WO2017043563A1 - Method for producing pyridinecarboxamide - Google Patents

Method for producing pyridinecarboxamide 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)
Japanese (ja)
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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.

Abstract

The present invention relates to a method for producing a compound represented by formula (1) or a salt thereof, comprising a step of reacting a compound represented by formula (2) or a salt thereof with a compound represented by formula (9) or a salt thereof in the presence of a base to produce the compound represented by formula (1) or a salt thereof.

Description

ピリジンカルボキサミドの製造方法Method for producing pyridinecarboxamide
　本発明は２－［［［２－［（ヒドロキシアセチル）アミノ］－４－ピリジニル］メチル］チオ］－Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－ピリジンカルボキサミドの新たな製造方法及びその製造中間体に関する。 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.
　特許文献１及び非特許文献１には、２－［［［２－［（ヒドロキシアセチル）アミノ］－４－ピリジニル］メチル］チオ］－Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－ピリジンカルボキサミド（以下、「本化合物」とする）がＶＥＧＦ誘発ＨＵＶＥＣ増殖反応評価系を用いた試験系において細胞増殖阻害作用を、マウス担癌モデルを用いた試験系において腫瘍増殖抑制作用を、ラットアジュバント関節炎モデルを用いた試験系において足浮腫抑制作用を、及びラット脈絡膜血管新生モデルを用いた試験系において脈絡膜血管新生阻害作用を示すことが知られている。また、その薬理作用から本化合物は、医薬として有用であり、特に癌、関節リウマチ、加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫などの疾患の予防又は治療剤として期待されることが記載されている。 In 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. It is known that a 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. In addition, it is described from the pharmacological action that 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.
　また、特許文献１には、本化合物及びその誘導体の製造方法が記載されている。特許文献１記載の本化合物の製造方法は、以下に示すステップ１～５の工程を含む直線的合成方法である。
（ステップ１）
　２－ブロモ－４－ピコリンを、Ｎ－クロロコハク酸イミドでクロロ化して、２－ブロモ－４－クロロメチルピリジンを得る工程（特許文献１：５７頁、参考化合物１－２）、
（ステップ２）
　２－ブロモ－４－クロロメチルピリジンを、トリエチルアミンの存在下、２－メルカプトニコチン酸と反応させて、２－（２－ブロモピリジン－４－イルメチルチオ）ピリジン－３－カルボン酸を得る工程（特許文献１：５８頁、参考化合物２－２）、
（ステップ３）
　２－（２－ブロモピリジン－４－イルメチルチオ）ピリジン－３－カルボン酸を、Ｎ，Ｎ－ジイソプロピルエチルアミン及びＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩の存在下、４－（トリフルオロメトキシ）アニリンと反応させて、２－（２－ブロモピリジン－４－イルメチルチオ）ピリジン－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミドを得る工程（特許文献１：６１頁、参考化合物３－５）、
（ステップ４）
　２－（２－ブロモピリジン－４－イルメチルチオ）ピリジン－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミドを、炭酸セシウム、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン、トリス（ジベンジリデンアセトン）ジパラジウム（０）の存在下、アセトキシアセトアミドと反応させて、２－（２－アセトキシアセチルアミノピリジン－４－イルメチルチオ）－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミドを得る工程（特許文献１：１７２頁、化合物１０－２）、
（ステップ５）
　２－（２－アセトキシアセチルアミノピリジン－４－イルメチルチオ）－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミドを、水酸化ナトリウム水溶液と反応させて、２－（２－ヒドロキシアセチルアミノピリジン－４－イルメチルチオ）－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミドを得る工程（特許文献１：１８５頁、化合物１２－１）。 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) -N, N, N ′, N Reaction with 4- (trifluoromethoxy) aniline in the presence of '-tetramethyluronium hexafluorophosphate to give 2- (2-bromopyridin-4-ylmethylthio) pyridine-N- (4-trifluoro A step of obtaining methoxyphenyl) pyridine-3-carboxamide (Patent Document 1: page 61, Reference Compound 3-5),
(Step 4)
2- (2-Bromopyridin-4-ylmethylthio) pyridine-N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide was converted to cesium carbonate, 4,5-bis (diphenylphosphino) -9,9- Reaction with acetoxyacetamide in the presence of dimethylxanthene, tris (dibenzylideneacetone) dipalladium (0) to give 2- (2-acetoxyacetylaminopyridin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) ) Step of obtaining pyridine-3-carboxamide (Patent Document 1: 172 pages, Compound 10-2),
(Step 5)
2- (2-Acetoxyacetylaminopyridin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide is reacted with an aqueous sodium hydroxide solution to give 2- (2-hydroxyacetylamino). A step of obtaining pyridin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Patent Document 1: 185 pages, Compound 12-1).
　また、特許文献１には、２－チオキソ－Ｎ－（４－トリフルオロメトキシ）－１，２－ジヒドロピリジン－３－カルボキサミドの合成方法が記載されている（特許文献１：７１頁、参考化合物１０－２）。　しかしながら、特許文献１には、２－チオキソ－Ｎ－（４－トリフルオロメトキシ）－１，２－ジヒドロピリジン－３－カルボキサミドを本化合物の合成中間体として用いることは記載されておらず、本化合物の合成中間体として、２－ヒドロキシアセチルアミノピリジン誘導体を用いることも一切記載されていない。 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.
　特許文献２には、本化合物のベンゼンスルホン酸塩、その結晶、その結晶多形及びそれらの製造方法が記載されている。 Patent Document 2 describes a benzenesulfonate salt of the present compound, its crystal, its crystal polymorph and a method for producing them.
　非特許文献１には、高価な原料である非特許文献１の化合物１２から、非特許文献１の化合物１７（本化合物の類縁体）を６ステップで合成する方法が開示されている（非特許文献１：Ｓｃｈｅｍｅ１）。一方、非特許文献１には、本化合物は記載されているが（非特許文献１：Ｔａｂｌｅ３、化合物１１ｂ）、その具体的な製造方法については開示されていない。更に、非特許文献１には、本化合物の合成中間体として、２－ヒドロキシアセチルアミノピリジン誘導体を用いることは一切記載も示唆もされていない。 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). Reference 1: Scheme 1). On the other hand, although 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. Furthermore, Non-Patent Document 1 does not describe or suggest any use of a 2-hydroxyacetylaminopyridine derivative as a synthetic intermediate of the present compound.
国際公開２００５－０８５２０１号パンフレットInternational Publication No. 2005-085201 Pamphlet 特開２０１１－３７８４４号公報JP 2011-37844 A
　本化合物を医薬品として工業レベルで製造するには、以下（Ａ）～（Ｃ）の課題があった。
（Ａ）特許文献１に記載の製造工程（図１）のステップ４では、金属パラジウム触媒を使用している。その為、安全性の観点からカラムクロマトグラフィーによる金属パラジウム触媒の除去が必須である。また、カラムクロマトグラフィーは、経済効率（製造コスト、製造時間等）の観点から工業レベルでの製造には不向きである。従って、金属パラジウム触媒を使用せず、カラムクロマトグラフィーを必要としない製造方法の開発が望まれる。
（Ｂ）特許文献１に記載の製造工程（図１）のステップ３～ステップ５では、メチルチオ結合の形成後に直線的な多段階合成法を使用するために本化合物の類縁体が多数生成する。安全性及び経済効率の観点からこれらの類縁体の分離・除去が必須であるが、これらの類縁体の分離・除去は困難である。従って、これらの類縁体の生成を最小限に抑えた製造方法の開発が望まれる。
（Ｃ）非特許文献１の化合物１２は非常に高価な原料である。従って経済的観点からより安価な原料を用いた製造方法の開発が望まれる。 In order to produce this compound as a pharmaceutical at an industrial level, there were the following problems (A) to (C).
(A) In 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.
(B) In Step 3 to Step 5 of the production process described in Patent Document 1 (FIG. 1), a large number of analogs of this compound are produced because a linear multi-step synthesis method is used after the formation of the methylthio bond. Separation / removal of these analogs is essential from the viewpoint of safety and economic efficiency, but separation / removal of these analogs is difficult. Therefore, development of a production method that minimizes the generation of these analogs is desired.
(C) Compound 12 of Non-Patent Document 1 is a very expensive raw material. Therefore, development of a manufacturing method using a cheaper raw material is desired from an economic viewpoint.
　本発明者は、前記課題を解決した新たな製造方法を見出すために鋭意検討した結果、本化合物、すなわち式（１）：
Figure JPOXMLDOC01-appb-C000021
で表される化合物又はその塩の製造方法であって、
式（２）：
Figure JPOXMLDOC01-appb-C000022
［式（２）中、Ｘはハロゲン原子を示す］
で表される化合物又はその塩と、式（９）：
Figure JPOXMLDOC01-appb-C000023
で表される化合物又はその塩を、塩基の存在下で反応させることを特徴とし、医薬品として工業レベルで製造することができる式（１）で表される化合物又はその塩の製造方法を見出した。また、本製造方法に用いられる新規な製造中間体を創製した。 As a result of intensive studies to find a new production method that has solved the above-mentioned problems, the present inventors have found that this compound, that is, the formula (1):
Figure JPOXMLDOC01-appb-C000021
A method for producing a compound represented by the formula:
Formula (2):
Figure JPOXMLDOC01-appb-C000022
[In formula (2), X represents a halogen atom]
And a compound represented by the formula (9):
Figure JPOXMLDOC01-appb-C000023
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. . Moreover, the novel manufacturing intermediate used for this manufacturing method was created.
　すなわち、本発明は以下の通りである。 That is, the present invention is as follows.
　（１）式（１）：
Figure JPOXMLDOC01-appb-C000024
で表される化合物又はその塩の製造方法であって、式（２）：
Figure JPOXMLDOC01-appb-C000025
［式（２）中、Ｘはハロゲン原子を示す］
で表される化合物又はその塩と、式（９）：
Figure JPOXMLDOC01-appb-C000026
で表される化合物又はその塩を、塩基の存在下で反応させて、式（１）で表される化合物又はその塩を得る工程を含む、製造方法。 (1) Formula (1):
Figure JPOXMLDOC01-appb-C000024
Wherein the compound represented by formula (2):
Figure JPOXMLDOC01-appb-C000025
[In formula (2), X represents a halogen atom]
And a compound represented by the formula (9):
Figure JPOXMLDOC01-appb-C000026
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.
　（２）式（３）：
Figure JPOXMLDOC01-appb-C000027
［式（３）中、Ｘは、前記式（２）中の定義と同一である］
で表される化合物又はその塩と、式（１２）：
Figure JPOXMLDOC01-appb-C000028
［式（１２）中、Ｒ１は低級アルキル基を示す］
で表される化合物又はその塩を反応させた後に、塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程をさらに含む、上記（１）記載の製造方法。 (2) Formula (3):
Figure JPOXMLDOC01-appb-C000027
[In formula (3), X is the same as defined in formula (2)]
And a compound represented by formula (12):
Figure JPOXMLDOC01-appb-C000028
[In formula (12), R 1 represents a lower alkyl group]
The method according to (1) above, further comprising a step of obtaining a compound represented by the formula (2) or a salt thereof by reacting with a compound represented by the formula or a salt thereof and then treating with a base.
