [A1] A method for producing an alkylated compound having an acidic functional group, wherein the mixture contains two or more kinds of compounds having an acidic functional group as a substrate, and in the presence of a base, the formula A, the formula B, or the formula.
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy. May be;
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • the compound comprises reacting the compound with an alkylating agent selected from the compounds represented by the above to alkylate the acidic functional group, wherein the base is an organic having a pKa of the conjugate acid in acetonitrile 23-34.
  • an alkylating agent selected from the compounds represented by the above to alkylate the acidic functional group, wherein the base is an organic having a pKa of the conjugate acid in acetonitrile 23-34.
  • the base is selected from the group consisting of a base and an inorganic base having a pKa of the conjugate acid in water of 9 to 20.
  • [A2] The method according to [A1], which comprises removing impurities after alkylation.
  • [A3] The method according to [A2], wherein the removal of the impurities is at least one selected from the group consisting of liquid-liquid separation, distillation under reduced pressure, and a method using a solid phase reagent.
  • [A4] The method according to [A2] or [A3], wherein the step of removing the impurities is liquid-liquid separation.
  • [A5] The method according to [A2] or [A3], wherein the step of removing the impurities is distillation under reduced pressure.
  • [A6] The method according to [A2] or [A3], wherein the step of removing the impurities is a method using a solid phase reagent.
  • the impurity is at least one selected from the group consisting of an alkylating agent, a base, an impurity derived from an alkylating agent, an impurity derived from a base, and a solvent remaining after alkylation, [A2] to [ A6] The method according to any one.
  • [A8] The method according to any one of [A1] to [A7], wherein the solubility of the base in dimethylformamide (DMF) is 120 mg / mL or more at 25 ° C.
  • DMF dimethylformamide
  • the base is selected from organic bases.
  • the base is a base selected from the group consisting of organic bases in which the pKa of the conjugate acid in acetonitrile is 24 to 34, 25 to 34, or 28 to 34, [A1] to [A9]. The method described in any of.
  • the pKa of the conjugate acid in acetonitrile is equal to or higher than the pKa value of 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), and / or 1-tert-butyl.
  • BTMG 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • -2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5,4 ⁇ 5 -catenadi (phosphazene) (P2tBu) is a base selected from the group consisting of organic bases having a pKa value or less.
  • [A12] The method according to any one of [A1] to [A9], wherein the base is selected from phosphazenes.
  • [A13] The method according to any one of [A1] to [A12], wherein the alkoxy produced by the alkylation has a
  • [A14] The method according to any one of [A1] to [A13], wherein the alkoxy produced by the alkylation is methoxy, ethoxy or allyloxy.
  • [A16] The method according to any one of [A1] to [A15], wherein the alkylation produces a methyl ester, an ethyl ester or an allyl ester.
  • [A17] The method according to any one of [A1] to [A16], wherein the reaction is carried out in a solvent.
  • the solvent is tetrahydrofuran (THF), 2-methyltetrahydrogen, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl.
  • Ether solvents such as ether (CPME) and isosorbidodimethyl ether, ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone), dichloromethane (DCM), 1,2- Halogen-based solvents such as dichloroethane (DCE) and chloroform, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), N-ethyl-2- Amido solvents such as pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea (TMU), N, N'-dimethylpropylene urea (DMPU), Urea solvent such as 1,3-dimethyl-2-imid
  • [A19] The method according to any one of [A1] to [A18], wherein the reaction is carried out at 25 to 130 ° C, 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C.
  • the alkylating agent has 1.0 to 100.0 equivalents, 2.0 to 50.0 equivalents, 3.0 to 30.0 equivalents, 5.0 to 25.0 equivalents, relative to the acidic functional group.
  • the base is 1.0 to 100.0 equivalents, 1.5 to 50.0 equivalents, 1.5 to 30.0 equivalents, 3.0 to 25.0 equivalents, 8.
  • the method according to any one of [A1] to [A20] which is used from 0 to 20.0 equivalents or 12.5 to 17.5 equivalents.
  • [A22] The method according to any one of [A1] to [A21], wherein the alkylating agent is selected from the group consisting of the compounds represented by the formulas A and B described in [A1].
  • [A23] The method according to any one of [A1] to [A22], wherein the alkylating agent is selected from the group consisting of the compounds represented by the formula A described in [A1].
  • [A24] The method according to any one of [A1] to [A23], wherein the alkylating agent is selected from the group consisting of trimethyl phosphate, triethyl phosphate and triallyl phosphate.
  • the base is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) (P2Et), 1-tert-butyl-2,2.
  • [A26] The method according to any one of [A1] to [A25], wherein the acidic functional group is a hydroxyl group substituted with an aromatic ring.
  • [A27] The method according to any one of [A1] to [A26], wherein the acidic functional group is a hydroxyl group substituting a benzene ring or a pyridine ring.
  • Alkylation C is the alkylation of a nitrogen atom contained in a nitrogen-containing structure selected from diarylamine, alkylarylamine, aniline, tertiary amine, amide, sulfonamide, acylsulfonamide, and pyridine.
  • a nitrogen-containing structure selected from diarylamine, alkylarylamine, aniline, tertiary amine, amide, sulfonamide, acylsulfonamide, and pyridine.
  • [A30] The method according to any one of [A1] to [A25], wherein the acidic functional group is a carboxy group.
  • Product formation ratio (alkylation D / alkylation E) by (alkylation D) and alkylation of nitrogen atom (alkylation E) is 1.5 or more, 3 or more, 5 or more, 7 or more, 9 or more, 10
  • Alkylation E is the alkylation of a nitrogen atom contained in a nitrogen-containing structure selected from diarylamine, alkylarylamine, aniline, tertiary amine, amide, sulfonamide, acylsulfonamide, and pyridine.
  • the substrate contains one or more phenolic hydroxyl groups and one or more carboxy groups as acidic functional groups, and alkylates any of the acidic functional groups of one or more phenolic hydroxyl groups and one or more carboxy groups [A1]. ⁇ The method according to any one of [A32].
  • [A34] In a substrate containing one or more phenolic hydroxyl groups and one or more carboxy groups as acidic functional groups, one or more after alkylating all of the acidic functional groups of one or more phenolic hydroxyl groups and one or more carboxy groups.
  • [A35] In a substrate containing one or more phenolic hydroxyl groups and one or more carboxy groups as acidic functional groups, one or more after alkylating all of the acidic functional groups of one or more phenolic hydroxyl groups and one or more carboxy groups.
  • [A36] The method according to any one of [A1] to [A35] for producing a compound constituting a compound library.
  • [B1] A method for producing a compound having an alkoxy-substituted aromatic ring, wherein a compound containing a hydroxyl group substituted with an aromatic ring is subjected to formula A, formula B, or formula C: in the presence of a base.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,.
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy. May be;
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • the method comprising reacting the compound with an alkylating agent selected from the compounds represented by to alkylate the hydroxyl group substituted with an aromatic ring, wherein the base is selected from phosphazenes.
  • [B2] The method according to [B1], which comprises removing impurities after alkylation.
  • [B3] The method according to [B1], wherein the removal of the impurities is at least one selected from the group consisting of liquid-liquid separation, distillation under reduced pressure, and a method using a solid phase reagent.
  • [B4] The method according to [B2] or [B3], wherein the step of removing the impurities is liquid-liquid separation.
  • [B5] The method according to [B2] or [B3], wherein the step of removing the impurities is distillation under reduced pressure.
  • [B6] The method according to [B2] or [B3], wherein the step of removing the impurities is a method using a solid phase reagent.
  • the impurity is at least one selected from the group consisting of an alkylating agent, a base, an impurity derived from an alkylating agent, an impurity derived from a base, and a solvent remaining after alkylation, [B1] to [B6]. ] The method described in any of. [B8] The method according to any one of [B1] to [B7], wherein the alkoxy produced by the alkylation has a ⁇ CH2 -O ⁇ structure.
  • [B9] The method according to any one of [B1] to [B8], wherein the alkoxy produced by the alkylation is methoxy, ethoxy or allyloxy.
  • the solvent is tetrahydrofuran (THF), 2-methyltetrahydrogen, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl.
  • Ether solvents such as ether (CPME) and isosorbidodimethyl ether, ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone), dichloromethane (DCM), 1,2- Halogen-based solvents such as dichloroethane (DCE) and chloroform, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), N-ethyl-2- Amido solvents such as pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea (TMU), N, N'-dimethylpropylene urea (DMPU), Urea solvent such as 1,3-dimethyl-2-imid
  • [B12] The method according to any one of [B1] to [B11], wherein the reaction is carried out at 25 to 130 ° C, 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C.
  • the alkylating agent has 1.0 to 100.0 equivalents, 2.0 to 50.0 equivalents, 3.0 to 30.0 equivalents, 5.0 to 25.0 equivalents, and 10.
  • the method according to any one of [B1] to [B12] which is used from 0 to 20.0 equivalents or 12.5 to 17.5 equivalents.
  • the base is 1.0 to 100.0 equivalents, 1.5 to 50.0 equivalents, 1.5 to 30.0 equivalents, 3.0 to 25.0 equivalents, 8.0 to 8.0 to the hydroxyl group.
  • the method according to any one of [B1] to [B13], wherein 20.0 equivalents or 12.5 to 17.5 equivalents are used.
  • [B16] The method according to any one of [B1] to [B15], wherein the alkylating agent is selected from the group consisting of trimethyl phosphate, triethyl phosphate and triallyl phosphate.
  • the base is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazene) (P2Et), 1-tert-butyl-2,2.
  • the hydroxyl group substituted with the aromatic ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrazole ring, an imidazole ring, a furan ring, a thiophene ring, an oxazole ring, a thiazole ring, a naphthalene ring, a quinoline ring, and the like.
  • the product formation ratio (alkylation A / alkylation C) due to the alkylation of the phenolic hydroxyl group (alkylation A) and the alkylation of the nitrogen atom (alkylation C) is 1.5.
  • [B21] The method according to any one of [B1] to [B20] for producing a compound constituting a compound library.
  • [B22] The method according to any one of [B1] to [B21], wherein the mixture contains 10 or more kinds of compounds as a substrate.
  • [B23] The method according to any one of [B1] to [B22], further comprising preparing a compound having a hydroxyl group by cutting out from a solid phase carrier.
  • [C1] A method for producing a compound constituting a compound library, which is alkylated by the method according to any one of [A1] to [A38], [B1] to [B23] and [E1] to [E21].
  • the above-mentioned method which comprises producing a compound thereof.
  • [C2] The method according to [C1], which is produced as a mixture containing 10 or more, 50 or more, 100 or more, 500 or more or 1000 or more compounds.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,. Alternatively, it may be substituted with one or more substituents independently selected from C 1-4 alkoxy;
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy.
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • [E1] A method for producing an ester compound, wherein a compound containing a carboxy group is subjected to a formula A, a formula B, or a formula C: in the presence of a base.
  • R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X;
  • X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,.
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy. May be;
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • C 1-4 alkoxy may be substituted with one or more substituents independently selected]
  • the method comprising reacting the compound with an alkylating agent selected from the compounds represented by to alkylate the carboxy group, wherein the base is selected from phosphazenes.
  • [E2] The method according to [E1], which comprises removing impurities after alkylation.
  • [E3] The method according to [E1], wherein the removal of the impurities is at least one selected from the group consisting of liquid-liquid separation, distillation under reduced pressure, and a method using a solid phase reagent.
  • [E4] The method according to [E2] or [E3], wherein the step of removing the impurities is liquid-liquid separation.
  • [E5] The method according to [E2] or [E3], wherein the step of removing the impurities is distillation under reduced pressure.
  • [E6] The method according to [E2] or [E3], wherein the step of removing the impurities is a method using a solid phase reagent.
  • [E10] The method according to any one of [E1] to [E9], wherein the reaction is carried out in a solvent.
  • the solvent is tetrahydrofuran (THF), 2-methyltetrahydrogen, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl.
  • Ether solvents such as ether (CPME) and isosorbidodimethyl ether, ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone), dichloromethane (DCM), 1,2- Halogen-based solvents such as dichloroethane (DCE) and chloroform, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), N-ethyl-2- Amido solvents such as pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea (TMU), N, N'-dimethylpropylene urea (DMPU), Urea solvent such as 1,3-dimethyl-2-imid
  • [E12] The method according to any one of [E1] to [E11], wherein the reaction is carried out at 25 to 130 ° C, 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C.
  • the alkylating agent has 1.0 to 100.0 equivalents, 2.0 to 50.0 equivalents, 3.0 to 30.0 equivalents, 5.0 to 25.0 equivalents, and 10.
  • the method according to any one of [E1] to [E12] which is used from 0 to 20.0 equivalents or 12.5 to 17.5 equivalents.
  • the base is 1.0 to 100.0 equivalents, 1.5 to 50.0 equivalents, 1.5 to 30.0 equivalents, 3.0 to 25.0 equivalents, 8.0 to 8.0 to the hydroxyl group.
  • the method according to any of [E1] to [E13], wherein 20.0 equivalents or 12.5 to 17.5 equivalents are used.
  • [E16] The method according to any one of [E1] to [E15], wherein the alkylating agent is selected from the group consisting of trimethyl phosphate, triethyl phosphate and triallyl phosphate.
  • the base is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazene) (P2Et), 1-tert-butyl-2,2.
  • [E18] The reaction is carried out using two or more compounds as substrates, and the substrate contains one or more compounds containing a nitrogen atom that can be alkylated with a carboxy group as an acidic functional group, and the alkylation proceeds most among the substrates.
  • the product formation ratio (alkylation D / alkylation E) due to the alkylation of the carboxy group (alkylation D) and the alkylation of the nitrogen atom (alkylation E) is 1.5 or more.
  • [E19] The method according to any one of [E1] to [E18] for producing a compound constituting a compound library.
  • [E20] The method according to any one of [E1] to [E19], wherein the mixture contains 10 or more kinds of compounds as a substrate.
  • [E21] The method according to any one of [E1] to [E20], further comprising preparing a compound having a carboxy group by excision from a solid phase carrier.
  • [F1] A method for producing a resin for solid-phase synthesis having a side chain containing an alkylated acidic functional group, which comprises a resin containing two or more types of side chains having an acidic functional group as a substrate and in the presence of a base.
  • Formula A, Formula B, or Formula C [In the formula, R 1 is selected independently of the C 1-6 alkyl which may be substituted with one or more substituents selected from X; X is independently selected from C 3-6 cycloalkyl, C 2-7 alkoxy, C 2-7 alkynyl, and C 6-10 aryl, wherein the aryl is a halogen atom, C 1-4 alkyl,.
  • R 2 is selected independently of ⁇ OR 1 and aryl, wherein the aryl is substituted with one or more substituents independently selected from the halogen atom, C 1-4 alkyl and C 1-4 alkoxy. May be;
  • R 3 is selected independently of C 1-6 alkyl, which may be substituted with one or more substituents selected from X, and aryl, wherein the aryl is a halogen atom, C 1-4 alkyl.
  • the resin comprises reacting the resin with an alkylating agent selected from the compounds represented by the above to alkylate the acidic functional group, wherein the base is an organic having a pKa of the conjugate acid in acetonitrile 23-34.
  • an alkylating agent selected from the compounds represented by the above to alkylate the acidic functional group, wherein the base is an organic having a pKa of the conjugate acid in acetonitrile 23-34.
  • the base is selected from the group consisting of a base and an inorganic base having a pKa of the conjugate acid in water of 9 to 20.
  • [F2] The method according to [F1], which comprises removing impurities after alkylation.
  • [F3] The method according to [F2], wherein the removal of the impurities is at least one selected from the group consisting of liquid-liquid separation, distillation under reduced pressure, and a method using a solid phase reagent.
  • [F4] The method according to [F2] or [F3], wherein the step of removing the impurities is liquid-liquid separation.
  • [F5] The method according to [F2] or [F3], wherein the step of removing the impurities is distillation under reduced pressure.
  • [F6] The method according to [F2] or [F3], wherein the step of removing the impurities is a method using a solid phase reagent.
  • the impurity is at least one selected from the group consisting of an alkylating agent, a base, an impurity derived from an alkylating agent, an impurity derived from a base, and a solvent remaining after alkylation, [F2] to [F2].
  • DMF dimethylformamide
  • the base is a base selected from the group consisting of organic bases in which the pKa of the conjugate acid in acetonitrile is 24 to 34, 25 to 34, or 28 to 34, [F1] to [F9]. The method described in any of.
  • the base is that the pKa of the conjugate acid in acetonitrile is greater than or equal to the pKa value of 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) and / or 1-tert-butyl.
  • BTMG 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • P2tBu 2-tert-butyl-1,1,3,3-tetramethylguanidine
  • [F12] The method according to any one of [F1] to [F9], wherein the base is selected from phosphazenes.
