WO2014133116A1 - Method for producing 4-halosenecioic acid derivative - Google Patents

Method for producing 4-halosenecioic acid derivative Download PDF

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WO2014133116A1
WO2014133116A1 PCT/JP2014/054994 JP2014054994W WO2014133116A1 WO 2014133116 A1 WO2014133116 A1 WO 2014133116A1 JP 2014054994 W JP2014054994 W JP 2014054994W WO 2014133116 A1 WO2014133116 A1 WO 2014133116A1
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production method
halide
phosphite
general formula
bromine
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PCT/JP2014/054994
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French (fr)
Japanese (ja)
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井上　宗宣
宏史 荒木
竜治 高田
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公益財団法人相模中央化学研究所
マナック株式会社
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Priority to KR1020157026267A priority Critical patent/KR20150121159A/en
Priority to JP2015503039A priority patent/JPWO2014133116A1/en
Priority to CN201480011040.4A priority patent/CN105102417A/en
Publication of WO2014133116A1 publication Critical patent/WO2014133116A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
    • 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 method for producing a 4-haußecioic acid derivative useful as an intermediate for producing medical and agricultural chemicals.
  • 4-Halocenecioic acid derivatives can be converted into Wittig-Horner reagents by reaction with triethyl phosphite, and thus are useful as intermediates for medicines and agrochemicals (see, for example, Patent Document 1, Patent Document 2, and Non-Patent Document 1).
  • Non-Patent Document 1 As a method for producing a 4-havantecioic acid derivative, a method for producing it by a halogenation reaction of 3-methylcrotonic acid ester is disclosed (for example, see Non-Patent Document 1). According to this method, since a polyhalogenated product is obtained as a by-product, it is difficult to say that it is an efficient method. Further, although a method for producing a 4-havantecioic acid derivative using ethyl diethylphosphonoacetate and ⁇ -haloacetone as production raw materials has been disclosed (see, for example, Non-Patent Document 2), Is hard to say.
  • An object of the present invention is to provide a method for producing a 4-havantecioic acid derivative with high selectivity and high yield using an inexpensive raw material.
  • the present invention relates to the general formula (1): (Wherein R represents a protecting group), an allyl alcohol derivative represented by the general formula (2): (Wherein R represents the same meaning as described above, and X represents a halogen atom).
  • the present invention provides a general formula (1): (Wherein R represents a protecting group), and an allyl alcohol derivative represented by the following general formula (3): (Wherein R represents the same meaning as described above, and X represents a halogen atom).
  • the present invention relates to a general formula (3): (Wherein R represents a protecting group and X represents a halogen atom), an allyl halide derivative represented by the general formula (2) is reacted with a halide at a temperature of more than 10 ° C. : (Wherein R and X represent the same meaning as described above).
  • the 4-haouslyecioic acid derivative (2) useful as an intermediate for the production of medical and agricultural chemicals can be produced with high selectivity and high yield.
  • the method of the present invention is excellent in industrial and economic aspects without using expensive raw materials and having high selectivity and yield.
  • the “protecting group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis generally used in organic synthetic chemistry.
  • the term “protecting group” relating to R of the present invention means a protecting group for a carboxyl group, which is not cleaved under the reaction conditions of the production method of the present invention and can be cleaved by other chemical methods. .
  • Such protecting groups are well known to those skilled in the art from reference books in synthetic organic chemistry such as “Protective Groups Organic Synthesis” (T. W. Greene et.al, John Wiley & Sons, inc.).
  • R is an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 19 carbon atoms.
  • the “alkyl group having 1 to 6 carbon atoms” is a monovalent group of a straight or branched aliphatic saturated hydrocarbon having 1 to 6 carbon atoms, alone or in combination with other terms.
  • methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be exemplified.
  • Alkoxy group having 1 to 6 carbon atoms means a group R′O— (where R ′ is an alkyl group having 1 to 6 carbon atoms), and represents a methoxy group, an ethoxy group, a propyloxy group. And isopropyloxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group, hexyloxy group and the like.