　（３）式（４）：
Figure JPOXMLDOC01-appb-C000029
で表される化合物又はその塩と、ハロゲン化剤を反応させて、前記式（３）で表される化合物又はその塩を得る工程をさらに含む、上記（２）記載の製造方法。 (3) Formula (4):
Figure JPOXMLDOC01-appb-C000029
The manufacturing method of the said (2) description further including the process of making the compound or its salt represented by these, and a halogenating agent react, and obtaining the compound or its salt represented by the said Formula (3).
　（４）式（５）：
Figure JPOXMLDOC01-appb-C000030
［式（５）中、
　Ｒ２は低級アルキル基を示し、
　Ｒ３及びＲ４は同一又は異なって、水素原子又は窒素原子の保護基を示すか、又は
　Ｒ３とＲ４が一緒になって窒素原子の保護基を形成してもよい］
で表される化合物又はその塩を、還元及び脱保護することで、前記式（４）で表される化合物又はその塩を得る工程をさらに含む、上記（３）記載の製造方法。 (4) Formula (5):
Figure JPOXMLDOC01-appb-C000030
[In Formula (5),
R 2 represents a lower alkyl group,
R 3 and R 4 are the same or different and each represents a hydrogen atom or a nitrogen atom protecting group, or R 3 and R 4 may form a nitrogen atom protecting group together.]
The manufacturing method of said (3) description which further includes the process of obtaining the compound or its salt represented by said Formula (4) by reducing and deprotecting the compound or its salt represented by these.
　（５）式（６）：
Figure JPOXMLDOC01-appb-C000031
［式（６）中、Ｒ２は、前記式（５）中の定義と同一である］
で表される化合物又はその塩と、式（１３）：
Figure JPOXMLDOC01-appb-C000032
［式（１３）中、Ｒ３及びＲ４は前記式（５）中の定義と同一である］
で表される化合物又はその塩を塩基の存在下で反応させて、前記式（５）で表される化合物又はその塩を得る工程をさらに含む、上記（４）記載の製造方法。 (5) Formula (6):
Figure JPOXMLDOC01-appb-C000031
[In formula (6), R 2 has the same definition as in formula (5)]
And a compound represented by the formula (13):
Figure JPOXMLDOC01-appb-C000032
[In Formula (13), R 3 and R 4 are the same as defined in Formula (5).]
The manufacturing method of the said (4) description further including the process of making the compound or its salt represented by these react in presence of a base, and obtaining the compound or its salt represented by the said Formula (5).
　（６）式（７）：
Figure JPOXMLDOC01-appb-C000033
［式（７）中、Ｒ２は前記式（５）中の定義と同一である］
で表される化合物又はその塩と、酸化剤を反応させることで、前記式（６）で表される化合物又はその塩を得る工程をさらに含む、上記（５）記載の製造方法。 (6) Formula (7):
Figure JPOXMLDOC01-appb-C000033
Wherein (7), R 2 are the same as those defined in formula (5)]
The manufacturing method of said (5) description which further includes the process of obtaining the compound or its salt represented by said Formula (6) by making the compound represented by these, or its salt, and an oxidizing agent react.
　（７）式（８）：
Figure JPOXMLDOC01-appb-C000034
で表される化合物又はその塩と、式（１４）：
Figure JPOXMLDOC01-appb-C000035
［式（１４）中、Ｒ２は、前記式（５）中の定義と同一である］
で表される化合物又はその塩を、反応させることで、前記式（７）で表される化合物又はその塩を得る工程をさらに含む、上記（６）記載の製造方法。 (7) Formula (8):
Figure JPOXMLDOC01-appb-C000034
And a compound represented by the formula (14):
Figure JPOXMLDOC01-appb-C000035
[In Formula (14), R 2 is the same as defined in Formula (5) above]
The manufacturing method of the said (6) description further including the process of obtaining the compound or its salt represented by said Formula (7) by making the compound or its salt represented by these react.
　（８）式（１０）：
Figure JPOXMLDOC01-appb-C000036
で表される化合物又はその塩と、式（１１）：
Figure JPOXMLDOC01-appb-C000037
で表される化合物又はその塩を、反応させることで、前記式（９）で表される化合物又はその塩を得る工程をさらに含む、上記（１）記載の製造方法。 (8) Formula (10):
Figure JPOXMLDOC01-appb-C000036
And a compound represented by the formula (11):
Figure JPOXMLDOC01-appb-C000037
The manufacturing method of said (1) description which further includes the process of obtaining the compound or its salt represented by said Formula (9) by making the compound or its salt represented by these react.
　（９）前記式（２）で表される化合物又はその塩の製造方法であって、前記式（３）で表される化合物又はその塩と前記式（１２）で表される化合物又はその塩を反応させた後に塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程を含む、製造方法。 (9) A method for producing a compound represented by the formula (2) or a salt thereof, wherein the compound represented by the formula (3) or a salt thereof and a compound represented by the formula (12) or a salt thereof The manufacturing method including the process of obtaining the compound or its salt represented by the said Formula (2) by processing with a base after making it react.
　（１０）前記式（４）で表される化合物又はその塩の製造方法であって、前記式（５）で表される化合物又はその塩を、還元及び脱保護することで、前記式（４）で表される化合物又はその塩を得る工程を含む、製造方法。 (10) A method for producing a compound represented by the formula (4) or a salt thereof, wherein the compound represented by the formula (5) or a salt thereof is reduced and deprotected, thereby reducing the formula (4). The manufacturing method including the process of obtaining the compound or its salt represented by this.
　（１１）前記式（３）で表される化合物又はその塩と、前記式（３）で表される化合物又はその塩の量に対して１．０～５．０モル当量の前記式（１２）で表される化合物又はその塩を反応させて
式（１５）：
Figure JPOXMLDOC01-appb-C000038
［式（１５）中、
　Ｘはハロゲン原子を示し、そして
　Ｒ１は低級アルキル基を示す］
で表される化合物又はその塩及び／又は；
　式（１６）：
Figure JPOXMLDOC01-appb-C000039
［式（１６）中、
　Ｘはハロゲン原子を示し、そして
　Ｒ１は低級アルキル基を示す］
で表される化合物又はその塩を含む組成物を、さらに塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程を含む、上記（２）～（７）、（９）又は（１０）記載の製造方法。 (11) The compound represented by the formula (3) or a salt thereof and 1.0 to 5.0 molar equivalents of the formula (12) relative to the amount of the compound represented by the formula (3) or a salt thereof. ) Or a salt thereof is reacted to form the formula (15):
Figure JPOXMLDOC01-appb-C000038
[In the formula (15),
X represents a halogen atom, and R 1 represents a lower alkyl group]
Or a salt thereof and / or;
Formula (16):
Figure JPOXMLDOC01-appb-C000039
[In the formula (16),
X represents a halogen atom, and R 1 represents a lower alkyl group]
(2) to (7), comprising a step of obtaining a compound represented by the formula (2) or a salt thereof by further treating the composition comprising the compound represented by the formula or a salt thereof with a base. (9) The manufacturing method of (10) description.
　（１２）前記窒素原子の保護基が、ｔ－ブチル基、ベンジル基、ｐ－メトキシベンジル基、アセチル基、ベンゼンスルホニル基、ｐ－トルエンスルホニル基、又は保護される窒素原子と一緒になってコハク酸イミド若しくはフタルイミドを形成する上記（１）～（７）、（９）～（１１）のうちいずれか１項記載の製造方法。 (12) 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. The production method according to any one of (1) to (7) and (9) to (11), wherein the acid imide or phthalimide is formed.
　（１３）前記ハロゲン化剤が、塩化チオニル、塩化オキサリル、オキシ塩化リン、臭化水素又はヨウ化水素である上記（３）記載の製造方法。 (13) The production method according to the above (3), wherein the halogenating agent is thionyl chloride, oxalyl chloride, phosphorus oxychloride, hydrogen bromide or hydrogen iodide.
　（１４）前記酸化剤が、過酸化水素、メタクロロ過安息香酸、モノ過フタル酸又は無水フタル酸と過酸化水素の混合物である上記（６）記載の製造方法。 (14) The production method according to (6), wherein the oxidizing agent is hydrogen peroxide, metachloroperbenzoic acid, monoperphthalic acid, or a mixture of phthalic anhydride and hydrogen peroxide.
　（１５）式（２）：
Figure JPOXMLDOC01-appb-C000040
［式（２）中、Ｘが塩素原子である］
で表される化合物又はその塩。 (15) Formula (2):
Figure JPOXMLDOC01-appb-C000040
[In formula (2), X is a chlorine atom]
Or a salt thereof.
　（１６）式（５）：
Figure JPOXMLDOC01-appb-C000041
［式（５）中、
　Ｒ２がｎ－ブチル基であり、そして
　Ｒ３とＲ４が、それらが結合する窒素原子と一緒になってフタルイミドを形成する］
で表される化合物又はその塩。 (16) Formula (5):
Figure JPOXMLDOC01-appb-C000041
[In Formula (5),
R 2 is an n-butyl group, and R 3 and R 4 together with the nitrogen atom to which they are attached form a phthalimide]
Or a salt thereof.
　（１７）式（６）：
Figure JPOXMLDOC01-appb-C000042
［式（６）中、Ｒ２がｎ－ブチル基である］
で表される化合物又はその塩。 (17) Formula (6):
Figure JPOXMLDOC01-appb-C000042
[In the formula (6), R 2 is an n-butyl group]
Or a salt thereof.
　（１８）式（１５）：
Figure JPOXMLDOC01-appb-C000043
［式（１５）中、
　Ｘが塩素原子であり、そして
　Ｒ１がメチルである］
で表される化合物又はその塩。 (18) Formula (15):
Figure JPOXMLDOC01-appb-C000043
[In the formula (15),
X is a chlorine atom and R 1 is methyl]
Or a salt thereof.
　本発明によれば、
（Ａ）式（１）で表される化合物又はその塩は、新規の製造中間体である式（２）で表される化合物又はその塩と式（９）で表される化合物又はその塩を使用することで、金属パラジウムを使用することなく、かつ、カラムクロマトグラフィーなしに、高効率かつ高収率で製造することができる。
　また、本発明によれば、
（Ｂ）新規の製造中間体である式（２）で表される化合物又はその塩を使用することで、メチルチオ結合の形成と同時に、本化合物を一段階（一工程）で合成できるので、、本化合物の類縁体の生成を最小限に抑えることができる。 According to the present invention,
(A) 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.
Moreover, according to the present invention,
(B) By using the compound represented by the formula (2) which is a novel production intermediate or a salt thereof, the compound can be synthesized in one step (one step) simultaneously with the formation of the methylthio bond. Formation of analogs of the compound can be minimized.
　また、本発明によれば、
（Ｃ）式（３）で表される化合物又はその塩は、安価で大量に入手容易な原材料（式（８）で表される化合物又はその塩）と試薬を使用して５工程で、カラムクロマトグラフィーによる精製なしに、高収率で製造できる。 Moreover, according to the present invention,
(C) 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.
　さらに、本発明によれば、新規な製造中間体を提供することができる。 Furthermore, according to the present invention, a novel production intermediate can be provided.
特許文献１記載の本化合物の製造工程である。It is a manufacturing process of this compound of patent document 1. 本願発明に基づく本化合物の製造工程である。It is a manufacturing process of this compound based on this invention.
　本明細書中で使用される文言（原子、基、環等）の定義について以下に詳しく説明する。また、以下の文言の定義が別の文言の定義に準用される場合、各定義の好ましい範囲及び特に好ましい範囲にも準用することができる。 The definitions of terms (atoms, groups, rings, etc.) used in this specification will be described in detail below. Moreover, when the definition of the following words is applied mutatis mutandis to the definition of another wording, it can apply mutatis mutandis also to the preferable range and especially preferable range of each definition.