  • [F13] The method according to any one of [F1] to [F12], wherein the alkoxy produced by the alkylation has a ⁇ CH2 -O ⁇ structure.
  • [F14] The method according to any one of [F1] to [F13], wherein the alkoxy produced by the alkylation is methoxy, ethoxy or allyloxy.
  • [F16] The method according to any one of [F1] to [F15], wherein the alkylation produces a methyl ester, an ethyl ester or an allyl ester.
  • [F17] The method according to any one of [F1] to [F16], wherein the reaction is carried out in a solvent.
  • the solvent is tetrahydrofuran (THF), 2-methyltetrahydrogen, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl.
  • Ether solvents such as ether (CPME) and isosorbidodimethyl ether, ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone), dichloromethane (DCM), 1,2- Halogen-based solvents such as dichloroethane (DCE) and chloroform, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), N-ethyl-2- Amido solvents such as pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea (TMU), N, N'-dimethylpropylene urea (DMPU), Urea solvent such as 1,3-dimethyl-2-imid
  • [F19] The method according to any one of [F1] to [F18], wherein the reaction is carried out at 25 to 130 ° C, 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C.
  • the alkylating agent has 1.0 to 100.0 equivalents, 2.0 to 50.0 equivalents, 3.0 to 30.0 equivalents, 5.0 to 25.0 equivalents, relative to the acidic functional group.
  • the base is 1.0 to 100.0 equivalents, 1.5 to 50.0 equivalents, 1.5 to 30.0 equivalents, 3.0 to 25.0 equivalents, 8.
  • the method according to any one of [F1] to [F20] which is used from 0 to 20.0 equivalents or 12.5 to 17.5 equivalents.
  • [F22] The method according to any one of [F1] to [F21], wherein the alkylating agent is selected from the group consisting of the compounds represented by the formulas A and B described in [F1].
  • [F23] The method according to any one of [F1] to [F22], wherein the alkylating agent is selected from the group consisting of the compounds represented by the formula A described in [F1].
  • [F24] The method according to any one of [F1] to [F23], wherein the alkylating agent is selected from the group consisting of trimethyl phosphate, triethyl phosphate and triallyl phosphate.
  • the base is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) (P2Et), 1-tert-butyl-2,2.
  • [F26] The method according to any one of [F1] to [F25], wherein the acidic functional group is a hydroxyl group substituted with an aromatic ring.
  • [F27] The method according to any one of [F1] to [F26], wherein the acidic functional group is a hydroxyl group substituting a benzene ring or a pyridine ring.
  • [F28] In a compound in which the resin for solid phase synthesis contains one or more side chains containing a phenolic hydroxyl group and a nitrogen atom that can be alkylated as an acidic functional group, and the resin has a nitrogen atom in which alkylation proceeds most.
  • Product formation ratio (alkylation A / alkylation C) by alkylation of phenolic hydroxyl group (alkylation A) and alkylation of nitrogen atom (alkylation C) is 1.5 or more, 3 or more, 5 or more,
  • Alkylation C is the alkylation of a nitrogen atom contained in a nitrogen-containing structure selected from diarylamines, alkylarylamines, anilines, tertiary amines, amides, sulfonamides, acylsulfonamides, and pyridines.
  • a nitrogen-containing structure selected from diarylamines, alkylarylamines, anilines, tertiary amines, amides, sulfonamides, acylsulfonamides, and pyridines.
  • [F30] The method according to any one of [F1] to [F25], wherein the acidic functional group is a carboxy group.
  • Alkylation E is the alkylation of a nitrogen atom contained in a nitrogen-containing structure selected from diarylamine, alkylarylamine, aniline, tertiary amine, amide, sulfonamide, acylsulfonamide, and pyridine.
  • the resin for solid phase synthesis contains one or more phenolic hydroxyl groups and one or more carboxy groups in the side chain as acidic functional groups, and any of the acidic functional groups of one or more phenolic hydroxyl groups and one or more carboxy groups.
  • [F38] An acidic functional group alkylated by decomposing the linker by a reaction under acidic conditions, a reaction under alkaline conditions, a hydrogenation reaction, a reaction using an oxidizing agent, or a reaction with Lewis acid.
  • [F37] The method according to [F37] or [F38], wherein the resin contains 10 or more compounds bonded to the resin via a linker.
  • the present specification provides a highly reactive and highly selective alkylation method to which a mixture containing a plurality of compounds can be applied as a substrate.
  • FIG. 1 is a diagram showing "diversity of core blocks" and “diversity of linkers” for compounds constituting a library produced by the method of the present invention, and is a diagram showing compounds produced in Example 6. ..
  • FIG. 2 is a diagram showing the structure of 1000 compounds produced in Example 6-6.
  • FIG. 3 is a diagram showing the structure of the 500 compound produced in Example 6-8.
  • One aspect of the present invention relates to a method for producing a compound having an alkylated acidic functional group.
  • the alkylation is not particularly limited, but for example, the alkylation forming C 1-6 alkoxy, specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec- Alkylation to form butoxy, t-butoxy, 1-pentyloxy, 1-hexyloxy and the like, more specifically to alkylation to form methoxy, ethoxy and the like.
  • the acidic functional group is not particularly limited as long as it is a group having an acidic proton, and examples thereof include a hydroxyl group substituted with an aromatic ring and a carboxylic acid.
  • the aromatic ring may be a carbocycle or a heterocycle containing a heteroatom, and may be combined with a fused ring with an aromatic ring or a fused ring with a non-aromatic ring.
  • Examples of the aromatic ring include a 5- to 10-membered monocyclic or fused ring aromatic ring, and examples thereof include a pyrrole ring, a thiophene ring, a furan ring, a pyridine ring, a thiazole ring, an isothazole ring, and a pyrazole ring.
  • Oxazole ring isoxazole ring, imidazole ring, triazole ring, pyrimidine ring, uridine ring, pyrazine ring, pyridazine ring, quinoline ring, isoquinoline ring, 4H-quinolidine ring, phthalazine ring, naphthylidine ring, quinoxalin ring, quinazoline ring, cinnoline ring.
  • the acidic functional group is a hydroxyl group substituted with an aromatic ring, for example, a benzene ring, a pyridine ring, an indole ring, a quinoline ring, a hydroxyl group substituted with a pyrazole ring, specifically, a benzene ring or a pyridine. It is a hydroxyl group substituted with a ring.
  • C 1-6 alkyl is a monovalent derivative derived by removing one arbitrary hydrogen atom from linear and branched saturated aliphatic hydrocarbons having 1 to 6 carbon atoms. It is the basis. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, Examples include 1-ethylpropyl, hexyl, 4-methylpentyl, and 2-ethylbutyl.
  • C 1-4 alkyl is a monovalent derivative derived by removing one arbitrary hydrogen atom from linear and branched saturated aliphatic hydrocarbons having 1 to 4 carbon atoms. It is the basis. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl and the like.
  • C 1-6 alkoxy means a C 1-6 alkyl-O- group, where C 1-6 alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 1-hexyloxy and the like.
  • C 1-4 alkoxy means a C 1-4 alkyl-O- group, where C 1-4 alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy and the like.
  • C 3-6 cycloalkyl means a cyclic saturated aliphatic hydrocarbon group having 3 to 6 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 2-7 alkenyl means a linear or branched alkenyl group having 2 to 7 carbon atoms, and for example, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl). , Propen-2-yl, and 3-butenyl (homoallyl), and the like.
  • C 2-7 alkynyl means a linear or branched alkynyl group having 2 to 7 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-. Butynyl, 3-butynyl, etc. are included.
  • C 6-10 aryl means a monovalent aromatic hydrocarbon ring group.
  • Examples of the C 6-10 aryl include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • preferred halogen atoms include a fluorine atom, a chlorine atom and a bromine atom.
  • halogen atom is an alkyl or a substituent of a group containing an alkyl as a part thereof (alkoxy, alkenyl, alkylthio, etc.)
  • a fluorine atom is mentioned as a preferable halogen atom.
  • Specific examples of the group having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.
  • the number of the groups when a predetermined group is substituted with one or more substituents, the number of the groups may be in the range of 1 to the number of substitutable sites. For example, it may be 1 to 5, 1 to 4, 1 to 3, 1 or 2, or one substituent.
  • the heteroatom constituting the aromatic heterocycle may be, for example, one or more atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, specifically, one to three atoms.
  • a compound selected from the formula A, the formula B, or the formula C can be used as an alkylating agent.
  • R 2 is ⁇ OR 1
  • R 3 may be, for example, aryl, specifically phenyl. Examples of R 1 include C 1-6 alkyl, specifically C 1-5 alkyl, and more specifically C 1-4 alkyl.
  • alkylating agent represented by the formula A examples include trimethyl phosphate, triethyl phosphate, dimethyl phenylphosphonate, diethyl phenylphosphonate, methyl diphenylphosphinate, ethyl diphenylphosphinate and the like, and among them, phosphorus.
  • Preferred examples include trimethyl acid acid, triethyl phosphate, tripropyl phosphate, triallyl phosphate and the like.
  • alkylating agent represented by the formula B examples include trimethylphenylammonium chloride, trimethylphenylammonium bromide, trimethylphenylammonium iodide, triethylphenylammonium chloride, triethylphenylammonium bromide, triethylphenylammonium iodide, tetramethylammonium chloride, and tetra.
  • the alkylating agent represented by the formula C examples include dimethyl carbonate, diethyl carbonate, di-n-propyl carbonate, diisopropyl carbonate, di-n-butyl carbonate, di-tert-butyl carbonate and the like. , Dimethyl carbonate, diethyl carbonate and the like are preferable.
  • the production method comprises removing impurities after alkylation. Impurity removal can be performed by a method commonly used in the art of the present invention.
  • the impurities include impurities derived from the reaction reagent consumed in the reaction, unreacted reaction reagents, decomposition products produced by the reaction, products in which coexisting bases are alkylated by an alkylating agent, reaction solvents and the like. .. Specifically, as impurities, triethyl phosphate, diethyl phosphate, tert-butylimino-tri (pyrrolidino) phosphorane (BTPP), an alkylated form of BTPP, 1,3-dimethyl-2-imidazolidinone (DMI) And so on.
  • impurities triethyl phosphate, diethyl phosphate, tert-butylimino-tri (pyrrolidino) phosphorane (BTPP), an alkylated form of BTPP, 1,3-dimethyl-2-imidazolidinone (DMI) And so on.
  • Examples of the method for removing impurities include liquid-liquid separation, distillation under reduced pressure, a method using a solid-phase reagent, purification by normal phase or reverse phase silica gel column chromatography, purification by GPC (molecular sieve), and the like.
  • Liquid-liquid separation for removing impurities can be performed by a method usually used in the technical field of the present invention.
  • the liquid-liquid separation is not particularly limited as long as it is a combination of solvents that separate into a plurality of layers for the purpose of separating a desired product group and an impurity (unnecessary substance) group.
  • ester solvents such as ethyl acetate and isopropyl acetate
  • ether solvents such as diethyl ether, diisopropyl ether, t-butylmethyl ether (TBME), cyclopentylmethyl ether (CPME), 2-methyltetrahydrocarbon and 4-methyltetrahydropyran.
  • Halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, aromatic hydrocarbon-based solvents such as benzene and toluene, hydrocarbon-based solvents such as hexane, cyclohexane and heptane, and water and hydrochloric acid. It can be carried out by combining a solvent selected from an acidic aqueous solution such as an aqueous solution and a basic aqueous solution such as a sodium hydrogen carbonate aqueous solution. A single solvent may be used, or a mixed medium in which a plurality of solvents are combined may be used.
  • organic solvents for layer separation such as a combination of hexane and acetonitrile can be used in combination.
  • Distillation under reduced pressure for removing impurities can be carried out by a method usually used in the technical field of the present invention.
  • the conditions for distillation under reduced pressure can be appropriately set depending on the impurities to be removed.
  • the pressure is 100 to 400 mbar, 50 to 100 mbar, 5 to 50 mbar or 0.1 to 5 mbar
  • the temperature is 20 to 100 ° C., 25 to 25 to It may be 50 ° C., 35 to 45 ° C., or the like.
  • Impurities can be removed using a solid phase reagent by a method usually used in the technical field of the present invention.
  • the solid phase reagent include macroporous triethylammonium methylpolystyrene carbonate, macroporous polystyrene sulfonic acid, amine-supported silica gel, and carboxylic acid-supported silica gel.
  • the bases used in the alkylation reaction are organic bases with a conjugate acid pKa of 23-34 in acetonitrile and inorganic bases with a conjugate acid pKa of 9-20 in water.
  • a base selected from the group can be used.
  • pKa of the conjugate acid of the base in acetonitrile is described in the known document J. Org. Chem. It can be measured at a measurement temperature of 25 ° C. by the method described in 1998, 63, 7868-7874.
  • the pKa of the conjugated acid of the inorganic base in water is the value measured at 25 ° C.
  • the values described in 2020, Attached Article (DOI: Chem.Eur.J 10.1002 / chem.202003580, as of December 25, 2020) or the values described in the catalog of Sigma-Aldrich can be referred to as appropriate.
  • the pKa value of the conjugated acid in MeCN described in the Sigma-Aldrich catalog is, for example, 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi for phosphazene bases.
  • Phosphazene P2Et
  • 1-tert-butyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5,4 ⁇ 5 - catenadi (phosphazene) (P2tBu)
  • P1tBu Tert-Butyl imino-tris (dimethylamino) phosphorane
  • BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin
  • BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin
  • BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin
  • BTPP tert-butylimino-tri (pyrrolidino) phosphorane
  • the base used in the alkylation reaction preferably has a solubility in dimethylformamide (DMF) of 120 mg / mL or more at 25 ° C. Solubility can be achieved by methods commonly used in the art of the present invention.
  • the base for example, an organic base can be used.
  • the publicly known document J. Org. Chem. The solubility of Cs 2 CO 3 in dimethylformamide (DMF) according to 1984, 49, 1122-1125 is 119 mg / mL at 25 ° C.
  • phosphazenes, amidines or guanidines can be used as bases in the alkylation reaction.
  • Phosphazenes, amidines or guanidines are not particularly limited as long as they can be used as a base.
  • the base used in the alkylation reaction is 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) in phosphazenes.
  • P2Et 1-tert-butyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5,4 ⁇ 5 -catenadi (phosphazen) (P2tBu), tert-butylimino-tris (dimethylamino) phosphorane ( Amidine from the group consisting of P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (BEMP) and tert-butylimino-tri (pyrrolidino) phosphorane (BTPP).
  • P1tBu 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin
  • BTPP tert-butylimino-tri (pyrrolidino) phosphorane
  • 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) in the class 1,1,3,3-tetramethylguanidine (TMG), 2-tert-butyl-1,1 in the guanidines. , 3,3-Tetramethylguanidine (BTMG), 7-Methyl-1,5,7-Triazabicyclo [4.4.0] Deca-5-ene (MTBD), 1,5,7-Triaza It is selected from the group consisting of bicyclo [4.4.0] deca-5-ene (TBD).
  • the alkylation reaction using the alkylating agent of the formula A can be carried out by appropriately selecting the conditions based on the description of the present specification.
  • the alkylation reaction using the alkylating agent of formula A is, for example, tetrahydrofuran (THF), 2-methyltetrahexyl, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxy.
  • Ethereal solvents such as ethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl ether (CPME), isosorbidodimethyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone) ) And other ester solvents, dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform and other halogen solvents, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), Amid solvents such as N, N-dimethylacetamide (DMA), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea.
  • DME ethane
  • Urea solvents such as (TMU), N, N'-dimethylpropylene urea (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in a solvent selected from aromatic solvents (a single solvent may be used, or a mixture of a plurality of solvents may be used in combination.
  • TNU TNU
  • DI 1,3-dimethyl-2-imidazolidinone
  • sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in
  • a medium may be used), and at a temperature of 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C, 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenate (phosphazen) (P2Et), 1-tert-butyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) (P2tBu), tert- Butylimino-tris (dimethylamino) phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (BEMP), tert-butylimino-tri (pyrrolidino) solvent (BTPP), tert-butylimino-tri (pyrrolidino) phosphorane
  • the alkylation reaction using the alkylating agent of the formula B can be carried out by appropriately selecting the conditions based on the description of the present specification.
  • the alkylation reaction using the alkylating agent of formula B is carried out, for example, in tetrahydrofuran (THF), 2-methyltetrahexyl, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxy.
  • Ethereal solvents such as ethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl ether (CPME), isosorbidodimethyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone) ) And other ester solvents, dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform and other halogen solvents, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), Amid solvents such as N, N-dimethylacetamide (DMA), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea.
