WO2017043563A1 - ピリジンカルボキサミドの製造方法 - Google Patents

ピリジンカルボキサミドの製造方法 Download PDF

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WO2017043563A1
WO2017043563A1 PCT/JP2016/076398 JP2016076398W WO2017043563A1 WO 2017043563 A1 WO2017043563 A1 WO 2017043563A1 JP 2016076398 W JP2016076398 W JP 2016076398W WO 2017043563 A1 WO2017043563 A1 WO 2017043563A1
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formula
compound
salt
represented
compound represented
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PCT/JP2016/076398
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French (fr)
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昌史 丹羽
裕 出口
寛幸 茂木
剛史 林
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参天製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel process for producing 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide and It relates to the production intermediate.
  • Patent Document 1 and Non-Patent Document 1 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3- Pyridinecarboxamide (hereinafter referred to as “the present compound”) has a cell growth inhibitory effect in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system, and a tumor growth inhibitory action in a test system using a mouse tumor-bearing model.
  • test system using an arthritis model exhibits a foot edema inhibitory action and a test system using a rat choroidal neovascularization model exhibits a choroidal neovascularization inhibitory action.
  • this compound is useful as a pharmaceutical, and is expected to be particularly useful as a preventive or therapeutic agent for diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, and diabetic macular edema. ing.
  • Patent Document 1 describes a method for producing the present compound and its derivatives.
  • the production method of the present compound described in Patent Document 1 is a linear synthesis method including the following steps 1 to 5.
  • Step 1 2-chloro-4-picoline is chlorinated with N-chlorosuccinimide to give 2-bromo-4-chloromethylpyridine (Patent Document 1: 57, Reference Compound 1-2),
  • Step 2 A step of reacting 2-bromo-4-chloromethylpyridine with 2-mercaptonicotinic acid in the presence of triethylamine to obtain 2- (2-bromopyridin-4-ylmethylthio) pyridine-3-carboxylic acid (patent)
  • Reference 1 Page 58, Reference compound 2-2
  • Step 3 2- (2-Bromopyridin-4-ylmethylthio) pyridine-3-carboxylic acid is converted to N, N-diisopropylethylamine and O- (7-azabenzotriazol-1-yl)
  • Patent Document 1 describes a synthesis method of 2-thioxo-N- (4-trifluoromethoxy) -1,2-dihydropyridine-3-carboxamide (Patent Document 1: page 71, Reference Compound 10). -2). However, Patent Document 1 does not describe the use of 2-thioxo-N- (4-trifluoromethoxy) -1,2-dihydropyridine-3-carboxamide as a synthetic intermediate of this compound. No mention is made of the use of 2-hydroxyacetylaminopyridine derivatives as synthetic intermediates.
  • Patent Document 2 describes a benzenesulfonate salt of the present compound, its crystal, its crystal polymorph and a method for producing them.
  • Non-patent document 1 discloses a method of synthesizing compound 17 of non-patent document 1 (analogue of the present compound) in 6 steps from compound 12 of non-patent document 1, which is an expensive raw material (non-patent document 1).
  • this compound is described in Non-Patent Document 1 (Non-Patent Document 1: Table 3, Compound 11b), a specific production method thereof is not disclosed.
  • Non-Patent Document 1 does not describe or suggest any use of a 2-hydroxyacetylaminopyridine derivative as a synthetic intermediate of the present compound.
  • step 4 of the manufacturing process (FIG. 1) described in Patent Document 1 a metal palladium catalyst is used. Therefore, removal of the metal palladium catalyst by column chromatography is essential from the viewpoint of safety. In addition, column chromatography is not suitable for production at an industrial level from the viewpoint of economic efficiency (production cost, production time, etc.). Therefore, it is desired to develop a production method that does not use a metal palladium catalyst and does not require column chromatography.
  • Step 3 to Step 5 of the production process described in Patent Document 1 (FIG.
  • this compound that is, the formula (1): A method for producing a compound represented by the formula: Formula (2): [In formula (2), X represents a halogen atom] And a compound represented by the formula (9): And a method for producing a compound represented by the formula (1) or a salt thereof, which can be produced as a pharmaceutical at an industrial level, wherein the compound represented by the formula (1) or a salt thereof is reacted in the presence of a base. .
  • the novel manufacturing intermediate used for this manufacturing method was created.
  • the present invention is as follows.
  • Formula (1) Wherein the compound represented by formula (2): [In formula (2), X represents a halogen atom] And a compound represented by the formula (9): A process for producing a compound represented by the formula (1) or a salt thereof by reacting the compound represented by the formula or a salt thereof in the presence of a base.