  • aryl or “aryl having 6 to 18 carbon atoms” means a monovalent group of aromatic hydrocarbon having 6 to 18 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, and an anthryl group. Can do.
  • an embodiment in which the monovalent group of the aromatic hydrocarbon is substituted with an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, or the like is also included.
  • Examples thereof include 2-methylphenyl group (o-tolyl group), 3-methylphenyl group (m-tolyl group), 4-methylphenyl group (p-tolyl group), 2,4-di-t-t- Examples thereof include a butylphenyl group, a 4-methoxyphenyl group, and a 4-chlorophenyl group.
  • the “aralkyl group having 7 to 19 carbon atoms” means an arylalkyl group having 7 to 19 carbon atoms (wherein the aryl moiety is an aryl having 6 to 18 carbon atoms, and the alkyl moiety has 1 to 6), and exemplifies benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-anthrylmethyl, 2-anthrylmethyl, 9-anthrylmethyl, etc. Can do.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the method for producing the 4-haußecioic acid derivative (2) of the present invention is as shown in the following scheme.
  • Step 1 is a step in which the allyl alcohol derivative (1) is reacted with a halogenating agent to produce a 4-haußecioic acid derivative (2).
  • the allyl alcohol derivative (1) which is a starting material for the production method of the present invention can be synthesized according to a known method (for example, JP-A-60-179147).
  • a halogenating agent selected from a fluorinating agent, a chlorinating agent, a brominating agent and an iodinating agent is used according to the target 4-havantecioic acid derivative (2).
  • the halogenating agent is known to those skilled in the art, and the reagents described in literatures and reference books (for example, ComprehensivereOrganic Transformations; Wiley-VCH; p689-697 (1999)) can be used. Such reagents are commercially available or can be prepared from commercially available reagents.
  • Nitrogen-containing fluorine such as N, N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, (2-chloro-1,1,2-trifluoroethyl) diethylamine, etc.
  • Oxidizing agents such as triphenylphosphine difluoride and diphenylphosphine trifluoride
  • sulfur-containing fluorinating agents such as diethylaminosulfur trifluoride and bis (2-methoxyethyl) aminosulfur trifluoride
  • hydrogen fluoride And a pyridinium hydrogen fluoride salt a pyridinium hydrogen fluoride salt.
  • Nitrogenous chlorinating agents such as (1-chloro-2-methyl-1-propenyl) dimethylamine as chlorinating agents; chlorine / triarylphosphine, N-chlorosuccinimide / triarylphosphine, 1,3-dichloro-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetrachloride / triarylphosphine, chlorine / triarylphosphite, N-chlorosuccinimide / triarylphosphite, 1,3-dichloro-5,5-dimethylhydantoin / Phosphorus chlorinating agents such as triaryl phosphite, carbon tetrachloride / triaryl phosphite, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride; N-chlorosuccinimide / dimethyl sulfide, p
  • Nitrogen-containing brominating agents such as (1-bromo-2-methyl-1-propenyl) dimethylamine as brominating agents; bromine / triarylphosphine, N-bromosuccinimide / triarylphosphine, 1,3-dibromo-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetrabromide / triarylphosphine, bromine / triarylphosphite, N-bromosuccinimide / triarylphosphite, 1,3-dibromo-5,5-dimethyl Phosphorus-containing brominating agents such as hydantoin / triaryl phosphite, carbon tetrabromide / triaryl phosphite, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide; N-bromosuccinimide / dimethyl sulfide, Sul
  • Nitrogen-containing iodinating agents such as (1-iodo-2-methyl-1-propenyl) dimethylamine as iodinating agents; iodine / triarylphosphine, N-iodosuccinimide / triarylphosphine, 1,3-diiodo-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetraiodide / triarylphosphine, iodine / triaryl phosphite, N-iodosuccinimide / triaryl phosphite, 1,3-diiodo-5,5-dimethyl Phosphorus iodinating agents such as hydantoin / triaryl phosphite, carbon tetraiodide / triaryl phosphite; N-iodosuccinimide / dimethyl sulfide, sulfur
  • triarylphosphine examples include triphenylphosphine, tri (p-tolyl) phosphine, tris (4-methoxyphenyl) phosphine, and tris (4-chlorophenyl) phosphine. it can. Triphenylphosphine is preferably used from the viewpoint of good yield.