  • DME ethane
  • Urea solvents such as (TMU), N, N'-dimethylpropylene urea (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in a solvent selected from aromatic solvents (a single solvent may be used, or a mixture of a plurality of solvents may be used in combination.
  • TNU TNU
  • DI 1,3-dimethyl-2-imidazolidinone
  • sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in
  • a medium may be used), and at a temperature of 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C, 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenate (phosphazen) (P2Et), 1-tert-butyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) (P2tBu), tert- Butylimino-tris (dimethylamino) phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (BEMP), tert-butylimino-tri (pyrrolidino) solvent (BTPP), tert-butylimino-tri (pyrrolidino) phosphorane
  • the alkylation reaction using the alkylating agent of the formula C can be carried out by appropriately selecting the conditions based on the description of the present specification.
  • the alkylation reaction using the alkylating agent of formula C is, for example, tetrahydrofuran (THF), 2-methyltetrahexyl, 4-methyltetrahydropyran, 1,4-dioxane, 1,2-dimethoxy.
  • Ethereal solvents such as ethane (DME), t-butylmethyl ether (TBME), cyclopentylmethyl ether (CPME), isosorbidodimethyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL ( ⁇ -valerolactone) ) And other ester solvents, dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform and other halogen solvents, and N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), Amid solvents such as N, N-dimethylacetamide (DMA), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N, N, N', N'-tetramethylurea.
  • DME ethane
  • Urea solvents such as (TMU), N, N'-dimethylpropylene urea (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in a solvent selected from aromatic solvents (a single solvent may be used, or a mixture of a plurality of solvents may be used in combination.
  • TNU TNU
  • DI 1,3-dimethyl-2-imidazolidinone
  • sulfoxide solvents such as dimethylsulfoxide (DMSO), anisole, toluene , ⁇ , ⁇ , ⁇ -trifluorotoluene, 1,2-dichlorobenzene, benzene, etc. in
  • a medium may be used), and at a temperature of 40 to 120 ° C, 60 to 100 ° C, or 75 to 85 ° C, 1-ethyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenate (phosphazen) (P2Et), 1-tert-butyl-2,2,4,4,4-pentakis (dimethylamino) -2 ⁇ 5 , 4 ⁇ 5 -catenadi (phosphazen) (P2tBu), tert- Butylimino-tris (dimethylamino) phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (BEMP), tert-butylimino-tri (pyrrolidino) solvent (BTPP), tert-butylimino-tri (pyrrolidino) phosphorane
  • phenolic hydroxyl groups can be selectively alkylated in substrates with possible alkylating nitrogen atoms to give the compound of interest in high yields and generate by-products. It can be suppressed.
  • the substrate comprises one or more compounds containing a nitrogen atom that can be alkylated with a phenolic hydroxyl group as an acidic functional group, and the substrate has a nitrogen atom that is most alkylated, and is phenolic.
  • Product formation ratio (alkylation A / alkylation C) by alkylation of hydroxyl group (alkylation A) and alkylation of nitrogen atom (alkylation C) is 1.5 or more, 3 or more, 5 or more, 7 or more, 9 or more, 10 or more, 12 or more, 15 or more, 20 or more, 30 or more, or 50 or more.
  • the production ratio can be determined by quantitative analysis using an analysis method usually performed, for example, HPLC, in which the amounts of the products produced by alkylation A and the products produced by alkylation C are respectively determined.
  • the nitrogen atom that can be alkylated is not particularly limited as long as it is a nitrogen atom for which alkylation proceeds under the conditions of the alkylation reaction of the present invention.
  • a ring nitrogen atom of a pyridine ring for example, a nitrogen atom of a tertiary amine, or an acyl sulfone.
  • examples thereof include a nitrogen atom of amide, a nitrogen atom of diarylamine, a nitrogen atom of alkylarylamine, a nitrogen atom of aniline, a nitrogen atom of amide, and a nitrogen atom of sulfonamide.
  • the alkylation C is the alkylation of the ring nitrogen atom of the pyridine ring.
  • the production ratio of alkylated A and alkylated C can be confirmed at the end of the reaction, and for example, the production ratio can be measured when the raw material of alkylated A having a phenolic hydroxyl group disappears.
  • phenol may mean a compound having an arbitrary substituent at any part of the phenol skeleton in addition to the phenol itself.
  • pyridinol means a compound having a hydroxyl group on an arbitrary carbon of the pyridine ring, and the compound may have an arbitrary substituent at an arbitrary position. be.
  • Silica gel for column chromatography is SHOKO Scientific Purif-Pack (registered trademark) SI (60 ⁇ m), SHOKO Purif-Pack (registered trademark) -EX SI (50 ⁇ m), Biotage (registered trademark) SNAP Cartridge KP-Si, registered trademark. ), SNAP Ultra, Biotage (registered trademark) Surface D (Duo) (60 ⁇ m) or Biotage (registered trademark) Surface HC D (Duo) (20 ⁇ m), etc. were appropriately used.
  • reaction tracking and purity measurement are carried out using a mass spectrometer, SQD (manufactured by Waters) or 2020 (manufactured by Shimadzu) under the analytical conditions shown in the table below, and measurement of retention time and mass spectrometry are performed. I went by doing.
  • the descriptions of m / z [M + H] + and (M + H) + described in the analysis results of LCMS in the examples are all the values detected in the positive mode. Further, the UV area% in LCMS showed a value in PDA (190-400 nm or 210-400 nm) unless otherwise specified. When a specific wavelength (for example, 290 nm) is described, the UV area% at wavelengths up to +/- 4 nm is described centering on the described wavelength.
  • concentration refers to the evaporation and removal of solvent under reduced pressure by a rotary evaporator, mechanical oil vacuum pump or mechanical oil-free vacuum pump.
  • dry overnight under reduced pressure refers to the evaporation and removal of solvent under reduced pressure by a rotary evaporator, mechanical oil vacuum pump or mechanical oil-free vacuum pump. Unless otherwise specified, the expressions “overnight” and “all night” refer to about 8 to 14 hours, but this is not the case.
  • the solid phase reaction can be carried out in any suitable container, for example a glass vial that can be sealed with a cap equipped with Teflon packing, a frit filter and a column with a suitable stopper.
  • a suitable container for example a glass vial that can be sealed with a cap equipped with Teflon packing, a frit filter and a column with a suitable stopper.
  • the container size allows the resin to be effectively agitated, taking into account that there is sufficient space for the solvent and that certain resins can swell significantly when treated with an organic solvent. Select a size that has ample room.
  • Stirring in solid phase reactions is a shaker suitable for ensuring sufficient mixing, which is a commonly accepted factor for successful reaction on resin (eg, Tokyo Rika Kikai, EYELA, MMS-320, It was carried out at 50-200 rpm using MMS-220H, or AS ONE, MyBL-100CS, or TAITEC, M.BR-104) as appropriate.
  • resin eg, Tokyo Rika Kikai, EYELA, MMS-320, It was carried out at 50-200 rpm using MMS-220H, or AS ONE, MyBL-100CS, or TAITEC, M.BR-104) as appropriate.
  • the equivalent of the reagents is a multiple (equivalent) number of moles with respect to the total number of moles of functional groups used in the reaction of each compound of the mixture on the solid phase side. Indicates whether to use the reagent of. For example, when describing 10 equivalents, it is recommended to use a reagent having a molar number 10 times (10 equivalents) the total number of moles of functional groups used in the reaction of each compound of the mixture on the solid phase side. show.
  • the equivalent of the reagents when the substrate is a mixture is a number of moles (equivalents) of the total number of moles of the functional groups used in the reaction of each compound of the mixture. Indicates whether to use. For example, when it is described as 10 equivalents, it means that a reagent having 10 times (10 equivalents) the number of moles is used with respect to the total number of moles of functional groups used in the reaction of each compound of the mixture.
  • the number of moles of the mixture for example, the following cases can be considered. Unless otherwise specified, any value may be adopted. When individual compounds whose number of moles is known in advance are mixed, the total may be considered as the number of moles of the mixture.
  • the total sum of the prepared solid-phase-supported substrate-supported amount (mmol / g) multiplied by the amount of the solid-phase-supported substrate used is added. It can be thought of as the number of moles of the mixture.
  • the conversion rate of each step may be considered as 100% (that is, the theoretical amount), and when cut out from the solid phase, it is cut out.
  • the reaction may be carried out in the subsequent liquid phase, assuming that the efficiency is 100% (that is, the theoretical amount has been cut out).
  • the notation indicates polystyrene resin, and indicates a state in which the compound is supported on the solid phase.
  • the number in “-01R” indicating that the compound supported on the solid phase used in the examples appears indicates the type of resin used.
  • "01" in “-01R” is supported for brominated Wang resin, 4- (bromomethyl) phenoxymethylpolystyrene (eg, Merck, 4- (benzyloxy) benzyl bromide, polymer-supported).
  • the compound in the state of benzene is shown.
  • "02" in “-02R” is 4- (bromomethyl) phenoxyethyl polystyrene (for example, Merck & Co., 2- (4-bromomethylphenoxy) ethyl polystyrene, sometimes referred to as modified Wang resin in the examples).
  • the compound in the supported state is shown.
  • the solid-phase support compound used for solid-phase synthesis shows the support amount (mmol / g), which indicates the support amount (initial support amount) calculated when the starting material is supported on the solid phase. There is. Since the molecular weight changes due to the ligation reaction of the building blocks, the loading amount after the reaction may differ from the initial loading amount, but the initial loading amount was used throughout the synthesis step. Even when the compounds supported on the solid phase are the same, the amount supported may differ depending on the lot, but the same compound number may be used for the compound number.
  • Example 1 Synthesis of compounds used in the present Example 1-1: Synthesis method of allenol compounds B-001 to B-015 Method of synthesis of substrate (allenol, model compound) used in Examples 2 and subsequent examples. Is shown from the method for synthesizing the building blocks BB-1 to BB-6 and the intermediates (INT1 to INT7) initially used for the synthesis of the allenol compounds (B-001 to B-015).
  • Examples 1-1-1 Synthesis of Building Blocks BB-1 to BB-6 2- (5-Hydroxypyridin-3-yl) benzaldehyde: Synthesis of BB-1
  • Methyl 4-3-fluorobenzoart (3) (1.0 g, 4.3 mmol, 1.0 eq) and MeOH / THF / H 2 O (7.0 mL / 7.0 mL / 7.) in a 100 mL flask under a nitrogen atmosphere. 0 mL) of the mixed solution was added. NaOH (0.5 g, 12.9 mmol, 3.0 eq) was added to this solution, and the obtained reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and the pH was adjusted to 5-6 acidity with 2M HCl.
  • Second step trimethyl- [2- [5- (oxane-2-yloxy) pyridin-3-yl] ethynyl] silane: Synthetic compound BB-4 in a 200 mL flask under a nitrogen atmosphere, 5- (2-trimethylsilylethynyl) Pyridine-3-ol (Compound 4) (2.6 g, 13.6 mmol, 1.0 eq), DHP (R-3) (8.0 g, 95.1 mmol, 7.0 eq) and THF (50 mL) were added. .. PPTS (170 mg, 0.7 mmol, 0.05 eq) was added to this solution, and the resulting reaction mixture was stirred at 70 ° C. for 16 hours.
  • Second step Synthesis of N, N-bis [(4-methoxyphenyl) methyl] -3-methyl-4- (2-phenylsulfanylethylamino) benzenesulfonamide (Compound 9) in a 100 mL flask under a nitrogen atmosphere, 4 -Bromo-N, N-bis [(4-methoxyphenyl) methyl] -3-methylbenzenesulfonamide (Compound 8) (9.0 g, 18.3 mmol, 1.0 eq), 2- (benzenesulfanyl) ethaneamine ( R-5) (3.5 g, 22.9 mmol, 1.25 eq), Cs 2 CO 3 (17.9 g, 55.0 mmol, 3.0 eq) and toluene (30 mL) were added.
  • Second step Synthesis of methyl 4- [4-[(2-bromophenyl) methyl] piperazine-1-yl] benzoato (Compound 12)
  • methyl 4-piperazine-1-ylbenzoato (Compound 11) ) 1.1 g, 5.0 mmol, 1.0 eq
  • DCE 25 mL
  • 2-bromobenzaldehyde (R-7) 1.8 g, 9.9 mmol, 2.0 eq
  • AcOH 0.6 mL
  • tert-butyl 4- (4-methoxycarbonylphenyl) piperazine-1-carboxylate synthesis of compound 13 Methyl 4-fluoro-benzoic acid (10) (5.0 g, 32) in a 200 mL flask under a nitrogen atmosphere. .4 mmol, 1.0 eq), K 2 CO 3 (6.7 g, 48.6 mmol, 1.5 eq) and DMSO (50 mL) were added.
  • Boc-piperazine (R-9) (6.0 g, 32.4 mmol, 1.0 eq) was added to this suspension, and the resulting reaction mixture was stirred at 120 ° C. for 16 hours.
  • Second step 4- [4-[(2-Methylpropan-2-yl) oxycarbonyl] piperazine-1-yl] Benzoic acid: Synthesis of compound 14 In a 200 mL flask under a nitrogen atmosphere, tert-butyl 4- (4) A mixed solution of ⁇ methoxycarbonylphenyl) piperazine-1-carboxylate (Compound 13) (3.7 g, 11.5 mmol, 1.0 eq) and MeOH / THF / H2O (25 mL / 25 mL / 25 mL) was added. NaOH (1.4 g, 34.6 mmol, 3.0 eq) was added to this solution at 35 ° C. and the resulting reaction mixture was stirred at 35 ° C. for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure.
  • N-benzylsulfonyl-4-piperazin-1-ylbenzamide Synthesis of INT3 tert-butyl 4- [4- (benzylsulfonylcarbamoyl) phenyl] piperazin-1-carboxylate (compound) in a 50 mL flask under a nitrogen atmosphere. 15) (0.9 g, 1.9 mmol, 1.0 eq) and DCM (2.0 mL) were added. To this solution was added a 4M-HCl 1,4-dioxane solution (15 mL) and the resulting reaction mixture was stirred at room temperature for 1 hour.
  • N-benzylsulfonyl-4-piperazin-1-ylbenzamide (INT3) (2.0 g, 5.6 mmol, 1.0 eq) and 5-bromopyridine-3-carboxylic acid (BB-2) in a 100 mL flask under a nitrogen atmosphere. ) (1.4 g, 6.7 mmol, 1.2 eq), DMAP (0.7 g, 5.6 mmol, 1.0 eq) and DCM (30 mL) were added.
  • EdCI HCl 2.1 g, 11.1 mmol, 2.0 eq
  • DIPEA 2.9 g, 22.3 mmol, 4.0 eq
  • N-benzylsulfonyl-4-piperazine-1-ylbenzamide (INT3) (0.9 g, 2.4 mmol, 1.0 eq) and N-benzylsulfonyl-4-piperazine-1-ylbenzamide in a 50 mL flask under a nitrogen atmosphere.
  • BB-3 (0.7 g, 3.2 mmol, 1.3 eq)
  • DMAP 0.3 g, 2.4 mmol, 1.0 eq
  • DCM 20 mL
  • Methyl 6- [4-[(2-methylpropan-2-yl) oxycarbonyl] piperazine-1-yl] pyridazine-3-carboxylate Synthesis of compound 17 Methyl 6 in a 1 L flask under a nitrogen atmosphere.
  • K2 CO 3 40 g, 290.7 mmol, 2.5 eq
  • 1,4-dioxane 400 mL
  • Boc-piperazine (R-9) (32.4 g, 174.4 mmol, 1.5 eq) was added to this suspension, and the resulting reaction mixture was stirred at 100 ° C.
  • Second step 6- [4-[(2-Methylpropan-2-yl) oxycarbonyl] piperazine-1-yl] pyridazine-3-carboxylic acid: Synthesis of compound 18 Methyl 6- in a 500 mL flask under a nitrogen atmosphere. [4-[(2-Methylpropan-2-yl) oxycarbonyl] piperazine-1-yl] pyridazine-3-carboxylate (Compound 17) (11.4 g, 35.4 mmol, 1.0 eq) and MeOH (200 mL) ) was added.
  • HATU (10.0 g, 26.3 mmol, 1.5 eq) and DIPEA (9.1 g, 70.1 mmol, 4.0 eq) were added to this solution, and the resulting reaction mixture was stirred at room temperature for 16 hours.
  • a saturated NH 4 Cl aqueous solution (75 mL) was added to the reaction solution, and the mixture was extracted 3 times with DCM (100 mL). The organic solvent was mixed, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • N-benzylsulfonyl-6-piperazine-1-ylpyridazine-3-carboxamide synthesis of INT6 In a 300 mL flask under a nitrogen atmosphere, 6- [4-[(2-methylpropan-2-yl) oxycarbonyl ] Piperazine-1-yl] Pyridazine-3-carboxylic acid (Compound 19) (5.1 g, 11.1 mmol, 1.0 eq) and DCM (30 mL) were added. To this solution was added a 4M-HCl 1,4-dioxane solution (60 mL) and the resulting reaction mixture was stirred at room temperature for 1 hour.
