WO2007055197A1 - Method for producing 4-(3-(4-(3-(4-cyanophenoxy)propyl)- 1-piperidinyl)propoxy)benzonitrile and intermediate thereof - Google Patents

Method for producing 4-(3-(4-(3-(4-cyanophenoxy)propyl)- 1-piperidinyl)propoxy)benzonitrile and intermediate thereof Download PDF

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Publication number
WO2007055197A1
WO2007055197A1 PCT/JP2006/322166 JP2006322166W WO2007055197A1 WO 2007055197 A1 WO2007055197 A1 WO 2007055197A1 JP 2006322166 W JP2006322166 W JP 2006322166W WO 2007055197 A1 WO2007055197 A1 WO 2007055197A1
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compound
salt
reaction
general formula
formula
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PCT/JP2006/322166
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French (fr)
Japanese (ja)
Inventor
Naokatu Aoki
Masahiro Takebayashi
Hidetaka Nakamura
Hyouei Kawai
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Toyama Chemical Co., Ltd.
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Priority to JP2007544140A priority Critical patent/JP5314284B2/en
Publication of WO2007055197A1 publication Critical patent/WO2007055197A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

  • the present invention relates to a process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) 1-piveridyl) propoxy) benzonitrile and intermediates thereof.
  • T-2307 4 (3- (4- (3- (4 (Amino) methyl) phenoxy) propyl) 1-piveridyl-) propoxy) benzamidine (hereinafter referred to as T-2307) is a strong antifungal It has activity and is useful as an antifungal agent (Non-patent Document 1).
  • Patent Document 1 describes a method for producing a T-2307 related compound.
  • this production method has disadvantages such as (1) a large number of steps, (2) using harmful reagents and solvents, (3) inconvenient reaction operation, and (4) using expensive raw materials. Have.
  • Patent Document 2 Patent Document 2 describes a method for producing T-2307. However, this production method involves a complicated reaction operation with many steps.
  • T-2307 which is safe for the human body, can be manufactured in large quantities using inexpensive raw materials with low environmental impact, is completely known.
  • Patent Document 1 Pamphlet of International Publication No. 03Z074476
  • Patent Document 2 International Publication No. 2006Z003881 Pamphlet
  • Non-Patent Document 1 44th ICAAC Abstracts, In Vitro and In Vivo Antifongal Activity of T— 23207: a Novel Arylamidine. 2004, p. 209
  • Y 1 and Y 2 are the same or different and each represents a hydroxyl group, a halogen atom, an alkyl sulfo-loxy group or an aryl sulfo-loxy group. It has been found to be a useful intermediate for the preparation of (3- (4 (3- (4 cyanophenoxy) propyl) 1-piberidyl-) propoxy) benzo-tolyl or its salts. That is, the inventors have the formula [la]
  • Y la and Y za are the same or different and each represents a halogen atom, an alkanesulfo-oxyl group or an aryl sulpho-oxy group. Then, by reacting with 4-hydroxybenzonitryl in the presence or absence of a catalyst, 4- (3- (4- (4- (3-cyanophenoxy) propyl) -one 1 We have found that -piveridyl) propoxy) benzo-tolyl or a salt thereof can be easily produced, and have completed the present invention.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • an alkanesulfonyloxy group means, for example, methanesulfonyloxy, trifluoromethanesulfonyl
  • the C alkanesulfo-oxy group may be substituted.
  • An arylsulfoloxy group means, for example, a benzenesulfoloxy group and a toluenesulfuroxy group.
  • Examples of the leaving group include a halogen atom, alkanesulfonyloxy group, and arylsulfo-oxy group.
  • preferable compounds include the following compounds.
  • preferred salts include p-toluenesulfonate and hydrochloride.
  • a method of reacting with a benzo-tolyl derivative represented by “wherein X has the same meaning as described above” is preferred.
  • the compound of the formula [3] or a salt thereof can be produced by reacting the compound of the formula [la] or a salt thereof with a compound of the general formula [2] in the presence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and Ethers such as tylene glycol dimethyl ether; amides such as ⁇ , ⁇ dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone ; -Tolyl such as acetonitrile, and the like, and these may be used as a mixture.
  • Preferred solvents include aromatic hydrocarbons and sulfoxides, more preferably toluene and dimethyl sulfoxide, and more preferably a mixed solvent of toluene and dimethyl sulfoxide.
  • the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [la]. is there.
  • Bases used in this reaction include, for example, triethylamine, ⁇ , ⁇ diisopropylethylamine, ⁇ -methylbiperidine, ⁇ -methylmorpholine, 1,8 diazabicyclic [5.4.0] DBU) and organic bases such as pyridine; sodium methoxide, sodium ethoxide, potassium tert butoxide and metal alkoxides such as sodium tert butoxide; and sodium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium carbonate, carbonate Inorganic bases such as cesium, barium carbonate, sodium hydride and potassium hydride.
  • Preferred bases include potassium tert butoxide and sodium tert butoxide.
  • the amount of the base used is preferably 2 to 3 times the mol of the compound of the formula [la], preferably 2 to 3 times the mol.
  • the amount of the compound of the general formula [2] to be used is preferably 2 to 3 times the mole of the compound of the formula [la], preferably 2 to 3 times the mole.
  • This reaction may be performed at 20 to 120 ° C, preferably 15 to 40 ° C for 1 minute to 24 hours.
  • a compound of the formula [3] or a salt thereof is obtained by reacting a compound of the general formula [lb] or a salt thereof with a compound of the formula [4] in the presence of a base in the presence or absence of a catalyst. Can be manufactured.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • aliphatic hydrocarbons such as hexane and cyclohexane
  • halogenated carbonization such as methylene chloride, dichloroethane, black benzene and dichlorobenzene Hydrogens
  • ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether
  • amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 1-methyl-2-pyrrolidone
  • sulfoxides such as dimethyl sulfoxide Ketones such as acetone and 2-butanone
  • -tolyls such as acetonitrile
  • water water.
  • Preferable solvents include amides, and ⁇
  • the amount of solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w), relative to the compound of general formula [lb]. It is.
  • Examples of the base used in this reaction include triethylamine, ⁇ , ⁇ -diisopropylethylamine, ⁇ -methylbiperidine, ⁇ -methylmorpholine, 1,8-diazabixic [5.4.0] undec-7- Organic bases such as benzene (DBU) and pyridine; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate And inorganic bases such as potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride.
  • Preferred bases include potassium carbonate and sodium carbonate.
  • the amount of the base used is preferably 2 to 3 times the mole of the compound of the general formula [lb], preferably 2 to 3 times the mole.
  • Examples of the catalyst that is optionally used in this reaction include potassium iodide and sodium iodide.
  • a preferred catalyst includes potassium iodide.
  • the amount of the catalyst used is preferably 0.01 to 10 times mol, more preferably 0.1 to 1 times mol for the compound of the general formula [lb].
  • the amount of the compound of the formula [4] used is preferably 2 to 3 times the mole of the compound of the general formula [lb], preferably 2 to 3 times the mole.
  • This reaction may be carried out at 0 to 150 ° C, preferably 60 to 120 ° C for 1 minute to 24 hours.
  • the compound of the general formula [1] or a salt thereof which is the compound of the present invention will be described. Light up.
  • the compound of the general formula [1] or a salt thereof is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
  • the compound of the formula [6] can be produced by reacting the compound of the formula [5] with the compound of the general formula [7].
  • Solvents optionally used in this reaction are not particularly limited as long as they do not affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene; hexane and cyclohexane Aliphatic hydrocarbons such as hexane; Halogenated hydrocarbons such as methyl chloride, dichloroethane, black benzene and dichlorobenzene; Ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and ethylene glycol dimethyl ether; -Amides such as dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 1-methyl-2-pyrrolidone; Esters such as ethyl acetate; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile As well as water Is, it may be used as a mixture.
  • Preferred solvents include water and toluene.
  • the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [5]. is there.
  • the amount of the compound of the general formula [7] used is preferably 1 to 2 moles or more, more preferably 1 to 2 moles compared to the compound of the formula [5].
  • This reaction may be carried out at 0 to 200 ° C., preferably 70 to 120 ° C. for 1 minute to 24 hours.
  • the compound of the formula [la] can be produced by subjecting the compound of the formula [6] to a reduction reaction.
  • Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • methanol, ethanol, 2- Alcohols such as propanol and 2-methyl 2-propanol
  • amides such as N, N-dimethylformamide, ⁇ , ⁇ dimethylacetamide and 1methyl-2-pyrrolidone
  • methylene chloride, black mouth form and dichloroethane Halogenated hydrocarbons aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether, and ethylene glycol monomethyl ether
  • -tolyl such as acetonitrile Kind
  • Ketones such as acetone and 2-butanone
  • esters such as acetic Echiru
  • carboxylic acids such as acet
  • the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [6]. is there.
  • the metal catalyst examples include palladium catalysts such as palladium-carbon, palladium oxide, palladium hydroxide and palladium black, nickel catalysts such as Raney nickel, and acid-platinum.
  • the amount may be 0.001 to 1 times (w / w), preferably 0.01 to 0.5 times (w / w) of the compound of formula [6].
  • reducing agents other than hydrogen examples include formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, and cyclohexadiene.
  • formate salts such as sodium formate, ammonium formate, and triethylammonium formate
  • cyclohexene and cyclohexadiene.
  • the amount should be 6 to 100 times mol, preferably 6 to 10 times mono to the compound of formula [6]!
  • the hydrogen pressure may be 1 to 30 atmospheres, preferably 1 to 10 atmospheres.
  • This reaction may be carried out at 0 to 200 ° C, preferably 50 to 100 ° C for 1 minute to 24 hours.
  • the compound of formula [8] or a salt thereof can be produced by subjecting the compound of formula [5] to a reduction reaction.
  • This reaction may be performed according to production method A-2.
  • a compound of formula [la] or a salt thereof can be produced by reacting a compound of formula [8] or a salt thereof with a compound of general formula [7] in the presence or absence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; —Amides such as dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; and-tolyls such as acetonitrile
  • Preferable solvents include amides, and ⁇ , ⁇ -dimethylacetamide is more preferable.
  • the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [8]. is there.
  • Bases optionally used in this reaction include, for example, triethylamine, ⁇ , ⁇ -diisopropylethylamine, ⁇ ⁇ ⁇ -methylbiperidine, ⁇ ⁇ ⁇ -methylmorpholine and 1,8-diazabicyclo
  • Organic bases such as sodium 7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, Sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride
  • inorganic bases such as Preferred bases include potassium carbonate and sodium carbonate.
  • the amount of the base to be used is preferably 1 to 3 times mol, more preferably 1 to 3 times mol of the compound of the formula [8].
  • the amount of the compound of the general formula [7] to be used is preferably 1 to 2 times the mole of the compound of the formula [8].
  • This reaction may be carried out at 0 to 200 ° C, preferably 30 to 120 ° C for 1 minute to 24 hours.
  • the compound of the general formula [lc] can be produced by reacting the compound of the formula [8] or a salt thereof with the compound of the general formula [9] in the presence or absence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene; hexane and cyclohexane Aliphatic hydrocarbons such as; halogenated hydrocarbons such as methylene chloride, dichloroethane, black benzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; Amides such as dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 1-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Esters such as ethyl acetate; Ketones such as acetone and 2-butanone; and Acetonitrile -Tolyls such as ru and the like may be mentioned, and these may be used as a mixture.
  • Preferred solvents such as
  • the amount of solvent used is not particularly limited, but is preferably 1 to The amount is 50 times (v / w), more preferably 1 to 15 times (v / w).
  • Bases optionally used in this reaction include, for example, triethylamine, ⁇ , ⁇ -diisopropylethylamine, ⁇ -methylbiperidine, ⁇ -methylmorpholine and 1,8-diazabicyclo
  • Organic bases such as sodium 7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, Examples thereof include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride.
  • Preferred bases include potassium carbonate and sodium carbonate.
  • the amount of the base to be used is preferably 1 to 3 times mol, more preferably 1 to 3 times mol of the compound of the formula [8].
  • the amount of the compound of the general formula [9] to be used is preferably 1 to 2 times the mol of the compound of the formula [8].
  • This reaction may be carried out at 0 to 200 ° C, preferably 30 to 120 ° C for 1 minute to 24 hours.
  • the compound of the general formula [lb] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [lc] or a salt thereof into a leaving group.