  • Examples of the triaryl phosphite that can be used in the halogenating agent include triphenyl phosphite, tri (p-tolyl) phosphite, and tri (2,4-di-t-phosphite). Butylphenyl) and the like. From the viewpoint of good yield, it is preferable to use triphenyl phosphite and tri (p-tolyl) phosphite.
  • Chlorine / triarylphosphine, bromine / triarylphosphine and iodine / triarylphosphine may be commercially available, but are formed in situ from triarylphosphine and chlorine, bromine or iodine, That is, what was prepared in the reaction container may be used as it is.
  • commercially available chlorine / triaryl phosphites, bromine / triaryl phosphites and iodine / triaryl phosphites may be used, but triaryl phosphites and chlorine, bromine Or what was formed in-situ from iodine, ie, what was prepared in the reaction container, may be used as it is.
  • halogenating agent examples include a nitrogen-containing halogenating agent (that is, a nitrogen-containing fluorinating agent, a nitrogen-containing chlorinating agent, a nitrogen-containing brominating agent, a nitrogen-containing iodinating agent), and a phosphorus-containing halogenating agent (that is, phosphorus-containing fluorine-containing agent).
  • a nitrogen-containing halogenating agent that is, a nitrogen-containing fluorinating agent, a nitrogen-containing chlorinating agent, a nitrogen-containing brominating agent, a nitrogen-containing iodinating agent
  • phosphorus-containing halogenating agent that is, phosphorus-containing fluorine-containing agent
  • phosphorus-containing chlorinating agent phosphorus-containing brominating agent, phosphorus-containing iodinating agent
  • sulfur-containing halogenating agent that is, sulfur-containing fluorinating agent, sulfur-containing chlorinating agent, sulfur-containing brominating agent, sulfur-containing
  • brominating agents bromine / triarylphosphine, N-bromosuccinimide / triarylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triarylphosphine, bromine / triarylphosphite, N -Selected from the group consisting of bromosuccinimide / triaryl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triaryl phosphite, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide It is preferable to use at least one phosphorus-containing brominating agent.
  • brominating agents include bromine / triphenylphosphine, N-bromosuccinimide / triphenylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triphenylphosphine, bromine / triphenylphosphite, N -Bromosuccinimide / triphenyl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triphenyl phosphite, bromine / triphosphite (p-tolyl), N-bromosuccinimide / phosphorous It is more preferable to use tri (p-tolyl) acid, 1,3-dibromo-5,5-dimethylhydantoin / tri (p-tolyl) phosphite.
  • the molar ratio of the allyl alcohol derivative (1) to the halogenating agent is preferably 1: 1 to 1: 5. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.
  • the reaction can be carried out in the presence of a base in order to improve the yield.
  • Bases that can be used include metal hydrides such as sodium hydride, potassium hydride and calcium hydride; aromatic amines such as imidazole, pyridine, 2,6-lutidine and s-collidine; N-methylpyrrolidine, N A cyclic amine such as methylpiperidine; an aliphatic amine such as tri (C 1 -C 4 alkyl) amine including ethyldiisopropylamine, triethylamine and tributylamine; an inorganic salt such as sodium hydroxide, potassium hydroxide and potassium carbonate; It can be illustrated. From the viewpoint of good yield, it is preferable to use an aromatic amine or an aliphatic amine, and it is more preferable to use pyridine or tri (C 1 -C 4 alkyl) amine.
  • the amount of base used is preferably about 1 to 5 moles per mole of allyl alcohol derivative (1).
  • a halide of the same halogen species as the halogenating agent to be used may be added to improve the yield.