  • the nitrogen atom protecting group is conjugated with a t-butyl group, benzyl group, p-methoxybenzyl group, acetyl group, benzenesulfonyl group, p-toluenesulfonyl group, or a protected nitrogen atom.
  • Formula (2) [In formula (2), X is a chlorine atom] Or a salt thereof.
  • the compound represented by the formula (1) or a salt thereof includes a compound represented by the formula (2) or a salt thereof and a compound represented by the formula (9) or a salt thereof, which are novel production intermediates. By using it, it can manufacture with high efficiency and a high yield, without using metal palladium and without column chromatography.
  • a compound represented by the formula (3) or a salt thereof is a five-step column using a raw material (a compound represented by the formula (8) or a salt thereof) and a reagent which are inexpensive and easily available in large quantities. It can be produced in high yield without chromatographic purification.
  • Halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
  • the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl group and the like. .
  • the “protecting group for nitrogen atom” means a substituent that protects the nitrogen atom, and is a substituent that forms a nitrogen-hydrogen bond under appropriate deprotection conditions. Specific examples include Protecting Groups (1994) by Philip J. Kocienski, PG Wuts and TW Greene, “Green's Protective Groups in Organics”. Synthesis (4th edition, 2006) "and the like. Specific protecting groups for nitrogen atoms include, for example, C 1-8 alkoxycarbonyl groups (eg, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, etc.), benzyloxycarbonyl group, methoxymethyl group, t-butyl.
  • C 1-8 alkoxycarbonyl groups eg, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, etc.
  • benzyloxycarbonyl group methoxymethyl group, t-butyl.
  • benzyl group o-methoxybenzyl group, p-methoxybenzyl group, formyl group, acetyl group, trifluoroacetyl group, phenoxycarbonyl group, methanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl
  • a specific nitrogen atom protecting group having a ring structure together with the nitrogen atom, for example, succinimide, 3,4-dimethylsuccinimide, tetramethylsuccinimide , Glutarimide, 4,4-dimethylglutarimide Piperazine-2,6-dione, 4-methylpiperazine-2,6-dione, maleimide, phthalimide ring and the like.
  • the raw materials, reagents, and other compounds described in the present specification used in the present invention may form a “salt” with an acid or a base.
  • Specific examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, bromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid.
  • Acid tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturon Salts with organic acids such as acids, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid, Quaternary ammonium salts such as methyl bromide and methyl iodide, bromine ion, chlorine ion, iodine ion Which salt with halogen
  • the raw materials, reagents, and other compounds described in the present specification used in the present invention may be in the form of hydrates or solvates.
  • the raw materials, reagents, and other compounds described in the present specification, hydrates or solvates thereof may be crystals, and crystal polymorphs and crystal polymorph groups (crystal polymorphs) are included in the crystals.
  • crystal polymorphs and crystal polymorph groups are also included in the present invention.
  • the crystal polymorph group means various crystal forms depending on conditions and states (including the formulated state in this state) such as production, crystallization, and storage of these crystals. It means the crystal form at each stage when changing and the whole process.
  • Step 1 Method for producing Compound (7) using Compound (8) and Compound (14) as raw materials
  • Step 2 Method for producing compound (6) from compound (7)
  • Step 3 A method for producing compound (5) from compound (6) and compound (13)
  • Step 4 Method for producing compound (4) from compound (5)
  • Step 5 Method for producing compound (3) from compound (4)
  • Step 6 A method for producing the compound (2) from the compound (3) and the compound (12) via the compound (15) or the compound (16)
  • Step 7 A method for producing compound (9) from compound (10) and compound (11)
  • Step 8 a method for producing compound (1) from compound (2) and compound (9)
  • Step 1 will be described below.
  • Step 1 is a step of producing compound (7) by reacting compound (8) with compound (14) in a solvent in the presence of an acid.
  • Compound (8) may be a commercially available product or a product produced by a known method.
  • R 2 represents a lower alkyl group, preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and still more preferably n -A butyl group.
  • Compound (14) is used, for example, in an amount of 1 to 20 molar equivalents, preferably 5 to 15 molar equivalents, relative to compound (8).
  • Examples of the acid used in Step 1 include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydrofluoric acid; trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include organic acids such as p-toluenesulfonic acid and aminosulfonic acid; Lewis acids such as boron tribromide, boron trichloride, boron trifluoride, and aluminum chloride.
  • the acid used in Step 1 is preferably an inorganic acid, and more preferably sulfuric acid.