  • the compound of the general formula [lc] or a salt thereof can be used in the presence or absence of a base, for example, methanesulfuryl. It may be reacted with alkanesulfonyl chloride such as chloride or arylsulfonyl chloride such as ⁇ -toluenesulfonic acid chloride.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide ⁇ and 1-methyl-2-pyrrolidone Amides such as; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol decyl Ether and ethylene glycol Examples include ethers such as rumonomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.
  • the amount of alkanesulfuryl chloride and allylsulfurol chloride used may be 2 to 10 times mol, preferably 2 to 3 times mol, of the compound of general formula [lc]!
  • Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, sodium bicarbonate, Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride and potassium hydride; and organic bases such as triethylamine, ⁇ , ⁇ diisopropylethylamine and pyridine.
  • the amount of the base used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [lc].
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 100 ° C for 1 minute to 48 hours.
  • the compound of the general formula [lc] can be converted into, for example, salts of sodium chloride, thionyl bromide, boron tribromide and carbon tetrabromide trif-phosphine. What is necessary is just to make it react with a reagent.
  • the amount of the reagent used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [lc]!
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction.
  • ⁇ , ⁇ dimethylformamide, ⁇ , ⁇ dimethylacetamide ⁇ and 1-methyl-2-pyrrolidone Amides Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol jetyl ether and Examples include ethers such as ethylene glycol monomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 100 ° C for 1 minute to 48 hours.
  • Y lb and Y 2b are the same and represent a halogen atom, an alkanesulfo-oxy group or an aryl sulfo-oxy group.”
  • the compound of the general formula [Id] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [la] or a salt thereof into a leaving group.
  • This reaction may be performed according to production method C2.
  • the compound of the general formula [Id] or a salt thereof may be used as it is in the next reaction without isolation.
  • the compound of the general formula [1] can also be used as a salt.
  • the salt include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid. ; Salts with organic carboxylic acids such as formic acid, acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichlorodiacetic acid and trifluoroacetic acid; and methanesulfone Examples thereof include sulfonic acids such as acid, benzenesulfonic acid, toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.
  • the mixing ratio in the eluent is a volume ratio.
  • the carrier in silica gel column chromatography is Fuji Silicon Chemical Co., Ltd., B. W. Silica Gel, BW-127ZH.
  • Ms methanesulfol
  • Ts p toluenesulfol
  • PTS p-toluenesulfonic acid
  • DMSO-d Heavy dimethyl sulfoxide
  • the organic layer was separated at 45 ° C, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in 210 mL of 2-propanol, insolubles were removed by filtration, and the residue was washed with 30 mL of 2-propanol.
  • the filtrate and washings were combined and 41.6 g of p-toluenesulfonic acid monohydrate was added.
  • the solid was collected by filtration to obtain 62.4 g of 3- (4- (3-hydroxypropyl) 1-piveridyl) 1 propanol p toluenesulfonate as a white solid.
  • the production method of 4- (3- (4-1 (3- (4-cyanophenoxy) propyl) 1-piveridyl) propoxy) benzonitrile is (1) less in number of steps and yield. (2) No harmful reagents and solvents are used, (3) The reaction procedure is simple, and (4) The raw materials are inexpensive.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

A production method using a piperidine derivative represented by the following general formula: [Chemical formula 1] (wherein Y1 and Y2 independently represent a hydroxyl group, a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group) or a salt thereof as an intermediate is useful as a method for safely and easily producing a 4-(3-(4-(3-(4- cyanophenoxy)propyl)-1-piperidinyl)propoxy)benzonitrile, which is important as a production intermediate for pharmaceutical products, with high yield.

Description

明 細 書  Specification
4- (3- (4- (3- (4_シァノフヱノキシ）プロピル）一 1—ピベリジニル） プロポキシ)ベンゾニトリルの製造法およびその中間体  4- (3- (4- (3- (4_Cyanoph ヱ noxy) propyl) -1- 1-piberidinyl) propoxy) benzonitrile and its intermediate
技術分野  Technical field
[0001] 本発明は、 4- (3 - (4- (3 - (4ーシァノフエノキシ）プロピル） 1ーピベリジ-ル) プロボキシ)ベンゾニトリルの製造法およびその中間体に関する。  [0001] The present invention relates to a process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) 1-piveridyl) propoxy) benzonitrile and intermediates thereof.
背景技術  Background art
[0002] 4一（3— (4— (3— (4 （ァミノ (ィミノ)メチル）フヱノキシ）プロピル） 1ーピベリジ -ル)プロボキシ)ベンズアミジン（以下、 T— 2307と称する。）は、強い抗真菌活性を 有し、抗真菌剤として有用である (非特許文献 1)。  [0002] 4 (3- (4- (3- (4 (Amino) methyl) phenoxy) propyl) 1-piveridyl-) propoxy) benzamidine (hereinafter referred to as T-2307) is a strong antifungal It has activity and is useful as an antifungal agent (Non-patent Document 1).
WO03Z074476号公報 (特許文献 1)には、 T— 2307類縁ィ匕合物の製造法が記 載されている。しかし、この製造法は、（1)工程数が多い、（2)有害性ある試薬および 溶媒を使用する、（3)反応操作が簡便でない、（4)高価な原材料を使用するなどの 欠点を有している。  WO03Z074476 (Patent Document 1) describes a method for producing a T-2307 related compound. However, this production method has disadvantages such as (1) a large number of steps, (2) using harmful reagents and solvents, (3) inconvenient reaction operation, and (4) using expensive raw materials. Have.
WO2006Z003881号公報（特許文献 2)には、 T— 2307の製造法が記載されて いる。しかし、この製造法は、工程数が多ぐ反応操作が煩雑である。  WO2006Z003881 (Patent Document 2) describes a method for producing T-2307. However, this production method involves a complicated reaction operation with many steps.
人体に対して安全で、環境負荷が少なぐかつ安価な原材料を用いて大量製造が 可能な T— 2307の簡便な製造法は、全く知られて 、な 、。  A simple method for manufacturing T-2307, which is safe for the human body, can be manufactured in large quantities using inexpensive raw materials with low environmental impact, is completely known.
[0003] 特許文献 1：国際公開第 03Z074476号パンフレット [0003] Patent Document 1: Pamphlet of International Publication No. 03Z074476
特許文献 2：国際公開第 2006Z003881号パンフレット  Patent Document 2: International Publication No. 2006Z003881 Pamphlet
非特許文献 1 :第 44回インターサイエンス会議アブストラクッ（44th ICAAC abstracts) 、 In Vitro and In Vivo Antifongal Activity of T— 23207: a Novel Arylamidine. 2004年 、 p. 209  Non-Patent Document 1: 44th ICAAC Abstracts, In Vitro and In Vivo Antifongal Activity of T— 23207: a Novel Arylamidine. 2004, p. 209
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 人体に対して安全で、環境負荷が少なぐかつ安価な原材料を用いて大量製造が 可能な T 2307の簡便な製造法が、強く望まれて 、る。 課題を解決するための手段 [0004] A simple manufacturing method of T 2307 that is safe for the human body, has a low environmental burden, and can be mass-produced using inexpensive raw materials is strongly desired. Means for solving the problem
このような状況下、本発明者らは鋭意研究を行った結果、 4一（3—（4一（3—（4一 シァノフエノキシ）プロピル） - 1 ピベリジ-ル）プロポキシ）ベンゾ-トリルが、 T— 23 07の製造において重要な製造中間体であることを見出した。さらに、一般式 [1] [化 1]
Figure imgf000004_0001
Under these circumstances, the present inventors have conducted intensive research. As a result, 4 ((3- (4 ((1- (Chanofenoxy) propyl) -1piveridyl) propoxy) benzo-tolyl is — It was found to be an important production intermediate in the production of 23 07. Furthermore, the general formula [1] [Chemical 1]
Figure imgf000004_0001
「式中、 Y1および Y2は、同一または異なって、ヒドロキシル基、ハロゲン原子、アル力 ンスルホ-ルォキシ基またはァリールスルホ-ルォキシ基を示す。」で表されるピペリ ジン誘導体またはその塩力 4一（3—（4一（3—（4 シァノフヱノキシ）プロピル） 1 ーピベリジ-ル)プロボキシ)ベンゾ-トリルまたはその塩の有用な製造中間体である ことを見出した。すなわち、本発明者らは、式 [la] In the formula, Y 1 and Y 2 are the same or different and each represents a hydroxyl group, a halogen atom, an alkyl sulfo-loxy group or an aryl sulfo-loxy group. It has been found to be a useful intermediate for the preparation of (3- (4 (3- (4 cyanophenoxy) propyl) 1-piberidyl-) propoxy) benzo-tolyl or its salts. That is, the inventors have the formula [la]
[化 2]
Figure imgf000004_0002
[Chemical 2]
Figure imgf000004_0002
の化合物またはその塩を塩基の存在下、一般式 [2] Or a salt thereof in the presence of a base of general formula [2]
[化 3]
Figure imgf000004_0003
[Chemical 3]
Figure imgf000004_0003
「式中、 Xは、ハロゲン原子を示す。」で表されるベンゾニトリル誘導体と反応させるか 、または、一般式 [lb]  It is reacted with a benzonitrile derivative represented by “wherein X represents a halogen atom” or represented by the general formula [lb]
[化 4]
Figure imgf000004_0004
[Chemical 4]
Figure imgf000004_0004
「式中、 Ylaおよび Yzaは、同一または異なって、ハロゲン原子、アルカンスルホ -ルォ キシ基またはァリールスルホ-ルォキシ基を示す。」で表されるピぺリジン誘導体また はその塩を塩基の存在下、触媒の存在下または不存在下、 4ーヒドロキシベンゾニト リルと反応させることにより、 4一（3—（4一（3—（4ーシァノフエノキシ)プロピル）一 1 ーピベリジ-ル)プロボキシ)ベンゾ-トリルまたはその塩が容易に製造できることを見 出し、本発明を完成させた。 In the formula, Y la and Y za are the same or different and each represents a halogen atom, an alkanesulfo-oxyl group or an aryl sulpho-oxy group. Then, by reacting with 4-hydroxybenzonitryl in the presence or absence of a catalyst, 4- (3- (4- (4- (3-cyanophenoxy) propyl) -one 1 We have found that -piveridyl) propoxy) benzo-tolyl or a salt thereof can be easily produced, and have completed the present invention.
発明の効果  The invention's effect
[0006] 本発明の製造法により、医薬の製造中間体として重要な 4一（3—（4一（3—（4ーシ ァノフエノキシ）プロピル）一 1—ピベリジ-ル）プロポキシ）ベンゾ-トリルを簡便に、か つ、工業的スケールで製造できる。本製造法は、（1)工程数が少なぐかつ、収率が 高い (2)有害性ある試薬および溶媒を使用しない、（3)反応操作が簡便である、（4) 原材料が安価である、などの特徴を有している。すなわち、本発明の製造法は、人体 に対して安全で、環境負荷が少なぐ安価で大量製造が可能な 4一（3—（4一（3— ( 4—シァノフエノキシ）プロピル） - 1—ピベリジ-ル）プロポキシ）ベンゾ-トリルの簡便 な製造法として有用である。  [0006] According to the production method of the present invention, 4- (3- (4- (3- (4-cyanophenoxy) propyl) 1-1-piveridyl) propoxy) benzo-tolyl, which is an important pharmaceutical intermediate, is obtained. It can be easily manufactured on an industrial scale. This production method has (1) a small number of steps and a high yield (2) no use of harmful reagents and solvents, (3) simple reaction operation, (4) inexpensive raw materials , Etc. In other words, the production method of the present invention is safe for the human body, inexpensive and can be mass-produced with low environmental impact. 4-1- (3- (4- (3-Cyanphenoxy) propyl) -1-piverige It is useful as a simple production method of -l) propoxy) benzo-tolyl.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 以下、本発明を詳細に説明する。  [0007] Hereinafter, the present invention will be described in detail.
本明細書において、特にことわらない限り、ハロゲン原子とは、フッ素原子、塩素原 子、臭素原子およびヨウ素原子を;アルカンスルホニルォキシ基とは、たとえば、メタ ンスルホニルォキシ、トリフルォロメタンスルホニルォキシおよびエタンスルホニルォ キシなどのハロゲン原子で置換されて 、てもよ 、C アルカンスルホ -ルォキシ基を  In this specification, unless otherwise specified, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkanesulfonyloxy group means, for example, methanesulfonyloxy, trifluoromethanesulfonyl Substituted with halogen atoms such as oxy and ethanesulfonyloxy, the C alkanesulfo-oxy group may be substituted.