  • the halide is not particularly limited as long as it can supply halide ions, but an aqueous solution of hydrogen halide such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; lithium, Halogens of alkali metals or alkaline earth metals such as sodium, potassium, magnesium, calcium; halides of transition metals such as zinc and copper; amines such as aliphatic amines and aromatic amines or hydrohalides of ammonia; Examples thereof include halides of quaternary ammonium: NR ′′ 4 + (wherein R ′′ independently represents an alkyl group or aryl group having 1 to 6 carbon atoms).
  • examples of the halide include lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, and tetrabutylammonium fluoride.
  • examples of the halide include lithium chloride, sodium chloride, potassium chloride, ammonium chloride, and tetrabutylammonium chloride.
  • examples of the halide include lithium bromide, sodium bromide, potassium bromide, ammonium bromide, tetrabutylammonium bromide and the like.
  • examples of the halide include lithium iodide, sodium iodide, potassium iodide, lithium iodide, ammonium iodide, and tetrabutylammonium iodide.
  • Alkali metal halides or quaternary ammonium halides are preferred, and lithium, sodium, potassium or tetra (C 1 -C 4 alkyl) ammonium halides are more preferred.
  • the amount of halide used is preferably about 0.01 to 5 moles per mole of allyl alcohol derivative (1).
  • any solvent that does not inhibit the reaction may be used.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether; hydrocarbon solvents such as hexane, pentane, cyclohexane; Aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene; halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene; N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1, Examples thereof include amide solvents such as 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfate, 1,2-dimethoxyethane,
  • the reaction temperature is not particularly limited, but it can usually be carried out at a temperature appropriately selected from the range of ⁇ 78 ° C. to 180 ° C. From the viewpoint of reaction rate, a range of more than 10 ° C to 130 ° C is preferable, and a range of room temperature (about 20 ° C) to 100 ° C is more preferable.
  • the method for isolating the target product from the solution after the reaction is not particularly limited.
  • the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.
  • Step 2 is a step of producing the allyl halide derivative (3) by reacting the allyl alcohol derivative (1) with a halogenating agent at a temperature of 10 ° C. or lower.
  • Reaction conditions such as a halogenating agent, a base, a solvent, and preferred embodiments thereof are the same as in Step 1, except that temperature conditions and a halide are not added.
  • the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography or the like.
  • Step 3 is a step in which the allyl halide derivative (3) is reacted with a halide at a temperature higher than 10 ° C. to produce the 4-havantecioic acid derivative (2).
  • the halide that can be used is in accordance with the halide listed in Step 1.
  • the amount of halide used is preferably about 0.01 to 5 moles per mole of allyl halide derivative (3).
  • the reaction solvent that can be used is the same as the solvent listed in Step 1, but an amide solvent such as N, N-dimethylformamide, N-methyl-2-pyrrolidone is preferably used.
  • the reaction temperature can be carried out at a temperature appropriately selected from the range of more than 10 ° C. to 180 ° C. A range from room temperature (about 20 ° C.) to 100 ° C. is more preferable.
  • GC gas chromatograph
  • AVANCE 400 (Bruker) A solution in which the compound was mixed with deuterated chloroform (Cambrige Isotope Laboratories, Inc., containing 0.05% TMS) was prepared, and 1 H-NMR measurement was performed.
  • Example 1 Production of ethyl 4-bromosenecioate In 10 mL of chlorobenzene, 2.8 g (9 mmol) of triphenyl phosphite was added and cooled to 5 ° C or lower, and 1.4 g (9 mmol) of bromine was added dropwise. After the reaction for 30 minutes, a mixed solution of ethyl 2-hydroxy-3-methyl-3-butenoate 1 g (7 mmol), triethylamine 0.9 g (9 mmol) and chlorobenzene 2 mL was added dropwise. After completion of the dropwise addition, the reaction was carried out at 80 ° C. for 1 hour, and the reaction rate was confirmed by GC.
  • the desired ethyl 4-bromosenecioate was 94% (mixture of E form + Z form).