  • the acid used in step 1 is, for example, from 0.01 to 5 molar equivalents, preferably 0.1 to 2 molar equivalents, more preferably 0.5 to 1.5 equivalents, relative to compound (8). Used.
  • the solvent used in step 1 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, ethers, amides, sulfoxides, lower alcohols, nitriles, or a mixed solvent thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • sulfoxides include dimethyl sulfoxide and sulfolane.
  • lower alcohols include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
  • nitriles include acetonitrile.
  • the solvent used in this step 1 is preferably an aromatic hydrocarbon or a lower alcohol, more preferably toluene, xylene, propanol, n-butanol or a mixed solvent thereof, more preferably toluene. N-butanol or a mixed solvent thereof.
  • the compound of the said Formula (14) may serve as the solvent.
  • the reaction temperature in step 1 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 to 200 ° C., preferably 60 to 140 ° C., more preferably 90 to 130 ° C. Done in The reaction time in Step 1 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 1 to 24 hours, preferably 2 to 6 hours.
  • Compound (7) can be obtained by the treatment usually performed after the above reaction.
  • the compound (7) can be extracted, washed, and separated using a base, a solvent, water, saturated saline and the like and used in the next step, preferably toluene, n-butanol or a mixed solvent thereof. Is used. These solvents can be used as a solvent for the next step after being used for extraction, washing, and liquid separation after the reaction.
  • the compound (7) can be further dried by removing the solvent under reduced pressure or the like, and purified by a conventional method such as recrystallization, reprecipitation, distillation or the like.
  • Step 2 will be described below.
  • Step 2 is a step of producing compound (6) by reacting compound (7) with an oxidizing agent in a solvent.
  • the definition of R 2 is the same as the definition explained in the step 1 above.
  • Examples of the oxidizing agent used in Step 2 include inorganic peracids such as hydrogen peroxide; peracetic acid, trifluoroperacetic acid, metachloroperbenzoic acid, monoperphthalic acid, N-hydroxyphthalimide, t-butyl nitrite, and the like. Organic peracids; organic metals such as ruthenium oxide and methyltrioxorhenium.
  • the oxidizing agent used in Step 2 is preferably hydrogen peroxide, metachlorobenzoic acid, monoperphthalic acid or N-hydroxyphthalimide, more preferably hydrogen peroxide or monoperphthalic acid. In this reaction, a co-oxidant may be added together with the oxidant.
  • Examples of the combination of the oxidizing agent and the co-oxidizing agent used in Step 2 include hydrogen peroxide and phthalic anhydride, hydrogen peroxide and sodium tungstate, and more preferably hydrogen peroxide and phthalic anhydride. It is a combination.
  • the oxidizing agent used in Step 2 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (7).
  • the oxidant and co-oxidant to be used are, for example, 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, respectively, relative to the compound (7). Used.
  • the solvent used in Step 2 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl carboxylic acid esters, amides, sulfoxides, lower alcohols, nitriles, water, and mixed solvents thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • Examples of lower alkyl carboxylic acid esters include ethyl acetate and isopropyl acetate.
  • Examples of amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • Examples of the sulfoxides include dimethyl sulfoxide and sulfolane.
  • Examples of lower alcohols include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
  • Examples of nitriles include acetonitrile.
  • the solvent used in Step 2 is preferably an aromatic hydrocarbon or a lower alcohol, more preferably toluene, xylene, propanol, n-butanol or a mixed solvent thereof, and further preferably toluene. N-butanol or a mixed solvent thereof.
  • the reaction temperature in step 2 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 to 80 ° C., preferably 0 to 50 ° C., more preferably 10 to 40 ° C. Done in The reaction time in Step 2 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 1 hour to 48 hours, preferably 6 hours to 30 hours.
  • Compound (6) can be obtained by the treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using sodium thiosulfate, a base, a solvent and saturated saline, removing the solvent under reduced pressure, and drying.
  • R 2 is n- butyl group
  • the compound (6) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Step 3 will be described below.
  • Step 3 is a step of producing compound (5) by reacting compound (6) with compound (13) in the presence of a base in a solvent.
  • R 3 and R 4 are the same or different and represent a hydrogen atom or a nitrogen atom protecting group, or R 3 and R 4 together form a nitrogen atom protecting group.
  • R 3 and R 4 are preferably the same or different and are a hydrogen atom or a t-butyl group, or R 3 and R 4 may be combined to form a succinimide or phthalimide, more preferably It is a phthalimide in which R 3 and R 4 are combined.