  • N-Benzylsulfonyl-6-piperazine-1-ylpyridazine-3-carboxamide (INT6) (2.0 g, 5.5 mmol, 1.0 eq), 5-bromopyridin-3-carboxylic acid in a 100 mL flask under a nitrogen atmosphere.
  • BB-2 (1.4 g, 6.6 mmol, 1.2 eq) and DCM (40 mL) were added.
  • HATU 3.2 g, 8.3 mmol, 1.5 eq
  • DIPEA DIPEA
  • N-Benzylsulfonyl-6- [4- (4-bromo-3-fluorobenzoyl) piperazine-1-yl] pyridazine-3-carboxamide synthesis of INT8 N-benzylsulfonyl-6-piperazine-1-ylpyridazine-3-carboxamide (INT6) (1.1 g, 3.0 mmol, 1.0 eq) and 4-bromo-3-fluorobenzoic acid in a 50 mL flask under a nitrogen atmosphere. (BB-3) (0.9 g, 4.0 mmol, 1.3 eq) and DCM (20 mL) were added.
  • HATU 1.7 g, 4.6 mmol, 1.5 eq
  • DIPEA 1.6 g, 12.2 mmol, 4.0 eq
  • a saturated NH 4 Cl aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted 3 times with DCM (40 mL). The organic solvent was mixed, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • N-benzylsulfonyl-4-piperazin-1-ylbenzamide (INT-3) (0.3 g, 0.9 mmol, 1.0 eq) and EtOH / DMSO (5.0 mL / 5.0 mL) in a 50 mL flask under a nitrogen atmosphere. ) was added.
  • 2- (5-hydroxypyridin-3-yl) benzaldehyde (BB-1) (0.3 g, 1.7 mmol, 2.0 eq) and AcOH (0.8 mL) was stirred at room temperature for 1 hour.
  • N-benzylsulfonyl-4- [4- [5- [2- [5- (oxane-2-yloxy) pyridine-3-yl] ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide compound 20 Synthesis of N-benzylsulfonyl-4- [4- (5-bromopyridin-3-carbonyl) piperazine-1-yl] benzamide (INT-4) (0.5 g, 0.9 mmol,) in a 50 mL flask under a nitrogen atmosphere.
  • N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide Synthesis of B-003 Under nitrogen atmosphere In a 30 mL flask, N-benzylsulfonyl-4- [4- [5- [2- [5- (oxan-2-yloxy) pyridin-3-yl] ethynyl] pyridine-3-carbonyl] piperazine-1-yl] A mixed solution of benzamide (Compound 20) (0.6 g, 0.9 mmol, 1.0 eq) and EtOH / NMP (5.0 mL / 3.0 mL) was added.
  • N-benzylsulfonyl-4- [4- (4-bromo-3-fluorobenzoyl) piperazin-1-yl] benzamide (INT-5) (0.3 g, 0.6 mmol, 1. 0 eq), 3-Hydroxy-5-Pyridineboronic acid pinacol ester (R-11) (276.1 mg, 1.2 mmol, 2.0 eq), Na 2 CO 3 (86.0 mg, 0.8 mmol, 1.3 eq) And DME / EtOH / H 2 O (6.0 mL / 6.0 mL / 6.0 mL) mixed solution was added.
  • reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative HPLC (XBridge C18 OBD Prep Colon) (33-50% CH 3 CN / 0.1% formic acid aqueous solution), and N-benzylsulfonyl- 6- [4- [5- [2- (5-Hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazin-1-yl] pyridazine-3-carboxamide (B-005) as a pale yellow solid Obtained (88.9 mg, 25.3%).
  • reverse phase preparative HPLC XBridge C18 OBD Prep Colon
  • N-benzylsulfonyl-6- [4- (4-bromo-3-fluorobenzoyl) piperazin-1-yl] pyridazine-3-carboxamide (INT-8) (0.3 g, 0. 6 mmol, 1.0 eq), 3-hydroxy-5-pyridineboronic acid pinacol ester (R-11) (275.0 mg, 1.2 mmol, 2.0 eq), Na 2 CO 3 (85.8 mg, 0.8 mmol, A mixed solution of 1.3 eq) and DME / EtOH / H 2 O (5.0 mL / 5.0 mL / 5.0 mL) was added.
  • N-benzylsulfonyl-6- [4- (4-bromo-3-fluorobenzoyl) piperazine-1-yl] pyridazine-3-carboxamide (INT-8) (0.5 g, 1. 0 mmol, 1.0 eq)
  • 4-hydroxybenzeneboronic acid (R-10) (269.8 mg, 2.0 mmol, 2.0 eq)
  • Na 2 CO 3 134.7 mg, 1.3 mmol, 1.3 eq
  • a mixed solution of DME / EtOH / H 2 O 7.0 mL / 7.0 mL / 7.0 mL
  • N-benzylsulfonyl-4- [4- [5- [2- [4- (oxane-2-yloxy) phenyl] ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide Synthesis of compound 22 Nitrogen atmosphere In the lower 30 mL flask, N-benzylsulfonyl-4- [4- (5-bromopyridin-3-carbonyl) piperazine-1-yl] benzamide (INT-4) (0.5 g, 0.9 mmol, 1.0 eq).
  • Trimethyl- [2- [4- (oxan-2-yloxy) phenyl] ethynyl] silane (BB-5) (378.8 mg, 1.4 mmol, 1.5 eq) and TEA / THF / NMP (4.0 mL / A mixed solution of 5.0 mL / 3.0 mL) was added.
  • CuI (17.5 mg, 0.09 mmol, 0.1 eq)
  • PPh 3 (24.1 mg, 0.09 mmol, 0.1 eq)
  • PdCl 2 (PPh 3 ) 2 (64.6 mg, 0.09 mmol) were added to this solution.
  • N-benzylsulfonyl-4- [4- [5- [2- (4-hydroxyphenyl) ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide Synthesis of B-008 In a 30 mL flask under a nitrogen atmosphere, N-benzylsulfonyl-4- [4- [5- [2- [4- (oxane-2-yloxy) phenyl] ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide (Compound 22) (0.
  • N-benzylsulfonyl-4- [4-[(2-bromophenyl) methyl] piperazine-1-yl] benzamide (INT-2) (2.0 g, 3.8 mmol, 1.0 eq) in a 100 mL flask under a nitrogen atmosphere. ), 5- (2-trimethylsilylethynyl) Pyridine-3-ol (Compound 4) (2.9 g, 15.1 mmol, 4.0 eq), Cs 2 CO 3 (3.7 g, 11.2 mmol, 3.0 eq) And NMP (20 mL) were added.
  • N-Benzylsulfonyl-4- [4- [[2- [2- [4- (Oxan-2-yloxy) phenyl] ethynyl] phenyl] methyl] piperazine-1-yl] benzamide Synthesis of compound 23 Under nitrogen atmosphere In a 30 mL flask, INT-2 (0.7 g, 1.3 mmol, 1.0 eq), BB-5 (1.4 g, 5.3 mmol, 4.0 eq), Cs 2 CO 3 (1.3 g, 4.0 mmol). , 3.0 eq) and NMP (7.0 mL) were added.
  • N-Benzylsulfonyl-4- [4- [[2- [2- (4-hydroxyphenyl) ethynyl] phenyl] methyl] piperazine-1-yl] benzamide Synthesis of B-010 In a 30 mL flask under a nitrogen atmosphere, N -Benzylsulfonyl-4- [4- [[2- [2- [4- (Oxan-2-yloxy) phenyl] ethynyl] phenyl] methyl] piperazine-1-yl] benzamide (Compound 23) (0.4 g, 0.6 mmol, 1.0 eq) and 4M-HCl 1,4-dioxane solution (5.0 mL) were added.
  • the obtained crude product was further purified (37 to 59% CH 3 CN / 10 mmol / L ammonium hydrogencarbonate aqueous solution) by reverse-phase preparative HPLC (XBridge Solid RP18 OBD column), and 4- [4- [[2]. -(4-Hydroxyphenyl) phenyl] methyl] piperazine-1-yl] -N- [3-methyl-4- (2-phenylsulfanylethylamino) phenyl] sulfonylbenzamide (B-011) is obtained as an off-white solid. (37.9 mg, 12.3%).
  • N- (benzenesulfonyl) -4-piperazin-1-ylbenzamide Synthesis of compound 27 In a 100 mL flask under a nitrogen atmosphere, tert-butyl 4- [4- (benzenesulfonylcarbamoyl) phenyl] piperazine-1- Carboxylate (Compound 26) (2.2 g, 4.9 mmol, 1.0 eq) and DCM (8.0 mL) were added. To this solution was added a 4M-HCl 1,4-dioxane solution (40 mL) and the resulting reaction mixture was stirred at room temperature for 1 hour.
  • N- (benzenesulfonyl) -4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl] methyl] piperazine-1-yl] benzamide Synthesis of B-014 Under a nitrogen atmosphere In a 50 mL flask, N- (benzenesulfonyl) -4-piperazin-1-ylbenzamide (Compound 27) (0.4 g, 1.0 mmol, 1.0 eq) and EtOH / DMSO (4.0 mL / 6.0 mL) The mixed solution was added.
  • N-benzylsulfonyl-4- [4- (4-bromo-3-fluorobenzoyl) piperazine-1-yl] benzamide (INT-5) (0.5 g, 0.8 mmol, 1. 0 eq), 3-hydroxybenzeneboronic acid (R-10) (221.5 mg, 1.6 mmol, 2.0 eq), Na 2 CO 3 (110.6 mg, 1.0 mmol, 1.3 eq) and DME / EtOH / A mixed solution of H2O (7.0 mL / 7.0 mL / 7.0 mL) was added.
  • Example 1-2 Model Substrate Synthesis
  • Example 1-21 Compound B-016 (tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazine-1-carboxylate) Synthetic
  • 6-Chloropyridazine-3-carboxylic acid (BR-32, CAS: 5096-73-1) (1.0 g, 6.3 mmol), 1-Boc piperazine (R-9, CAS:) in a 50 mL eggplant flask. 57260-71-6) (1.8 g, 9.5 mmol, 1.5 eq), DIPEA (3.3 mL, 18.9 mmol, 3.0 eq) and CH 3 CN (15 mL) were added and the flask was decompressed. After the air, the inside of the reaction mixture was converted into a nitrogen atmosphere by introducing nitrogen. The reaction was heated at 100 ° C. for 16 hours. After cooling the reaction solution to room temperature, the reaction solvent was concentrated under reduced pressure.
  • Example 1 using 3-bromopyridine (BR-24) (241.0 ⁇ L, 2.5 mmol) and aniline (BR-25) (273.0 ⁇ L, 3.0 mmol, 1.2 eq). The synthesis was carried out in the same manner as in -2-5 to obtain the title compound (N-phenylpyridine-3-amine) (Compound B-047) (358.0 mg, 84.0%) as an off-white solid.
  • LCMS (ESI, m / z): 170.9 [M + H] + . Retention time: 0.471 minutes (analytical conditions SMD-FA05-1).
  • Example 1-2-8 Synthesis of N-Pyridine-3-ylpyridine-3-amine: B-049 3-bromopyridine (BR-24) (241.0 ⁇ L, 2.5 mmol), 3-aminopyridine (BR-27) (282.0 mg, 3.0 mmol, 1.2 equivalents) were used. Synthesized in the same manner as in Example 1-2-5, the title compound (N-pyridin-3-ylpyridine-3-amine) (Compound B-049) (354.8 mg, 83.0%) as a brown solid was obtained. Obtained.
  • Example 1-2-9 Synthesis of N-Phenylpyridine-2-amine: B-050
  • Example 1 using 2-bromopyridine (BR-28) (238.0 ⁇ L, 2.5 mmol) and aniline (BR-25) (273.0 ⁇ L, 3.0 mmol, 1.2 eq). The synthesis was carried out in the same manner as in -2-5 to obtain the title compound (N-phenylpyridine-2-amine) (Compound B-050) (57.5 mg, 13.5%) as an off-white solid.
  • Example 1-3 Ethylized product standard of model substrate: Synthesis of B-053 to B075 Four methods shown in Examples 1-3-1 to 1-3-4 for the ethylened product standard of the model substrate. The retention time was measured and mass spectrometry was performed by LCMS.
  • Examples 1-3-1 Ethylation reaction using NaH as a base: Synthesis method A The reaction to the model substrate (tert-butyl 4- [4- (2,2,2-trifluoroethylcarbamoyl) phenyl] piperazine-1-carboxylate: B-044) was carried out in the ethylation reaction using NaH as a base. It is shown as a representative example.
  • reaction follow -up Two hours after the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. Retention time was measured and mass spectrometry was performed by LCMS. According to the synthesis method A, the reaction was carried out using the group mass and the solvent shown in Table 1-3, and the retention time was measured and mass spectrometry was performed by LCMS.
  • Example 1-3-2 Ethylation reaction using K 2 CO 3 as a base: Synthesis method B The reaction to the reagent (N-butylaniline: BR-11) is shown as a typical example of the ethylation reaction using K2 CO 3 as a base.
  • N- butylaniline (BR-11) (75.0 mg, 0.5 mmol) and K2 CO 3 ( 104.0 mg, 0.75 mmol, 1.5 eq).
  • NMP (1.3 mL) was added.
  • Ethyl iodide (48.0 ⁇ L, 0.6 mmol, 1.2 eq) was added to the suspension. The obtained reaction solution was stirred at 100 ° C. for 3 hours.
  • reaction follow -up After 3 hours from the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. Retention time was measured and mass spectrometry was performed by LCMS. According to the synthesis method B, the reaction was carried out with the group mass, solvent and reaction temperature shown in Table 1-3, and the retention time was measured and mass spectrometry was performed by LCMS.
  • N, N-dimethylbenzylamine (BR-1) 5 (68.0 mg, 0.5 mmol) and CH 3 CN (1.0 mL) were added to a 2.0 mL glass vial.
  • the obtained reaction solution was stirred at 80 ° C. for 1.5 hours.
  • reaction follow -up After 1.5 hours from the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. Retention time was measured and mass spectrometry was performed by LCMS.
  • reaction follow -up One hour after the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The retention time was measured by LCMS. According to the synthesis method D, the reaction was carried out at the base mass shown in Table 1-3, and the retention time was measured by LCMS.
  • ethylated products in Tables 1-3 and Run1 and 2 are described as N-ethyl products, they may be O-ethyl products. Further, although it is described as a diallylamine-N-ethyl form in Runs 5 to 10, since it has two or more reaction points, it may be other than the N-ethyl form. In particular, in Run 5 to 8, two types of monoethyl compounds are observed, so two retention times are shown.
  • Example 1-4 Allenol compound B-080 (6- [4-[[2- (3-hydroxyphenyl) phenyl] methyl] piperazine-1-yl] -N- (4-methoxyphenyl) pyridazine-3- Carboxamide) synthesis method
  • N- (4-methoxyphenyl) -6-piperazine-1-ylpyridazine-3-carboxamide synthesis of compound 31 tert-butyl 4- [6-[(4-methoxy) in a 100 mL flask under a nitrogen atmosphere. Phenyl) carbamoyl] pyridazine-3-yl] piperazine-1-carboxylate (Compound 30) (1.4 g, 3.4 mmol, 1.0 eq) and DCM (30 mL) were added. To this solution was added a 4M-HCl 1,4-dioxane solution (20 mL) and the resulting reaction mixture was stirred at room temperature for 16 hours.
  • Example 1-5 Carboxylic acid compound B-082 (3- [2-[[4- [4-[[3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonylcarbamoyl] phenyl] piperazine- 1-Il] Methyl] Phenyl] Benzoic acid) synthesis method
  • Example 1-6 Carboxylic acid compound B-084 (5- [2-[[4- [4- [[3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonylcarbamoyl] phenyl] piperazine- 1-yl] methyl] phenyl] pyridine-3-carboxylic acid) synthesis method
  • Second step 5- [2-[[4- [4- [[3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonylcarbamoyl] phenyl] piperazine-1-yl] methyl] phenyl] pyridine -3-Carboxylic acid: Synthesis of carboxylic acid compound B-084 In a 30 mL flask under a nitrogen atmosphere, methyl 5- [2-[[4- [4- [[3-Nitro-4- (2-phenylsulfanyl ethylamino)) Phenyl] sulfonylcarbamoyl] phenyl] piperazin-1-yl] methyl] phenyl] pyridine-3-carboxylate (Compound 33) (0.4 g, 0.5 mmol, 1.0 eq) and THF (8.0 mL) were added.