  • 20 mL of water was added to the reaction solution, and the organic layer was separated and purified by silica gel column chromatography (ethyl acetate / hexane; 1/2) to obtain 86% of ethyl 4-bromosenecioate (E-form + Z-form). Mixture).
  • Example 2-12 The reactions of Examples 2 to 12 were carried out in the same manner as in Example 1. In Examples 11 to 12, 1.3 equivalents of each halide was used with respect to ethyl 2-hydroxy-3-methyl-3-butenoate. Table 1 shows the brominating agent, base, halide, reaction temperature, reaction time, and production rate (%) of the target product used in the examples.
  • Example 15 In 1 mL of DMF, 50 mg (0.2 mmol) of ethyl 2-bromo-3-methyl-3-butenoate and 155 mg (0.5 mmol) of TBAB were added and reacted at room temperature for 24 hours. When the reaction rate was confirmed by GC, the target ethyl 4-bromosenecioate was 95% (mixture of E-form and Z-form).
  • Example 16 and 17 The reactions of Examples 16 and 17 were carried out in the same manner as in Example 15. Table 2 shows the halide, solvent, reaction temperature, reaction time, and reaction rate (%) of the target product used in the examples.

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Abstract

The purpose of the present invention is to provide a method for producing a 4-halosenecioic acid derivative inexpensively and with a high yield. The method for producing a 4-halosenecioic acid derivative represented by general formula (2) (in the formula, R represents a protecting group and X denotes a halogen atom) is characterized by reacting an allyl alcohol derivative represented by general formula (1) (in the formula, R is synonymous with R in general formula (1)) with a halogenating agent.

Description

４－ハロセネシオ酸誘導体の製造方法Method for producing 4-halosenecioic acid derivative
　本発明は、医農薬の製造中間体として有用な４－ハロセネシオ酸誘導体の製造方法に関する。 The present invention relates to a method for producing a 4-halosenecioic acid derivative useful as an intermediate for producing medical and agricultural chemicals.
　４－ハロセネシオ酸誘導体は、亜リン酸トリエチルとの反応によりWittig-Horner試薬に変換できることから、医農薬中間体として有用である（例えば、特許文献１、特許文献２、非特許文献１参照）。 4-Halocenecioic acid derivatives can be converted into Wittig-Horner reagents by reaction with triethyl phosphite, and thus are useful as intermediates for medicines and agrochemicals (see, for example, Patent Document 1, Patent Document 2, and Non-Patent Document 1).
　４－ハロセネシオ酸誘導体の製造方法として、３－メチルクロトン酸エステルのハロゲン化反応で製造する方法が開示されている（例えば、非特許文献１参照）。この方法によると、ポリハロゲン化体が副生成物として得られることから、効率的な方法とは言い難い。また、ジエチルホスホノ酢酸エチルとα－ハロアセトンを製造原料として用いた４－ハロセネシオ酸誘導体の製造方法も開示されているが（例えば、非特許文献２参照）、収率が低く効率的な方法とは言い難い。一方、ハロゲン化剤を用いて第２級アリルアルコールを二重結合の転位を伴いながら第１級ハロゲン化アリルに変換する方法が報告されているが、一般に生成物として第１級ハロゲン化アリルとアリル転位を伴わずハロゲン化が起こった第２級ハロゲン化アリルとの混合物を与える（例えば、非特許文献３参照）。 As a method for producing a 4-halosenecioic acid derivative, a method for producing it by a halogenation reaction of 3-methylcrotonic acid ester is disclosed (for example, see Non-Patent Document 1). According to this method, since a polyhalogenated product is obtained as a by-product, it is difficult to say that it is an efficient method. Further, although a method for producing a 4-halosenecioic acid derivative using ethyl diethylphosphonoacetate and α-haloacetone as production raw materials has been disclosed (see, for example, Non-Patent Document 2), Is hard to say. On the other hand, a method for converting secondary allyl alcohol to primary allyl halide with a double bond rearrangement using a halogenating agent has been reported. A mixture with a secondary allyl halide in which halogenation has occurred without allylic rearrangement is provided (see, for example, Non-Patent Document 3).