　「ハロゲン原子」とは、フッ素、塩素、臭素又は沃素原子を示す。 “Halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.
　「低級アルキル基」とは、炭素原子数が１～８個、好ましくは１～６個、より好ましくは１～４個の直鎖又は分枝のアルキル基を示す。具体例として、メチル、エチル、ｎ－プロピル、ｎ－ブチル、ｎ－ペンチル、ｎ－ヘキシル、ｎ－ヘプチル、ｎ－オクチル、イソプロピル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、イソペンチル基等が挙げられる。 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. .
　「窒素原子の保護基」とは、窒素原子を保護する置換基を意味し、適切な脱保護の条件で窒素－水素結合が形成される置換基である。その具体例として、コシエンスキー（Ｐｈｉｌｉｐ　Ｊ．　Ｋｏｃｉｅｎｓｋｉ）著　Ｐｒｏｔｅｃｔｉｎｇ　Ｇｒｏｕｐｓ（１９９４年）や、ウッツ（Ｐ．Ｇ．Ｍ．Ｗｕｔｓ）及びグリーン（Ｔ．Ｗ．Ｇｒｅｅｎｅ）著、「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（第４版、２００６年）」に記載の保護基などが挙げられる。具体的な窒素原子の保護基として、例えば、Ｃ１－８アルコキシカルボニル基（例えば、メトキシカルボニル基、エトキシカルボニル基、ｔ－ブトキシカルボニル基など）、ベンジルオキシカルボニル基、メトキシメチル基、ｔ－ブチル基、ベンジル基、ｏ－メトキシベンジル基、ｐ－メトキシベンジル基、ホルミル基、アセチル基、トリフルオロアセチル基、フェノキシカルボニル基、メタンスルホニル基、ベンゼンスルホニル基、ｐ－トルエンスルホニル基、２－ニトロベンゼンスルホニル基などが挙げられ、また、環構造である具体的な窒素原子の保護基として、窒素原子と一緒になって、例えば、コハク酸イミド、３，４－ジメチルコハク酸イミド、テトラメチルコハク酸イミド、グルタルイミド、４，４－ジメチルグルタルイミド、ピペラジン－２，６－ジオン、４－メチルピペラジン－２，６－ジオン、マレイミド、フタルイミド環などが挙げられる。 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. Group, 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 In addition, as 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.
　本発明において使用する原料、試薬、その他本願明細書に記載の化合物は、酸又は塩基と「塩」を形成してもよい。当該塩の具体例として、塩酸、臭化水素酸、臭素酸、ヨウ化水素酸、硝酸、硫酸、リン酸などの無機酸との塩、炭酸、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、１０－カンファースルホン酸、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸などの有機酸との塩、臭化メチル、ヨウ化メチルなどの四級アンモニウム塩、臭素イオン、塩素イオン、ヨウ素イオンなどのハロゲンイオンとの塩、リチウム、ナトリウム、カリウムなどのアルカリ金属との塩、カルシウム、マグネシウムなどのアルカリ土類金属との塩、銅、鉄、亜鉛などとの金属塩、アンモニアとの塩、トリエチレンジアミン、２－アミノエタノール、２，２－イミノビス（エタノール）、１－デオキシ－１－（メチルアミノ）－２－Ｄ－ソルビトール、２－アミノ－２－（ヒドロキシメチル）－１，３－プロパンジオール、プロカイン、Ｎ，Ｎ－ジメチルアニリン又はＮ，Ｎ－ビス（フェニルメチル）－１，２－エタンジアミンなどの有機アミンとの塩、ピリジンとの塩などが挙げられる。 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 ion, salt with alkali metal such as lithium, sodium, potassium, salt with alkaline earth metal such as calcium, magnesium, metal salt with copper, iron, zinc, salt with ammonia, tri Ethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol , Salts with organic amines such as procaine, N, N-dimethylaniline or N, N-bis (phenylmethyl) -1,2-ethanediamine, and salts with pyridine.
　本発明において使用する原料、試薬、その他本願明細書に記載の化合物は、水和物又は溶媒和物の形態をとっていてもよい。 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.
　本発明において使用する原料、試薬、その他本願明細書に記載の化合物に幾何異性体又は光学異性体が存在する場合は、その異性体も本発明の範囲に含まれる。 In the case where geometrical isomers or optical isomers exist in the raw materials, reagents, and other compounds described in the present specification, such isomers are also included in the scope of the present invention.
　本発明において使用する原料、試薬、その他本願明細書に記載の化合物にプロトン互変異性が存在する場合は、その互変異性体も本発明に含まれる。 In the case where proton tautomerism exists in the raw materials, reagents and other compounds described in the present specification used in the present invention, such tautomers are also included in the present invention.
　本発明において使用する原料、試薬、その他本願明細書に記載の化合物、それらの水和物又は溶媒和物は結晶であってもよく、該結晶に結晶多形及び結晶多形群（結晶多形システム）が存在する場合には、それらの結晶多形体及び結晶多形群（結晶多形システム）も本発明に含まれる。ここで、結晶多形群（結晶多形システム）とは、それら結晶の製造、晶出、保存などの条件及び状態（尚、本状態には製剤化した状態も含む）により、結晶形が種々変化する場合の各段階における結晶形及びその過程全体を意味する。 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. When the system is present, the crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the present invention. Here, the crystal polymorph group (crystal polymorph system) 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.
　以下に示す工程１～８の方法を含む、化合物（１）の製造方法について説明する。本発明の式（１）で表される化合物又はその塩を、以下、「化合物（１）」ともいう。他の番号の式で表される化合物又はその塩も同様である。 The production method of compound (1) including the methods of steps 1 to 8 shown below will be described. Hereinafter, the compound represented by the formula (1) of the present invention or a salt thereof is also referred to as “compound (1)”. The same applies to compounds represented by other numbers of formulas or salts thereof.
　具体的には、
　工程１：化合物（８）及び化合物（１４）を原料として化合物（７）を製造する方法、
　工程２：化合物（７）から化合物（６）を製造する方法、
　工程３：化合物（６）と化合物（１３）から化合物（５）を製造する方法、
　工程４：化合物（５）から化合物（４）を製造する方法、
　工程５：化合物（４）から化合物（３）を製造する方法、
　工程６：化合物（３）と化合物（１２）から化合物（１５）又は化合物（１６）を経て化合物（２）を製造する方法、
　工程７：化合物（１０）と化合物（１１）から化合物（９）を製造する方法、及び
　工程８：化合物（２）と化合物（９）から化合物（１）を製造する方法について、それぞれ説明する。 In particular,
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), and Step 8: a method for producing compound (1) from compound (2) and compound (9) will be described.
　工程１について、以下に説明する。
Figure JPOXMLDOC01-appb-C000044
 Step 1 will be described below.
Figure JPOXMLDOC01-appb-C000044
　工程１は、化合物（８）を溶媒中、酸存在下、化合物（１４）と反応させて化合物（７）を製造する工程である。なお、化合物（８）は市販されているものや公知の方法により製造したものを用いることができる。式（７）及び（１４）中、Ｒ２は低級アルキル基を示し、好ましくは炭素原子数が１～６個であり、より好ましくは炭素原子数が１～４個であり、さらに好ましくはｎ－ブチル基である。 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. In formulas (7) and (14), 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.
　化合物（１４）は、化合物（８）に対し、例えば１モル当量以上２０モル当量以下、好ましくは５～１５モル当量で用いられる。 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).
　工程１で使用される酸としては、例えば、塩酸、硫酸、硝酸、リン酸、臭化水素酸、フッ酸などの無機酸類；トリフルオロ酢酸、メタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、アミノスルホン酸などの有機酸類；三臭化ホウ素、三塩化ホウ素、三フッ化ホウ素、塩化アルミニウムなどのルイス酸などが挙げられる。この工程１で使用される酸として、好ましくは無機酸類であり、より好ましくは硫酸である。 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.
　工程１で使用される酸は、化合物（８）に対し、例えば０．０１モル当量以上５モル当量以下、好ましくは０．１～２モル当量、より好ましくは０．５～１．５当量で用いられる。 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.
　工程１で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、エーテル類、アミド類、スルホキシド類、低級アルコール類、ニトリル類又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔ－ブタノールなどが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。この工程１で使用される溶媒として、好ましくは芳香族炭化水素類又は低級アルコール類であり、より好ましくは、トルエン、キシレン、プロパノール、ｎ－ブタノール又はこれらの混合溶媒であり、さらに好ましくは、トルエン、ｎ－ブタノール又はこれらの混合溶媒である。また、上記式（１４）の化合物が溶媒を兼ねていてもよい。 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. Preferable examples of 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. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like. 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 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. Moreover, the compound of the said Formula (14) may serve as the solvent.
　工程１の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から２００℃で行われ、好ましくは６０℃から１４０℃、より好ましくは９０℃から１３０℃で行われる。工程１の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１時間から２４時間であり、好ましくは２時間から６時間である。 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.
　化合物（７）は、上記反応の後、通常行われる処理により得ることができる。例えば、化合物（７）は塩基、溶媒、水及び飽和食塩水などを使用して抽出、洗浄、分液して次工程に用いることができ、好ましくは、トルエン、ｎ－ブタノール又はこれらの混合溶媒を使用する。これらの溶媒は反応後の抽出、洗浄、分液に用いた後でさらに次工程の溶媒としても用いることができる。また、必要ならば、化合物（７）はさらに減圧下等で溶媒を除去して乾燥し、通常行われる方法、例えば再結晶、再沈殿、蒸留などによって精製することができる。 Compound (7) can be obtained by the treatment usually performed after the above reaction. For example, 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. If necessary, 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.
　工程２について、以下に説明する。
Figure JPOXMLDOC01-appb-C000045
 Step 2 will be described below.
Figure JPOXMLDOC01-appb-C000045
　工程２は、化合物（７）を溶媒中、酸化剤と反応させて化合物（６）を製造する工程である。式（６）及び式（７）中、Ｒ２の定義は、上記工程１で説明した定義と同一である。 Step 2 is a step of producing compound (6) by reacting compound (7) with an oxidizing agent in a solvent. In the formula (6) and the formula (7), the definition of R 2 is the same as the definition explained in the step 1 above.
　工程２で使用する酸化剤としては、例えば、過酸化水素などの無機過酸類；過酢酸、トリフルオロ過酢酸、メタクロロ過安息香酸、モノ過フタル酸、Ｎ－ヒドロキシフタルイミド、亜硝酸ｔ－ブチルなどの有機過酸類；酸化ルテニウム、メチルトリオキソレニウムなどの有機金属類などが挙げられる。この工程２で使用される酸化剤として、好ましくは過酸化水素、メタクロロ安息香酸、モノ過フタル酸又はＮ－ヒドロキシフタルイミドであり、より好ましくは過酸化水素又はモノ過フタル酸である。また本反応は酸化剤と一緒に共酸化剤を加えてもよい。この工程２で使用される酸化剤と共酸化剤の組み合わせとして、例えば、過酸化水素と無水フタル酸、過酸化水素とタングステン酸ナトリウムなどが挙げられ、より好ましくは、過酸化水素と無水フタル酸の組み合わせである。 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.