1 -6  1 -6
；ァリールスルホ-ルォキシ基とは、たとえば、ベンゼンスルホ-ルォキシおよびトル エンスルホ-ルォキシ基を意味する。  An arylsulfoloxy group means, for example, a benzenesulfoloxy group and a toluenesulfuroxy group.
脱離基としては、たとえば、ハロゲン原子、アルカンスルホニルォキシ基およびァリ 一ルスルホ -ルォキシ基が挙げられる。  Examples of the leaving group include a halogen atom, alkanesulfonyloxy group, and arylsulfo-oxy group.
[0008] 一般式 [1]で表されるピぺリジン誘導体またはその塩において、好ましい化合物と しては、以下の化合物が挙げられる。  [0008] In the piperidine derivative represented by the general formula [1] or a salt thereof, preferable compounds include the following compounds.
Y1および Y2が同一で、ヒドロキシル基またはハロゲン原子である化合物が好ましぐ Y1および Y2が、ヒドロキシル基である化合物がより好まし!/、。 Compounds in which Y 1 and Y 2 are the same and are a hydroxyl group or a halogen atom are preferred. Compounds in which Y 1 and Y 2 are a hydroxyl group are more preferred! /.
一般式 [1]で表されるピぺリジン誘導体において、好ましい塩としては、 p—トルエン スルホン酸塩および塩酸塩が挙げられる。  In the piperidine derivative represented by the general formula [1], preferred salts include p-toluenesulfonate and hydrochloride.
[0009] 本発明にお 、て、好ま 、製造法としては、以下の方法が挙げられる。 4- (3- (4- (3- (4ーシァノフエノキシ）プロピル） 1ーピベリジ-ル）プロポキシ )ベンゾニトリルまたはその塩の製造法において、式 [la] [0009] In the present invention, the following production method is preferable. 4- (3- (4- (3- (4-Cyanofenoxy) propyl) 1-piberidyl-) propoxy) benzonitrile or a salt thereof in the process of formula [la]
[化 4]
Figure imgf000006_0001
[Chemical 4]
Figure imgf000006_0001
で表される化合物またはその塩を塩基の存在下、一般式 [2]  Or a salt thereof in the presence of a base in the general formula [2]
[化 5]
Figure imgf000006_0002
[Chemical 5]
Figure imgf000006_0002
「式中、 Xは、前記と同様の意味を有する。」で表されるベンゾ-トリル誘導体と反応さ せる方法が好ましぐ Xがフッ素原子である一般式 [2]の化合物を用いる方法がさら に好ましい。  A method of reacting with a benzo-tolyl derivative represented by “wherein X has the same meaning as described above” is preferred. A method using a compound of the general formula [2] wherein X is a fluorine atom. Further preferred.
[0010] 次に、本発明の製造方法について説明する。  Next, the production method of the present invention will be described.
[0011] [製造法 1]
Figure imgf000006_0003
[0011] [Production method 1]
Figure imgf000006_0003
[ 1 a] [3] [1 a] [3]
「式中、 Xは、前記と同様の意味を有する。」 “Wherein X has the same meaning as described above.”
[0012] 一般式 [2]の化合物として、たとえば、 4 フルォ口べンゾ-トリルおよび 4 クロ口 ベンゾニトリルなどが巿販されて 、る。  [0012] As the compound represented by the general formula [2], for example, 4-fluobenzobenzoyl and 4-chlorobenzonitrile are commercially available.
[0013] 式 [3]の化合物またはその塩は、式 [la]の化合物またはその塩を塩基の存在下、 一般式 [2]の化合物と反応させることにより製造することができる。 [0013] The compound of the formula [3] or a salt thereof can be produced by reacting the compound of the formula [la] or a salt thereof with a compound of the general formula [2] in the presence of a base.
この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素 類；ジォキサン、テトラヒドロフラン、エチレングリコールジメチルエーテルおよびジェ チレングリコールジメチルエーテルなどのエーテル類； Ν,Ν ジメチルホルムアミド、 Ν,Ν -ジメチルァセトアミドおよび 1—メチルー 2 -ピロリドンなどのアミド類；ジメチル スルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；ならび にァセトニトリルなどの-トリル類などが挙げられ、これらは混合して使用してもよい。 好ましい溶媒としては、芳香族炭化水素類およびスルホキシド類が挙げられ、トルェ ンおよびジメチルスルホキシドがより好ましく、トルエンおよびジメチルスルホキシドの 混合溶媒がさらに好ましい。 The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and Ethers such as tylene glycol dimethyl ether; amides such as Ν, Ν dimethylformamide, Ν, Ν-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone ; -Tolyl such as acetonitrile, and the like, and these may be used as a mixture. Preferred solvents include aromatic hydrocarbons and sulfoxides, more preferably toluene and dimethyl sulfoxide, and more preferably a mixed solvent of toluene and dimethyl sulfoxide.
溶媒の使用量は、特に限定されないが、好ましくは、式 [la]の化合物に対して、 1 〜50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。  The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [la]. is there.
[0014] この反応で使用される塩基としては、たとえば、トリェチルァミン、 Ν,Ν ジイソプロ ピルェチルァミン、 Ν—メチルビペリジン、 Ν—メチルモルホリン、 1, 8 ジァザビシク 口 [5. 4. 0]ゥンデク— 7 ェン (DBU)およびピリジンなどの有機塩基;ナトリウムメト キシド、ナトリウムエトキシド、カリウム tert ブトキシドおよびナトリウム tert ブトキシ ドなどの金属アルコキシド;ならびに水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸ナトリウム 、炭酸カリウム、炭酸セシウム、炭酸バリウム、水素化ナトリウムおよび水素化カリウム などの無機塩基などが挙げられる。好ましい塩基としては、カリウム tert ブトキシド およびナトリウム tert ブトキシドなどが挙げられる。塩基の使用量は、式 [la]の化 合物に対して、 2倍モル以上であればよぐ好ましくは、 2〜3倍モルである。  [0014] Bases used in this reaction include, for example, triethylamine, Ν, Ν diisopropylethylamine, Ν-methylbiperidine, Ν-methylmorpholine, 1,8 diazabicyclic [5.4.0] DBU) and organic bases such as pyridine; sodium methoxide, sodium ethoxide, potassium tert butoxide and metal alkoxides such as sodium tert butoxide; and sodium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium carbonate, carbonate Inorganic bases such as cesium, barium carbonate, sodium hydride and potassium hydride. Preferred bases include potassium tert butoxide and sodium tert butoxide. The amount of the base used is preferably 2 to 3 times the mol of the compound of the formula [la], preferably 2 to 3 times the mol.
[0015] 一般式 [2]の化合物の使用量は、式 [la]の化合物に対して、 2倍モル以上であれ ばよぐ好ましくは、 2〜3倍モルである。  [0015] The amount of the compound of the general formula [2] to be used is preferably 2 to 3 times the mole of the compound of the formula [la], preferably 2 to 3 times the mole.
この反応は、 20〜120°C、好ましくは、 15〜40°Cで 1分間〜 24時間実施すれば よい。  This reaction may be performed at 20 to 120 ° C, preferably 15 to 40 ° C for 1 minute to 24 hours.
[0016] [製造法 2]  [0016] [Production method 2]
HO ^~CN
Figure imgf000007_0001
HO ^ ~ CN
Figure imgf000007_0001
[ 1 b] [3] [1 b] [3]
「式中、 Ylaおよび Y2aは、前記と同様の意味を有する。」 “Wherein Y la and Y 2a have the same meaning as described above.”
[0017] 式 [3]の化合物またはその塩は、一般式 [lb]の化合物またはその塩を塩基の存在 下、触媒の存在下または不存在下、式 [4]の化合物と反応させることにより製造する ことができる。 [0017] A compound of the formula [3] or a salt thereof is obtained by reacting a compound of the general formula [lb] or a salt thereof with a compound of the formula [4] in the presence of a base in the presence or absence of a catalyst. Can be manufactured.
この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素 類；へキサンおよびシクロへキサンなどの脂肪族炭化水素類；塩化メチレン、ジクロロ ェタン、クロ口ベンゼンおよびジクロロベンゼンなどのハロゲン化炭化水素類；ジォキ サン、テトラヒドロフラン、エチレングリコールジメチルエーテルおよびジエチレングリコ ールジメチルエーテルなどのエーテル類； Ν,Ν—ジメチルホルムアミド、 Ν,Ν—ジメチ ルァセトアミドおよび 1ーメチルー 2—ピロリドンなどのアミド類；ジメチルスルホキシド などのスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；ァセトニトリルなど の-トリル類;ならびに水などが挙げられ、これらは混合して使用してもよい。好ましい 溶媒としては、アミド類が挙げられ、 Ν,Ν—ジメチルァセトアミドがより好ましい。 The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Although not specified, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated carbonization such as methylene chloride, dichloroethane, black benzene and dichlorobenzene Hydrogens; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide Ketones such as acetone and 2-butanone; -tolyls such as acetonitrile; and water. These may be used as a mixture. Preferable solvents include amides, and Ν, Ν-dimethylacetamide is more preferable.
溶媒の使用量は、特に限定されないが、好ましくは、一般式 [lb]の化合物に対し て、 1〜50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。  The amount of solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w), relative to the compound of general formula [lb]. It is.
[0018] この反応で使用される塩基としては、たとえば、トリェチルァミン、 Ν,Ν—ジイソプロ ピルェチルァミン、 Ν—メチルビペリジン、 Ν—メチルモルホリン、 1, 8—ジァザビシク 口 [5. 4. 0]ゥンデク— 7—ェン (DBU)およびピリジンなどの有機塩基;ナトリウムメト キシド、ナトリウムエトキシド、カリウム tert—ブトキシドおよびナトリウム tert—ブトキシ ドなどの金属アルコキシド;ならびに水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸ナトリウム 、炭酸カリウム、炭酸セシウム、炭酸バリウム、水素化ナトリウムおよび水素化カリウム などの無機塩基などが挙げられる。好ましい塩基としては、炭酸カリウムおよび炭酸 ナトリウムなどが挙げられる。塩基の使用量は、一般式 [lb]の化合物に対して、 2倍 モル以上であればよぐ好ましくは、 2〜3倍モルである。  [0018] Examples of the base used in this reaction include triethylamine, Ν, Ν-diisopropylethylamine, Ν-methylbiperidine, Ν-methylmorpholine, 1,8-diazabixic [5.4.0] undec-7- Organic bases such as benzene (DBU) and pyridine; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate And inorganic bases such as potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride. Preferred bases include potassium carbonate and sodium carbonate. The amount of the base used is preferably 2 to 3 times the mole of the compound of the general formula [lb], preferably 2 to 3 times the mole.
[0019] この反応で所望により使用される触媒としては、たとえば、ヨウ化カリウムおよびヨウ 化ナトリウムなどが挙げられる。好ましい触媒としては、ヨウ化カリウムが挙げられる。 触媒の使用量は、一般式 [lb]の化合物に対して、 0.01〜10倍モル用いればよぐ好 ましくは、 0.1〜1倍モルである。  [0019] Examples of the catalyst that is optionally used in this reaction include potassium iodide and sodium iodide. A preferred catalyst includes potassium iodide. The amount of the catalyst used is preferably 0.01 to 10 times mol, more preferably 0.1 to 1 times mol for the compound of the general formula [lb].
[0020] 式 [4]の化合物の使用量は、一般式 [lb]の化合物に対して、 2倍モル以上であれ ばよぐ好ましくは、 2〜3倍モルである。  [0020] The amount of the compound of the formula [4] used is preferably 2 to 3 times the mole of the compound of the general formula [lb], preferably 2 to 3 times the mole.
この反応は、 0〜150°C、好ましくは、 60〜120°Cで 1分間〜 24時間実施すればよい。  This reaction may be carried out at 0 to 150 ° C, preferably 60 to 120 ° C for 1 minute to 24 hours.