  • Example 2 Examination of O-selective methylation of allenol to a substrate having various functional groups in the molecule
  • Example 2-1 Compound B-001: N-benzylsulfonyl-4- [4-[[ Examination of various methylating agents using 2- (4-hydroxyphenyl) phenyl] methyl] piperazin-1-yl] benzamide (phenol) O-selective methylation of allenol to substrates with various functional groups
  • a methylating agent electrostatic agent
  • Example 2-1-1 Methylation of phenol with trimethylphenylammonium chloride BR-01
  • N-benzylsulfonyl-4- [4-[[2- (4-hydroxyphenyl) phenyl] methyl] piperazine-1-yl] benzamide (B) -001) (2.7 mg, 5.0 ⁇ mol, 1.0 equivalent) and DMF (50.0 ⁇ L) were added.
  • K 2 CO 3 2.1 mg, 15.0 ⁇ mol, 3.0 eq
  • trimethylphenylammonium chloride BR-01
  • 25.0 ⁇ mol, 5.0 eq was added.
  • the resulting reaction mixture was stirred at 80 ° C. and 1400 rpm. Note that rpm is an abbreviation for "rotations per minute” and indicates the number of revolutions per minute. "Stirring at 1400 rpm” means stirring at 1400 rpm.
  • Example 2-1-2 Methylation of phenol using dimethyl B-R-02 carbonate, trimethyl BR-03 phosphate, methyl para-toluenesulfonate BR-04
  • Example 2-1-1 In the same manner as above, instead of trimethylphenylammonium chloride (BR-01), dimethyl carbonate (BR-02) (2.3 mg, 25.0 ⁇ mol, 5.0 equivalents), trimethyl phosphate (B). -R-03) (2.9 ⁇ L, 25.0 ⁇ mol, 5.0 equivalents) Methyl para-toluenesulfonate (BR-04) (4.7 mg, 25.0 ⁇ mol, 5.0 equivalents) was used, respectively. And reacted.
  • BR-01 trimethylphenylammonium chloride
  • BR-02 dimethyl carbonate
  • B trimethyl phosphate
  • -R-03 2.9 ⁇ L, 25.0 ⁇ mol, 5.0 equivalents
  • methyl para-toluenesulfonate (BR-04) which is used as a general methylating agent, has decreased functional group selectivity due to its high reactivity, and there are two sites in the substrate. It was confirmed that it was methylated (it has not been identified at which position in the molecule it was methylated in two places). Therefore, it was confirmed that the use of methyl para-toluenesulfonate (BR-04) for this purpose is inappropriate (Table 2-1 and Run4).
  • Example 2-2 Compound B-002: N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridine-3-yl) phenyl] methyl] piperazine-1-yl] benzamide (pyridinol) as a substrate ) was used to examine the combination of various methylating agents and bases.
  • the range of suitable methylating agents could be specified.
  • the substrate B-002 (pyridinol), which has more types of functional groups than the substrate B-001 (phenol), was used, and the specified range of methylating agents and bases was confirmed.
  • the term "pyridinol” refers to a compound having a hydroxy group on any carbon of the pyridine ring. At this time, it also refers to a carbon having an arbitrary substituent on other carbons constituting the pyridine ring.
  • Example 2-2-1 Pyridinol B-002: N-benzylsulfonyl-4- [4-[[2- (4-methoxyphenyl) phenyl] methyl) using trimethylphenylammonium chloride (BR-01) ] Piperazine-1-yl] Methylation of benzamide (correlation between the size of the stirrer and the conversion rate due to the difference in the number of revolutions) (Table 2-2, Run1 (350 rpm))
  • N-benzylsulfonyl-4- [4-[[2- (4-methoxyphenyl) phenyl] methyl] piperazine-1-yl] benzamide (B) -002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • Cs 2 CO 3 (6.8 mg, 21.0 ⁇ mol, 3.0 eq) was added to the obtained solution to confirm mixing, and then trimethylphenylammonium chloride (BR-01) (6.0 mg, 35.0 ⁇ mol,). 5.0 equivalent) was added.
  • the resulting reaction mixture was stirred at a rotation speed of 350 rpm at 80 ° C.
  • Example 2-2-2 Pyridinol B-002 using trimethylphenylammonium chloride
  • BR-01 N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl) ] Methyl] Piperazine-1-yl] Methylation of benzamide (correlation between the size of the stirrer and the conversion rate due to the difference in the number of revolutions) (Table 2-2, Run2 (1400 rpm))
  • Benzamide (B-002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • Example 2-2-3 Pyridinol B-002 using trimethylphenylammonium chloride
  • BR-01 N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl) ] Methyl] Piperazine-1-yl] Methylation of benzamide (Phenyl group base study) (Table 2-2, Run3-5)
  • Benzamide (B-002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • Phosphazene base P1tBu (5.3 ⁇ L, 21.0 ⁇ mol, 3.0 eq, Run3) was added to the obtained solution to confirm mixing, and then trimethylphenylammonium chloride (BR-01) (6.0 mg, 35.0 ⁇ mol). , 5.0 equivalents) was added. The resulting reaction mixture was stirred at 80 ° C. for 3 hours at a rotation speed of 1400 rpm.
  • a reaction using BEMP (6.1 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run4) or P2Et (7.0 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run5) instead of the phosphazene base P1tBu. was carried out in the same manner.
  • Example 2-2-4 Pyrizinol B-002 using P2Et as a base: N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl] methyl] piperazine-1 -Il] Benzamide: Methylation (examination of Me agent) (Table 2-2, Run6-7) In a nitrogen-substituted glove bag, in a 0.6 mL screw cap vial, N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl] methyl] piperazine-1-yl ] Benzamide (B-002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • Examples 2-3 Compound B-003: N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazin-1 as a substrate -Il] Examination of methylation using benzamide (pyridinol) Regarding the reaction conditions for methylation confirmed in Example 2-2, further substrate B-003: N-benzylsulfonyl-4- [4- [5- [5-] The functional group selectivity of the reaction was confirmed using [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazine-1-yl] benzamide.
  • the holding time of the raw material ArOH is 0.888 minutes (analytical condition SMD-FA05-1).
  • the substrate B-003 containing an acetylene group and a pyridine ring (pyridinol: N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3] It was shown that this reaction condition can be applied as a highly selective O-methylation method of allenol even when ⁇ carbonyl] piperazin-1-yl] benzamide) is used.
  • O-selective methylation of allenol can be achieved for a substrate having many functional groups that can be methylated (specifically, a pyridine ring, a tertiary amine, an acyl sulfonamide). Shown. This result shows that O- is highly selective not only for application to a single substrate having various functional groups in the molecule, but also for a compound library containing multiple substrates containing these functional groups. It shows that selective methylation is possible.
  • Example 3 Examination of O-selective ethylation of allenol to a substrate having various functional groups in the molecule As shown in Example 2, O-selective methylation of allenol is carried out by an organic base / trimethylammonium salt. Alternatively, it could be achieved by using trimethyl phosphate as a methylating agent. Based on this finding, O-selective ethylation was investigated using an ammonium salt and triethyl phosphate.
  • Examples 3-1 Compound B-002: N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl] methyl] piperazine-1-yl] benzamide (pyridinol) as a substrate ) O-selective ethylation of pyridinol
  • Example 3-1-1 Compound B-002 using an ammonium salt as an ethyling agent
  • B-002 N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridin-3-yl) phenyl] methyl] N- Benzylsulfonyl -4- [4-[2-( 5-Hydroxypyridin-3-yl) phenyl] methyl] piperazine-1-yl] benzamide (B-002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • Example 3-1-2 Substrate using triethyl phosphate as an ethyling agent B-002: N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridine-3-yl) phenyl] methyl] ] Piperazin-1-yl] benzamide: N-benzylsulfonyl-4- [4-[[2- (5-hydroxypyridine-3-yl) phenyl] methyl] piperazin-1-yl] benzamide (pyridinol) O- Selective ethylation
  • Benzamide (B-002) (3.8 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • P2Et 7.0 ⁇ L, 21.0 ⁇ mol, 3.0 eq
  • BR-05 triethyl phosphate
  • Example 3-1-3 Substrate using P2tBu which is a bulky phosphazene base and using triethyl phosphate as an ethyling agent
  • B-002 N-benzylsulfonyl-4- [4-[[2- (5- (5- (5-) Hydroxypyridine-3-yl) phenyl] methyl] piperazin-1-yl] benzamide (pyridinol) in an O-selective ethylened nitrogen-substituted glove bag in a 0.6 mL screw cap vial with N-benzylsulfonyl.
  • the Ratio (O- / N-) shown in Table 3-1 is (area% of O-ethylated product (B-023)) / (area% of N-ethylated product (B-024)). Calculated as. The results of Example 3-1 are shown in Table 3-1. [Table 3-1]
  • substrate B-002 achieved O-selective ethylation (Table 3-1 and Run2).
  • O-selective ethylation could be achieved by using P2tBu as a base, which has the same basicity (pKBH + value) and is bulkier than P2Et (Table 3-1 and Run3).
  • Example 3-2 Compound B-004: N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl] benzamide as a substrate. O-selective ethylation of the pyridinol used
  • Example 3-2-1 Substrate using ammonium salt as an ethyling agent B-004: N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl) ] Piperazin-1-yl] benzamide) (pyridinol) in an O-selective ethylened nitrogen-substituted glove bag in a 0.6 mL screw cap vial, N-benzylsulfonyl-4- [4- [3- [3- [3-]
  • N-benzylsulfonyl-4- [4- [4- (5-ethoxypyridin-3-yl) -3-fluorobenzoyl] piperazine-1-yl] benzamide compound B-025.
  • Example 3-2-2 Substrate using triethyl phosphate as an ethyling agent B-004: Pyrizinol, N-benzylsulfonyl-4- [4- [3-Fluoro-4- (5-hydroxypyridine-3-3)] Il) Benzoyl] piperazin-1-yl] benzamide in an O-selective ethylened nitrogen-substituted glove bag, in a 0.6 mL screw cap vial, pyridinol, N-benzylsulfonyl-4- [4- [3].
  • the reaction was carried out in the same manner as in 1-2, and the degree of reaction progress was measured. The results are as shown in Table 3-2 and Run2.
  • Example 3-2 The results of Example 3-2 are shown in Table 3-2.
  • the Ratio (O- / N-) shown in Table 3-2 is (area% of O-ethylated product (B-025)) / (area% of N-ethylated product (B-026)). Calculated as.
  • the substrate B-004 is also capable of O-selective ethylation under the reaction conditions using triethyl phosphate / P2Et (Table 3-2, Run2). ..
  • the pyridine of the substrate B-004 with respect to the substrate B-002 becomes more electron deficient due to the influence of the fluoro group and the amide group (carbonyl group) on the adjacent benzene ring.
  • N-ethylation was suppressed.
  • the O-selectivity was improved as compared with the case where B-002 was used as a substrate.
  • Example 3-3 As a compound having an acetylene functional group, substrate B-003: N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3] -Carbonyl] piperazin-1-yl] benzamide, B-005: N-benzylsulfonyl-6- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazine -1-Il] O-selective ethylation of pyridinol with pyridazine-3-carboxamide
  • Example 3-3-1 Substrate using triethyl phosphate as an ethyling agent B-005: N-benzylsulfonyl-6- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl) ] Pyridine-3-carbonyl] Piperazine-1-yl] Pyridazine-3-carboxamide (pyridinol) O-selective ethylation
  • Example 3-3-2 Substrate by triethyl phosphate using P2Et as a base
  • B-003 N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridin-3-yl) ethynyl) ] Pyridine-3-carbonyl] piperazin-1-yl] O-selective ethylened nitrogen-substituted glove bag of benzamide (pyridinol) in a 0.6 mL screw cap vial, N-benzylsulfonyl-4- [ 4- [5- [2- (5-Hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazin-1-yl] benzamide (B-003) (4.1 mg, 7.0 ⁇ mol, 1.0) Equivalent amount) and DMF (70.0 ⁇ L) were added.
  • Example 3-3-3 Substrate using P2tBu, which is a bulky phosphazene base, and using triethyl phosphate as an ethyling agent
  • B-003 N-benzylsulfonyl-4- [4- [5- [2- ( 5-Hydroxypyridin-3-yl) ethynyl] pyridine-3-carbonyl] piperazin-1-yl] O-selective ethylation of benzamide (pyridinol) (avoiding the formation of base adducts)
  • Benzamide (B-003) (4.1 mg, 7.0 ⁇ mol, 1.0 equivalent) and D
  • Example 3-4 Experiment for confirming selectivity for amide group during ethylization
  • the O-selective ethylation condition of allenol by the combination with triethyl phosphate / phosphazene base shown so far can be carried out in the presence of the amide group. I confirmed that. Specifically, as confirmed in Examples 3-1 to 3-3, the selectivity is not evaluated using a substrate in which allenol and other functional groups coexist in one molecule, but here.
  • An amide substrate (tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazin-1-carboxylate) (B-016) was used as a model substrate, and allenol could be selectively ethylened. It was decided to confirm by showing that the amide substrate B-016 was not ethylened under the conditions found in Example 3-3.
  • Examples 3-4-1 tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazine-1-carboxylate using P2tBu as a base and triethyl phosphate as an ethyling agent ( In a 0.6 mL screw cap vial in a glove bag substituted with ethylened nitrogen of B-016) (amide model substrate) , tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazine.
  • -1-carboxylate (B-016) (4.1 mg, 10.0 ⁇ mol, 1.0 equivalent) and DMF (100.0 ⁇ L) were added.
  • Example 3-4-2 tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazine-1-carboxylate using P2Et as a base and triethyl phosphate as an ethyling agent ( In a 0.6 mL screw cap vial in a glove bag substituted with ethylened nitrogen of B-016) (amide model substrate) , tert-butyl 4- [4-[(4-fluorophenyl) methylcarbamoyl] phenyl] piperazine.
  • -1-carboxylate (B-016) (4.1 mg, 10.0 ⁇ mol, 1.0 equivalent) and DMF (100.0 ⁇ L) were added.
  • Example 3-4-3 tert-butyl 4- [4-[()) using phosphazene (BEMP, P1tBu) having a pKBH + (pKa of a conjugate acid) of 30 or less as a base and triethyl phosphate as an ethyling agent.
  • B-016 amide model substrate
  • Example 3-4-2 The extent of reaction was measured in the same manner as in Example 3-4-2. The results are as shown in Tables 3-4 and Runs 3 and 4. The results of Example 3-4 are shown in Table 3-4.
  • the pKBH + value in CH 3 CN shown in Table 3-4 is the website of Aldrich, Phosphazene Bases site (https://www.sigmaaldrich.com/chemistry/chemical-synthesis/techn). Posted from https) (viewed on December 2, 2020).
  • Run1 & 2 when a highly basic base with pKBH + (pKa of conjugate acid) of 30 or more is present, the amide reacts with triethyl phosphate to form an N- or O-ethylated product. Gave. This indicates that the amide functional group cannot withstand the ethylation condition under the basic condition of pKBH + of 30 or more.
  • Run3 & 4 when a base having pKBH + of 30 or less was present in the reaction, ethylation of the amide did not proceed.
  • Example 3-5 Confirmation of optimum conditions for ethylation reaction assuming that the substrate has an amide bond. As shown in Example 3-4, pKBH + (pKa of conjugated acid) is 30 or less. O-selective ethylation of allenol using a base is performed by N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazin-1-yl].
  • Benzamide (B-004) and N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridin-3-carbonyl] piperazin-1-yl] benzamide (B) -003) was used as a substrate for examination.
  • Examples 3-5-1 N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl] benzamide (B-004) ( Optimal base study in O-selective ethylation using pyridinol) as a substrate
  • Benzamide (B-004) (4.0 mg, 7.0 ⁇ mol, 1.0 equivalent) and DMF (70.0 ⁇ L) were added.
  • P1tBu (5.3 ⁇ L, 21.0 ⁇ mol, 3.0 eq, Run1) was added to the solution to confirm mixing, and then triethyl phosphate (BR-05) (6.0 ⁇ L, 35.0 ⁇ mol, 5.0 eq) was added. ) was added.
  • the resulting reaction mixture was stirred at a rotation speed of 800 rpm at 80 ° C.
  • the same reaction was carried out using BEMP (6.1 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run2) or BTPP (6.4 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run3) instead of P1tBu. did.
  • Example 3-5-1 The results of Example 3-5-1 are shown in Table 3-5-1.
  • the pKBH + value in CH 3 CN shown in Table 3-5-1 is the Phosphazene Bases site (https://www.sigmaaldrich.com/chemistry/chemical-synthesis/techn) of Aldrich. Posted from phosphazenes.html) (viewed December 2, 2020).