　工程２で使用される酸化剤は、化合物（７）に対し、例えば１モル当量以上５モル当量以下、好ましくは１～３モル当量で用いられる。また酸化剤と一緒に共酸化剤を加える場合、使用される酸化剤と共酸化剤は、化合物（７）に対し、例えば各々１モル当量以上５モル当量以下、好ましくは１～３モル当量で用いられる。 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). When the co-oxidant is added together with the oxidant, 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.
　工程２で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、低級アルキルカルボン酸エステル類、アミド類、スルホキシド類、低級アルコール類、ニトリル類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。低級アルキルカルボン酸エステル類としては、酢酸エチル、酢酸イソプロピルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔ－ブタノールなどが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。この工程２で使用される溶媒として、好ましくは芳香族炭化水素類又は低級アルコール類であり、より好ましくは、トルエン、キシレン、プロパノール、ｎ－ブタノール又はこれらの混合溶媒であり、さらに好ましくは、トルエン、ｎ－ブタノール又はこれらの混合溶媒である。 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. Preferable examples of 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. Examples of 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.
　工程２の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から８０℃で行われ、好ましくは０℃から５０℃、より好ましくは１０℃から４０℃で行われる。工程２の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１時間から４８時間であり、好ましくは６時間から３０時間である。 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.
　化合物（６）は、上記反応の後、通常行われる処理により得ることができる。例えば、チオ硫酸ナトリウム、塩基、溶媒及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。特に式（６）中、Ｒ２がｎ－ブチル基である場合、その高い脂溶性のために抽出、分液操作において効率良く化合物（６）を得ることができる。さらに化合物（６）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. In particular in the formula (6), when R 2 is n- butyl group, it can be obtained extract due to its high lipid solubility, efficient compounds in the separation operation (6). Furthermore, if necessary, the compound (6) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　工程３について、以下に説明する。
Figure JPOXMLDOC01-appb-C000046
 Step 3 will be described below.
Figure JPOXMLDOC01-appb-C000046
　工程３は、化合物（６）を溶媒中、塩基存在下、化合物（１３）と反応させて化合物（５）を製造する工程である。式（６）及び式（５）中、Ｒ２の定義は、上記工程１で説明した定義と同一である。式（１３）及び式（５）中、Ｒ３及びＲ４は同一又は異なって、水素原子、窒素原子の保護基を示し、又はＲ３とＲ４が一緒になって窒素原子の保護基を示し、好ましくはＲ３及びＲ４は同一又は異なって水素原子又はｔ－ブチル基であり、又はＲ３とＲ４が一緒になってコハク酸イミド又はフタルイミドを形成してもよく、より好ましくはＲ３とＲ４が一緒になったフタルイミドである。
化合物（１３）は、化合物（６）に対し、例えば１モル当量以上３モル当量以下、好ましくは１～１．５モル当量で用いられる。 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. In the formula (6) and the formula (5), the definition of R 2 is the same as the definition explained in the step 1 above. In Formula (13) and Formula (5), 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).
　工程３は化合物（６）と化合物（１３）の反応効率を高めるために添加物を加えることができる。好ましい添加物として、例えば、塩化メタンスルホニル、塩化トリフルオロメタンスルホニル、塩化ベンゼンスルホニル、塩化ｐ－トルエンスルホニルなどの塩化スルホニル類；塩化ジメチルカルバモイルなどの塩化カルバモイル類などが挙げられ、より好ましくは、塩化ｐ－トルエンスルホニルである。 In step 3, 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.
　工程３で使用される添加物は、化合物（６）に対し、例えば１モル当量以上３モル当量以下、好ましくは１～１．５モル当量で用いられる。 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).
　工程３で使用される塩基としては、無機塩基類、有機塩基類のいずれでも良い。無機塩基類としては、例えば、アルカリ金属炭酸塩類、アルカリ金属炭酸水素塩類、アルカリ金属水酸化物類、アルカリ金属水素化物類が挙げられる。ここで、アルカリ金属炭酸塩類としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウムなどが挙げられる。アルカリ金属炭酸水素塩類としては、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムなどが挙げられる。アルカリ金属水酸化物類としては、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水酸化リチウムなどが挙げられる。アルカリ金属水素化物類としては、水素化リチウム、水素化ナトリウム、水素化カリウムなどが挙げられる。さらに有機塩基類としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド、カリウムエトキシド、カリウムｔ－ブトキシド、リチウムメトキシドなどのアルカリ金属アルコキシド類やＮ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、Ｎ，Ｎ，Ｎ’，Ｎ’，Ｎ’’，Ｎ’’－ヘキサメチルリン酸トリアミド（ＨＭＰＡ）などが挙げられる。この工程３で使用される塩基として、好ましくは、有機塩基類であり、より好ましくはトリエチルアミンである。 The base used in step 3 may be either an inorganic base or an organic base. Examples of inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides. Here, examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. Examples of 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. Examples of the alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like. Furthermore, examples of 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. 2] Octane (DABCO), 1,8 Diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ', N', N '', N '' - hexamethylphosphoric triamide (HMPA) and the like. The base used in Step 3 is preferably an organic base, and more preferably triethylamine.
　工程３で使用される塩基は、化合物（６）に対し、例えば１モル当量以上５モル当量以下、好ましくは１．５～３モル当量で用いられる。 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).
　工程３で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、低級アルキルカルボン酸エステル類、アミド類、スルホキシド類、低級アルコール類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。ケトン類としては、アセトン、２－ブタノン等が挙げられる。低級アルキルカルボン酸エステル類としては、酢酸エチル、酢酸イソプロピルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔ－ブタノールなどが挙げられる。この工程３で使用される溶媒として、好ましくはケトン類であり、より好ましくは、アセトンである。 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. Preferable examples of 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like. Examples of ketones include acetone and 2-butanone. 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. The solvent used in Step 3 is preferably a ketone, and more preferably acetone.
　工程３の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から８０℃で行われ、好ましくは０℃から６０℃、より好ましくは１５℃から６０℃で行われる。工程３の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１時間から１２時間であり、好ましくは２時間から６時間である。 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.
　化合物（５）は、上記反応の後、通常行われる処理により得ることができる。例えば、溶媒及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（５）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　工程４について、以下に説明する。
Figure JPOXMLDOC01-appb-C000047
 Step 4 will be described below.
Figure JPOXMLDOC01-appb-C000047
　工程４は、化合物（５）を溶媒中、還元剤と反応させて（エステルをアルコールとし）、さらに窒素原子の保護基を脱保護することにより化合物（４）を製造する工程である。式（５）中、Ｒ２、Ｒ３及びＲ４の定義は、上記工程３で説明した定義と同一である。 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. In formula (5), the definitions of R 2 , R 3, and R 4 are the same as those described in Step 3 above.
　工程４で使用される還元剤としては、例えば、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、水素化ホウ素リチウム、水素化トリエチルホウ素リチウム、水素化トリ（ｓ－ブチル）ホウ素リチウム、ボラン錯体、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウムなどの金属水素化物、トリエチルシランなどのアルキルシランなどが挙げられる。好ましくは、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、水素化ホウ素リチウムであり、より好ましくは水素化ホウ素ナトリウムである。 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.
　工程４で使用される還元剤は、化合物（５）に対し、例えば１モル当量以上１０モル当量以下、好ましくは３～６モル当量で用いられる。 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).
　工程４で行う脱保護とは、Ｒ３及びＲ４のどちらか又は両方が窒素原子の保護基を示す場合、適当な反応を行うことにより保護基を外して、窒素－水素結合を形成させることである。脱保護に用いられる添加物は、保護基の種類によって異なるが、例えば、塩酸、塩化水素、トリフルオロ酢酸などの酸類；水酸化カリウム、水酸化ナトリウムなどの塩基類；水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウムなどの金属水素化物；パラジウム、水酸化パラジウム、白金などの金属物、ヒドラジン、メチルアミン、エチルアミンなどの有機アミン類などを用いることができる。好ましくは、Ｒ３及びＲ４のどちらかがｔ－ブチル基である場合には塩化水素、トリフルオロ酢酸を用いることができ、又はＲ３とＲ４が一緒になってコハク酸イミド又はフタルイミドを形成する場合には、水素化カリウム、水素化ナトリウムの塩基、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウムなどの金属水素化物又はヒドラジン、メチルアミン、エチルアミンなどの有機アミン類を用いることができる。より好ましくは、Ｒ３とＲ４が一緒になってフタルイミドを形成する場合であり、この場合、水素化ホウ素ナトリウム又はヒドラジンを用いることができる。 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. Preferably, 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. When forming, use 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. More preferably, R 3 and R 4 are combined to form phthalimide. In this case, sodium borohydride or hydrazine can be used.
　工程４で使用される脱保護に用いられる添加物は、化合物（５）に対し、例えば１モル当量以上１０モル当量以下、好ましくは３～６モル当量で用いられる。 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).
　工程４で用いられる還元剤により、Ｒ３及びＲ４の窒素の保護基を外すことができる場合は、還元剤のみを加えてエステルからアルコールへの還元と脱保護を同時に行ってもよく、好ましくはＲ３とＲ４が一緒になってフタルイミドを形成する場合である。
Ｒ３及びＲ４が水素原子を示す場合には、還元剤を加えるだけでよく、脱保護は行われない。
また、Ｒ３及びＲ４の窒素の保護基の種類、使用する還元剤の種類又は脱保護に用いられる添加物の種類によっては、窒素原子の脱保護を行った後で還元剤と反応させてもよい。 When 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.
When 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.
　工程４で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、アミド類、スルホキシド類、低級アルコール類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール又はｔ－ブタノールなどが挙げられる。この工程４で使用される溶媒として、好ましくは低級アルコール類であり、より好ましくは、エタノール、プロパノール、イソプロパノール、ｎ－ブタノールであり、さらに好ましくはｎ－ブタノールである。 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. Preferable examples of 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like. 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. 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.
　工程４の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１００℃で行われ、好ましくは２０℃から９０℃、より好ましくは６０℃から９０℃で行われる。工程４の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１０分間から１２時間であり、好ましくは１時間から６時間である。 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.
　化合物（４）は、上記反応の後、通常行われる処理により得ることができる。例えば、溶媒、酸及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（４）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　工程５について、以下に説明する。
Figure JPOXMLDOC01-appb-C000048
 Step 5 will be described below.
Figure JPOXMLDOC01-appb-C000048
　工程５は、化合物（４）を溶媒中、ハロゲン化剤と反応させて化合物（３）を製造する工程である。式（３）中、Ｘはハロゲン原子を示し、好ましくは塩素原子又は臭素原子であり、より好ましくは塩素原子である。 Step 5 is a step of producing compound (3) by reacting compound (4) with a halogenating agent in a solvent. In formula (3), X represents a halogen atom, preferably a chlorine atom or a bromine atom, and more preferably a chlorine atom.
　工程５で使用されるハロゲン化剤としては、例えば、塩化オキサリル、塩化チオニル、塩化スルフリル、塩化メタンスルホニル、Ｎ－クロロコハク酸イミド、オキシ塩化リン、シアヌル酸クロリド、トリクロロイソシアヌル酸などの塩素化剤；臭素、臭化水素、三臭化ホウ素、Ｎ－ブロモアセトアミド、Ｎ－ブロモコハク酸イミド、Ｎ－ブロモフタルイミド、１，３－ジブロモ－５，５－ジメチルヒダントイン、ジブロモイソシアヌル酸、トリメチルフェニルアンモニウムトリブロミド、テトラブチルアンモニウムトリブロミドなどの臭素化剤；ヨウ素、ヨウ化水素、Ｎ－ヨードコハク酸イミド、１，３－ジヨード－５，５－ジメチルヒダントイン、トリメチルシリルヨードなどの沃素化剤が挙げられる。この工程５で使用されるハロゲン化剤として、好ましくは塩素化剤であり、より好ましくは塩化オキサリル、塩化チオニル、塩化メタンスルホニル、オキシ塩化リンであり、さらに好ましくは塩化チオニルである。 Examples of the halogenating agent used in Step 5 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-dimethylhydantoin, and trimethylsilyliodo. 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.