  • Compound (13) is used, for example, in an amount of 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents, relative to compound (6).
  • an additive can be added to increase the reaction efficiency between the compound (6) and the compound (13).
  • Preferable additives include, for example, sulfonyl chlorides such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride; carbamoyl chlorides such as dimethylcarbamoyl chloride, and more preferably p chloride chloride. -Toluenesulfonyl.
  • the additive used in Step 3 is used in an amount of, for example, 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents, relative to compound (6).
  • the base used in step 3 may be either an inorganic base or an organic base.
  • inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides.
  • examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate.
  • alkali metal hydrogen carbonates include sodium hydrogen carbonate, potassium hydrogen carbonate, and lithium hydrogen carbonate.
  • Examples of the alkali metal hydroxides include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
  • alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like.
  • organic bases include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide, N-methylmorpholine, triethylamine, and tripropylamine.
  • Tributylamine diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4- Methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.
  • DBN non-5-ene
  • the base used in Step 3 is preferably an organic base, and more preferably triethylamine.
  • the base used in Step 3 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1.5 to 3 molar equivalents, relative to compound (6).
  • the solvent used in step 3 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, lower alkyl carboxylic acid esters, amides, sulfoxides, lower alcohols, water, or a mixed solvent thereof. It is done.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • ketones include acetone and 2-butanone.
  • lower alkyl carboxylic acid esters include ethyl acetate and isopropyl acetate.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • sulfoxides include dimethyl sulfoxide and sulfolane.
  • lower alcohols include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
  • the solvent used in Step 3 is preferably a ketone, and more preferably acetone.
  • the reaction temperature in step 3 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 ° C to 80 ° C, preferably 0 ° C to 60 ° C, more preferably 15 ° C to 60 ° C.
  • Done in The reaction time in Step 3 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 1 hour to 12 hours, preferably 2 hours to 6 hours.
  • Compound (5) can be obtained by a treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using a solvent and saturated saline, removing the solvent under reduced pressure, and drying. Furthermore, if necessary, the compound (5) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Step 4 will be described below.
  • Step 4 is a step for producing compound (4) by reacting compound (5) with a reducing agent in a solvent (using ester as an alcohol) and further deprotecting the protecting group of the nitrogen atom.
  • a solvent using ester as an alcohol
  • Examples of the reducing agent used in Step 4 include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, triethylboron hydride.
  • Examples thereof include lithium, hydrogenated tri (s-butyl) borohydride, borane complex, metal hydride such as sodium bis (2-methoxyethoxy) aluminum hydride, and alkylsilane such as triethylsilane.
  • Preferred are sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and lithium borohydride, and more preferred is sodium borohydride.
  • the reducing agent used in step 4 is used, for example, in an amount of 1 to 10 molar equivalents, preferably 3 to 6 molar equivalents, relative to compound (5).
  • the deprotection performed in Step 4 is to remove a protecting group by carrying out an appropriate reaction to form a nitrogen-hydrogen bond when either or both of R 3 and R 4 represent a protecting group of a nitrogen atom. It is.
  • the additive used for the deprotection varies depending on the type of protecting group, for example, acids such as hydrochloric acid, hydrogen chloride, and trifluoroacetic acid; bases such as potassium hydroxide and sodium hydroxide; sodium borohydride, hydrogenated Metal hydrides such as aluminum lithium and diisobutylaluminum hydride; metal substances such as palladium, palladium hydroxide and platinum; organic amines such as hydrazine, methylamine and ethylamine can be used.
  • R 3 or R 4 when either R 3 or R 4 is a t-butyl group, hydrogen chloride, trifluoroacetic acid can be used, or R 3 and R 4 can be combined to form succinimide or phthalimide.
  • metal hydrides such as potassium hydride, sodium hydride base, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, or organic amines such as hydrazine, methylamine, ethylamine, etc. Can do.
  • R 3 and R 4 are combined to form phthalimide.
  • sodium borohydride or hydrazine can be used.
  • the additive used in the deprotection used in Step 4 is, for example, 1 to 10 molar equivalents, preferably 3 to 6 molar equivalents, relative to compound (5).
  • the reducing agent used in Step 4 can remove the nitrogen protecting group of R 3 and R 4 , the reduction from the ester to the alcohol and the deprotection may be carried out simultaneously by adding only the reducing agent. Is the case where R 3 and R 4 together form phthalimide.