  • the Ratio (O- / N-) shown in Table 3-5-1 is (area% of O-ethylated product (B-025)) / (area% of N-ethylated product (B-026)). %). [Table 3-5-1]
  • Example 3-5-2 N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazine-1-with acetylene bond Il]
  • the resulting reaction mixture was stirred at a rotation speed of 800 rpm at 80 ° C.
  • the same reaction was carried out using BEMP (6.1 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run2) or BTPP (6.4 ⁇ L, 21.0 ⁇ mol, 3.0 equivalent, Run3) instead of P1tBu. did.
  • Example 3-5-2 The results of Example 3-5-2 are shown in Table 3-5-2.
  • the pKBH + value in CH 3 CN shown in Table 3-5-2 is the Phosphazene Bases site (https://www.sigmaaldrich.com/chemistry/chemical-synthesis/techn) of Aldrich. Posted from phosphazenes.html) (viewed December 2, 2020).
  • the Ratio (O- / N-) shown in Table 3-5-2 is (area% of O-ethylated product (B-029)) / (area% of N-ethylated product (B-030)). %).
  • Examples 3-5 show that when the base used in the reaction is pKBH +30 or less and a bulky base, particularly BTPP, is selected as the base, a sufficient reaction rate for synthesis and high O-selectivity can be achieved. It is shown (Table 3-5-1, Run3, Table 3-5-2, Run3).
  • Example 3-5-3 N-benzylsulfonyl-6- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl] pyridazine- as a substrate having pyridazine
  • B-006 Optimal base study in O-selective ethylation with 3-carboxamide
  • P2Et (34.9 ⁇ L, 105.0 ⁇ mol, 15.0 eq) was added to the solution to confirm mixing, and then triethyl phosphate (BR-05) (17.9 ⁇ L, 105.0 ⁇ mol, 15.0 eq) was added. added.
  • the resulting reaction mixture was stirred at a rotation speed of 800 rpm at 80 ° C.
  • the Ratio (O- / N-) shown in Table 3-5-3 is (area% of O-ethylated product (B-034)) / (area% of N-ethylated product (B-035)). %).
  • the pKBH + value in CH 3 CN shown in Table 3-5-3 is the Phosphazene Bases site (https://www.sigmaaldrich.com/chemistry/chemical-synthesis/techn) of Aldrich. Phosphazenes. Html) (accessed December 2, 2020), as well as non-patent literature (Chem. Eur. J. 2021,27, 4216-4229).
  • Example 3-6 Confirmation of the effect when a large excess of the reagent is used for the substrate assuming a compound library which is a mixture of a plurality of substrates When a plurality of substrates are mixed, a reagent for one substrate is used. Will have a large excess.
  • the effects of the large excess of reagents are described in N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl]. Confirmation was performed using benzamide (B-004) as a substrate.
  • Example 3-6-1 N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl] benzamide (B-004) ( Examination of O-selective ethylation under excess reagent conditions using pyridinol) as a substrate
  • reaction follow -up 2.5, 7, 23 hours after the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The extent of reaction was measured by performing LCMS measurement.
  • Examples 3-6-2 N-benzylsulfonyl-4- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazine-1-yl] benzamide (B-004) ( Examination of O-selective ethylation using pyridinol) as a substrate and DMI as a reaction solvent Using DMI (70.0 ⁇ L) as a reaction solvent, the reaction was carried out in the same manner as in Example 3-6-1.
  • Example 3-7 Confirmation of substrate generality under the reaction conditions set in Example 3-6-3
  • the reaction conditions set in Example 3-6-3 are applied to the substrate having various functional groups, and the substrate is generally used. I confirmed the sex.
  • Example 3-7-1 N-benzylsulfonyl-6- [4- [3-fluoro-4- (5-hydroxypyridin-3-yl) benzoyl] piperazin-1-yl] pyridazine- as a substrate having pyridazine Confirmation of O-selective ethylation with 3-carboxamide (B-006)
  • BTPP 32.1 ⁇ L, 105.0 ⁇ mol, 15.0 eq
  • BR-05 triethyl phosphate
  • Example 3-7-1 The results of Example 3-7-1 are shown in Table 3-7-1.
  • the Ratio (O- / N-) shown in Table 3-7-1 is (area% of O-ethylated product (B-034)) / (area% of N-ethylated product (B-035)). %). [Table 3-7-1]
  • Example 3-7-2 N-benzylsulfonyl-6- [4- [3-fluoro-4- (4-hydroxyphenyl) benzoyl] piperazine-1-yl] pyridazine-3-carboxamide as a substrate having pyridazine ( Confirmation of O-selective ethylation using B-007)
  • N-benzylsulfonyl-6- [4- [3-fluoro-4- (4-hydroxyphenyl) benzoyl] piperazine-1-yl] pyridazine-3-carboxamide (B-007) (4.0 mg, 7.0 ⁇ mol
  • the reaction was carried out in the same manner as in Example 3-7-1 using 1.0 equivalent), and the extent of reaction was measured. The results are as shown in Table 3-7-2, Run1.
  • Example 3-7-2 The results of Example 3-7-2 are shown in Table 3-7-2. [Table 3-7-2]
  • Example 3-7-3 N-benzylsulfonyl-6- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] piperazine as a substrate having an acetylene functional group -1-yl] pyridazine-3-carboxamide (B-005) and N-benzylsulfonyl-4- [4- [5- [2- (5-hydroxypyridine-3-yl) ethynyl] pyridine-3-carbonyl] O-selective ethylation of pyridinol with piperazin-1-yl] benzamide (B-003)
  • Example 3-7-3 The results of Example 3-7-3 are shown in Table 3-7-3.
  • the Ratio (O ⁇ / N ⁇ ) shown in Table 3-7-3 was calculated as (area% of O-ethylated product) / (area% of N-ethylated product).
  • Examples 3-7-4 N-benzylsulfonyl-4- [4- [5- [2- (4-hydroxyphenyl) ethynyl] pyridine-3-carbonyl] piperazine-1-yl as a substrate having an acetylene functional group ] O-selective ethylation of phenol with benzamide (B-008)
  • N-benzylsulfonyl-4- [4-5- [2- (4-hydroxyphenyl) ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide (B-008) (4.1 mg, 7.0 ⁇ mol, The reaction was carried out in the same manner as in Example 3-7-1 using 1.0 equivalent), and the degree of reaction progress was measured. The results are as shown in Table 3-7-4, Run1. N-benzylsulfonyl-4- [4- [5- [2- (4-ethoxyphenyl) ethynyl] pyridin-3-carbonyl] piperazine-1-yl] benzamide: compound B-037.
  • Example 3-7-5 N-benzylsulfonyl-4- [4-[[2- [2- (5-hydroxypyridin-3-yl) ethynyl] phenyl] methyl] piperazine as a substrate having an acetylene functional group 1-Il] O-selective ethylation of pyridinol with benzamide (B-009)
  • the holding time of the raw material ArOH is 0.749 minutes (analytical condition SMD-FA05-1).
  • Example 3-7-5 The results of Examples 3-7-5 are shown in Table 3-7-5.
  • the Ratio (O- / N-) shown in Table 3-7-5 is (area% of O-ethylated product (B-038)) / (area% of N-ethylated product (B-039)). %). [Table 3-7-5]
  • Example 3-7-6 N-benzylsulfonyl-4- [4-[[2- [2- (4-hydroxyphenyl) ethynyl] phenyl] methyl] piperazine-1-yl] as a substrate having an acetylene functional group O-selective ethylation of phenol with benzamide (B-010)
  • the holding time of the raw material ArOH is 0.846 minutes (analytical condition SMD-FA05-1).
  • Example 3-7-7 As a substrate having an aniline NH group, 4- [4- [[2- (4-hydroxyphenyl) phenyl] methyl] piperazine-1-yl] -N- [3-methyl-4- (2-Phenylsulfanylethylamino) phenyl] sulfonylbenzamide (B-011), 4- [4- [[2- (4-hydroxyphenyl) phenyl] methyl] piperazin-1-yl] -N- [3-nitro -4- (2-Phenylsulfanylethylamino) phenyl] sulfonylbenzamide (B-012) and 4- [4- [[2- (3-hydroxyphenyl) phenyl] methyl] piperazin-1-yl] -N- [3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] O-selective ethylation of phenol with sulfony
  • Examples 3-7-7 B-043 produced by the reaction exemplified in Examples 3-7-7 may be referred to as compound B2Q045-01 or AG005 in the present specification.
  • the results of Examples 3-7-7 are shown in Table 3-7-7. [Table 3-7-7]
  • the reaction conditions set in Examples 3-6-3 are O-selectively ethyl with respect to allanol having various functional groups. It was confirmed that it could be converted. Specifically, we have found O-selective ethylening conditions for allenol in the presence of functional groups such as tertiary amines, acylsulfonamides, anilines, alkynes, and pyridine rings.
  • the method of the present invention is not limited to the functional groups exemplified in the present examples, and is a method that can be widely applied.
  • Example 3-7-8 Pyridazineamide As a substrate having an NH group, 6- [4-[[2- (3-hydroxyphenyl) phenyl] methyl] piperazine-1-yl] -N- (4-methoxyphenyl) Effect of ethanol addition on O-selective ethylation of phenol with pyridazine-3-carboxamide (B-080)
  • Run 2 DMF-EtOH mixed solvent reaction
  • DMF 84.0 ⁇ L
  • EtOH (17.0 ⁇ L)
  • the reaction was carried out in the same manner as in Examples 3-7-8 and Run1, and the extent of reaction was measured. The results are as shown in Table 3-7-8, Run1 to Run2.
  • Example 3-8 Further confirmation of functional group selectivity under the reaction conditions set in Example 3-6-3
  • the reaction conditions set in Example 3-6-3 have many functionalities. It was confirmed that O-ethylation of allenol can be selectively performed even when the groups coexist. Under these reaction conditions, further functional group selectivity was confirmed.
  • Example 3-8-1 Confirmation of ethylening reaction in the presence of an amide having the same acidity as phenol
  • an amide having the same acidity as phenol As an example of a functional group exhibiting the same acidity as phenol, the NH group of a secondary —amide functional group is mentioned. Be done. The possibility of ethylation of the NH group of the secondary-amide functional group was investigated under the reaction conditions set in Examples 3-6-3.
  • reaction follow -up After 20 hours from the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The extent of reaction was measured by performing LCMS measurement. The results are as shown in Table 3-8-1, Run1. 1-ethoxy-4- (4-methoxyphenyl) benzene: compound B-076. Retention time: 1.340 minutes (analytical condition SMD-FA05-1). (The holding time of the raw material ArOH is 0.993 minutes (analytical condition SMD-FA05-1).
  • Example 3-8-1 The results of Example 3-8-1 are shown in Table 3-8-1.
  • the percentage ratio (%) (BR-21 / B-076) shown in Table 3-8-1 is (BR-211, area%) / [(BR-21, area%). ) + (B-076, area%)] ⁇ 100. Further, the percentage rate (%) (additive) was calculated as (additive ethylened body, area%) / [(additive ethylened body, area%) + (additive, area%)] ⁇ 100.
  • the specimens when the additive was ethylened were synthesized as shown in Examples 1-3, and confirmed with reference to the Retition time and the detection MS in Table 1-3.
  • Example 3-8-2 Confirmation of ethylation reaction in the presence of diarylamine The possibility of N-ethylation of diarylamine in the presence of the NH group of secondary-diarylamine was investigated. The following is an example of a method for specifying the applicable range of the diarylamine functional group.
  • the percentage rate (%) (additive) was calculated as (additive ethylened body, area%) / [(additive ethylened body, area%) + (additive, area%)] ⁇ 100.
  • the specimens when the additive was ethylened were synthesized as shown in Examples 1-3, and confirmed with reference to the Retition time and the detection MS in Table 1-3.
  • Example 3-8-3 Confirmation of ethylation reaction in the presence of various amines
  • the possibility of N-ethylation of amines was investigated in the presence of various amines during the reaction.
  • the following is an example of a method for specifying the applicable range of various amine functional groups.
  • N-butylaniline (BR-11), 5-bromoindoline (BR-12) (10.4 mg, 53.0 ⁇ mol, 1.5 equivalents, Run2), (3-phenylpropyl).
  • Methylamine (BR-13) (14.0 ⁇ L, 88.0 ⁇ mol, 2.5 equivalents, Run3), prop-2-enyl 4-piperazin-1-ylbenzoato (BB-27) (8.6 mg, 35) .0 ⁇ mol, 1.0 equivalent, Run4), 5- (4-methylphenyl) pyridin-2-amine (B-051) (6.5 mg, 35.0 ⁇ mol, 1.0 equivalent, Run5), 6- (4) -Methylphenyl) Pyridine-3-amine (B-052) (6.5 mg, 35.0 ⁇ mol, 1.0 equivalent, Run6), 3-Phenyl-1-propylamine (BR-14) (12.0 ⁇ L) , 88.0 ⁇ mol, 2.5 equivalents, Run7), N, N-dimethylbenzylamine (BR-15)
  • reaction follow -up After 20 hours from the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The extent of reaction was measured by performing LCMS measurement. The results are as shown in Table 3-8-3.
  • Example 3-8-3 The results of Example 3-8-3 are shown in Table 3-8-3.
  • the percentage ratio (%) (BR-21 / B-076) shown in Table 3-8-3 is (BR-211, area%) / [(BR-21, area%). ) + (B-076, area%)] ⁇ 100. Further, the percentage rate (%) (additive) was calculated as (additive ethylened body, area%) / [(additive ethylened body, area%) + (additive, area%)] ⁇ 100.
  • the specimens when the additive was ethylened were synthesized as shown in Examples 1-3, and confirmed with reference to the Retition time and the detection MS in Table 1-3.
  • Example 3-8-4 Confirmation of ethylation reaction in the presence of various alcohols The possibility of O-ethylation of alcohols was investigated in the presence of various alcohols during the reaction. The following is an example of a method for specifying the applicable range of various alcohol functional groups.
  • reaction follow -up At 16.5 hours after the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The extent of reaction was measured by performing LCMS measurement.
  • Example 3-8-4 The results of Example 3-8-4 are shown in Table 3-8-4.
  • the percentage ratio (%) (BR-21 / B-076) shown in Table 3-8-4 is (BR-211, area%) / [(BR-21, area%). ) + (B-076, area%)] ⁇ 100. Further, the percentage rate (%) (additive) was calculated as (additive ethylened body, area%) / [(additive ethylened body, area%) + (additive, area%)] ⁇ 100.
  • the specimens when the additive was ethylened were synthesized as shown in Examples 1-3, and confirmed with reference to the Retition time in Table 1-3.
  • the alcohol functional group is not limited to the alcohol functional group exemplified in this example because the progress of alkylation of the alcohol functional group is 5% or less even under these conditions, and the alcohol functional group is not limited to the alcohol functional group. It was confirmed that allenol can be selectively alkylated even in the presence of a group.
  • Example 3-9 O-selective ethyling of allenol in a mixture of three substrates Using the findings in Example 3, the actual mixture of substrates, N-benzylsulfonyl-4- [4- [3].
  • reaction follow -up at 1, 2.5, 5, 21 hours after the start of the reaction, 5 ⁇ L of the reaction solution was sampled in a glove bag and diluted with CH 3 CN (1000 ⁇ L) to prepare an LC sample. The extent of reaction was measured by performing LCMS measurement.
  • Example 3-9 The results of Example 3-9 are shown in Table 3-9.
  • Example 4 Examination of removal of residual reagents and reagent-derived impurities when ethylization is performed on a plurality of substrate mixtures
  • functional group-selective reaction conditions are set.
  • purification with normal and reverse phase columns commonly used in the laboratory is not always applicable as the optimal separation method. In the following, the removal of unnecessary reagents was examined.
  • Example 4-1 Distillation under reduced pressure when ethylation was performed with a mixture of a plurality of substrates and examination of removal of unnecessary reagents using a solid phase reagent Multiple substrates shown in Table 4-1, N-benzylsulfonyl- 4- [4- [5- [2- (5-Hydroxypyridine-3-yl) ethynyl] pyridin-3-carbonyl] piperazin-1-yl] benzamide (B-003), 4- [4- [[2] -(3-Hydroxyphenyl) phenyl] methyl] piperazine-1-yl] -N- [3-nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonylbenzamide (B-013), N- (benzenesulfonyl) ) -4- [4- [[2- (5-Hydroxypyridin-3-yl) phenyl]
  • cpKa acidity
  • cpKBH + conjugate acid acidity
  • ADMET predictor version 9.5
  • BTPP 151.0 ⁇ L, 495.0 ⁇ mol
  • BR-05 triethyl phosphate
  • the obtained reaction solution was stirred at 80 ° C. for 30 hours. After 30 hours, 3 ⁇ L of the reaction solution was sampled, diluted with MeCN (1000 ⁇ L), an LC sample was prepared, and LCMS measurement was performed. This solution was used as the initial solution during the reagent removal operation.