　工程５で使用されるハロゲン化剤は、化合物（４）に対し、例えば１モル当量以上５モル当量以下、好ましくは１～２モル当量で用いられる。 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).
　工程５で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、アミド類、スルホキシド類、ニトリル類又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。この工程５で使用される溶媒として、好ましくはニトリル類であり、より好ましくはアセトニトリルである。 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. Preferable examples of 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like. 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 nitriles include acetonitrile. The solvent used in Step 5 is preferably a nitrile, and more preferably acetonitrile.
　工程５の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１００℃で行われ、好ましくは２０℃から８０℃、より好ましくは２０℃から６０℃で行われる。工程５の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１０分間から１２時間であり、好ましくは１時間から６時間である。 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.
　化合物（３）は、上記反応の後、通常行われる処理により得ることができる。例えば、溶媒、水及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（３）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　工程６について、以下に説明する。
Figure JPOXMLDOC01-appb-C000049
 Step 6 will be described below.
Figure JPOXMLDOC01-appb-C000049
　工程６は、工程６－１及び工程６－２からなる。工程６－１は、化合物（３）を溶媒中、化合物（１２）と反応させて化合物（１５）、化合物（１６）又はこれらの混合物を得る工程であり、工程６－２は化合物（１５）、化合物（１６）又はこれらの混合物を塩基で処理することにより、化合物（２）を製造する工程である。式（３）、式（１５）、式（１６）及び式（２）中、Ｘの定義は、上記工程５で説明した定義と同一である。式（１２）、式（１５）及び式（１６）中、Ｒ１は低級アルキル基を示し、好ましくは炭素原子数が１～６個であり、より好ましくは炭素原子数が１～３個であり、さらに好ましくはメチル基である。 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, and step 6-2 is compound (15). In this step, compound (2) is produced by treating compound (16) or a mixture thereof with a base. In the formula (3), the formula (15), the formula (16), and the formula (2), the definition of X is the same as the definition explained in the above step 5. In formula (12), formula (15) and formula (16), 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.
　工程６－１では、化合物（１２）の当量を厳密に用いて化合物（１６）を、又は大過剰量の化合物（１２）を用いて化合物（１５）を主生成物として得ることもできるが、化合物（３）を消費する量の化合物（１２）を用いることが好ましく、工程６－１で得られた生成物が化合物（１５）及び化合物（１６）を含む混合物であっても、溶媒の除去や通常行われる精製をすることなく効率的に次の工程６－２を行うことができる。すなわち、工程６－１で使用される化合物（１２）は、化合物（３）に対し、例えば１モル当量以上５モル当量以下、好ましくは１～３モル当量で用いられる。 In 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. In addition, 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).
　工程６－１及び工程６－２で使用される塩基としては、無機塩基類、有機塩基類のいずれでも良い。無機塩基類としては、例えば、アルカリ金属炭酸塩類、アルカリ金属炭酸水素塩類、アルカリ金属水酸化物類、アルカリ金属水素化物類が挙げられる。ここで、アルカリ金属炭酸塩類としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウムなどが挙げられる。アルカリ金属炭酸水素塩類としては、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムなどが挙げられる。アルカリ金属水酸化物類としては、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水酸化リチウムなどが挙げられる。アルカリ金属水素化物類としては、水素化リチウム、水素化ナトリウム、水素化カリウムなどが挙げられる。さらに有機塩基類としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド、カリウムエトキシド、カリウムｔ－ブトキシド、リチウムメトキシドなどのアルカリ金属アルコキシド類やＮ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、Ｎ，Ｎ，Ｎ’，Ｎ’，Ｎ’’，Ｎ’’－ヘキサメチルリン酸トリアミド（ＨＭＰＡ）などが挙げられる。この工程６－１で使用される塩基として、好ましくは、有機塩基類であり、より好ましくはＮ，Ｎ－ジイソプロピルエチルアミンである。またこの工程６－２で使用される塩基として、好ましくは、無機塩基類であり、より好ましくは水酸化ナトリウムである。 The base used in Step 6-1 and Step 6-2 may be either an inorganic base or an organic base. Examples of inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides. Here, examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. Examples of 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. Examples of the alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like. Furthermore, examples of 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, 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 preferably N, N-diisopropylethylamine. The base used in Step 6-2 is preferably an inorganic base, and more preferably sodium hydroxide.
　工程６－１で使用される塩基は、化合物（３）に対し、例えば１モル当量以上５モル当量以下、好ましくは２～４モル当量で用いられる。また工程６－２で使用される塩基は、化合物（３）に対し、例えば１モル当量以上１０モル当量以下、好ましくは３～６モル当量で用いられる。 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).
　工程６－１及び工程６－２で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、低級アルキルカルボン酸エステル類、アミド類、スルホキシド類、低級アルコール類、ニトリル類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。低級アルキルカルボン酸エステル類としては、酢酸エチル、酢酸イソプロピルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔ－ブタノール又はこれらの無水物などが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。工程６－１で使用される溶媒として、好ましくはニトリル類であり、より好ましくはアセトニトリルである。また工程６－２で使用される溶媒として、好ましくは低級アルコール類、ニトリル類、水又はこれらの混合溶媒であり、より好ましくはアセトニトリルとメタノールと水の混合溶媒である。 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether 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, 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. Further, 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.
　工程６－１の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１００℃で行われ、好ましくは０℃から５０℃、より好ましくは０℃から３０℃で行われる。また工程６－２の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１００℃で行われ、好ましくは０℃から５０℃、より好ましくは０℃から３０℃で行われる。 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. In addition, 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.
　工程６－１の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１０分間から１２時間であり、好ましくは３０分間から３時間である。また工程６－２の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１分間から８時間であり、好ましくは１０分間から３時間である。 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.
　工程６－１で得られた化合物（１５）、化合物（１６）又はこれらを含む混合物は、溶媒の除去や通常行われる精製をすることなく次の工程６－２に用いることができる。また、化合物（１５）及び化合物（１６）は、工程６－１の反応の後、必要ならば、通常行われる処理により得ることもできる。例えば、溶媒及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（１５）及び化合物（１６）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. In addition, 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. Furthermore, if necessary, 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. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　化合物（２）は、工程６－２の反応の後、通常行われる処理により得ることができる。例えば、溶媒、酸及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（２）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。
　なお、次の工程８において化合物（１）を収率及び純度良く得るためには、この工程６において化合物（２）を純度良く製造することが好ましい。具体的には、化合物（２）の純度が、通常化学合成が良好に実施できる純度、例えば９０％純度以上において次の工程８を実施することが好ましく、９５％純度以上において実施することが特に好ましい。また、化合物（２）の純度が、例えば９０％を超えない場合においても次の工程８を実施することはできるが、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することにより、純度を向上させてから実施することもできる。純度の算出は、通常簡便に行われる方法、例えば、サンプルを高速液体クロマトグラフィー（ＨＰＬＣ）、ガスクロマトグラフィー（ＧＣ）、核磁気共鳴（ＮＭＲ）などで測定することによって簡易的に決定してもよい。 Compound (2) can be obtained by a treatment usually performed after the reaction in Step 6-2. 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 (2) can be purified by a usual method such as washing with a solvent, recrystallization, reprecipitation and the like. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
In order to obtain the compound (1) with good yield and purity in the next step 8, it is preferable to produce the compound (2) with good purity in this step 6. Specifically, 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.
　工程７について、以下に説明する。
Figure JPOXMLDOC01-appb-C000050
 Step 7 will be described below.
Figure JPOXMLDOC01-appb-C000050
　工程７は、化合物（１０）を溶媒中、縮合剤存在下、化合物（１１）と反応させて化合物（９）を製造する工程である。なお、化合物（１０）及び化合物（１１）は市販されているものや公知の方法により製造したものを用いることができる。
化合物（１１）は、化合物（１０）に対し、例えば０．８モル当量以上３モル当量以下、好ましくは０．９～１．２モル当量で用いられる。 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. In addition, 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).
　工程７で使用される縮合剤としては、例えば、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、Ｎ，Ｎ’－カルボニルジイミダゾール、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、１Ｈ－ベンゾトリアゾール－１－イルオキシトリス（ジメチルアミノ）ホスホニウムヘキサフルオロリン酸塩、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩などが挙げられ、好ましくはＮ，Ｎ’－カルボニルジイミダゾールである。 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.
　工程７で使用される縮合剤は、化合物（１０）に対し、例えば１モル当量以上５モル当量以下、好ましくは１～３モル当量で用いられる。 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).
　工程７で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、低級アルキルカルボン酸エステル類、アミド類、スルホキシド類、ニトリル類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。低級アルキルカルボン酸エステル類としては、酢酸エチル、酢酸イソプロピルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。この工程７で使用される溶媒として、好ましくはエーテル類であり、より好ましくは、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルであり、さらに好ましくは、テトラヒドロフランである。 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. Preferable examples of 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether 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 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.
　工程７の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１２０℃で行われ、好ましくは０℃から１００℃で行われる。工程７の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１時間から２４時間であり、好ましくは１時間から６時間である。
化合物（９）は、上記反応の後、通常行われる処理により得ることができる。例えば、溶媒、水及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で溶媒を除去し、乾燥することにより得ることができる。さらに化合物（９）は、必要ならば、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。
　なお、次の工程８において化合物（１）を収率及び純度良く得るためには、この工程７において化合物（９）を純度良く製造することが好ましい。具体的には、化合物（９）の純度が、通常化学合成が良好に実施できる純度、例えば９０％純度以上において次の工程８を実施することが好ましく、９５％純度以上において実施することが特に好ましい。また、化合物（９）の純度が、例えば９０％を超えない場合においても次の工程８を実施することはできるが、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することにより、純度を向上させてから実施することもできる。純度の算出は、通常簡便に行われる方法、例えば、サンプルを高速液体クロマトグラフィー（ＨＰＬＣ）、ガスクロマトグラフィー（ＧＣ）、核磁気共鳴（ＮＭＲ）などで測定することによって簡易的に決定してもよい。 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. Furthermore, if necessary, compound (9) can be purified by a conventional method such as washing with a solvent, recrystallization, reprecipitation and the like. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
In order to obtain the compound (1) with good yield and purity in the next step 8, it is preferable to produce the compound (9) with good purity in this step 7. Specifically, it is preferable to carry out the following step 8 when 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.
　工程８について、以下に説明する。
Figure JPOXMLDOC01-appb-C000051
 Step 8 will be described below.
Figure JPOXMLDOC01-appb-C000051
　工程８は、化合物（９）を溶媒中、塩基存在下、化合物（２）と反応させて化合物（１）を製造する工程である。式（２）中、Ｘの定義は、上記工程５で説明した定義と同一である。化合物（２）は、化合物（９）に対し、例えば０．７モル当量以上１．３モル当量以下、好ましくは０．８～１．２モル当量で用いられる。 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. In formula (2), 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).