　本発明のアリルアルコール誘導体を原料として用いてハロゲン化を行い、４－ハロセネシオ酸誘導体を得る製造方法はこれまでに報告されていない。 No production method has been reported so far in which a halogenation is performed using the allyl alcohol derivative of the present invention as a raw material to obtain a 4-halosenecioic acid derivative.
国際公開第２０１２／１４７８３１号International Publication No. 2012/147831 国際公開第９４／２４０８２号International Publication No. 94/24082
　従来の４－ハロセネシオ酸誘導体の製造方法は、副生成物が生じることから、総収率が悪く製造コストが高くなるという問題があった。本発明の課題は、安価な原料を用いて、高選択的かつ高収率に４－ハロセネシオ酸誘導体を製造する方法を提供することにある。 The conventional method for producing a 4-halosenecioic acid derivative has a problem in that since a by-product is generated, the total yield is poor and the production cost is increased. An object of the present invention is to provide a method for producing a 4-halosenecioic acid derivative with high selectivity and high yield using an inexpensive raw material.
　本発明者らは、前記課題を鑑み鋭意検討を重ねた結果、一般式（１）で示されるアリルアルコール誘導体から、高選択的かつ高収率に４－ハロセネシオ酸誘導体を製造できることを見出し、本発明を完成するに至った。 As a result of intensive studies in view of the above problems, the present inventors have found that 4-halosenecioic acid derivatives can be produced with high selectivity and high yield from allyl alcohol derivatives represented by the general formula (1). The invention has been completed.
　すなわち本発明は、一般式（１）：
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｒは、保護基を表す）で示されるアリルアルコール誘導体を、ハロゲン化剤と反応させることを特徴とする、一般式（２）：
Figure JPOXMLDOC01-appb-C000008
 （式中、Ｒは、前記と同じ意味を表し、Ｘは、ハロゲン原子を表す）で示される４－ハロセネシオ酸誘導体の製造方法に関する。 That is, the present invention relates to the general formula (1):
Figure JPOXMLDOC01-appb-C000007
 (Wherein R represents a protecting group), an allyl alcohol derivative represented by the general formula (2):
Figure JPOXMLDOC01-appb-C000008
 (Wherein R represents the same meaning as described above, and X represents a halogen atom).
　また、本発明は一般式（１）：
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒは、保護基を表す）で示されるアリルアルコール誘導体を、１０℃以下の温度でハロゲン化剤と反応させることを特徴とする、一般式（３）：
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｒは、前記と同じ意味を表し、Ｘは、ハロゲン原子を表す）で示されるアリルハライド誘導体の製造方法に関する。 In addition, the present invention provides a general formula (1):
Figure JPOXMLDOC01-appb-C000009
 (Wherein R represents a protecting group), and an allyl alcohol derivative represented by the following general formula (3):
Figure JPOXMLDOC01-appb-C000010
 (Wherein R represents the same meaning as described above, and X represents a halogen atom).
　さらに本発明は、一般式（３）：
Figure JPOXMLDOC01-appb-C000011
 （式中、Ｒは、保護基を表し、Ｘは、ハロゲン原子を表す）で示されるアリルハライド誘導体を、１０℃超の温度でハロゲン化物と反応させることを特徴とする、一般式（２）：
Figure JPOXMLDOC01-appb-C000012
 （式中、Ｒ及びＸは、前記と同じ意味を表す）で示される４－ハロセネシオ酸誘導体の製造方法に関する。 Furthermore, the present invention relates to a general formula (3):
Figure JPOXMLDOC01-appb-C000011
 (Wherein R represents a protecting group and X represents a halogen atom), an allyl halide derivative represented by the general formula (2) is reacted with a halide at a temperature of more than 10 ° C. :
Figure JPOXMLDOC01-appb-C000012
 (Wherein R and X represent the same meaning as described above).