  • mesitylene (151.0 ⁇ L, 33.0 ⁇ mol) was added to the reaction solution, 10 ⁇ L of the reaction solution was sampled, diluted with DMSO-d 6 (580.0 ⁇ L), and the initial stage for confirming the residual amount of the reagent by 1 H-NMR. It was made into a solution.
  • Carboxylic acid-supported silica gel (ISOLUTE® CBA, 1 g / 6 mL, 0. It was adsorbed on 7 meq / g) and allowed to stand for 10 minutes. MeCN (1.0 mL) was added, pressure was applied, and the filtrate was collected in a test tube. Carboxylic acid-supported silica gel was washed twice with MeCN (1.0 mL) and filtered under pressure, and all the filtrates were collected together to prepare Solution A. Further, a group of substrates (B-003, B-013, B-014, B-015) or a group of products (N-benzylsulfonyl-4- [4- [5- [2- (5)) on carboxylic acid-supported silica gel.
  • Table 4-3 shows the analysis results by LCMS when the carboxylic acid-supported silica gel treatment was performed. [Table 4-3]
  • Et 3 PO 4 oiling point: 216 ° C., Tokyo Kaseisha Web (https://www.tcychemicals.com/JP/ja/p/P0270), November 18, 2020). Since (see) is a neutral compound, it was not removed by carboxylic acid-bearing silica gel, but by concentration under reduced pressure.
  • Example 4-2 Examination of removal of unnecessary reagents by liquid-liquid separation and vacuum distillation when ethylation is performed with a mixture of a plurality of substrates.
  • Example 4-2-1 Liquid-liquid separation using ethyl acetate as an organic solvent and a saturated aqueous solution of ammonium chloride as an acidic solution, and removal of insoluble reagents by distillation under reduced pressure.
  • 3-bromoquinoline-6-ol (B-092) (15.7 mg, 70.0 ⁇ mol) and DMI (1.0 mL) were added to a 2.0 mL screw cap vial. ..
  • BTPP (64.2 ⁇ L, 210 ⁇ mol, 3.0 eq) was added to the solution, and after confirming the mixing, triethyl phosphate (BR-05) (59.5 ⁇ L, 350 ⁇ mol, 5.0 eq) was added. The obtained reaction solution was stirred at 80 ° C. for 22 hours.
  • the reaction solution is diluted with ethyl acetate (10 mL, 10 times the amount of DMI) and transferred to a 50 mL separatory funnel, and the base (BTPP) used in the reaction is washed and removed with an acidic aqueous solution, and saturated ammonium chloride is used.
  • An aqueous solution (3 mL, 3 times the amount of DMI) was added to perform liquid-liquid separation.
  • a saturated ammonium chloride aqueous solution (3 mL, 3 times the amount with respect to DMI) was added to the ethyl acetate solution, and the liquid-liquid separation by washing was repeated 8 times (washing 9 times in total).
  • Centrifugal evaporator for the purpose of collecting the sample subjected to 1 H-NMR measurement after liquid-liquid separation and removing the neutral compounds (triethyl phosphate and DMI) remaining in the liquid-liquid separation concentrate.
  • the solvent was distilled off under reduced pressure at 40 ° C., ⁇ 0.5 mbar for 16 hours after reducing the pressure at 50-200 mbar until it was detected that the distillation of the low boiling point solvent was completed), and B-093.
  • the obtained substance was dissolved in DMSO-d 6 and 1 H-NMR was measured to confirm the residual reagent.
  • Table 4-5 shows the analysis results of 1 1 H-NMR data prepared from the wax-like solid substance after the concentration treatment. From the analysis results, it was confirmed that triethyl phosphate was not detected and was completely removed. BTPP is removed at a molar ratio of about 0.06 times to 3-bromo-6-ethoxyquinoline (B-093), and DMI is removed to the extent that it is confirmed at a molar ratio of about 0.085 times. I was able to confirm that.
  • Example 4-2-2 Liquid-liquid separation using ethyl acetate as an organic solvent and a 5% potassium hydrogensulfate aqueous solution as an acidic solution, and removal of insoluble reagents by distillation under reduced pressure.
  • BTPP 257.0 ⁇ L, 840 ⁇ mol, 12.0 eq
  • BR-05 triethyl phosphate
  • the reaction solution is diluted with ethyl acetate (15 mL, 15 times the amount of DMI) and transferred to a 50 mL separatory funnel, and the base (BTPP) used in the reaction is washed and removed with an acidic aqueous solution, and 5% sulfuric acid is used.
  • Liquid-liquid separation was performed by adding an aqueous potassium hydrogen hydrogen solution (4 mL, 4 times the amount of DMI). After draining the aqueous solution, a 5% potassium hydrogensulfate aqueous solution (4 mL, 4 times the amount with respect to DMI) was added to the ethyl acetate solution, and the liquid-liquid separation by washing was repeated 5 times (washing 6 times in total).
  • the residual amount of BTPP was reduced to 0 in molar ratio with respect to B-095 by washing the ethyl acetate solution of the reaction solution with a 5% potassium hydrogensulfate aqueous solution. It was confirmed that it could be reduced to about 0.03 times.
  • triethyl phosphate and DMI which are neutral compounds, remained in molar ratios of about 3.5 times and about 0.2 times, respectively, with respect to B-095.
  • Centrifugal evaporator for the purpose of collecting the sample subjected to 1 H-NMR measurement after liquid-liquid separation and removing the neutral compounds (triethyl phosphate and DMI) remaining in the liquid-liquid separation concentrate.
  • the solvent was distilled off under reduced pressure at 40 ° C., ⁇ 0.5 mbar for 16 hours after reducing the pressure at 50-200 mbar until it was detected that the distillation of the low boiling point solvent was completed), and B-095. was obtained as a wax-like solid substance.
  • the obtained substance was dissolved in DMSO-d 6 and 1 H-NMR was measured to confirm the residual reagent.
  • Table 4-6 shows the analysis results of 1 1 H-NMR data prepared from the wax-like solid substance after the concentration treatment. From the analysis results, it was confirmed that triethyl phosphate was not detected and was completely removed. BTPP is confirmed at a molar ratio of about 0.05 times to 4- (4-ethoxyphenyl) -N, N-dimethylbenzamide (B-095), and DMI is confirmed at a molar ratio of about 0.15 times. It was confirmed that it was removed to a certain extent.
  • Example 4-2-3 Liquid-liquid separation and removal of insoluble reagent by distillation under reduced pressure when ethylation is performed with a mixture of a plurality of substrates.
  • Ethyl 6-ethoxyquinoline-3-carboxylate Compound B-091.
  • the holding time of the raw material ArOH is 0.708 minutes (analytical condition SMD-FA05-1).
  • the reaction solution is diluted with ethyl acetate (15 mL, 15 times the amount of DMI) and transferred to a 50 mL separatory funnel, and the base (BTPP) used in the reaction is washed and removed with an acidic aqueous solution, and 5% sulfuric acid is used.
  • Liquid-liquid separation was performed by adding an aqueous potassium hydrogen hydrogen solution (4 mL, 4 times the amount of DMI). After draining the aqueous solution, a 5% potassium hydrogensulfate aqueous solution (4 mL, 4 times the amount with respect to DMI) was added to the ethyl acetate solution, and the liquid-liquid separation by washing was repeated 5 times (washing 6 times in total).
  • Centrifugal evaporator for the purpose of collecting the sample subjected to 1 H-NMR measurement after liquid-liquid separation and removing the neutral compounds (triethyl phosphate and DMI) remaining in the liquid-liquid separation concentrate.
  • the solvent was distilled off under reduced pressure at 40 ° C., ⁇ 0.5 mbar for 16 hours after reducing the pressure at 50-200 mbar until it was detected that the distillation of the low boiling point solvent was completed), and B-076. , B-091 and B-095 were obtained as a wax-like solid material.
  • the obtained substance was dissolved in DMSO-d 6 and 1 H-NMR was measured to confirm the residual reagent.
  • Table 4-7 shows the analysis results of 1 1 H-NMR data prepared from the wax-like solid substance after the concentration treatment. From the analysis results, it was confirmed that triethyl phosphate was not detected and was completely removed. BTPP was removed at a molar ratio of about 0.05 times that of ethyl 6-ethoxyquinoline-3-carboxylate (B-091), and DMI was removed to the extent that it was confirmed at a molar ratio of about 1.0 times. I was able to confirm that.
  • Example 5 Examination of O-selective allylation of allenol to a substrate having multiple reactive functional groups in the molecule
  • N-benzylsulfonyl-4- [4-[[2- (4-hydroxyphenyl) phenyl] methyl] piperazine-1-yl] benzamide (B) -001) (2.7 mg, 5.0 ⁇ mol, 1.0 equivalent) and DMF (50.0 ⁇ L) were added.
  • K 2 CO 3 (2.1 mg, 15.0 ⁇ mol, 3.0 eq) was added to the obtained solution and mixed for 15 to 20 seconds, and then triallyl phosphate (5.1 ⁇ L, 25.0 ⁇ mol, 5.0 eq) was added. ) was added.
  • the resulting reaction mixture was stirred at 1400 rpm at 80 ° C. for 46 hours.
  • the holding time of the raw material ArOH is 0.55 minutes (analytical condition SQD-FA05-2). From the above results, it was shown that allylation is also applicable as an O-selective alkylation of allenol to a substrate having a plurality of reactive functional groups.
  • Example 6 Production of a compound library having a variety of functional groups using the O-selective ethylation method of allenol
  • the findings obtained in Examples 2 to 5 are utilized in various ways.
  • An example of application to the synthesis of a compound library having a variety of functional groups by performing highly selective ethylation of allenol having a reactive functional group and performing post-treatment that does not require a purification operation by a column. Is shown. Bcl- using AS-MS of the synthesized mixture for the purpose of exemplifying the practicality of the compound library prepared by the method of the present invention and demonstrating that the desired compound group is obtained.
  • Example 6 a compound carried against brominated modified Wang resin: 4- (bromomethyl) phenoxyethyl polystyrene, for example, Merck, 2- (4-bromomethylphenoxyethyl polystyrene) was used in the solid phase. "-02R" is indicated at the end of the compound number of the carried compound. In the table in Example 6, only the name of the compound after excision is indicated in the conversion reaction in the solid-phase-supported compound. In some cases, it is indicated by a compound number excluding "-02R".
  • Examples 6-1-1-A Synthesis of mixtures mixEG01-02R to mixEG04-02R and mixEG18-02R
  • a 1.7 M aqueous solution of K 3 PO 4 was prepared by using a 5 mL volumetric flask under a nitrogen atmosphere and measuring up K 3 PO 4 (1.8 g, 8.48 mmol) with distilled water.
  • Examples 6-1-1-B Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) and compound EF01-02 of the mixtures mixEG02-02R to mixEG04-02R and mixEG18-02R.
  • the title compound shown in the same method as -A [Table EG01] was synthesized. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG01].
  • Example 6-1-2-B Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) of the mixture mixEG06-02R and compound EF01-02-02R (43 mg, carrying amount 0). .733 mmol / g, 0.032 mmol) and [1- [3-ethoxycarbonyl-5- (trifluoromethyl) phenyl] pyrazole-4-yl] boronic acid (BB06) shown in [Table LBB02].
  • the title compound shown in [Table EG05] was synthesized by the same method as in Example 6-1-2-A. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG05].
  • Examples 6-1-3-B Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) of the mixture mixEG08-02R to mixEG17-02R , compound EF01-02-02R (43 mg). , Carrying amount 0.733 mmol / g, 0.032 mmol) and the boronic acid or boronic acid ester reagent (BB08-17) shown in [Table LBB02], the same method as in Example 6-1-3-A. The title mixture shown in [Table EG07] was synthesized. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG07].
  • Examples 6-1-4-B Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) of the mixture mixEG20-02R, compound EF01-02-02R (43 mg, carrying amount 0). .733 mmol / g, 0.032 mmol) and 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate shown in [Table LBB02]. (BB20) was used to synthesize the title compound shown in [Table EG19] in the same manner as in Example 6-1-4-A. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG19].
  • Examples 6-1-6 Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) of the mixture mixEG22-02R, compound EF01-02-02R (43 mg, carrying amount 0.733 mmol). / G, 0.032 mmol) and the boronic acid reagent (BB22) shown in [Table LBB02] were synthesized in the same manner as in Example 6-1-5, and the title mixture mixEG22 shown in [Table EG22] was synthesized. -02R was obtained. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG22]. [Table EG22]
  • Examples 6-1-7-B Synthetic compound EF01-01-02R (57 mg, carrying amount 0.556 mmol / g, 0.032 mmol) of the mixture mixEG24-02R to mixEG26-02R , compound EF01-02-02R (43 mg). , Carrying amount 0.733 mmol / g, 0.032 mmol) and the acetylene reagent (BB23 to 26) shown in [Table LBB02] in the same manner as in Example 6-1-7-A [Table EG23]. The title mixture shown in 1 was synthesized. The building blocks used, the compounds contained in the obtained mixture, and the reaction times are shown in [Table EG23].
  • mixEG07-02R (20.3 mg), mixEG08-02R (21.0 mg), mixEG09-02R (21.6 mg), mixEG10-02R (19.8 mg), mixEG13-02R (19.8 mg) shown in [Table EGH04].
  • mixEG14-02R (21.1 mg), mixEG15-02R (20.5 mg), mixEG16-02R (20.5 mg), mixEG17-02R (20.5 mg), mixEG19-02R (20.1 mg), Mix EG21-02R (21.9 mg), mixEG22-02R (20.4 mg), and mixEG23-02R (20.6 mg) were transferred to a 10 mL screw cap vial and solid-phase-supported aromatic aldehyde used in this example.
  • MixEI01-02R (155.9 mg, carrying amount 0.651 mmol / g, 0.101 mmol), mixEI02 shown in [Table EI01], [Table EI02], [Table EI03], [Table EI04], and [Table EI05].
  • Examples 6-3-7-B Synthesis of Mixtures mixEI08-02R to mixEI10-02R Mixture mixEI06-02R (50 mg, carrier amount 0.648 mmol / g, 0.0324 mmol) and amine reagent (50 mg, carrying amount 0.648 mmol / g, 0.0324 mmol) shown in [Table EI06].
  • amine reagent 50 mg, carrying amount 0.648 mmol / g, 0.0324 mmol
  • BB31 to BB33 synthesis was carried out in the same manner as in Example 6-3-7-A to obtain the title mixture shown in [Table EI08] to [Table EI10].
  • the names of the compounds contained in the obtained mixture are shown in [Table EI08] to [Table EI10].
  • Example 6 using the mixture mixEI06-02R (50 mg, carrier amount 0.648 mmol / g, 0.0324 mmol) and 1- (1-adamantyl) -N-methylmethaneamine (BB35) shown in [Table EI06].
  • the synthesis was carried out in the same manner as in -3-8 to obtain the title mixture shown in [Table EI12].
  • the names of the compounds contained in the obtained mixture are shown in [Table EI12].
  • n-Propylamine (27 ⁇ L, 0.324 mmol) was added at room temperature and shaken for 1 hour. Transfer the reaction and resin suspension to a filtered syringe using NMP, NMP (1.2 mL) 3 times, HOAt / NMP (0.2 M, 1.2 mL) 3 times, NMP (1. 2 mL) 3 times, MeOH (1.2 mL) 3 times, DCM (1.2 mL) 3 times, Heptane (1.2 mL) 3 times, then dried under reduced pressure [Table EI13]. The title mixture shown in the above was obtained. The names of the compounds contained in the obtained mixture are shown in [Table EI13].
  • Examples 6-3-10-B Synthesis of Mixtures mixEI14-02R to mixEI18-02R Mixture mixEI06-02R (50 mg, carrier amount 0.648 mmol / g, 0.0324 mmol) and amine reagent (50 mg, carrying amount 0.648 mmol / g, 0.0324 mmol) shown in [Table EI06].
  • Mixture mixEI06-02R 50 mg, carrier amount 0.648 mmol / g, 0.0324 mmol
  • amine reagent 50 mg, carrying amount 0.648 mmol / g, 0.0324 mmol
  • Mixture mixEI07-02R (mixture containing 100 compounds, 49.2 mg, carrying amount 0.648 mmol / g, 31.9 ⁇ mol) and 1, as shown in [Table EI07] in a 1.6 mL glass vial under a nitrogen atmosphere.
  • 2,3-trimethylbenzene / DCM (0.23M, 700 ⁇ L) was added and shaken at room temperature for 1 hour.