　工程８で使用される塩基としては、無機塩基類、有機塩基類のいずれでも良い。無機塩基類としては、例えば、アルカリ金属炭酸塩類、アルカリ金属炭酸水素塩類、アルカリ金属水酸化物類、アルカリ金属水素化物類が挙げられる。ここで、アルカリ金属炭酸塩類としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウムなどが挙げられる。アルカリ金属炭酸水素塩類としては、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムなどが挙げられる。アルカリ金属水酸化物類としては、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水酸化リチウムなどが挙げられる。アルカリ金属水素化物類としては、水素化リチウム、水素化ナトリウム、水素化カリウムなどが挙げられる。さらに有機塩基類としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド、カリウムエトキシド、カリウムｔ－ブトキシド、リチウムメトキシドなどのアルカリ金属アルコキシド類やＮ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、Ｎ，Ｎ，Ｎ’，Ｎ’，Ｎ’’，Ｎ’’－ヘキサメチルリン酸トリアミド（ＨＭＰＡ）などが挙げられる。この工程８で使用される塩基として、好ましくは有機塩基類であり、より好ましくはトリエチルアミンである。 The base used in step 8 may be either an inorganic base or an organic base. Examples of inorganic bases include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, and alkali metal hydrides. Here, examples of the alkali metal carbonates include sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. Examples of 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. Examples of the alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride and the like. Furthermore, examples of 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. 2] Octane (DABCO), 1,8 Diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ', N', N '', N '' - hexamethylphosphoric triamide (HMPA) and the like. The base used in Step 8 is preferably an organic base, more preferably triethylamine.
　工程８で使用される塩基は、化合物（９）に対し、例えば１モル当量以上５モル当量以下、好ましくは１．５～３モル当量で用いられる。 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).
　工程８で使用される溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はない。好ましい溶媒としては、例えば、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、低級アルキルカルボン酸エステル類、アミド類、スルホキシド類、低級アルコール類、ニトリル類、水又はこれらの混合溶媒が挙げられる。芳香族炭化水素類としては、ベンゼン、トルエン、キシレンなどが挙げられる。ハロゲン化炭化水素類としては、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジグロロベンゼンなどが挙げられる。エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル、メチル－ｔ－ブチルエーテル、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルなどが挙げられる。低級アルキルカルボン酸エステル類としては、酢酸エチル、酢酸イソプロピルなどが挙げられる。アミド類としては、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドなどが挙げられる。スルホキシド類としては、ジメチルスルホキシド、スルホランなどが挙げられる。低級アルコール類としては、メタノール、エタノール、プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔ－ブタノール又はこれらの無水物などが挙げられる。ニトリル類としては、アセトニトリルなどが挙げられる。この工程８で使用される溶媒として、好ましくはハロゲン化炭化水素類又は低級アルコール類であり、より好ましくは、トルエン、キシレン、プロパノール又はｎ－ブタノールであり、さらに好ましくは、メタノールである。 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. Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, and the like. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-t-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether 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, t-butanol, and anhydrides thereof. Examples of nitriles include acetonitrile. 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.
　工程８の反応温度は、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、例えば、０℃から１２０℃で行われ、好ましくは１０℃から９０℃で行われる。工程８の反応時間は、反応温度、原料化合物、反応試薬又は使用される溶媒の種類によって異なるが、通常、１時間から２４時間であり、好ましくは１時間から１２時間である。
化合物（１）は、上記反応の後、通常行われる処理により得ることができる。例えば、溶媒、水及び飽和食塩水などを使用して抽出、洗浄、分液し、減圧下で乾燥することにより得ることができる。さらに化合物（１）は、通常行われる方法、例えば、溶媒による洗浄、再結晶、再沈殿などによって精製することができる。当該の後処理及び精製で使用され得る溶媒としては、上記に列記した溶媒を使用することができる。 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. As the solvent that can be used in the post-treatment and purification, the solvents listed above can be used.
　以下に、本発明の製造例を示す。これらの例示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 The production examples of the present invention are shown below. These illustrations are for better understanding of the present invention and are not intended to limit the scope of the present invention.
［製造例］
工程１　４－ｎ－ブトキシカルボニルピリジン（化合物（７）－１）
　イソニコチン酸（化合物（８）－１、２０．２ｇ，１６４ｍｍｏｌ）、１－ブタノール（１６０ｍＬ）及びトルエン（１６０ｍＬ）の混合物に室温で硫酸（９．５ｍＬ、１７８ｍｍｏｌ）を加えた。この混合物を３時間加熱還流した。室温で放冷後、この混合物を炭酸水素ナトリウム水溶液（炭酸水素ナトリウム３０．３ｇ／水３００ｍＬ）に注ぎ込んだ。この混合物を撹拌した後に、有機層と水層に分配した。得られた有機層は、標記化合物を含む混合物として、そのまま次の工程２の出発物質として使用した。なお、化合物（７）－１の単離、構造決定を行うために、上記の操作で得られる有機層少量を、さらに減圧下で溶媒を留去し、減圧下で乾燥することにより、標記化合物を無色油状物として得た。 [Production example]
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. The obtained organic layer was used as a starting material in the next step 2 as a mixture containing the title compound. In order to isolate and determine the structure of compound (7) -1, 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. Was obtained as a colorless oil.
　前記の通り、工程１の生成物をある程度溶解する溶媒かつ工程２の反応条件を阻害しない溶媒を抽出溶媒とすることを見出したことにより、工程１の反応後の処理を簡略、効率化した。 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.
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
工程２　４－ｎ－ブトキシカルボニルピリジン－Ｎ－オキシド（化合物（６）－１）
　工程１で得られた４－ｎ－ブトキシカルボニルピリジン（化合物（７）－１）を含む混合物に、室温で無水フタル酸（２６．４ｇ、１７８ｍｍｏｌ）、３０％過酸化水素水（１９．８ｍＬ，１９７ｍｍｏｌ）を順次加えた。この混合物を室温で２３時間撹拌した。氷水で冷しながら、この混合物にチオ硫酸ナトリウム水溶液（チオ硫酸ナトリウム１２．３ｇ／水４０ｍＬ）、炭酸水素ナトリウム水溶液（炭酸水素ナトリウム３０．０ｇ／水４００ｍＬ）を順に添加した。この混合物を室温で撹拌した後に、有機層と水層に分配した。有機層を減圧下で溶媒を留去した。溶媒が留去されなくなった時点で析出した固体を濾取した。濾液を減圧下で溶媒を留去した。溶媒が留去されなくなった時点で析出した固体を再度濾取した。得られた固体を合わせて、その固体を減圧下で乾燥することにより標記化合物（２７．１ｇ）を白色固体として得た（２工程収率８５％） 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%).
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
　工程２において、以下の化合物（６）－２も製造した。 In step 2, the following compound (6) -2 was also produced.
　４－メトキシカルボニルピリジン－Ｎ－オキシド（化合物（６）－２）
　市販のイソニコチン酸メチル（２．０４ｇ、１４．９ｍｍｏｌ）及びジクロロメタン（２０．０ｍＬ）及び無水フタル酸（２．３９ｇ、１６．１ｍｍｏｌ）の混合物に、室温で３０％過酸化水素水（１．８０ｍＬ，１７．５ｍｍｏｌ）を加えた。この混合物を室温で２３時間撹拌した。不溶物を濾去した後、濾液が塩基性になるまで飽和炭酸水素ナトリウム水溶液を添加した。この混合物を有機層と水層に分配し、水層をジクロロメタン（４回）で抽出した。有機層をすべて合わせて減圧下で溶媒を留去した。残渣の固体を減圧下で乾燥することにより標記化合物（２．２２ｇ）を白色固体として得た（９７％）。 4-methoxycarbonylpyridine-N-oxide (compound (6) -2)
To a mixture of commercially available methyl isonicotinate (2.04 g, 14.9 mmol) and dichloromethane (20.0 mL) and phthalic anhydride (2.39 g, 16.1 mmol), 30% aqueous hydrogen peroxide (1. 80 mL, 17.5 mmol) was added. The mixture was stirred at room temperature for 23 hours. Insoluble material was removed by filtration, and saturated aqueous sodium hydrogen carbonate solution was added until the filtrate became basic. The mixture was partitioned between organic and aqueous layers and the aqueous layer was extracted with dichloromethane (4 times). All the organic layers were combined and the solvent was distilled off under reduced pressure. The residual solid was dried under reduced pressure to give the title compound (2.22 g) as a white solid (97%).
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
工程３　２－（１，３－ジオキソ－２，３－ジヒドロ－１Ｈ－イソインドール－２－イル）－４－ｎ－ブトキシカルボニルピリジン（化合物（５）－１）
　４－ｎ－ブトキシカルボニルピリジン－Ｎ－オキシド（化合物（６）－１、１９．８ｇ、１０１ｍｍｏｌ）、フタルイミド（１６．７ｇ、１１４ｍｍｏｌ）、トリエチルアミン（３４．０ｍＬ、２４５ｍｍｏｌ）及びアセトン（１９７ｍＬ）の混合物に、内温が５０℃を超えないように塩化ｐ－トルエンスルホニル（２３．４ｇ、１２３ｍｍｏｌ）を分割して加えて、室温で１５時間撹拌した。その混合物に水（４００ｍＬ）を加えて、析出した固体を濾取した。その固体を減圧下で乾燥することにより、標記化合物（３２．０ｇ）を淡黄色固体として得た（収率９８％）。 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%).
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
　工程３において、化合物（６）－２を用いて、以下の化合物（５）－２も製造した。 In Step 3, the following compound (5) -2 was also produced using the compound (6) -2.
　２－（ｔ－ブチルアミノ）－４－ｎ－メトキシカルボニルピリジン（化合物（５）－２）
　４－メトキシカルボニルピリジン－Ｎ－オキシド（化合物（６）－２、３．０４ｇ、１９．９ｍｍｏｌ）、ｔ－ブチルアミン（２．６８ｍＬ、２５．５ｍｍｏｌ）、トリエチルアミン（５．５０ｍＬ、３９．５ｍｍｏｌ）及びジクロロメタン（６０．０ｍＬ）の混合物を室温で撹拌した。その混合物に、塩化ｐ－トルエンスルホニル（３．８０ｇ、１９．９ｍｍｏｌ）を加えた。さらに反応の進行をモニタリングしながら、その混合物にｔ－ブチルアミン（２．７０ｍＬ、計７回）及び塩化ｐ－トルエンスルホニル（３．７ｇ、計３回）を適宜添加して、３時間撹拌した。固体を濾去した後、減圧下で溶媒を留去した。得られた残渣に酢酸エチル（６０ｍＬ）と飽和炭酸水素ナトリウム水溶液（３０ｍＬ）を加えて、この混合物を有機層と水層に分配した。有機層に１Ｎ塩酸（４０ｍＬ）を加えて、この混合物を有機層と水層に分配した。この水層に塩基性になるまで飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで抽出した。有機層を減圧下で溶媒を留去することにより、標記化合物（３．７０ｇ）を淡黄色固体として得た（収率９１％）。 2- (t-Butylamino) -4-n-methoxycarbonylpyridine (Compound (5) -2)
4-methoxycarbonylpyridine-N-oxide (compound (6) -2, 3.04 g, 19.9 mmol), t-butylamine (2.68 mL, 25.5 mmol), triethylamine (5.50 mL, 39.5 mmol) and A mixture of dichloromethane (60.0 mL) was stirred at room temperature. To the mixture was added p-toluenesulfonyl chloride (3.80 g, 19.9 mmol). Further, while monitoring the progress of the reaction, t-butylamine (2.70 mL, 7 times in total) and p-toluenesulfonyl chloride (3.7 g, 3 times in total) were appropriately added to the mixture and stirred for 3 hours. After filtering off the solid, the solvent was distilled off under reduced pressure. Ethyl acetate (60 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the obtained residue, and the mixture was partitioned between an organic layer and an aqueous layer. 1N hydrochloric acid (40 mL) was added to the organic layer, and the mixture was partitioned between the organic and aqueous layers. Saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer until basic, and the mixture was extracted with ethyl acetate. The solvent was distilled off from the organic layer under reduced pressure to obtain the title compound (3.70 g) as a pale yellow solid (yield 91%).