[0021] 次に、本発明化合物である一般式 [1]の化合物またはその塩の製造法について説 明する。一般式 [1]の化合物またはその塩は、自体公知の方法を組み合わせること により製造されるが、たとえば次に示す製造法により製造することができる。 Next, a method for producing the compound of the general formula [1] or a salt thereof which is the compound of the present invention will be described. Light up. The compound of the general formula [1] or a salt thereof is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
[0022] [製造法 A]
Figure imgf000009_0001
[0022] [Production method A]
Figure imgf000009_0001
「式中、 L1は、脱離基を示す。」 “Wherein L 1 represents a leaving group.”
[0023] (A- 1) [0023] (A- 1)
一般式 [7]の化合物として、たとえば、 3—クロロー 1ープロノ V—ルなどが市販され ている。  As the compound of the general formula [7], for example, 3-chloro-1-pronool V-ol is commercially available.
[0024] 式 [6]の化合物は、式 [5]の化合物を一般式 [7]の化合物と反応させることにより製 造することができる。  [0024] The compound of the formula [6] can be produced by reacting the compound of the formula [5] with the compound of the general formula [7].
[0025] この反応で所望により使用される溶媒としては、反応に影響を及ぼさないものであ れば特に限定されないが、たとえば、ベンゼン、トルエンおよびキシレンなどの芳香 族炭化水素類；へキサンおよびシクロへキサンなどの脂肪族炭化水素類；塩化メチレ ン、ジクロロエタン、クロ口ベンゼンおよびジクロロベンゼンなどのハロゲン化炭化水素 類；ジォキサン、テトラヒドロフラン、エチレングリコールジメチルエーテルおよびジェ チレングリコールジメチルエーテルなどのエーテル類； Ν,Ν—ジメチルホルムアミド、 Ν,Ν—ジメチルァセトアミドおよび 1—メチル—2—ピロリドンなどのアミド類；酢酸ェチ ルなどのエステル類；アセトンおよび 2—ブタノンなどのケトン類；ァセトニトリルなどの 二トリル類;ならびに水などが挙げられ、これらは、混合して使用してもよい。好ましい 溶媒としては水およびトルエンが挙げられる。  [0025] Solvents optionally used in this reaction are not particularly limited as long as they do not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; hexane and cyclohexane Aliphatic hydrocarbons such as hexane; Halogenated hydrocarbons such as methyl chloride, dichloroethane, black benzene and dichlorobenzene; Ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and ethylene glycol dimethyl ether; -Amides such as dimethylformamide, Ν, Ν-dimethylacetamide and 1-methyl-2-pyrrolidone; Esters such as ethyl acetate; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile As well as water Is, it may be used as a mixture. Preferred solvents include water and toluene.
溶媒の使用量は、特に限定されないが、好ましくは、式 [5]の化合物に対して、 1〜 50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。  The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [5]. is there.
[0026] 一般式 [7]の化合物の使用量は、式 [5]の化合物に対して 1倍モル以上であれば よぐ好ましくは、 1〜2倍モルである。  [0026] The amount of the compound of the general formula [7] used is preferably 1 to 2 moles or more, more preferably 1 to 2 moles compared to the compound of the formula [5].
この反応は、 0〜200°C、好ましくは、 70〜120°Cで 1分間〜 24時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C., preferably 70 to 120 ° C. for 1 minute to 24 hours.
[0027] 式 [6]の化合物は、単離せずにそのまま次の反応に用いてもよい。  [0027] The compound of the formula [6] may be used as it is in the next reaction without isolation.
[0028] (A- 2) 式 [la]の化合物は、式 [6]の化合物を還元反応に付すことにより製造することがで きる。 [0028] (A-2) The compound of the formula [la] can be produced by subjecting the compound of the formula [6] to a reduction reaction.
還元反応としては、たとえば、金属触媒を用いる接触水素添加反応が挙げられる。  Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
[0029] 式 [6]の化合物を接触水素添加反応に付す場合、使用される溶媒としては、反応 に影響を及ぼさないものであれば特に限定されないが、たとえば、メタノール、ェタノ ール、 2—プロパノールおよび 2—メチル 2—プロパノールなどのアルコール類； N, N -ジメチルホルムアミド、 Ν,Ν ジメチルァセトアミドおよび 1 メチル— 2—ピロリド ンなどのアミド類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化 炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジォキサ ン、テトラヒドロフラン、ァニソール、ジエチレングリコールジメチルエーテル、ジェチレ ングリコールジェチルエーテルおよびエチレングリコールモノメチルエーテルなどの エーテル類；ァセトニトリルなどの-トリル類；アセトンおよび 2—ブタノンなどのケトン 類；酢酸ェチルなどのエステル類；酢酸などのカルボン酸類；ならびに水などが挙げ られ、これらは混合して使用してもよい。好ましい溶媒としては水およびトルエンが挙 げられる。 [0029] When the compound of formula [6] is subjected to a catalytic hydrogenation reaction, the solvent used is not particularly limited as long as it does not affect the reaction. For example, methanol, ethanol, 2- Alcohols such as propanol and 2-methyl 2-propanol; amides such as N, N-dimethylformamide, Ν, Ν dimethylacetamide and 1methyl-2-pyrrolidone; such as methylene chloride, black mouth form and dichloroethane Halogenated hydrocarbons; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether, and ethylene glycol monomethyl ether; -tolyl such as acetonitrile Kind; Ketones such as acetone and 2-butanone; esters such as acetic Echiru; carboxylic acids such as acetic acid; such as water. These may be used in these mixed. Preferred solvents include water and toluene.
溶媒の使用量は、特に限定されないが、好ましくは、式 [6]の化合物に対して、 1〜 50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。  The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [6]. is there.
[0030] 金属触媒としては、たとえば、パラジウム—炭素、酸化パラジウム、水酸化パラジゥ ムおよびパラジウム黒などのパラジウム触媒、ラネーニッケルなどのニッケル触媒なら びに酸ィ匕白金などが挙げられ、その使用量は、式 [6]の化合物に対して 0.001〜1倍 量 (w/w)、好ましくは 0.01〜0.5倍量 (w/w)であればよい。 [0030] Examples of the metal catalyst include palladium catalysts such as palladium-carbon, palladium oxide, palladium hydroxide and palladium black, nickel catalysts such as Raney nickel, and acid-platinum. The amount may be 0.001 to 1 times (w / w), preferably 0.01 to 0.5 times (w / w) of the compound of formula [6].
水素以外の還元剤としては、たとえば、ギ酸;ギ酸ナトリウム、ギ酸アンモ-ゥムおよ びギ酸トリェチルアンモニゥムなどのギ酸塩；シクロへキセンならびにシクロへキサジ ェンなどが挙げられ、その使用量は、式 [6]の化合物に対して 6〜100倍モル、好まし くは 6〜 10倍モノレであればよ!、。  Examples of reducing agents other than hydrogen include formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, and cyclohexadiene. The amount should be 6 to 100 times mol, preferably 6 to 10 times mono to the compound of formula [6]!
水素圧は、 1〜30気圧、好ましくは、 1〜10気圧であればよい。  The hydrogen pressure may be 1 to 30 atmospheres, preferably 1 to 10 atmospheres.
この反応は、 0〜200°C、好ましくは 50〜100°Cで 1分間〜 24時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 50 to 100 ° C for 1 minute to 24 hours.
[0031] 式 [la]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよい。 [0032] [製造法 B]
Figure imgf000011_0001
[0031] The compound of the formula [la] or a salt thereof may be used as it is in the next reaction without isolation. [0032] [Production method B]
Figure imgf000011_0001
「式中、 L1は、前記と同様の意味を有する。」 “Wherein L 1 has the same meaning as described above.”
[0033] (B- 1) [0033] (B- 1)
式 [8]の化合物またはその塩は、式 [5]の化合物を還元反応に付すことにより製造 できる。  The compound of formula [8] or a salt thereof can be produced by subjecting the compound of formula [5] to a reduction reaction.
この反応は、製造法 A— 2に準じて行えばよい。  This reaction may be performed according to production method A-2.
式 [8]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよ!、。  The compound of the formula [8] or a salt thereof may be used as it is in the next reaction without isolation!
[0034] (B- 2) [0034] (B-2)
式 [ la]の化合物またはその塩は、式 [8]の化合物またはその塩を塩基の存在下ま たは不存在下、一般式 [7]の化合物と反応させることにより製造することができる。  A compound of formula [la] or a salt thereof can be produced by reacting a compound of formula [8] or a salt thereof with a compound of general formula [7] in the presence or absence of a base.
[0035] この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、ジォキサン、テトラヒドロフラン、エチレングリコールジメチル エーテルおよびジエチレングリコールジメチルエーテルなどのエーテル類； Ν,Ν—ジ メチルホルムアミド、 Ν,Ν—ジメチルァセトアミドおよび 1—メチル— 2—ピロリドンなど のアミド類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンな どのケトン類;ならびにァセトニトリルなどの-トリル類などが挙げられ、これらは混合し て使用してもよい。好ましい溶媒としては、アミド類が挙げられ、 Ν,Ν—ジメチルァセト アミドがより好ましい。 [0035] The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; —Amides such as dimethylformamide, Ν, Ν-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; and-tolyls such as acetonitrile These may be used as a mixture. Preferable solvents include amides, and Ν, Ν-dimethylacetamide is more preferable.
溶媒の使用量は、特に限定されないが、好ましくは、式 [8]の化合物に対して、 1〜 50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。  The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [8]. is there.
[0036] この反応で所望により使用される塩基としては、たとえば、トリェチルァミン、 Ν,Ν— ジイソプロピルェチルァミン、 Ν—メチルビペリジン、 Ν—メチルモルホリンおよび 1, 8 —ジァザビシクロ [5. 4. 0]ゥンデク一 7—ェン（DBU)などの有機塩基；ナトリウムメト キシド、ナトリウムエトキシド、カリウム tert—ブトキシドおよびナトリウム tert—ブトキシ ドなどの金属アルコキシド;ならびに水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸ナトリウム 、炭酸カリウム、炭酸セシウム、炭酸バリウム、水素化ナトリウムおよび水素化カリウム などの無機塩基などが挙げられる。好ましい塩基としては、炭酸カリウムおよび炭酸 ナトリウムなどが挙げられる。塩基の使用量は、式 [8]の化合物に対して、 1倍モル以 上であればよぐ好ましくは、 1〜3倍モルである。 [0036] Bases optionally used in this reaction include, for example, triethylamine, Ν, Ν-diisopropylethylamine, メ チ ル -methylbiperidine, メ チ ル -methylmorpholine and 1,8-diazabicyclo [5.4.0] Organic bases such as sodium 7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, Sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride And inorganic bases such as Preferred bases include potassium carbonate and sodium carbonate. The amount of the base to be used is preferably 1 to 3 times mol, more preferably 1 to 3 times mol of the compound of the formula [8].
[0037] 一般式 [7]の化合物の使用量は、式 [8]の化合物に対して 1倍モル以上であれば よぐ好ましくは、 1〜2倍モルである。 [0037] The amount of the compound of the general formula [7] to be used is preferably 1 to 2 times the mole of the compound of the formula [8].
この反応は、 0〜200°C、好ましくは、 30〜120°Cで 1分間〜 24時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 30 to 120 ° C for 1 minute to 24 hours.
[0038] 式 [la]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよい。 [0038] The compound of the formula [la] or a salt thereof may be used as it is in the next reaction without isolation.
[0039] [製造法 C]
Figure imgf000012_0001
[0039] [Production Method C]
Figure imgf000012_0001
[8] [ 1 c] [ 1 b]  [8] [1 c] [1 b]
「式中、 L2は、脱離基を; Ylaおよび Y2aは、前記と同様の意味を有する。」 “Wherein L 2 represents a leaving group; Y la and Y 2a have the same meaning as described above.”
[0040] (C- 1) [0040] (C-1)
一般式 [9]の化合物として、たとえば、 1ーブロモー 3—クロ口プロパンなどが巿販さ れている。  As a compound of the general formula [9], for example, 1-bromo-3-chloropropane is commercially available.
[0041] 一般式 [lc]の化合物は、式 [8]の化合物またはその塩を塩基の存在下または不 存在下、一般式 [9]の化合物と反応させることにより製造することができる。  [0041] The compound of the general formula [lc] can be produced by reacting the compound of the formula [8] or a salt thereof with the compound of the general formula [9] in the presence or absence of a base.