　本発明により、アリルアルコール誘導体（１）をハロゲン化することで、医農薬の製造中間体として有用な４－ハロセネシオ酸誘導体（２）を高選択的かつ高収率に製造することができる。また本発明の方法は、高価な原料を用いることなく、また選択性や収率も高いことから、工業的及び経済的側面においても優れたものである。 According to the present invention, by halogenating the allyl alcohol derivative (1), the 4-halosenecioic acid derivative (2) useful as an intermediate for the production of medical and agricultural chemicals can be produced with high selectivity and high yield. In addition, the method of the present invention is excellent in industrial and economic aspects without using expensive raw materials and having high selectivity and yield.
　以下に、本発明を詳細に説明する。先ず、本明細書及び特許請求の範囲において用いられる用語について説明する。各用語は、他に断りのない限り、以下の意義を有する。 Hereinafter, the present invention will be described in detail. First, terms used in the present specification and claims will be described. Each term has the following significance unless otherwise specified.
　本発明において、「保護基」は、有機合成化学で一般的に用いられる、加水素分解、加水分解、電気分解、光分解のような化学的方法により開裂し得る保護基を意味する。特に本発明のＲに関する用語「保護基」は、カルボキシル基の保護基であって、本発明の製造方法の反応条件下で開裂せず、他の化学的方法により開裂し得る保護基を意味する。そのような保護基は、例えば「Protective Groups in Organic Synthesis」（T.W.Greene et.al, John Wiley & Sons, inc.）等の有機合成化学における参考書により当業者には公知である。典型的には、Ｒは、炭素数１～６のアルキル基又は炭素数７～１９のアラルキル基である。 In the present invention, the “protecting group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis generally used in organic synthetic chemistry. In particular, the term “protecting group” relating to R of the present invention means a protecting group for a carboxyl group, which is not cleaved under the reaction conditions of the production method of the present invention and can be cleaved by other chemical methods. . Such protecting groups are well known to those skilled in the art from reference books in synthetic organic chemistry such as “Protective Groups Organic Synthesis” (T. W. Greene et.al, John Wiley & Sons, inc.). Typically, R is an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 19 carbon atoms.
　本発明において「炭素数１～６のアルキル基」は、単独で又は他の用語との組み合わせにおいて、炭素数１～６の、直鎖状又は分岐状の脂肪族飽和炭化水素の一価の基を意味し、メチル基、エチル基、プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等を例示することができる。また「炭素数１～６のアルコキシ基」は、基Ｒ′Ｏ－（ここで、Ｒ′は、炭素数１～６のアルキル基である）を意味し、メトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、イソブチルオキシ基、ｓｅｃ－ブチルオキシ基、ｔｅｒｔ－ブチルオキシ基、ヘキシルオキシ基等を例示することができる。 In the present invention, the “alkyl group having 1 to 6 carbon atoms” is a monovalent group of a straight or branched aliphatic saturated hydrocarbon having 1 to 6 carbon atoms, alone or in combination with other terms. And methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be exemplified. “Alkoxy group having 1 to 6 carbon atoms” means a group R′O— (where R ′ is an alkyl group having 1 to 6 carbon atoms), and represents a methoxy group, an ethoxy group, a propyloxy group. And isopropyloxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group, hexyloxy group and the like.
　本発明において「アリール」又は「炭素数６～１８のアリール」は、炭素数６～１８の芳香族炭化水素の一価の基を意味し、フェニル基、ナフチル基、アントリル基等を例示することができる。なお、前記芳香族炭化水素の一価の基が、炭素数１～６のアルキル基、炭素数１～６のアルコキシ基、ハロゲン原子等により置換されている態様も包含する。そのような例として、２－メチルフェニル基（ｏ－トリル基）、３－メチルフェニル基（ｍ－トリル基）、４－メチルフェニル基（ｐ－トリル基）、２，４－ジ－ｔ－ブチルフェニル基、４－メトキシフェニル基、４－クロロフェニル基等を例示することができる。 In the present invention, “aryl” or “aryl having 6 to 18 carbon atoms” means a monovalent group of aromatic hydrocarbon having 6 to 18 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, and an anthryl group. Can do. In addition, an embodiment in which the monovalent group of the aromatic hydrocarbon is substituted with an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, or the like is also included. Examples thereof include 2-methylphenyl group (o-tolyl group), 3-methylphenyl group (m-tolyl group), 4-methylphenyl group (p-tolyl group), 2,4-di-t-t- Examples thereof include a butylphenyl group, a 4-methoxyphenyl group, and a 4-chlorophenyl group.