  • R 3 and R 4 represents a hydrogen atom may just adding a reducing agent, deprotection is not performed. Further, depending on the type of protecting group for nitrogen of R 3 and R 4 , the type of reducing agent used or the type of additive used for deprotection, the nitrogen atom is deprotected and then reacted with the reducing agent. Also good.
  • the solvent used in Step 4 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides, sulfoxides, lower alcohols, water, or a mixed solvent thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • sulfoxides include dimethyl sulfoxide and sulfolane.
  • lower alcohols examples include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
  • the solvent used in Step 4 is preferably a lower alcohol, more preferably ethanol, propanol, isopropanol, or n-butanol, and still more preferably n-butanol.
  • the reaction temperature in step 4 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 to 100 ° C., preferably 20 to 90 ° C., more preferably 60 to 90 ° C. Done in The reaction time in Step 4 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 12 hours, preferably 1 hour to 6 hours.
  • Compound (4) can be obtained by a treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using a solvent, acid and saturated saline, removing the solvent under reduced pressure, and drying. Furthermore, if necessary, the compound (4) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Step 5 will be described below.
  • Step 5 is a step of producing compound (3) by reacting compound (4) with a halogenating agent in a solvent.
  • X represents a halogen atom, preferably a chlorine atom or a bromine atom, and more preferably a chlorine atom.
  • halogenating agent used in Step 5 examples include chlorinating agents such as oxalyl chloride, thionyl chloride, sulfuryl chloride, methanesulfonyl chloride, N-chlorosuccinimide, phosphorus oxychloride, cyanuric chloride, and trichloroisocyanuric acid; Bromine, hydrogen bromide, boron tribromide, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, trimethylphenylammonium tribromide, Examples include brominating agents such as tetrabutylammonium tribromide; iodizing agents such as iodine, hydrogen iodide, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhy
  • the halogenating agent used in Step 5 is preferably a chlorinating agent, more preferably oxalyl chloride, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, and further preferably thionyl chloride.
  • the halogenating agent used in Step 5 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (4).
  • the solvent used in step 5 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides, sulfoxides, nitriles, or a mixed solvent thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • the sulfoxides include dimethyl sulfoxide and sulfolane.
  • nitriles include acetonitrile.
  • the solvent used in Step 5 is preferably a nitrile, and more preferably acetonitrile.
  • the reaction temperature in step 5 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 to 100 ° C., preferably 20 to 80 ° C., more preferably 20 to 60 ° C. Done in The reaction time in Step 5 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 12 hours, preferably 1 hour to 6 hours.
  • Compound (3) can be obtained by a treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using a solvent, water and saturated saline, removing the solvent under reduced pressure, and drying. Furthermore, if necessary, the compound (3) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Step 6 includes step 6-1 and step 6-2.
  • Step 6-1 is a step of reacting compound (3) with compound (12) in a solvent to obtain compound (15), compound (16) or a mixture thereof
  • step 6-2 is compound (15).
  • compound (2) is produced by treating compound (16) or a mixture thereof with a base.
  • the definition of X is the same as the definition explained in the above step 5.
  • R 1 represents a lower alkyl group, preferably having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. More preferably a methyl group.
  • Step 6-1 compound (16) can be obtained as the main product by using compound (12) in an exact amount or compound (16) using a large excess of compound (12). It is preferable to use an amount of compound (12) that consumes compound (3), and even if the product obtained in step 6-1 is a mixture containing compound (15) and compound (16), removal of the solvent.
  • the next step 6-2 can be carried out efficiently without the usual purification. That is, the compound (12) used in Step 6-1 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to the compound (3).
  • the base used in Step 6-1 and Step 6-2 may be either an inorganic base or an organic base.
  • inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides.
  • examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate.
  • alkali metal hydrogen carbonates include sodium hydrogen carbonate, potassium hydrogen carbonate, and lithium hydrogen carbonate.
  • Examples of the alkali metal hydroxides include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
  • alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like.
  • organic bases include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide, N-methylmorpholine, triethylamine, and tripropylamine.
  • the base used in Step 6-1 is preferably an organic base, and more preferably N, N-diisopropylethylamine, N, N-dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (T-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DA CO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ′, N ′, N ′′, N ′′ -hexamethylphosphoric triamide (HMPA) Etc.
  • the base used in Step 6-1 is preferably an organic base, and more
  • the base used in Step 6-1 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 2 to 4 molar equivalents, relative to compound (3).
  • the base used in Step 6-2 is used, for example, in an amount of 1 to 10 molar equivalents, preferably 3 to 6 molar equivalents, relative to compound (3).