[0042] この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素 類；へキサンおよびシクロへキサンなどの脂肪族炭化水素類；塩化メチレン、ジクロロ ェタン、クロ口ベンゼンおよびジクロロベンゼンなどのハロゲン化炭化水素類；ジォキ サン、テトラヒドロフラン、エチレングリコールジメチルエーテルおよびジエチレングリコ ールジメチルエーテルなどのエーテル類； Ν,Ν—ジメチルホルムアミド、 Ν,Ν—ジメチ ルァセトアミドおよび 1ーメチルー 2—ピロリドンなどのアミド類；ジメチルスルホキシド などのスルホキシド類；酢酸ェチルなどのエステル類；アセトンおよび 2—ブタノンなど のケトン類;ならびにァセトニトリルなどの-トリル類などが挙げられ、これらは、混合し て使用してもよい。好ましい溶媒としてはエステル類が挙げられ、酢酸ェチルがより好 ましい。  [0042] The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; hexane and cyclohexane Aliphatic hydrocarbons such as; halogenated hydrocarbons such as methylene chloride, dichloroethane, black benzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; Amides such as dimethylformamide, Ν, Ν-dimethylacetamide and 1-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Esters such as ethyl acetate; Ketones such as acetone and 2-butanone; and Acetonitrile -Tolyls such as ru and the like may be mentioned, and these may be used as a mixture. Preferred solvents include esters, with ethyl acetate being more preferred.
溶媒の使用量は、特に限定されないが、好ましくは、式 [8]の化合物に対して、 1〜 50倍量 (v/w)、より好ましくは、 1〜15倍量 (v/w)である。 The amount of solvent used is not particularly limited, but is preferably 1 to The amount is 50 times (v / w), more preferably 1 to 15 times (v / w).
[0043] この反応で所望により使用される塩基としては、たとえば、トリェチルァミン、 Ν,Ν- ジイソプロピルェチルァミン、 Ν—メチルビペリジン、 Ν—メチルモルホリンおよび 1, 8 —ジァザビシクロ [5. 4. 0]ゥンデク一 7—ェン（DBU)などの有機塩基；ナトリウムメト キシド、ナトリウムエトキシド、カリウム tert—ブトキシドおよびナトリウム tert—ブトキシ ドなどの金属アルコキシド;ならびに水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸ナトリウム 、炭酸カリウム、炭酸セシウム、炭酸バリウム、水素化ナトリウムおよび水素化カリウム などの無機塩基などが挙げられる。好ましい塩基としては、炭酸カリウムおよび炭酸 ナトリウムなどが挙げられる。塩基の使用量は、式 [8]の化合物に対して、 1倍モル以 上であればよぐ好ましくは、 1〜3倍モルである。  [0043] Bases optionally used in this reaction include, for example, triethylamine, Ν, Ν-diisopropylethylamine, Ν-methylbiperidine, Ν-methylmorpholine and 1,8-diazabicyclo [5.4.0] Organic bases such as sodium 7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, Examples thereof include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride. Preferred bases include potassium carbonate and sodium carbonate. The amount of the base to be used is preferably 1 to 3 times mol, more preferably 1 to 3 times mol of the compound of the formula [8].
[0044] 一般式 [9]の化合物の使用量は、式 [8]の化合物に対して 1倍モル以上であれば よぐ好ましくは、 1〜2倍モルである。  [0044] The amount of the compound of the general formula [9] to be used is preferably 1 to 2 times the mol of the compound of the formula [8].
この反応は、 0〜200°C、好ましくは、 30〜120°Cで 1分間〜 24時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 30 to 120 ° C for 1 minute to 24 hours.
[0045] 一般式 [lc]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよ い。  [0045] The compound of the general formula [lc] or a salt thereof may be used as it is in the next reaction without isolation.
[0046] (C- 2)  [0046] (C-2)
一般式 [lb]の化合物またはその塩は、一般式 [ lc]の化合物またはその塩のヒドロ キシル基を脱離基へと変換することにより製造することができる。  The compound of the general formula [lb] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [lc] or a salt thereof into a leaving group.
脱離基が、アル力ンスルホ-ルォキシ基またはァリ一ルスルホ -ルォキシ基である 場合は、一般式 [lc]の化合物またはその塩を塩基の存在下または不存在下、たと えば、メタンスルホユルクロリドなどのアルカンスルホユルクロリドまたは ρ—トルエンス ルホン酸クロリドなどのァリールスルホニルクロリドと反応させればよい。  When the leaving group is an alkyl sulfo-loxy group or aryl sulfo-loxy group, the compound of the general formula [lc] or a salt thereof can be used in the presence or absence of a base, for example, methanesulfuryl. It may be reacted with alkanesulfonyl chloride such as chloride or arylsulfonyl chloride such as ρ-toluenesulfonic acid chloride.
この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、 Ν,Ν—ジメチルホルムアミド、 Ν,Ν—ジメチルァセトアミドぉ よび 1ーメチルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジク ロロェタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳 香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、ジエチレングリコール ジメチルエーテル、ジエチレングリコールジェチルエーテルおよびエチレングリコー ルモノメチルエーテルなどのエーテル類；ァセトニトリルなどの-トリル類；ジメチルス ルホキシドなどのスルホキシド類；ならびにピリジンなどのへテロ芳香族類などが挙げ られ、これらは混合して使用してもよい。 The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide ぉ and 1-methyl-2-pyrrolidone Amides such as; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol decyl Ether and ethylene glycol Examples include ethers such as rumonomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.
[0047] アルカンスルホユルクロリドおよびァリールスルホユルク口リドの使用量は、一般式 [ lc]の化合物に対して 2〜10倍モル、好ましくは 2〜3倍モルであればよ!、。 [0047] The amount of alkanesulfuryl chloride and allylsulfurol chloride used may be 2 to 10 times mol, preferably 2 to 3 times mol, of the compound of general formula [lc]!
この反応において所望により使用される塩基としては、たとえば、ナトリウムメトキシド 、ナトリウムエトキシド、カリウム tert ブトキシドおよびナトリウム tert ブトキシドなど の金属アルコキシド;水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸ナ トリウム、炭酸カリウム、水素化ナトリウムおよび水素化カリウムなどの無機塩基;なら びにトリエチルァミン、 Ν,Ν ジイソプロピルェチルァミンおよびピリジンなどの有機塩 基などが挙げられる。塩基の使用量は、一般式 [lc]の化合物に対して 1〜10倍モル 、好ましくは 1〜3倍モルであればよい。  Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, sodium bicarbonate, Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride and potassium hydride; and organic bases such as triethylamine, Ν, Ν diisopropylethylamine and pyridine. The amount of the base used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [lc].
この反応は、 0〜200°C、好ましくは 0〜100°Cで 1分間〜 48時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 0 to 100 ° C for 1 minute to 48 hours.
[0048] 脱離基が、ハロゲン原子である場合は、一般式 [lc]の化合物をたとえば、塩ィ匕チ ォニル、臭化チォニル、三臭化ホウ素および四臭化炭素 トリフ -ルホスフィンな どの試薬と反応させればよい。試薬の使用量は、一般式 [lc]の化合物に対して 1〜1 0倍モル、好ましくは 1〜3倍モルであればよ!、。 [0048] When the leaving group is a halogen atom, the compound of the general formula [lc] can be converted into, for example, salts of sodium chloride, thionyl bromide, boron tribromide and carbon tetrabromide trif-phosphine. What is necessary is just to make it react with a reagent. The amount of the reagent used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [lc]!
この反応で使用される溶媒としては、反応に影響を及ぼさないものであれば特に限 定されないが、たとえば、 Ν,Ν ジメチルホルムアミド、 Ν,Ν ジメチルァセトアミドぉ よび 1ーメチルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジク ロロェタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳 香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、ジエチレングリコール ジメチルエーテル、ジエチレングリコールジェチルエーテルおよびエチレングリコー ルモノメチルエーテルなどのエーテル類；ァセトニトリルなどの-トリル類；ジメチルス ルホキシドなどのスルホキシド類；ならびにピリジンなどのへテロ芳香族類などが挙げ られ、これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, Ν, Ν dimethylformamide, Ν, Ν dimethylacetamide ぉ and 1-methyl-2-pyrrolidone Amides; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol jetyl ether and Examples include ethers such as ethylene glycol monomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.
この反応は、 0〜200°C、好ましくは 0〜100°Cで 1分間〜 48時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 0 to 100 ° C for 1 minute to 48 hours.
[0049] 一般式 [lb]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよ い。 [0049] The compound of the general formula [lb] or a salt thereof may be used as it is in the next reaction without isolation. Yes.
[0050] [製造法 D]
Figure imgf000015_0001
[0050] [Production Method D]
Figure imgf000015_0001
[ l a] [ 1 d]  [l a] [1 d]
「式中、 Ylbおよび Y2bは、同一であり、ハロゲン原子、アルカンスルホ -ルォキシ基ま たはァリールスルホ-ルォキシ基を示す。」 “Wherein Y lb and Y 2b are the same and represent a halogen atom, an alkanesulfo-oxy group or an aryl sulfo-oxy group.”
[0051] 一般式 [Id]の化合物またはその塩は、一般式 [la]の化合物またはその塩のヒドロ キシル基を脱離基へと変換することにより製造することができる。  [0051] The compound of the general formula [Id] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [la] or a salt thereof into a leaving group.
この反応は、製造法 C 2に準じて行えばよい。  This reaction may be performed according to production method C2.
一般式 [Id]の化合物またはその塩は、単離せずにそのまま次の反応に用いてもよ い。  The compound of the general formula [Id] or a salt thereof may be used as it is in the next reaction without isolation.
[0052] 上記の製造法において、一般式 [1]の化合物は、塩として用いることもでき、それら の塩としては、たとえば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ 酸、酢酸、クェン酸、シユウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、ァ スパラギン酸、トリクロ口酢酸およびトリフルォロ酢酸などの有機カルボン酸との塩；な らびにメタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、メシチレンスルホ ン酸およびナフタレンスルホン酸などのスルホン酸などが挙げられる。  [0052] In the above production method, the compound of the general formula [1] can also be used as a salt. Examples of the salt include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid. ; Salts with organic carboxylic acids such as formic acid, acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichlorodiacetic acid and trifluoroacetic acid; and methanesulfone Examples thereof include sulfonic acids such as acid, benzenesulfonic acid, toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.
[0053] このようにして得られた式 [la]の化合物またはその塩ならびに一般式 [lb]、 [lc] および [Id]の化合物またはそれらの塩は、たとえば、縮合または加水分解などの自 体公知の反応に付すことによって、または、それらの反応を適宜組み合わせることに よって他の一般式 [ 1 ]の化合物またはその塩に誘導することができる。  [0053] The thus obtained compound of the formula [la] or a salt thereof, and the compounds of the general formulas [lb], [lc] and [Id] or a salt thereof are, for example, self-condensed such as condensation or hydrolysis. It can be derived into other compounds of the general formula [1] or salts thereof by subjecting them to known reactions or by appropriately combining these reactions.
[0054] 次に、本発明を参考例、実施例および製造例を挙げて説明する力 本発明はこれ らに限定されるものではない。  Next, the power to explain the present invention with reference examples, examples and production examples The present invention is not limited to these.
溶離液における混合比は、容量比である。特に記載のない場合、シリカゲルカラム クロマトグラフィーにおける担体は、富士シリシァ化学株式会社、 B. W.シリカゲル、 BW— 127ZHである。  The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silicon Chemical Co., Ltd., B. W. Silica Gel, BW-127ZH.
各実施例において各略号は、以下の意味を有する。  In each example, each abbreviation has the following meaning.
Ms：メタンスルホ -ル、 Ts： p トルエンスルホ -ル、 PTS： p -トルエンスルホン酸、 DMSO-d：重ジメチルスルホキシド Ms: methanesulfol, Ts: p toluenesulfol, PTS: p-toluenesulfonic acid, DMSO-d: Heavy dimethyl sulfoxide
6  6
[0055] 実施例 1
Figure imgf000016_0001
[0055] Example 1
Figure imgf000016_0001
3— (ピペリジン— 4—ィル）プロパン— 1—オール 5.00gを Ν,Ν ジメチルァセトアミ ド 25mLに溶解し、 1—ブロモ 3 クロ口プロパン 5.77gおよび炭酸カリウム 9.65gをカロ え、 50°Cで 1時間撹拌した。反応液を冷却後、トルエンおよび水を加えた。有機層を 分取し、水および飽和食塩水で順次洗浄後、減圧下で溶媒を留去し、黄色固体の 3 - (1— (3 クロ口プロピル）ピぺリジン— 4—ィル）プロパン— 1—オール 5.21gを得た  Dissolve 5.00 g of 3- (piperidine-4-yl) propan-1-ol in 25 mL of Ν, Ν dimethylacetamide, and add 5.77 g of 1-bromo 3-chloropropane and 9.65 g of potassium carbonate. Stir at ° C for 1 hour. After cooling the reaction solution, toluene and water were added. The organic layer was separated, washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure to give 3- (1- (3-chloropropyl) piperidine-4-yl) propane as a yellow solid. — 1—All obtained 5.21 g.