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
工程４　２－アミノ－４－（ヒドロキシメチル）ピリジン塩酸塩（化合物（４）－１）
　２－（１，３－ジオキソ－２，３－ジヒドロ－１Ｈ－イソインドール－２－イル）－４－ｎ－ブトキシカルボニルピリジン（化合物（５）－１、３０．３ｇ、９３．４ｍｍｏｌ）及び１－ブタノール（３００ｍＬ）の混合物に水素化ホウ素ナトリウム（１５．８ｇ，４１８ｍｍｏｌ）を室温で加え、８０℃で３時間撹拌した。その混合物に水（１５０ｍＬ）、トルエン（３００ｍＬ）を順に加え、室温で終夜撹拌した。その混合物を５０℃で１時間撹拌した後で、有機層と水層に分配した。この水層をトルエン（１５０ｍＬ）と１－ブタノール（１５０ｍＬ）の混合溶媒で抽出し、有機層を一つに合わせた。この有機層に６Ｎ塩酸（２４．０ｍＬ）を加えた後で、減圧下で溶媒が約３０ｍＬ残るまで留去した。析出した固体を濾取し、固体を減圧下で乾燥することにより、標記化合物（１３．７ｇ）を白色固体として得た（収率９１％）。 Step 4 2-Amino-4- (hydroxymethyl) pyridine hydrochloride (compound (4) -1)
2- (1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl) -4-n-butoxycarbonylpyridine (compound (5) -1, 30.3 g, 93.4 mmol) and 1 To a mixture of butanol (300 mL) was added sodium borohydride (15.8 g, 418 mmol) at room temperature and stirred at 80 ° C. for 3 hours. Water (150 mL) and toluene (300 mL) were sequentially added to the mixture, and the mixture was stirred overnight at room temperature. The mixture was stirred at 50 ° C. for 1 hour and then partitioned between organic and aqueous layers. This aqueous layer was extracted with a mixed solvent of toluene (150 mL) and 1-butanol (150 mL), and the organic layers were combined. 6N Hydrochloric acid (24.0 mL) was added to the organic layer, and the solvent was distilled off under reduced pressure until about 30 mL of solvent remained. The precipitated solid was collected by filtration, and the solid was dried under reduced pressure to obtain the title compound (13.7 g) as a white solid (yield 91%).
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
工程５　２－アミノ－４－クロロメチルピリジン塩酸塩（化合物（３）－１）
　２－アミノ－４－ヒドロキシメチルピリジン塩酸塩（化合物（４）－１、１０．０ｇ、６２．３ｍｍｏｌ）をアセトニトリル（１００ｍＬ）に加え、４５℃で撹拌した。その混合物に塩化チオニル（６．３ｍＬ，８７．４ｍｍｏｌ）を加えて１時間撹拌した後、減圧下で溶媒を留去した。残渣にｔ－ブチルメチルエーテル（１００ｍＬ）を加えて、析出した固体を濾取した。得られた固体を減圧下で乾燥することにより、標記化合物（１０．９ｇ）を白色固体として得た（収率９９％）。 Step 5 2-Amino-4-chloromethylpyridine hydrochloride (compound (3) -1)
2-Amino-4-hydroxymethylpyridine hydrochloride (compound (4) -1, 10.0 g, 62.3 mmol) was added to acetonitrile (100 mL), and the mixture was stirred at 45 ° C. Thionyl chloride (6.3 mL, 87.4 mmol) was added to the mixture and stirred for 1 hour, and then the solvent was distilled off under reduced pressure. T-Butyl methyl ether (100 mL) was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (10.9 g) as a white solid (yield 99%).
　以上の結果より、化合物（３）－１は、安価で大量に入手容易な原材料（化合物（８）－１）及び試薬から化合物（７）－１、化合物（６）－１、化合物（５）－１及び化合物（４）－１を経た５工程で、カラムクロマトグラフィーによる精製なしに、収率７５％で製造した。 From the above results, 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.
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
工程６　２－（２－ヒドロキシアセチルアミノ）－４－クロロメチルピリジン（化合物（２）－１）
　氷水冷下、２－アミノ－４－クロロメチルピリジン塩酸塩（化合物（３）－１、１０．５ｇ、５８．６ｍｍｏｌ）とアセトキシアセチルクロリド（１２．９ｍＬ，１２０ｍｍｏｌ）をアセトニトリル（３１．５ｍＬ）に加えた。さらに、その混合物にＮ，Ｎ－ジイソプロピルエチルアミン（３０．９ｍＬ，１７９ｍｍｏｌ）を加えて、氷水冷下で１時間撹拌した。その混合物にメタノール（１０．５ｍＬ）、４Ｎ水酸化ナトリウム水溶液（４５．０ｍＬ）、及び２Ｎ水酸化ナトリウム水溶液（５９．０ｍＬ）を順に加えて、氷水冷下で３０分間撹拌した。その混合物に６Ｎ塩酸（２８ｍＬ）を加えてｐＨ７～８の間に調整した後、酢酸エチル（１５０ｍＬ）とアセトニトリル（１５ｍＬ）を加えて室温で１時間撹拌した。その混合物を有機層と水層に分配した後、水層を酢酸エチル（１５０ｍＬ）で抽出した。有機層を合わせた後、減圧下で溶媒が約５０ｍＬ残るまで留去した。残渣にトルエン（５０ｍＬ）を加え、析出した固体を濾取した。その固体を減圧下で乾燥することにより標記化合物（１０．５ｇ）を褐色固体として得た（収率９０％）。得られた標記化合物については、高速液体クロマトグラフィー（ＨＰＬＣ）による分析を行い、純度９９％（面積百分率により算出）であることを確認した。 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. Methanol (10.5 mL), 4N aqueous sodium hydroxide solution (45.0 mL), and 2N aqueous sodium hydroxide solution (59.0 mL) were sequentially added to the mixture, and the mixture was stirred for 30 minutes under ice water cooling. The mixture was adjusted to pH 7-8 by adding 6N hydrochloric acid (28 mL), ethyl acetate (150 mL) and acetonitrile (15 mL) were added, and the mixture was stirred at room temperature for 1 hr. The mixture was partitioned into an organic layer and an aqueous layer, and the aqueous layer was extracted with ethyl acetate (150 mL). After the organic layers were combined, the solvent was distilled off under reduced pressure until about 50 mL of solvent remained. Toluene (50 mL) was added to the residue, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (10.5 g) as a brown solid (yield 90%). The obtained title compound was analyzed by high performance liquid chromatography (HPLC), and it was confirmed that the purity was 99% (calculated by area percentage).
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
工程７　Ｎ－（４－トリフルオロメトキシフェニル）－１，２－ジヒドロ－２－チオキソピリジン－３－カルボキサミド（化合物（９）－１）
　２－メルカプトニコチン酸（化合物（１０）－１、１８．７ｇ，１２１ｍｍｏｌ）、１，１’－カルボニルジイミダゾール（２７．７ｇ，１７１ｍｍｏｌ）及びテトラヒドロフラン（１００ｍＬ）の混合物を、室温下で１時間撹拌した。この混合物に水（１．０ｍＬ）を加え、氷水冷下３０分撹拌した。この混合物に４－トリフルオロメトキシアニリン（１５．２ｍＬ，１１３ｍｍｏｌ）を加えて、３．５時間加熱還流した。放冷後、減圧下で溶媒が約３０ｍＬ残るまで留去した。残渣に２－プロパノール（１００ｍＬ）を加えて、氷水冷下で２時間撹拌した。析出した固体を濾取し、その固体を減圧下で乾燥することにより標記化合物（２６．８ｇ）を黄色固体として得た（収率７６％）。得られた標記化合物については、高速液体クロマトグラフィー（ＨＰＬＣ）による分析を行い、純度９１％（面積百分率により算出）であることを確認した。 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. 4-trifluoromethoxyaniline (15.2 mL, 113 mmol) was added to the mixture, and the mixture was heated to reflux for 3.5 hours. After standing to cool, the solvent was distilled off under reduced pressure until about 30 mL of solvent remained. 2-Propanol (100 mL) was added to the residue, and the mixture was stirred for 2 hours under ice water cooling. The precipitated solid was collected by filtration, and the solid was dried under reduced pressure to obtain the title compound (26.8 g) as a yellow solid (yield 76%). The obtained title compound was analyzed by high performance liquid chromatography (HPLC), and it was confirmed that the purity was 91% (calculated by area percentage).
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
工程８　２－（２－ヒドロキシアセチルアミノピリジン－４－イルメチルチオ）－Ｎ－（４－トリフルオロメトキシフェニル）ピリジン－３－カルボキサミド（化合物（１）－１）
　２－（２－ヒドロキシアセチルアミノ）－４－クロロメチルピリジン（化合物（２）－１、５．０１ｇ、２５．０ｍｍｏｌ）とＮ－（４－トリフルオロメトキシフェニル）－１，２－ジヒドロ－２－チオキソピリジン－３－カルボキサミド（化合物（９）－１、７．８３ｇ、２４．９ｍｍｏｌ）、トリエチルアミン（７．０ｍＬ、５０．２ｍｍｏｌ）及びメタノール（２５ｍＬ）の混合物を１時間加熱還流した。放冷後、この混合物に室温で水（３０ｍＬ）を加えて、１時間撹拌した。析出した固体を濾取することにより標記化合物（９．８２ｇ）を淡褐色固体として得た（収率８８％）。 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) and methanol (25 mL) was heated to reflux for 1 hour. After allowing to cool, water (30 mL) was added to the mixture at room temperature, and the mixture was stirred for 1 hr. The precipitated solid was collected by filtration to give the title compound (9.82 g) as a light brown solid (yield 88%).
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
　以上より、本発明において化合物（１）－１は、原材料化合物（８）－１から製造された化合物（３）－１を出発原料として、化合物（２）－１を経た２工程で、カラムクロマトグラフィーによる精製なしに、収率７９％で製造した。さらに、化合物（１）－１は、安価で大量に入手容易な原材料化合物（８）－１及び試薬から化合物（７）－１、化合物（６）－１、化合物（５）－１、化合物（４）－１、化合物（３）－１及び化合物（２）－１を経た７工程で、カラムクロマトグラフィーによる精製なしに、収率５９％で製造した。 From the above, in the present invention, 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.
　また、本発明による、新規の製造中間体である式（２）で表される化合物又はその塩を用いることにより、化合物（１）が効率良く製造できることが確認された。 Further, it was confirmed that 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.
　本発明により、安価な原料から化合物（１）をカラムクロマトグラフィーによる精製なしに、高収率で製造することが可能となり、化合物（１）を工業的に供給することができる。 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.