  • the solvent used in Step 6-1 and Step 6-2 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Examples thereof include aromatic hydrocarbons, halogenated hydrocarbons, ethers, lower alkyl carboxylic acid esters, amides, sulfoxides, lower alcohols, nitriles, water, or a mixed solvent thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • lower alkyl carboxylic acid esters include ethyl acetate and isopropyl acetate.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • the sulfoxides include dimethyl sulfoxide and sulfolane.
  • Examples of lower alcohols include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, and anhydrides thereof.
  • Examples of nitriles include acetonitrile.
  • the solvent used in Step 6-1 is preferably a nitrile, and more preferably acetonitrile.
  • the solvent used in Step 6-2 is preferably a lower alcohol, nitrile, water or a mixed solvent thereof, more preferably a mixed solvent of acetonitrile, methanol and water.
  • the reaction temperature in step 6-1 varies depending on the raw material compound, the reaction reagent or the kind of the solvent used, but is, for example, 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., more preferably 0 ° C. Performed at 30 ° C.
  • the reaction temperature in Step 6-2 varies depending on the raw material compound, the reaction reagent, or the type of the solvent used, but is, for example, 0 to 100 ° C., preferably 0 to 50 ° C., more preferably 0 ° C. To 30 ° C.
  • the reaction time in Step 6-1 varies depending on the reaction temperature, the raw material compound, the reaction reagent, or the type of solvent used, but is usually 10 minutes to 12 hours, preferably 30 minutes to 3 hours.
  • the reaction time in Step 6-2 varies depending on the reaction temperature, the raw material compound, the reaction reagent, and the type of solvent used, but is usually 1 minute to 8 hours, preferably 10 minutes to 3 hours.
  • the compound (15), compound (16) or a mixture containing these obtained in the step 6-1 can be used in the next step 6-2 without removing the solvent or performing purification usually performed.
  • the compound (15) and the compound (16) can be obtained by a usual treatment after the reaction in the step 6-1, if necessary. For example, it can be obtained by extraction, washing, liquid separation using a solvent and saturated saline, removing the solvent under reduced pressure, and drying.
  • the compound (15) and the compound (16) can be purified by a usual method, for example, washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Compound (2) can be obtained by a treatment usually performed after the reaction in Step 6-2.
  • it can be obtained by extraction, washing, liquid separation using a solvent, acid and saturated saline, removing the solvent under reduced pressure, and drying.
  • the compound (2) can be purified by a usual method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • next step 8 it is preferable to carry out the next step 8 when the purity of the compound (2) is usually such that chemical synthesis can be carried out satisfactorily, for example, 90% purity or higher, and particularly when the purity is 95% purity or higher preferable. Further, the next step 8 can be carried out even when the purity of the compound (2) does not exceed 90%, for example, but it is purified by a usual method such as washing with a solvent, recrystallization, reprecipitation, etc. By carrying out, it can also implement after improving purity.
  • the calculation of purity may be simply determined by a method that is usually performed simply, for example, by measuring a sample by high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), or the like. Good.
  • Step 7 will be described below.
  • Step 7 is a step for producing compound (9) by reacting compound (10) with compound (11) in the presence of a condensing agent in a solvent.
  • the compound (10) and the compound (11) can use what was marketed and what was manufactured by the well-known method.
  • Compound (11) is used in an amount of 0.8 molar equivalent to 3 molar equivalents, preferably 0.9 to 1.2 molar equivalents, relative to compound (10).
  • Examples of the condensing agent used in Step 7 include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, 4- ( 4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, O— (7-Azabenzotriazol-1-yl) -N, N, N′N′-tetramethyluronium hexafluorophosphate and the like can be mentioned, and N, N′-carbonyldiimidazole is preferred.
  • the condensing agent used in Step 7 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (10).
  • the solvent used in step 7 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons, halogenated hydrocarbons, ethers, lower alkyl carboxylic acid esters, amides, sulfoxides, nitriles, water, and mixed solvents thereof.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • lower alkyl carboxylic acid esters include ethyl acetate and isopropyl acetate.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • the sulfoxides include dimethyl sulfoxide and sulfolane.
  • nitriles include acetonitrile.
  • the solvent used in Step 7 is preferably an ether, more preferably tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and still more preferably tetrahydrofuran.
  • the reaction temperature in Step 7 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, but is, for example, 0 to 120 ° C., preferably 0 to 100 ° C.
  • the reaction time in Step 7 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of the solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.
  • Compound (9) can be obtained by the treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using a solvent, water and saturated saline, removing the solvent under reduced pressure, and drying.