'H-NMRCCDCI ) δ値： 1.15- 2.15(13H,m),2.42- 2.46(2H,m),2.80- 3.00(2H,m),3.50- 3.'H-NMRCCDCI) δ value: 1.15- 2.15 (13H, m), 2.42- 2.46 (2H, m), 2.80-3.00 (2H, m), 3.50-3.
75(4H,m) 75 (4H, m)
[0056] 実施例 2
Figure imgf000016_0002
[0056] Example 2
Figure imgf000016_0002
3 （ピペリジン 4 ィル）プロパン 1 オール炭酸塩 2.00gを酢酸ェチル lOmL に懸濁し、 1ーブロモー 3 クロ口プロパン 3.4mLおよび炭酸カリウム 4.77gをカ卩え、 40 °Cで 6時間撹拌した。反応液を冷却後、水および塩酸を加え pHl.Oとした。水層を分 取し、 20%水酸ィ匕ナトリウム水溶液およびトルエンをカ卩え、 pHIOとした。有機層を分 取し、トリェチルァミン 2.40mLおよびメタンスルホユルクロリド 1.16mLをカ卩え、室温で 30 分間撹拌した。反応液に水および 20%水酸ィ匕ナトリウム水溶液を加え、 pHIOとし、有 機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマト グラフィー (溶離液;クロ口ホルム:メタノール = 50 : 1)で精製し、淡黄色油状の 3—（1 一（3 クロ口プロピル）ピぺリジンー4 ィル）プロピル =メタンスルホナート 2.21gを得 た。  2.00 g of 3 (piperidine 4-yl) propane 1-ol carbonate was suspended in lOmL of ethyl acetate, 3.4 mL of 1-bromo-3-chloropropane and 4.77 g of potassium carbonate were added, and the mixture was stirred at 40 ° C for 6 hours. After cooling the reaction solution, water and hydrochloric acid were added to adjust pHl.O. The aqueous layer was separated, and 20% aqueous sodium hydroxide solution and toluene were added to obtain pHIO. The organic layer was separated, and 2.40 mL of triethylamine and 1.16 mL of methanesulfuryl chloride were added and stirred at room temperature for 30 minutes. Water and 20% aqueous sodium hydroxide solution were added to the reaction solution to adjust to pHIO, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; black mouth form: methanol = 50: 1) to give pale yellow oil 3- (1 (3 black mouth propyl) piperidine-4-yl). 2.21 g of propyl methanesulfonate was obtained.
'H-NMRCCDCl ) δ値： 1.15- 1.40(5H,m),1.60- 2.00(8H,m),2.44(2H,t,J=7.2Hz),2.84- 2  'H-NMRCCDCl) δ value: 1.15- 1.40 (5H, m), 1.60-2.00 (8H, m), 2.44 (2H, t, J = 7.2Hz), 2.84-2
3  Three
.92(2H,m),3.00(3H,s),3.58(2H,t,J=6.6Hz),4.21(2H,t,J=6.6Hz)  .92 (2H, m), 3.00 (3H, s), 3.58 (2H, t, J = 6.6Hz), 4.21 (2H, t, J = 6.6Hz)
[0057] 実施例 3
Figure imgf000017_0001
[0057] Example 3
Figure imgf000017_0001
炭酸塩  Carbonate
3 （ピペリジン 4 ィル）プロパン 1 オール炭酸塩 2.00gを酢酸ェチル 10mL に懸濁し、 1ーブロモー 3 クロ口プロパン 2.3mLおよび炭酸カリウム 3.18gをカ卩え、 50 °Cで 5時間撹拌した。反応液を冷却後、水および塩酸を加え、 pHl.Oとした。水層を分 取し、 20%水酸ィ匕ナトリウム水溶液およびトルエンをカ卩え、 pHIOとした。有機層を分 取し、トリェチルァミン 2.40mLおよび p—トルエンスルホユルクロリド 2.85gをカ卩え、 60°C で 4時間撹拌した。反応液に水および 20%水酸ィ匕ナトリウム水溶液を加え、 pHIOとし 、有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー (溶離液;酢酸ェチル)で精製し、淡黄色油状の 3 （1— (3—クロロブ 口ピル）ピぺリジンー4 ィル）プロピル =4 メチルベンゼンスルホナート 2.00gを得た  2.00 g of 3 (piperidine 4-yl) propane 1-ol carbonate was suspended in 10 mL of ethyl acetate, 2.3 mL of 1-bromo-3-chloropropane and 3.18 g of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 5 hours. After cooling the reaction solution, water and hydrochloric acid were added to adjust pHl.O. The aqueous layer was separated, and 20% aqueous sodium hydroxide solution and toluene were added to obtain pHIO. The organic layer was separated, and 2.40 mL of triethylamine and 2.85 g of p-toluenesulfuryl chloride were added and stirred at 60 ° C. for 4 hours. Water and 20% aqueous sodium hydroxide solution were added to the reaction solution to adjust to pHIO, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate), and was obtained as a pale yellow oily 3 (1- (3-chlorobutyl) piperidine-4-yl) propyl = 4 methylbenzenesulfone. Obtained 2.00 g of nat.
^-NMRCCDCl ) δ値： 1.05- 1.30(5H,m),1.50- 2.00(8H,m),2.43(2H,t,J=7.2Hz),2.45(3 ^ -NMRCCDCl) δ value: 1.05- 1.30 (5H, m), 1.50-2.00 (8H, m), 2.43 (2H, t, J = 7.2Hz), 2.45 (3
3  Three
H,s),2.80-2.88(2H,m),3.57(2H,t,J=6.6Hz),4.01(2H,t,J=6.6Hz),7.35(2H,d,J=8.4Hz),7 .79(2H,d,J=8.4Hz)  H, s), 2.80-2.88 (2H, m), 3.57 (2H, t, J = 6.6Hz), 4.01 (2H, t, J = 6.6Hz), 7.35 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.4Hz)
実施例 4
Figure imgf000017_0002
Example 4
Figure imgf000017_0002
3- (ピペリジン— 4—ィル）プロパン— 1—オール 0.50gをアセトン 5mLに溶解し、 1 ーブロモー 3 クロ口プロパン 0.60gおよび炭酸カリウム 0.48gをカ卩え、室温で 1時間 30 分間、ついで 40°Cで 2時間撹拌した。反応液にトルエンおよび水を加え、有機層を分 取し、水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下で溶媒を留去した。得られ た残留物をトルエン 5mLに溶解し、塩化チォ -ル 0.51mLをカ卩え、 70°Cで 5分間撹拌し た。反応液の溶媒を減圧下で留去した。得られた残留物にトルエンを加え、固形物を ろ取し、淡黄色固体の 1, 4 ビス（3 クロ口プロピル）ピぺリジン塩酸塩 0.66gを得た  Dissolve 0.50 g of 3- (piperidine-4-yl) propan-1-ol in 5 mL of acetone, add 0.60 g of 1-bromo-3 black-mouthed propane and 0.48 g of potassium carbonate, and then at room temperature for 1 hour and 30 minutes. The mixture was stirred at 40 ° C for 2 hours. Toluene and water were added to the reaction solution, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 5 mL of toluene, 0.51 mL of chlorochloride was added, and the mixture was stirred at 70 ° C. for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure. Toluene was added to the obtained residue, and the solid matter was collected by filtration to obtain 0.66 g of 1,4 bis (3-clopropyl) piperidine hydrochloride as a pale yellow solid.
1H-NMR(CDC1 ) δ値： 1.45- 1.60(3H,m),1.75- 1.95(4H,m),2.00- 2.15(2H,m),2.40- 2.5 1H-NMR (CDC1) δ value: 1.45- 1.60 (3H, m), 1.75- 1.95 (4H, m), 2.00-2.15 (2H, m), 2.40-2.5
3  Three
5(2H,m),2.60-2.75(2H,m),3.05-3.15(2H,m),3.53(2H,t,J=6.5Hz),3.55-3.65(2H,m),3.6 8(2H,t,J=5.9Hz), 12.45(lH,s) 5 (2H, m), 2.60-2.75 (2H, m), 3.05-3.15 (2H, m), 3.53 (2H, t, J = 6.5Hz), 3.55-3.65 (2H, m), 3.6 8 (2H, t, J = 5.9Hz), 12.45 (lH, s)
[0059] 実施例 5
Figure imgf000018_0001
[0059] Example 5
Figure imgf000018_0001
3 - (ピペリジン 4—ィル）プロパン— 1 オール 1.00gを Ν,Ν -ジメチルァセトアミ ド 5mLに溶解し、トリェチルァミン lmLおよび 3 クロ口 1—プロパノール 0.66gをカロえ 、 100°Cで 2時間 30分間撹拌した。反応液を冷却後、室温で塩ィ匕チォ-ル 1.5mLを加 え、同温度で 30分間撹拌した。反応液に酢酸ェチル、炭酸水素ナトリウム水溶液お よび 20%水酸ィ匕ナトリウム水溶液を加えた。有機層を分取し、希塩酸を加えた。水層 を分取し、水酸ィ匕ナトリウムおよびトルエンを加えた。有機層を分取し、無水硫酸ナト リウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマ トグラフィー (溶離液;クロ口ホルム:メタノール = 20 : 1)で精製し、淡黄色油状の 1, 4 —ビス（3 クロ口プロピル）ピぺリジン 1.06gを得た。  Dissolve 1.00 g of 3- (piperidine 4-yl) propane-1-ol in 5 mL of Ν, Ν-dimethylacetamide, add 1 mL of triethylamine and 0.66 g of 1-propanol at 2 ° C., and add 2 at 100 ° C. Stir for 30 minutes. After cooling the reaction solution, 1.5 mL of sodium chloride was added at room temperature, followed by stirring at the same temperature for 30 minutes. Ethyl acetate, aqueous sodium hydrogen carbonate solution and 20% aqueous sodium hydroxide solution were added to the reaction solution. The organic layer was separated and diluted hydrochloric acid was added. The aqueous layer was separated and sodium hydroxide and toluene were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; black mouth form: methanol = 20: 1) to give 1.06 g of 1,4-bis (3 black mouth propyl) piperidine as a pale yellow oil. Obtained.
1H-NMR(CDC1 ) δ値： 1.15- 1.45(5H,m),1.60- 2.00(8H,m),2.44(2H,t,J=7.2Hz),2.80- 2  1H-NMR (CDC1) δ value: 1.15- 1.45 (5H, m), 1.60-2.00 (8H, m), 2.44 (2H, t, J = 7.2Hz), 2.80-2
3  Three
.95(2H,m),3.52(2H,t,J=6.8Hz),3.58(2H,t,J=6.6Hz)  .95 (2H, m), 3.52 (2H, t, J = 6.8Hz), 3.58 (2H, t, J = 6.6Hz)
[0060] 実施例 6
Figure imgf000018_0002
[0060] Example 6
Figure imgf000018_0002
(1) 3— (4—ピリジル）プロパン— 1—オール 150gを水 150mLに溶解し、 3 クロ口— 1—プロパノ—ル 109gを加え、還流下で 3時間撹拌した。反応液を冷却後、 10%パラ ジゥム 炭素（50%Wet) 15.0gをカ卩え、水素加圧下（5kg/cm2)、 75°Cで 7時間 30分間 撹拌した。反応液を冷却後、不溶物をろ去し、残渣を水 140mLで洗浄した。ろ液と洗 液を合わせ、水酸ィ匕ナトリウム 48.1gを加え、室温まで冷却した。塩化メチレンをカロえ、 有機層を分取し、常圧下で溶媒を留去した。得られた残留物を 2 プロパノール 1.20 Lに溶解し、 p—トルエンスルホン酸 1水和物 208gをカ卩えた。固形物をろ取し、白色固 体の 3— (4— (3 ヒドロキシプロピル）— 1—ピベリジ-ル）— 1—プロパノール p ト ルエンスルホン酸塩 292gを得た。 (1) 150 g of 3- (4-pyridyl) propan-1-ol was dissolved in 150 mL of water, 109 g of 3-chloro-1-propanol was added, and the mixture was stirred under reflux for 3 hours. After cooling the reaction solution, 15.0 g of 10% palladium carbon (50% Wet) was added, and the mixture was stirred at 75 ° C for 7 hours and 30 minutes under hydrogen pressure (5 kg / cm 2 ). After cooling the reaction solution, the insoluble material was removed by filtration, and the residue was washed with 140 mL of water. The filtrate and washings were combined, 48.1 g of sodium hydroxide was added, and the mixture was cooled to room temperature. The methylene chloride was removed, the organic layer was separated, and the solvent was distilled off under normal pressure. The obtained residue was dissolved in 1.20 L of 2-propanol to obtain 208 g of p-toluenesulfonic acid monohydrate. The solid matter was collected by filtration to obtain 292 g of 3- (4- (3 hydroxypropyl) -1-piveridyl) -1-propanol p-toluenesulfonate as a white solid.