Claims (18)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
    で表される化合物又はその塩の製造方法であって、式（２）：
    Figure JPOXMLDOC01-appb-C000002
    ［式（２）中、Ｘはハロゲン原子を示す］
    で表される化合物又はその塩と、式（９）：
    Figure JPOXMLDOC01-appb-C000003
    で表される化合物又はその塩を塩基の存在下で反応させて、式（１）で表される化合物又はその塩を得る工程を含む、製造方法。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
    Wherein the compound represented by formula (2):
    Figure JPOXMLDOC01-appb-C000002
    [In formula (2), X represents a halogen atom]
    And a compound represented by the formula (9):
    Figure JPOXMLDOC01-appb-C000003
    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.
  2. 　式（３）：
    Figure JPOXMLDOC01-appb-C000004
    ［式（３）中、Ｘは、前記式（２）中の定義と同一である］
    で表される化合物又はその塩と、式（１２）：
    Figure JPOXMLDOC01-appb-C000005
    ［式（１２）中、Ｒ１は低級アルキル基を示す］
    で表される化合物又はその塩を反応させた後に、塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程をさらに含む、請求項１記載の製造方法。     Formula (3):
    Figure JPOXMLDOC01-appb-C000004
    [In formula (3), X is the same as defined in formula (2)]
    And a compound represented by formula (12):
    Figure JPOXMLDOC01-appb-C000005
    Wherein (12), R 1 represents a lower alkyl group]
    The manufacturing method of Claim 1 which further includes the process of obtaining the compound or its salt represented by said Formula (2) by processing with a base after making the compound or its salt represented by these react.
  3. 　式（４）：
    Figure JPOXMLDOC01-appb-C000006
    で表される化合物又はその塩と、ハロゲン化剤を反応させて、前記式（３）で表される化合物又はその塩を得る工程をさらに含む、請求項２記載の製造方法。     Formula (4):
    Figure JPOXMLDOC01-appb-C000006
    The manufacturing method of Claim 2 which further includes the process of making the compound or its salt represented by these, and a halogenating agent react, and obtaining the compound or its salt represented by said Formula (3).
  4. 　式（５）：
    Figure JPOXMLDOC01-appb-C000007
    ［式（５）中、
    　Ｒ２は低級アルキル基を示し、
    　Ｒ３及びＲ４は同一又は異なって、水素原子又は窒素原子の保護基を示すか、又は
    　Ｒ３とＲ４が一緒になって窒素原子の保護基を形成してもよい］
    で表される化合物又はその塩を、還元及び脱保護することで、前記式（４）で表される化合物又はその塩を得る工程をさらに含む、請求項３記載の製造方法。     Formula (5):
    Figure JPOXMLDOC01-appb-C000007
    [In Formula (5),
    R 2 represents a lower alkyl group,
    R 3 and R 4 are the same or different and each represents a hydrogen atom or a nitrogen atom protecting group, or R 3 and R 4 may form a nitrogen atom protecting group together.]
    The manufacturing method of Claim 3 which further includes the process of obtaining the compound or its salt represented by said Formula (4) by reduce | restoring and deprotecting the compound or its salt represented by these.
  5. 　式（６）：
    Figure JPOXMLDOC01-appb-C000008
    ［式（６）中、Ｒ２は、前記式（５）中の定義と同一である］
    で表される化合物又はその塩と、式（１３）：
    Figure JPOXMLDOC01-appb-C000009
    ［式（１３）中、Ｒ３及びＲ４は前記式（５）中の定義と同一である］
    で表される化合物又はその塩を塩基の存在下で反応させて、前記式（５）で表される化合物又はその塩を得る工程をさらに含む、請求項４記載の製造方法。     Formula (6):
    Figure JPOXMLDOC01-appb-C000008
    [In formula (6), R 2 has the same definition as in formula (5)]
    And a compound represented by the formula (13):
    Figure JPOXMLDOC01-appb-C000009
    Wherein (13), R 3 and R 4 are the same as those defined in formula (5)]
    The manufacturing method of Claim 4 which further includes the process of making the compound or its salt represented by these react in presence of a base, and obtaining the compound or its salt represented by said Formula (5).
  6. 　式（７）：
    Figure JPOXMLDOC01-appb-C000010
    ［式（７）中、Ｒ２は前記式（５）中の定義と同一である］
    で表される化合物又はその塩と、酸化剤を反応させることで、前記式（６）で表される化合物又はその塩を得る工程をさらに含む、請求項５記載の製造方法。     Formula (7):
    Figure JPOXMLDOC01-appb-C000010
    [In formula (7), R 2 has the same definition as in formula (5)]
    The manufacturing method of Claim 5 which further includes the process of obtaining the compound or its salt represented by said Formula (6) by making the compound represented by these, or its salt, and an oxidizing agent react.
  7. 　式（８）
    Figure JPOXMLDOC01-appb-C000011
    で表される化合物又はその塩と、式（１４）：
    Figure JPOXMLDOC01-appb-C000012
    ［式（１４）中、Ｒ２は、前記式（５）中の定義と同一である］
    で表される化合物又はその塩を、反応させることで、前記式（７）で表される化合物又はその塩を得る工程をさらに含む、請求項６記載の製造方法。     Formula (8)
    Figure JPOXMLDOC01-appb-C000011
    And a compound represented by the formula (14):
    Figure JPOXMLDOC01-appb-C000012
    [In Formula (14), R 2 is the same as defined in Formula (5) above]
    The manufacturing method of Claim 6 which further includes the process of obtaining the compound or its salt represented by said Formula (7) by making the compound or its salt represented by these react.
  8. 　式（１０）：
    Figure JPOXMLDOC01-appb-C000013
    で表される化合物又はその塩と、式（１１）：
    Figure JPOXMLDOC01-appb-C000014
    で表される化合物又はその塩を、反応させることで、前記式（９）で表される化合物又はその塩を得る工程をさらに含む、請求項１記載の製造方法。     Formula (10):
    Figure JPOXMLDOC01-appb-C000013
    And a compound represented by the formula (11):
    Figure JPOXMLDOC01-appb-C000014
    The manufacturing method of Claim 1 which further includes the process of obtaining the compound or its salt represented by said Formula (9) by making the compound or its salt represented by these react.
  9. 　前記式（２）で表される化合物又はその塩の製造方法であって、前記式（３）で表される化合物又はその塩と前記式（１２）で表される化合物又はその塩を反応させた後に塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程を含む、製造方法。 A method for producing a compound represented by formula (2) or a salt thereof, comprising reacting a compound represented by formula (3) or a salt thereof with a compound represented by formula (12) or a salt thereof. The manufacturing method including the process of obtaining the compound or its salt represented by the said Formula (2) by processing with a base after.
  10. 　前記式（４）で表される化合物又はその塩の製造方法であって、前記式（５）で表される化合物又はその塩を、還元及び脱保護することで、前記式（４）で表される化合物又はその塩を得る工程を含む、製造方法。 A method for producing a compound represented by the formula (4) or a salt thereof, wherein the compound represented by the formula (5) or a salt thereof is reduced and deprotected, thereby being represented by the formula (4). The manufacturing method including the process of obtaining the compound or its salt.
  11. 　前記式（３）で表される化合物又はその塩と、前記式（３）で表される化合物又はその塩の量に対して１．０～５．０モル当量の前記式（１２）で表される化合物又はその塩を反応させて
    式（１５）：
    Figure JPOXMLDOC01-appb-C000015
    ［式（１５）中、
    　Ｘはハロゲン原子を示し、そして
    　Ｒ１は低級アルキル基を示す］
    で表される化合物又はその塩及び／又は；
    式（１６）：
    Figure JPOXMLDOC01-appb-C000016
    ［式（１６）中、
    　Ｘはハロゲン原子を示し、そして
    　Ｒ１は低級アルキル基を示す］
    で表される化合物又はその塩を含む組成物を、さらに塩基で処理することで、前記式（２）で表される化合物又はその塩を得る工程をさらに含む、請求項９記載の製造方法。     The compound represented by the formula (3) or a salt thereof and the compound represented by the formula (12) in an amount of 1.0 to 5.0 molar equivalents relative to the amount of the compound represented by the formula (3) or a salt thereof. A compound of formula (15):
    Figure JPOXMLDOC01-appb-C000015
    [In the formula (15),
    X represents a halogen atom, and R 1 represents a lower alkyl group]
    Or a salt thereof and / or;
    Formula (16):
    Figure JPOXMLDOC01-appb-C000016
    [In the formula (16),
    X represents a halogen atom, and R 1 represents a lower alkyl group]
    The manufacturing method of Claim 9 which further includes the process of obtaining the compound or its salt represented by the said Formula (2) by processing the composition containing the compound or its salt further with a base.
  12. 　前記窒素原子の保護基が、ｔ－ブチル基、ベンジル基、ｐ－メトキシベンジル基、アセチル基、ベンゼンスルホニル基、ｐ－トルエンスルホニル基又は保護される窒素原子と一緒になってコハク酸イミド若しくはフタルイミドを形成する、請求項４記載の製造方法。 When the protecting group of the nitrogen atom is t-butyl group, benzyl group, p-methoxybenzyl group, acetyl group, benzenesulfonyl group, p-toluenesulfonyl group or the nitrogen atom to be protected, succinimide or phthalimide The manufacturing method of Claim 4 which forms.
  13. 　前記ハロゲン化剤が、塩化チオニル、塩化オキサリル、オキシ塩化リン、臭化水素又はヨウ化水素である、請求項３記載の製造方法。 The production method according to claim 3, wherein the halogenating agent is thionyl chloride, oxalyl chloride, phosphorus oxychloride, hydrogen bromide or hydrogen iodide.
  14. 　前記酸化剤が、過酸化水素、メタクロロ過安息香酸、モノ過フタル酸又は無水フタル酸と過酸化水素の混合物である、請求項６記載の製造方法。 The production method according to claim 6, wherein the oxidizing agent is hydrogen peroxide, metachloroperbenzoic acid, monoperphthalic acid or a mixture of phthalic anhydride and hydrogen peroxide.
  15. 　式（２）：
    Figure JPOXMLDOC01-appb-C000017
    ［式（２）中、Ｘが塩素原子である］
    で表される化合物又はその塩。     Formula (2):
    Figure JPOXMLDOC01-appb-C000017
    [In formula (2), X is a chlorine atom]
    Or a salt thereof.
  16. 　式（５）：
    Figure JPOXMLDOC01-appb-C000018
    ［式（５）中、
    　Ｒ２がｎ－ブチル基であり、そして
    　Ｒ３とＲ４が、それらが結合する窒素原子と一緒になってフタルイミドを形成する］
    で表される化合物又はその塩。     Formula (5):
    Figure JPOXMLDOC01-appb-C000018
    [In Formula (5),
    R 2 is an n-butyl group, and R 3 and R 4 together with the nitrogen atom to which they are attached form a phthalimide]
    Or a salt thereof.
  17. 　式（６）：
    Figure JPOXMLDOC01-appb-C000019
    ［式（６）中、Ｒ２がｎ－ブチル基である］
    で表される化合物又はその塩。     Formula (6):
    Figure JPOXMLDOC01-appb-C000019
    [In the formula (6), R 2 is an n-butyl group]
    Or a salt thereof.
  18. 　式（１５）：
    Figure JPOXMLDOC01-appb-C000020
    ［式（１５）中、
    　Ｘが塩素原子であり、そして
    　Ｒ１がメチルである］
    で表される化合物又はその塩。     Formula (15):
    Figure JPOXMLDOC01-appb-C000020
    [In the formula (15),
    X is a chlorine atom and R 1 is methyl]
    Or a salt thereof.
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