  • compound (9) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • the purity of the compound (9) is usually such that chemical synthesis can be carried out satisfactorily, for example, 90% purity or higher, and particularly when the purity is 95% purity or higher preferable.
  • the next step 8 can be carried out even when the purity of the compound (9) does not exceed 90%, for example, but it is purified by a usual method such as washing with a solvent, recrystallization, reprecipitation, etc. By carrying out, it can also implement after improving purity.
  • the calculation of purity may be simply determined by a method that is usually performed simply, for example, by measuring a sample by high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), or the like. Good.
  • Step 8 will be described below.
  • Step 8 is a step of producing compound (1) by reacting compound (9) with compound (2) in the presence of a base in a solvent.
  • the definition of X is the same as the definition explained in the above step 5.
  • Compound (2) is used in an amount of, for example, 0.7 to 1.3 molar equivalents, preferably 0.8 to 1.2 molar equivalents, relative to Compound (9).
  • the base used in step 8 may be either an inorganic base or an organic base.
  • inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides.
  • examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate.
  • alkali metal hydrogen carbonates include sodium hydrogen carbonate, potassium hydrogen carbonate, and lithium hydrogen carbonate.
  • Examples of the alkali metal hydroxides include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
  • alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like.
  • organic bases include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide, N-methylmorpholine, triethylamine, and tripropylamine.
  • Tributylamine diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4- Methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.
  • DBN non-5-ene
  • the base used in Step 8 is preferably an organic base, more preferably triethylamine.
  • the base used in Step 8 is used, for example, in an amount of 1 to 5 molar equivalents, preferably 1.5 to 3 molar equivalents, relative to compound (9).
  • the solvent used in step 8 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Preferred solvents include, for example, aromatic hydrocarbons, halogenated hydrocarbons, ethers, lower alkyl carboxylic acid esters, amides, sulfoxides, lower alcohols, nitriles, water or a mixed solvent thereof. It is done.
  • Aromatic hydrocarbons include benzene, toluene, xylene and the like.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • lower alkyl carboxylic acid esters include ethyl acetate and isopropyl acetate.
  • amides include formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide and the like.
  • the sulfoxides include dimethyl sulfoxide and sulfolane.
  • the solvent used in Step 8 is preferably a halogenated hydrocarbon or a lower alcohol, more preferably toluene, xylene, propanol or n-butanol, and still more preferably methanol.
  • the reaction temperature in step 8 varies depending on the raw material compound, the reaction reagent, or the type of solvent used, and is, for example, 0 to 120 ° C., preferably 10 to 90 ° C.
  • the reaction time in Step 8 varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of the solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound (1) can be obtained by the treatment usually performed after the above reaction. For example, it can be obtained by extraction, washing, liquid separation using a solvent, water and saturated saline, and drying under reduced pressure. Furthermore, the compound (1) can be purified by a commonly performed method, for example, washing with a solvent, recrystallization, reprecipitation and the like.
  • the solvent that can be used in the post-treatment and purification the solvents listed above can be used.
  • Step 1 4-n-Butoxycarbonylpyridine (Compound (7) -1) Sulfuric acid (9.5 mL, 178 mmol) was added to a mixture of isonicotinic acid (compound (8) -1, 20.2 g, 164 mmol), 1-butanol (160 mL) and toluene (160 mL) at room temperature. The mixture was heated to reflux for 3 hours. After cooling at room temperature, this mixture was poured into an aqueous sodium hydrogen carbonate solution (30.3 g of sodium hydrogen carbonate / 300 mL of water). The mixture was stirred and then partitioned into an organic layer and an aqueous layer.
  • aqueous sodium hydrogen carbonate solution 30.3 g of sodium hydrogen carbonate / 300 mL of water
  • the obtained organic layer was used as a starting material in the next step 2 as a mixture containing the title compound.
  • a small amount of the organic layer obtained by the above operation was further distilled off under reduced pressure, and the residue was dried under reduced pressure to give the title compound.
  • Step 1 As described above, by finding that a solvent that dissolves the product of Step 1 to some extent and a solvent that does not inhibit the reaction conditions of Step 2 as an extraction solvent, the treatment after the reaction in Step 1 is simplified and made efficient.
  • Step 2 4-n-Butoxycarbonylpyridine-N-oxide (Compound (6) -1) To a mixture containing 4-n-butoxycarbonylpyridine (compound (7) -1) obtained in Step 1, phthalic anhydride (26.4 g, 178 mmol), 30% aqueous hydrogen peroxide (19.8 mL, 197 mmol) was added sequentially. The mixture was stirred at room temperature for 23 hours. While cooling with ice water, an aqueous solution of sodium thiosulfate (12.3 g of sodium thiosulfate / 40 mL of water) and an aqueous solution of sodium hydrogencarbonate (30.0 g of sodium bicarbonate / 400 mL of water) were sequentially added to the mixture.