'H-NMRCD 0) δ値： 1.25— 1.70(7H,m),1.90— 2.10(4H,m),2.40(3H,s),2.85— 3.00(2H,m),  'H-NMRCD 0) δ value: 1.25— 1.70 (7H, m), 1.90— 2.10 (4H, m), 2.40 (3H, s), 2.85— 3.00 (2H, m),
2  2
3.10-3.25(2H,m),3.50-3.65(4H,m),3.69(2H,t,J=6.1Hz),7.38(2H,d,J=8.0Hz),7.70(2H, d,J=8.0Hz) 3.10-3.25 (2H, m), 3.50-3.65 (4H, m), 3.69 (2H, t, J = 6.1Hz), 7.38 (2H, d, J = 8.0Hz), 7.70 (2H, d, J = 8.0Hz)
[0061] (2) 3— (4—ピリジル）プロパン 1 オール 30gおよび 3 クロロー 1 プロパノー ル 21.7gをトルエン 180mLに溶解し、還流下で 9時間撹拌した。反応液を冷却後、水 3 OmLおよび 10%パラジウム 炭素（50%Wet) 3.0gを加え、水素加圧下（5kg/cm2)、 75 °Cで 5時間撹拌した。反応液を冷却後、不溶物をろ去し、残渣を水 30mLで洗浄した。 ろ液と洗液を合わせ、水酸ィ匕ナトリウム 9.6gの水 30mL溶液および塩ィ匕ナトリウム 9.0g を加えた。 45°Cで有機層を分取し、減圧下で溶媒を留去した。得られた残留物を 2— プロパノール 210mLに溶解した後、不溶物をろ去し、残渣を 2 プロパノール 30mLで 洗浄した。ろ液と洗液を合わせ、 p—トルエンスルホン酸 1水和物 41.6gを加えた。固 形物をろ取し、白色固体の 3—（4一（3 ヒドロキシプロピル） 1ーピベリジ-ル） 1 プロパノール p トルエンスルホン酸塩 62.4gを得た。 (0061) (2) 30 g of 3- (4-pyridyl) propane 1 ol and 21.7 g of 3 chloro-1 propanol were dissolved in 180 mL of toluene and stirred for 9 hours under reflux. After cooling the reaction mixture, 3 OmL of water and 3.0 g of 10% palladium on carbon (50% Wet) were added, and the mixture was stirred at 75 ° C for 5 hours under hydrogen pressure (5 kg / cm 2 ). After cooling the reaction solution, the insoluble material was removed by filtration, and the residue was washed with 30 mL of water. The filtrate and washings were combined, and 9.6 g of sodium hydroxide solution in 30 mL of water and 9.0 g of sodium chloride salt were added. The organic layer was separated at 45 ° C, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 210 mL of 2-propanol, insolubles were removed by filtration, and the residue was washed with 30 mL of 2-propanol. The filtrate and washings were combined and 41.6 g of p-toluenesulfonic acid monohydrate was added. The solid was collected by filtration to obtain 62.4 g of 3- (4- (3-hydroxypropyl) 1-piveridyl) 1 propanol p toluenesulfonate as a white solid.
D 0中における1 H-NMRは、実施例 6 (1)の値と一致した。 1 H-NMR in D 0 agreed with the value of Example 6 (1).
2  2
[0062] 実施例 7
Figure imgf000019_0001
[0062] Example 7
Figure imgf000019_0001
3 （ピペリジン 4 ィル）プロパン 1ーォール 65.0gを酢酸ェチル 325mLに懸濁 し、 1ーブロモー 3 クロ口プロパン 143gおよび炭酸カリウム 125gを加え、 50°Cで 3時 間撹拌した。反応液を冷却後、水 325mLおよび塩酸 160mLを加えた。水層を分取し、 20%水酸化ナトリウム水溶液 75mLおよびトルエン 325mLをカ卩えた。有機層を分取し、 水 160mLで 2回洗浄した。分取した有機層 374gのうち、 185gにトリエチルァミン 33.8g およびメタンスルホユルクロリド 33.2gをカ卩え、室温で 1時間撹拌した。反応液に水 160 mLおよび 20%水酸化ナトリウム水溶液 25mLをカ卩えた。分取した有機層 208gのうち、 3 2.5gに Ν,Ν ジメチルァセトアミド 25mL、 4 シァノフエノール 8.31g、炭酸カリウム 10. 6gおよびヨウ化カリウム 0.58gを加え、 100°Cで 5時間撹拌した。反応液を冷却後、水 10 OmLを加え、固形物をろ取し、淡黄色固体の 4一（3—（4一（3—（4一シァノフエノキ シ）プロピル） - 1 ピベリジ-ル）プロポキシ）ベンゾ-トリル 8.70gを得た。  65.0 g of 3 (piperidine 4-yl) propane was suspended in 325 mL of ethyl acetate, 143 g of 1-bromo-3-chloropropane and 125 g of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling the reaction solution, 325 mL of water and 160 mL of hydrochloric acid were added. The aqueous layer was separated and 75 mL of 20% aqueous sodium hydroxide and 325 mL of toluene were collected. The organic layer was separated and washed twice with 160 mL of water. Of 374 g of the separated organic layer, 33.8 g of triethylamine and 33.2 g of methanesulfuryl chloride were added to 185 g and stirred at room temperature for 1 hour. In the reaction solution, 160 mL of water and 25 mL of 20% aqueous sodium hydroxide were added. Of 208 g of the separated organic layer, 32.5 g were added with 25 mL of dimethylacetamide, 8.31 g of 4 cyanophenol, 10.6 g of potassium carbonate and 0.58 g of potassium iodide, and stirred at 100 ° C. for 5 hours. After cooling the reaction solution, add 10 OmL of water, filter the solid, and extract a light yellow solid. 4- (3- (4-1 (3- (4-Cyanofenoxy) propyl) -1piveridyl) propoxy) 8.70 g of benzo-tolyl was obtained.
1H-NMR(CDC1 ) δ値： 1.20- 1.45(5H,m),1.65- 2.05(8H,m),2.48(2H,t,J=7.3Hz),2.88- 2  1H-NMR (CDC1) δ value: 1.20-1.45 (5H, m), 1.65-2.05 (8H, m), 2.48 (2H, t, J = 7.3Hz), 2.88-2
3  Three
.98(2H,m),3.99(2H,t,J=6.5Hz),4.06(2H,t,J=6.3Hz),6.89-6.97(4H,m),7.53-7.60(4H,m ) .98 (2H, m), 3.99 (2H, t, J = 6.5Hz), 4.06 (2H, t, J = 6.3Hz), 6.89-6.97 (4H, m), 7.53-7.60 (4H, m )
[0063] 実施例 8
Figure imgf000020_0001
[0063] Example 8
Figure imgf000020_0001
3 （ピペリジン 4 ィル）プロパン 1ーォール 65.0gを酢酸ェチル 325mLに懸濁 し、 1ーブロモー 3 クロ口プロパン 143gおよび炭酸カリウム 125gを加え、 50°Cで 3時 間撹拌した。反応液を冷却後、水 325mLおよび塩酸 160mLを加えた。水層を分取し、 20%水酸化ナトリウム水溶液 75mLおよびトルエン 325mLをカ卩えた。有機層を分取し、 水 160mLで 2回洗浄した。分取した有機層 374gのうち、 185gにトリエチルァミン 33.8g および p トルエンスルホユルクロリド 55.3gをカ卩え、 60°Cで 4時間撹拌した。反応液を 冷却後、水 160mLおよび 20%水酸ィ匕ナトリウム水溶液 25mLを加えた。分取した有機 層 215gのうち、 33.6gに Ν,Ν ジメチルァセトアミド 25mL、 4—シァノフエノール 8.31g、 炭酸カリウム 10.6gおよびヨウ化カリウム 0.58gをカ卩え、 100°Cで 5時間撹拌した。反応液 を冷却後、水 lOOmLをカ卩え、固形物をろ取し、淡黄色固体の 4— (3- (4— (3— (4— シァノフエノキシ）プロピル） - 1 ピベリジ-ル）プロポキシ）ベンゾ-トリル 7.09gを得 た。  65.0 g of 3 (piperidine 4-yl) propane was suspended in 325 mL of ethyl acetate, 143 g of 1-bromo-3-chloropropane and 125 g of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling the reaction solution, 325 mL of water and 160 mL of hydrochloric acid were added. The aqueous layer was separated and 75 mL of 20% aqueous sodium hydroxide and 325 mL of toluene were collected. The organic layer was separated and washed twice with 160 mL of water. From 374 g of the separated organic layer, 33.8 g of triethylamine and 55.3 g of p-toluenesulfuryl chloride were added to 185 g and stirred at 60 ° C. for 4 hours. After cooling the reaction solution, 160 mL of water and 25 mL of 20% aqueous sodium hydroxide solution were added. Of 215 g of the collected organic layer, 33.6 g was charged with 25 mL of Ν, ト dimethylacetamide, 8.31 g of 4-cyanophenol, 10.6 g of potassium carbonate and 0.58 g of potassium iodide, and stirred at 100 ° C for 5 hours. . After cooling the reaction solution, add lOOmL of water, filter the solid, and extract a light yellow solid 4— (3- (4— (3— (4—Cyanofenoxy) propyl) -1 piveridyl) propoxy) 7.09 g of benzo-tolyl was obtained.
CDC1中における1 H-NMRは、実施例 7の値と一致した。 1 H-NMR in CDC1 agreed with the value of Example 7.
3  Three
[0064] 実施例 9
Figure imgf000020_0002
[0064] Example 9
Figure imgf000020_0002
1 , 4 ビス（3 クロ口プロピル）ピぺリジン塩酸塩 4.00gおよび 4 シァノフエノール 3 .48gを Ν,Ν ジメチルァセトアミド 24mLに溶解し、炭酸カリウム 6.05gおよびヨウ化カリ ゥム 0.24gを加え、 100°Cで 2時間撹拌した。反応液を冷却後、炭酸カリウム l.Olgをカロ え、 100°Cで 1時間撹拌した。反応液を冷却後、水 50mLを加え、固形物をろ取し、淡 褐色固体の 4一（3—（4一（3—（4 シァノフヱノキシ）プロピル） 1ーピベリジ-ル） プロポキシ）ベンゾ-トリル 5.18gを得た。  Dissolve 4.00 g of 1,4 bis (3 cyclopropyl) piperidine hydrochloride and 3.48 g of 4 cyanophanol in 24 mL of Ν, Ν dimethylacetamide, and add 6.05 g of potassium carbonate and 0.24 g of potassium iodide. The mixture was stirred at 100 ° C for 2 hours. After cooling the reaction solution, potassium carbonate l.Olg was added and stirred at 100 ° C for 1 hour. After cooling the reaction mixture, add 50 mL of water, filter the solid, and remove a light brown solid of 4- (3- (4-((3- (4 cyanophenoxy) propyl) 1-piveridyl) propoxy) benzo-tolyl 5.18 g was obtained.
CDC1中における1 H-NMRは、実施例 7の値と一致した。 1 H-NMR in CDC1 agreed with the value of Example 7.