  • TFA 300 ⁇ L, 3.89 mmol
  • the reaction and resin suspension were transferred to a filtered syringe using DCM solution and charged with DMI (0.5 mL). The test tube was filtered under nitrogen pressure.
  • [Table EJ01] shows the observed UV peak retention time (min), observed during the UV peak (M + H) + , MS peak retention time in the MS chromatogram, UV peak and MS peak attribution. The numbers of the compounds used are listed. Since there is a possibility that 2 compounds are missing in Example 6-2-2 and 2 compounds are missing in Example 6-2-3, 4 of the 100 compounds shown in Table [EJ01] are missing. It may be.
  • Example 6-4-2 Synthesis of Mixtures mixEJ02 to mixEJ12 The same method as in Example 6-4-1 using the mixture mixEI08-02R to mixEI18-02R shown in [Table EI08] to [Table EI18]. The title mixture mixEJ02 to mixEJ12 shown in [Table EIJ02] to [Table EIJ12] was obtained. Analytical conditions were analyzed under SMD-FA05-long-25 min, and the UV area was confirmed at a UV wavelength of 290 nm. Regarding the analysis results of the mixture. The analysis results of the mixture are shown in [Table EJ02] to [Table EJ12].
  • [Table EJ02] to [Table EJ12] show the observed UV peak retention time (min), the observed UV peak (M + H) + , the MS peak retention time in the MS chromatogram, and the UV peak. In addition, the numbers of the compounds attributed to the MS peak are listed. Since there is a possibility that 2 compounds are missing in Example 6-2-2 and 2 compounds are missing in Example 6-2-3, among the 1100 compounds shown in [Table EIJ02] to [Table EIJ12]. , 44 compounds may be missing.
  • Example 6-5 Post-treatment after excision from the solid phase and selective ethylation reaction of the allenol moiety The allenol moiety of the obtained compound after performing an operation for removing TFA from the mixture excised from the resin. Selective ethylation was carried out and functional group conversion was carried out. Using the mixtures mixEJ01 to mixEJ12 shown in [Table EIJ01] to [Table EIJ12] obtained in Examples 6-4-1 and 6-4-2, the method shown below was carried out. An experimental operation in which ethylation was performed after removing TFA using mixEJ-11 to obtain mixAI-B2Q-01 is shown as an example.
  • the solid-phase-supported morpholine was washed with MeCN (1 mL) three times and filtered under pressure, and all the filtrates were collected together. Distill off the collected solution with Genevac under reduced pressure (40 ° C, after depressurizing at 50-200 mbar until it is detected that the distillation of the low boiling point solvent is completed, then 40 ° C, ⁇ 0.5 mbar for 16 hours). The solvent was distilled off under reduced pressure. After adding DMI (500 ⁇ L) to the residue and stirring to dissolve it, the residue was transferred to a glass vial and washed twice with DMI (250 ⁇ L). The obtained solution was distilled off under reduced pressure with Genevac (40 ° C., 50-200 mbar until it was detected that the distillation of the low boiling point solvent was completed, and the concentrate used for subsequent ethylation was obtained. ..
  • the carboxylic acid-supported silica gel was washed twice with MeCN (1 mL) and filtered under pressure, and the filtrate was collected. After adding DMSO (1 mL), reduce the pressure at 50-200 mbar until it is detected that the distillation of the low boiling point solvent is completed at 40 ° C, then the solvent at 40 ° C, ⁇ 0.5 mbar for 16 hours). Was distilled off under reduced pressure to obtain the mixture mixAI-B2Q-01 (25.0 mg) of the title shown in [Table AI-03-B2Q-01] as an oily substance.
  • Example 6-5-2 Implementation of TFA removal and ethylation for 11 other types of mixtures Also for the mixtures mixEJ01 to mixEJ10 and mixEJ12 shown in [Table EJ01] to [Table EJ10] and [Table EJ12], Example 6-. Perform the same operations as in 5-1 [Table AI-03-B4J-01], [Table AI-03-B1M-01], [Table AI-03-B1K-01], [Table AI-03-B1O].
  • Example 6-5-3 Preparation of mixture solution and analysis by LCMS DMSO was added to each of the 12 mixtures obtained in Examples 6-5-1 and 6-5-2, and approximately 10 mM was added. Twelve types of DMSO solutions were prepared. Of that amount, 100 ⁇ L was subjected to a binding evaluation experiment for Bcl-2 by AS-MS shown in Example 7. In addition, a part of 12 kinds of 10 mM DMSO solutions was diluted with MeCN and analyzed by LCMS. The analysis results are shown in [Table AI-03-02].
  • Table AI-03-02 shows the retention time of the UV and MDS peaks to which each compound was assigned, and the m / z (M + H) + values detected during that time period. Since there is a possibility that 2 compounds are deficient in Example 6-2-2 and 2 compounds are deficient in Example 6-2-3, 48 compounds derived from these 4 compounds are also deficient. There is a possibility. Therefore, as shown in "Table AI-03-02", the m / z (M + H) + peak corresponding to 1152 compounds among the 1200 compounds set as the library compounds can be confirmed.
  • Example 6-6 Production Example 2 of a compound library having a variety of functional groups using an O-selective ethylation method of allenol.
  • Examples 6-1 to 6-5 highly selective ethylation of allenol in 12 kinds of mixtures in which 100 compounds are mixed is performed, and post-treatment that does not require a purification operation by a column is performed.
  • An example applied to the synthesis of a compound library having a variety of functional groups is shown.
  • Examples 6-6 show an example of constructing a library by carrying out a highly selective ethylation reaction for allenol on a mixture containing 1000 compounds.
  • FIG. 2 may be contained in the mixture 2-1-m1E01-1 separately prepared as a raw material.
  • the compounds are shown in [Table 6-6-2]. The notation method in the table will be described.
  • each compound that can be contained in the mixture 2-1-m1E01-1 is indicated by ID, and the combination of the core block and the linker in the structure of the mixture 2-1-m1E01-1 is symbolized. Alternatively, it is indicated by a chemical formula.
  • the correspondence between the symbols and the concrete structure is shown in FIG.
  • " ⁇ ⁇ ⁇ " is represented by a chemical formula.
  • the mixture 2-1-m1E01-2 was synthesized as follows. DMF (154 ⁇ L), EtOH (38.6 ⁇ L), BTPP (41.3 ⁇ L, 0) in a mixture 2-1-m1E01-1 (9.6 mg, 13.5 ⁇ mol) in a 0.5-2 mL microwave vessel. .135 mmol) and Et 3 PO 4 (34.4 ⁇ L, 0.203 mmol) were added and shaken at 70 ° C. for 27 hours. The reaction was transferred to a 6 mL filtered column packed with ISOLATE® CBA (0.7 mmol / g, 189 mg) using MeCN (0.2 mL) twice.
  • Example 6-7 Analysis of the mixture The mixture synthesized in Example 6-6 was subjected to retention time measurement and mass spectrometry under the analysis conditions shown below, and was used with Compound Discoverer 3.2 (Thermo Fisher Scientific). Was analyzed.
  • Example 6-8 Production Example 3 of a compound library having a variety of functional groups using an O-selective ethylation method of allenol.
  • Examples 6-8 show an example of constructing a library by carrying out an ethylation reaction on a mixture containing 500 compounds.
  • FIG. 3 shows a separately prepared mixture 2-2-d1E01-1 containing allanol as a raw material. Is shown in [Table 6-8-2].
  • each compound that can be contained in the mixture 2-2-d1E01-1 is indicated by ID, and the combination of the core block and the linker in the structure of the mixture 2-2-d1E01-1 is symbolized. Alternatively, it is indicated by a chemical formula.
  • the correspondence between the symbols and the concrete structure is shown in FIG.
  • " ⁇ ⁇ ⁇ " is represented by a chemical formula.
  • Example 6-9 Analysis of the mixture The mixture synthesized in Example 6-8 was subjected to retention time measurement and mass spectrometry under the analysis conditions shown below, and was used with Compound Discoverer 3.2 (Thermo Fisher Scientific). Was analyzed.
  • Example 6-5-1, 6-5-2 the group of compounds ethylenized by the method of the present invention is exemplified as being practically practical as a mixture library.
  • the binding evaluation of the synthesized mixture to Bcl-2 using AS-MS Example 7
  • the Bcl-2 binding compound identified by AS-MS Example 8
  • evaluation of binding to Bcl-2 by surface plasmon resonance (SPR) of the individually synthesized compound Example 9) were carried out.
  • Example 7 Synthetic mixture library compound for Bcl-2 using AS-MS (Example 6-5-1 and Example 6-5-2) A mixture in which the presence of 1152 compounds has been confirmed.
  • Tris-HCl buffer 25 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.025% Protein-20, 1 mM.
  • Bcl-2 protein Novus, NBP2-34889, Recombinant Human Bcl-2 Protein, Lot E60145051 (19.2 ⁇ L) prepared to 20.9 ⁇ M using DTT) was prepared in 1200 compounds (Example 6-5-3). When this was done, it was added to the wells to which 1152 compounds had been identified (final compound concentration 20 nm, final Bcl-2 concentration 20 ⁇ M), and incubated in the dark at 23 ° C. for 1 hour.
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  • Example 8 Individual compound synthesis of Bcl-2 binding compound identified by AS-MS experiment
  • Example 8-1-1 4- [4- [[4- (3-ethoxyphenyl) -3-methylphenyl]] Synthesis of Methyl] Piperazine-1-yl] -N- [3-Nitro-4- (2-Phenylsulfanylethylamino) Phenyl] sulfonylbenzamide [AG016 (B2Q047-01)]
  • Examples 8-2-1 4- [4- [[4- (5-ethoxypyridine-3-yl) -3-methylphenyl] methyl] piperazine-1-yl] -N- [3-nitro-4 -Synthesis of [2- (2-phenylsulfanylethylamino) phenyl] sulfonylbenzamide [AG018 (B2Q048-01)]
  • N- [3-nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonyl-4-piperazin-1-ylbenzamide (AG0144, CAS: 406233-75-8) (100.00 mg, 0.185 mmol) DMSO of 4- (5-ethoxypyridin-3-yl) -3-methylbenzaldehyde (AG017, CAS: 1545014-81-0) (89.10 mg, 0.370 mmol), acetic acid (0.05 mL, 0.873 mmol)
  • the / ethanol (1 mL / 1 mL) solution was stirred at room temperature for 1 hour.
  • Example 8-3-1 Synthesis of 4- (5-ethoxypyridin-3-yl) -2-methoxybenzaldehyde (AG021)
  • N- [3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonyl-4-piperazin-1-ylbenzamide (AG0144, CAS: 406233-75-8) (150 mg, 0.277 mmol) and 4- A DMSO / ethanol (3 mL / 3 mL) solution of (5-ethoxypyridin-3-yl) -2-methoxybenzaldehyde (AG021) (106.9 mg, 0.416 mmol) and acetic acid (0.20 mL, 3.490 mmol) at room temperature. Was stirred for 1 hour.
  • Examples 8-4-1 Synthesis of 4- (5-ethoxypyridin-3-yl) naphthalene-1-carbaldehyde (AG024)
  • Examples 8-4-2 4- [4- [[4- (5-ethoxypyridine-3-yl) naphthalene-1-yl] methyl] piperazine-1-yl] -N- [3-nitro-4 -Synthesis of [2- (2-phenylsulfanylethylamino) phenyl] sulfonylbenzamide [AG025 (B2Q066-01)]
  • N- [3-Nitro-4- (2-phenylsulfanylethylamino) phenyl] sulfonyl-4-piperazin-1-ylbenzamide (AG0144, CAS: 406233-75-8) (180 mg, 0.332 mmol) and 4- A DMSO / ethanol (2 mL / 2 mL) solution of (5-ethoxypyridin-3-yl) naphthalene-1-carbaldehyde (AG024) (184 mg, 0.664 mmol) and acetic acid (0.05 mL, 0.873 mmol) at room temperature. The mixture was stirred for 1 hour.
  • Examples 8-5-1 4- [4- [[2- (3-ethoxyphenyl) phenyl] methyl] piperazine-1-yl] -N- [3-nitro-4- (2-phenylsulfanylethylamino) ) Phenyl] sulfonylbenzamide [AG005 (B2Q045-01)] synthesis
  • Examples 8-6-1 4- [4- [[2- (5-ethoxypyridine-3-yl) phenyl] methyl] piperazine-1-yl] -N- [3-nitro-4- (2-yl) Synthesis of Phenyl Sulfanyl Ethyl Amino) Phenyl] Sulfonyl Benzamide [AG007 (B2Q046-01)]
  • Examples 8-7-1 Synthesis of 4- (2-phenylsulfanilethylamino) -3- (trifluoromethyl) benzenesulfonamide [AG010 (BB42)]
  • Examples 8-7-2 tert-butyl 4- [6-[[4- (2-phenylsulfanylethylamino) -3- (trifluoromethyl) phenyl] sulfonylcarbamoyl] pyridazine-3-yl] piperazine-1 -Synthesis of carboxylate (AG027)
  • Examples 8-7-3 Synthesis of N- [4- (2-phenylsulfanylethylamino) -3- (trifluoromethyl) phenyl] sulfonyl-6-piperazine-1-ylpyridazine-3-carboxamide (AG028)
  • Examples 8-7-4 6- [4- [4- (3-ethoxyphenyl) -3-fluorobenzoyl] piperazine-1-yl] -N- [4- (2-phenylsulfanylethylamino) -3 -Synthesis of (trifluoromethyl) phenyl] sulfonylpyridazine-3-carboxamide [AG030 (B2R005-01)]
  • N- [4- (2-Phenylsulfanylethylamino) -3- (trifluoromethyl) phenyl] sulfonyl-6-piperazin-1-ylpyridazine-3-carboxamide (AG028) (70 mg, 0.124 mmol) and 4- (3-ethoxyphenyl) -3-fluorobenzoic acid (AG029, CAS: 1261964-16.2) (32.2 mg, 0.124 mmol), EDCI (47.4 mg, 0.248 mmol), DMAP (15.1 mg, DIPEA (63.9 mg, 0.496 mmol) was added to a solution of 0.124 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 16 hours.
  • the obtained residue was purified by reverse phase column chromatography (C18,0-50% acetonitrile / 10 mM ammonium hydrogencarbonate aqueous solution).
  • the obtained crude product was purified by preparative HPLC (XBride Prep OBD C18 column, 36-66% acetonitrile / 10 mM ammonium hydrogencarbonate aqueous solution) to obtain the title compound AG030 (20 mg, 19.6%) as a white solid. ..
  • Examples 8-8-1 6- [4- [3- (3-ethoxyphenyl) -5- (trifluoromethyl) benzoyl] piperazine-1-yl] -N- [4- (2-phenylsulfanylethyl) Synthesis of Amino) -3- (Trifluoromethyl) Phenyl] sulfonylpyridazine-3-carboxamide [AG032 (B2R017-01)]
  • N- [4- (2-Phenylsulfanylethylamino) -3- (trifluoromethyl) phenyl] sulfonyl-6-piperazin-1-ylpyridazine-3-carboxamide (AG028) (70 mg, 0.124 mmol) and 3- (3-ethoxyphenyl) -5- (trifluoromethyl) benzoic acid (AG031, CAS: 1261907-60-1) (69.00 mg, 0.223 mmol), EDCI (47.37 mg, 0.248 mmol), DMAP ( DIPEA (63.87 mg, 0.496 mmol) was added to a solution of 15.09 mg, 0.124 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 16 hours.
  • DIPEA DIPEA
  • the obtained residue was purified by reverse phase column chromatography (C18,0-45% acetonitrile / 10 mM aqueous ammonium hydrogen carbonate solution).
  • the obtained crude product was purified by preparative HPLC (Xselect CSH OBD column, 68-83% acetonitrile / 0.1% formic acid aqueous solution) to obtain the title compound AG032 (30 mg, 28.2%) as a white solid. ..
  • Examples 8-9-2 4- [4- [[2- (3-ethoxyphenyl) phenyl] methyl] piperazine-1-yl] -N- [4- (2-phenylsulfanylethylamino) -3- Synthesis of (trifluoromethyl) phenyl] sulfonylbenzamide [AG012 (B2R045-01)]
  • Examples 8-10-1 4- [4- [[2- (5-ethoxypyridin-3-yl) phenyl] methyl] piperazine-1-yl] -N- [4- (2-phenylsulfanylethylamino) ) -3- (Trifluoromethyl) phenyl] sulfonylbenzamide [AG013 (B2R046-01)]
  • Example 8-11 1: Synthesis of tert-butyl 4- [6- (1-adamantylmethylcarbamoyl) pyridazine-3-yl] piperazine-1-carboxylate (AG034)

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