  • the mixture was stirred at room temperature and then partitioned between an organic layer and an aqueous layer.
  • the solvent was distilled off from the organic layer under reduced pressure. When the solvent was not distilled off, the precipitated solid was collected by filtration. The solvent was distilled off from the filtrate under reduced pressure. When the solvent was not distilled off, the precipitated solid was again collected by filtration. The obtained solids were combined and the solid was dried under reduced pressure to give the title compound (27.1 g) as a white solid (2 step yield 85%).
  • step 2 the following compound (6) -2 was also produced.
  • Step 3 2- (1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl) -4-n-butoxycarbonylpyridine (compound (5) -1)
  • a mixture of 4-n-butoxycarbonylpyridine-N-oxide (compound (6) -1, 19.8 g, 101 mmol), phthalimide (16.7 g, 114 mmol), triethylamine (34.0 mL, 245 mmol) and acetone (197 mL) P-Toluenesulfonyl chloride (23.4 g, 123 mmol) was added in portions so that the internal temperature did not exceed 50 ° C., and the mixture was stirred at room temperature for 15 hours. Water (400 mL) was added to the mixture, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (32.0 g) as a pale yellow solid (yield 98%).
  • Step 3 the following compound (5) -2 was also produced using the compound (6) -2.
  • compound (3) -1 was obtained from raw materials (compound (8) -1) and reagents that were inexpensive and easily available in large quantities and from compounds (7) -1, compound (6) -1, and compound (5).
  • -1 and compound (4) -1 were prepared in 75 steps with a yield of 75% without purification by column chromatography.
  • Step 6 2- (2-hydroxyacetylamino) -4-chloromethylpyridine (compound (2) -1) Under cooling with ice water, 2-amino-4-chloromethylpyridine hydrochloride (compound (3) -1, 10.5 g, 58.6 mmol) and acetoxyacetyl chloride (12.9 mL, 120 mmol) were added to acetonitrile (31.5 mL). added. Further, N, N-diisopropylethylamine (30.9 mL, 179 mmol) was added to the mixture, and the mixture was stirred for 1 hour under cooling with ice water.
  • Step 7 N- (4-Trifluoromethoxyphenyl) -1,2-dihydro-2-thioxopyridine-3-carboxamide (Compound (9) -1)
  • a mixture of 2-mercaptonicotinic acid (compound (10) -1, 18.7 g, 121 mmol), 1,1′-carbonyldiimidazole (27.7 g, 171 mmol) and tetrahydrofuran (100 mL) was stirred at room temperature for 1 hour. did. Water (1.0 mL) was added to the mixture, and the mixture was stirred for 30 minutes under cooling with ice water.
  • Step 8 2- (2-Hydroxyacetylaminopyridin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide
  • Compound (1) -1 2- (2-hydroxyacetylamino) -4-chloromethylpyridine (compound (2) -1, 5.01 g, 25.0 mmol) and N- (4-trifluoromethoxyphenyl) -1,2-dihydro-2
  • a mixture of -thioxopyridine-3-carboxamide compound (9) -1, 7.83 g, 24.9 mmol
  • triethylamine 7.0 mL, 50.2 mmol
  • methanol 25 mL
  • the compound (1) -1 was prepared by column chromatography in two steps through the compound (2) -1 using the compound (3) -1 produced from the raw material compound (8) -1 as a starting material. Prepared in 79% yield without graphic purification. Further, the compound (1) -1 is obtained from the raw material compound (8) -1 which is inexpensive and easily available in large quantities and from the reagent to the compound (7) -1, compound (6) -1, compound (5) -1, compound ( The product was produced in 59% yield without purification by column chromatography in 7 steps through 4) -1, compound (3) -1 and compound (2) -1.
  • the compound (1) can be efficiently produced by using the compound represented by the formula (2) or a salt thereof, which is a novel production intermediate according to the present invention.
  • the compound (1) can be produced in high yield from an inexpensive raw material without purification by column chromatography, and the compound (1) can be supplied industrially.

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PCT/JP2016/076398 2015-09-08 2016-09-08 ピリジンカルボキサミドの製造方法 WO2017043563A1 (ja)

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Citations (5)

* Cited by examiner, † Cited by third party
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