3  Three
[0065] 実施例 10
Figure imgf000021_0001
[0065] Example 10
Figure imgf000021_0001
(1) 3- (4- (3 ヒドロキシプロピル）一 1—ピベリジ-ル）一 1—プロパノール p— トルエンスルホン酸塩 8.00gをジメチルスルホキシド 40mLに溶解し、カリウム tert ブト キシド 7.5gをカ卩えた後、 50〜57°Cで 40分間撹拌した。反応液を冷却後、 23〜26°Cで 4 フルォ口べンゾ-トリル 5.4gのジメチルスルホキシド 8mL溶液を滴下し、同温度で 2 時間撹拌した。反応液を冷却後、酢酸 0.6mLを加え、 90〜94°Cで水 48mLを滴下した 後、 20°Cまで冷却した。ついで、同温度で炭酸カリウム 1.5gの水 8mL溶液を加え、固 形物をろ取し、淡黄色固体の 4一（3—（4一（3—（4ーシァノフエノキシ)プロピル）一 1 ピベリジ-ル）プロポキシ）ベンゾ-トリル 7.26gを得た。  (1) 3- (4- (3 Hydroxypropyl) 1-piberidyl) 1-propanol p-Toluenesulfonate 8.00g was dissolved in dimethyl sulfoxide 40mL, and potassium tert-butoxide 7.5g was prepared. Thereafter, the mixture was stirred at 50 to 57 ° C for 40 minutes. After cooling the reaction solution, a solution of 5.4 g of 4-fluorobenzoic tolyl in dimethyl sulfoxide at 23 to 26 ° C was added dropwise and stirred at the same temperature for 2 hours. After cooling the reaction solution, 0.6 mL of acetic acid was added, 48 mL of water was added dropwise at 90 to 94 ° C, and then cooled to 20 ° C. Next, 8 mL of water of 1.5 g of potassium carbonate was added at the same temperature, and the solid product was collected by filtration to obtain a light yellow solid of 4- (3- (4- (4-Cyanofenoxy) propyl) 1 Piberidyl) propoxy) benzo-tolyl 7.26 g was obtained.
CDC1中における1 H-NMRは、実施例 7の値と一致した。 1 H-NMR in CDC1 agreed with the value of Example 7.
3  Three
[0066] (2) カリウム tert ブトキシド 326gをトルエン 1.75Lおよびジメチルスルホキシド 700m Lに懸濁し、 3— (4— (3 ヒドロキシプロピル）一 1—ピベリジ-ル）一 1—プロパノー ル p トルエンスルホン酸塩 350gをカ卩えた後、 50〜60°Cで 30分間撹拌した。反応液 を冷却後、 0〜15°Cで 4 フルォ口べンゾ-トリル 238gのトルエン 350mL溶液を滴下し 、 25°Cまで昇温後、同温度で 1時間撹拌した。反応液に酢酸 28.1gの水溶液 175mLお よび水 875mLをカ卩えた。還流下で 30分間撹拌した後、 20°Cまで冷却した。ついで、同 温度で炭酸カリウム 64.8gの水 350mL溶液をカ卩え、固形物をろ取し、淡黄色固体の 4 一（3— (4— (3—（4 シァノフヱノキシ）プロピル） 1ーピベリジ-ル）プロポキシ） ベンゾニトリル 328gを得た。  [0066] (2) Suspension of 326 g of potassium tert butoxide in 1.75 L of toluene and 700 mL of dimethyl sulfoxide, and 3— (4- (3 hydroxypropyl) -1-1-piberidyl) -1-1-propanol p-toluenesulfonate After 350 g was collected, the mixture was stirred at 50-60 ° C for 30 minutes. After cooling the reaction solution, a solution of 238 g of 4-fluorobenzoyl tolyl in 350 mL of toluene was added dropwise at 0 to 15 ° C., the temperature was raised to 25 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 175 mL of an aqueous solution of 28.1 g of acetic acid and 875 mL of water. The mixture was stirred for 30 minutes under reflux and then cooled to 20 ° C. Then, at the same temperature, add a solution of 64.8 g of potassium carbonate in 350 mL of water, filter the solid, and extract a light yellow solid 4 ((3— (4— (3— (4 Cyanofenoxy) propyl) 1-piveridyl) ) Propoxy) 328 g of benzonitrile were obtained.
CDC1中における1!" I- NMRは、実施例 10 (1)の値と一致した。 1 ! ”I-NMR in CDC1 was consistent with the value of Example 10 (1).
3  Three
[0067] 製造例 1  [0067] Production Example 1
Figure imgf000021_0002
Figure imgf000021_0002
4— (3— (4— (3— (4 シァノフエノキシ）プロピル）一 1—ピベリジ-ル）プロポキシ )ベンゾニトリル 1.15gのエタノール 20mL懸濁液に、氷冷下、塩化水素を導入した後、 室温で 24時間攪拌した。減圧下で溶媒を留去し、得られた残留物をエタノール 20mL に溶解した。ついで、酢酸アンモ-ゥム 1.54gを加え、 3時間 45分間加熱還流した。反 応混合物を室温まで冷却し、水を加えた後、減圧下でエタノールを留去した。得られ た残留物にクロ口ホルムをカ卩え、 5.0mol/L水酸化ナトリウム水溶液をカ卩え、 pH12.5に 調整した。固形物をろ取し、白色固体の 4— (3— (4— (3— (4— (ァミノ (ィミノ)メチ ル）フエノキシ）プロピル） 1ーピベリジ-ル）プロポキシ）ベンズアミジン 1.13gを得た 4- (3— (4 -— (3- (4 Cyanophenoxy) propyl) -1-1-piberidyl) propoxy) benzonitrile 1.15 g of ethanol in 20 mL suspension of hydrogen chloride under ice-cooling, then at room temperature For 24 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with 20 mL of ethanol. Dissolved in. Next, 1.54 g of ammonium acetate was added, and the mixture was refluxed for 3 hours and 45 minutes. The reaction mixture was cooled to room temperature, water was added, and ethanol was distilled off under reduced pressure. The resulting residue was filled with black mouth form, 5.0 mol / L aqueous sodium hydroxide solution was added, and the pH was adjusted to 12.5. The solid was collected by filtration to obtain 1.13 g of 4- (3— (4— (3— (4— (Amino (imino) methyl) phenoxy) propyl) 1-piveridyl) propoxy) benzamidine.
'H-NMRCDMSO-d ) δ値： 1.00— 1.40(5H,m),1.60— 1.80(4H,m),1.80— 1.95(4H,m),2.35— 'H-NMRCDMSO-d) δ: 1.00— 1.40 (5H, m), 1.60— 1.80 (4H, m), 1.80— 1.95 (4H, m), 2.35—
6  6
2.45(2H,m),2.80-2.90(2H,m),3.98(2H,t,J=6.5Hz),4.03(2H,t,J=6.3Hz),6.30-7.20(4H, broad),6.85-7.00(4H,m),7.65-7.80(4H,m)  2.45 (2H, m), 2.80-2.90 (2H, m), 3.98 (2H, t, J = 6.5Hz), 4.03 (2H, t, J = 6.3Hz), 6.30-7.20 (4H, broad), 6.85 -7.00 (4H, m), 7.65-7.80 (4H, m)
産業上の利用可能性 Industrial applicability
本発明の 4一（3—（4一（3—（4ーシァノフエノキシ）プロピル） 1ーピベリジ-ル） プロボキシ）ベンゾニトリルの製造法は、（1)工程数が少なぐかつ、収率が高い（2) 有害性ある試薬および溶媒を使用しない、（3)反応操作が簡便である、（4)原材料 が安価である、などの特徴を有するため工業的な製造法として有用である。  According to the present invention, the production method of 4- (3- (4-1 (3- (4-cyanophenoxy) propyl) 1-piveridyl) propoxy) benzonitrile is (1) less in number of steps and yield. (2) No harmful reagents and solvents are used, (3) The reaction procedure is simple, and (4) The raw materials are inexpensive.

Claims

請求の範囲 [1] 一般式 Claim [1] General formula
[化 1]
Figure imgf000023_0001
[Chemical 1]
Figure imgf000023_0001
「式中、 Υ1および Υ2は、同一または異なって、ヒドロキシル基、ハロゲン原子、アル力 ンスルホ-ルォキシ基またはァリールスルホ-ルォキシ基を示す。」で表されるピペリ ジン誘導体またはその塩。 [Wherein, Υ 1 and Υ 2 are the same or different and each represents a hydroxyl group, a halogen atom, an alkane sulfo-oxy group or an aryl sulfo-oxy group] or a salt thereof.
[2] Υ1および Υ2が同一で、ヒドロキシル基またはハロゲン原子である請求項 1記載のピぺ リジン誘導体またはその塩。 [2] Upsilon 1 and Upsilon 2 are identical, piperidine derivative or a salt thereof according to claim 1, wherein a hydroxyl group or a halogen atom.
[3] Υ1および Υ2が、ヒドロキシル基である請求項 1〜2記載のピぺリジン誘導体またはそ の塩。 [3] Upsilon 1 and Upsilon 2 is piperidine derivative or its salt according to claim 1 or 2 wherein the hydroxyl group.
[4] 式 [4] Expression
[化 2]
Figure imgf000023_0002
[Chemical 2]
Figure imgf000023_0002
で表される化合物またはその塩を塩基の存在下、一般式  Or a salt thereof in the presence of a base in the general formula
[化 3]
Figure imgf000023_0003
[Chemical 3]
Figure imgf000023_0003
「式中、 Xは、ハロゲン原子を示す。」で表されるベンゾニトリル誘導体と反応させるこ とを特徴とする 4 (3- (4- (3- (4ーシァノフエノキシ）プロピル） 1ーピベリジ- ル)プロボキシ）ベンゾニトリルまたはその塩の製造法。  4 (3- (4- (3- (4-Cyanofenoxy) propyl) 1 characterized by reacting with a benzonitrile derivative represented by “wherein X represents a halogen atom”. -Piveridyl) Proboxy) Benzonitrile or a salt thereof.
[5] 一般式 [5] General formula
[化 4]
Figure imgf000023_0004
[Chemical 4]
Figure imgf000023_0004
「式中、 Ylaおよび Y2aは、同一または異なって、ハロゲン原子、アルカンスルホ -ルォ キシ基またはァリールスルホ-ルォキシ基を示す。」で表されるピぺリジン誘導体また はその塩を塩基の存在下、触媒の存在下または不存在下、 4ーヒドロキシベンゾニト リルと反応させることを特徴とする 4 (3- (4- (3- (4ーシァノフエノキシ)プロピル) 1ーピベリジ-ル)プロボキシ)ベンゾ-トリルまたはその塩の製造法。 "In the formula, Y la and Y 2a are the same or different and each represents a halogen atom, an alkanesulfo A xyl group or an arylsulfuroxy group; 4 (3- (4- (4)), which is reacted with 4-hydroxybenzonitryl in the presence of a base and in the presence or absence of a catalyst. 3- (4-Cyanofenoxy) propyl) 1-piveridyl) propoxy) benzo-tolyl or a salt thereof.
X力 フッ素原子である請求項 4記載の 4一（3—（4一（3—（4ーシァノフエノキシ)プ 口ピル） - 1—ピベリジ-ル）プロポキシ）ベンゾ-トリルまたはその塩の製造法。 The X force is a fluorine atom. 4 (3— (4— (3— (4-Cyanofenoxy) propyl) -1—piveridyl) propoxy) benzo-tolyl or a salt thereof according to claim 4 Manufacturing method.
PCT/JP2006/322166 2005-11-09 2006-11-07 Method for producing 4-(3-(4-(3-(4-cyanophenoxy)propyl)- 1-piperidinyl)propoxy)benzonitrile and intermediate thereof WO2007055197A1 (en)

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US8173157B2 (en) 2006-10-06 2012-05-08 Toyama Chemical Co., Ltd. Pharmaceutical composition comprising phenylamidine derivative and method of using the pharmaceutical composition in combination with antifungal agent

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WO2003074476A1 (en) * 2002-03-06 2003-09-12 Toyama Chemical Co., Ltd. Novel arylamidine derivative or salt thereof

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Publication number Priority date Publication date Assignee Title
WO2003074476A1 (en) * 2002-03-06 2003-09-12 Toyama Chemical Co., Ltd. Novel arylamidine derivative or salt thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8173157B2 (en) 2006-10-06 2012-05-08 Toyama Chemical Co., Ltd. Pharmaceutical composition comprising phenylamidine derivative and method of using the pharmaceutical composition in combination with antifungal agent

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