　本発明において「炭素数７～１９のアラルキル基」は、炭素数７～１９のアリールアルキル基（ここで、アリール部分は、炭素数６～１８のアリールであり、アルキル部分は、炭素数１～６のアルキル基である）を意味し、ベンジル基、１－ナフチルメチル基、２－ナフチルメチル基、１－アントリルメチル基、２－アントリルメチル基、９－アントリルメチル等を例示することができる。 In the present invention, the “aralkyl group having 7 to 19 carbon atoms” means an arylalkyl group having 7 to 19 carbon atoms (wherein the aryl moiety is an aryl having 6 to 18 carbon atoms, and the alkyl moiety has 1 to 6), and exemplifies benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-anthrylmethyl, 2-anthrylmethyl, 9-anthrylmethyl, etc. Can do.
　本発明において「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子、ヨウ素原子等を例示することができる。 In the present invention, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　次に、本発明の製造方法について詳しく述べる。本発明の４－ハロセネシオ酸誘導体（２）の製造方法は、下記スキームに示すとおりである。 Next, the production method of the present invention will be described in detail. The method for producing the 4-halosenecioic acid derivative (2) of the present invention is as shown in the following scheme.
Figure JPOXMLDOC01-appb-C000013
 （式中、Ｒ及びＸは、前記と同じ意味を表す。）
Figure JPOXMLDOC01-appb-C000013
 (In the formula, R and X have the same meaning as described above.)
　工程１は、アリルアルコール誘導体（１）を、ハロゲン化剤と反応させ、４－ハロセネシオ酸誘導体（２）を製造する工程である。 Step 1 is a step in which the allyl alcohol derivative (1) is reacted with a halogenating agent to produce a 4-halosenecioic acid derivative (2).
　本発明の製造方法の出発原料であるアリルアルコール誘導体（１）は、公知の方法（例えば、特開昭６０－１７９１４７号公報）に準じて合成することができる。 The allyl alcohol derivative (1) which is a starting material for the production method of the present invention can be synthesized according to a known method (for example, JP-A-60-179147).
　工程１の反応では、目的とする４－ハロセネシオ酸誘導体（２）に応じて、フッ素化剤、塩素化剤、臭素化剤及びヨウ素化剤から選択されるハロゲン化剤を用いる。ハロゲン化剤は、当業者に公知であり、文献や参考書等（例えば、Comprehensive Organic Transformations; Wiley-VCH; p689-697 (1999)）に記載の試薬を用いることができる。そのような試薬は、市販されているか、あるいは市販の試薬から調製可能である。 In the reaction of Step 1, a halogenating agent selected from a fluorinating agent, a chlorinating agent, a brominating agent and an iodinating agent is used according to the target 4-halosenecioic acid derivative (2). The halogenating agent is known to those skilled in the art, and the reagents described in literatures and reference books (for example, ComprehensivereOrganic Transformations; Wiley-VCH; p689-697 (1999)) can be used. Such reagents are commercially available or can be prepared from commercially available reagents.
　フッ素化剤としては、Ｎ，Ｎ－ジエチル－１，１，２，３，３，３－ヘキサフルオロプロピルアミン、（２－クロロ－１，１，２－トリフルオロエチル）ジエチルアミン等の含窒素フッ素化剤；トリフェニルホスフィンジフルオリド、ジフェニルホスフィントリフルオリド等の含リンフッ素化剤；ジエチルアミノ三フッ化硫黄、ビス（２－メトキシエチル）アミノ三フッ化硫黄等の含硫黄フッ素化剤；フッ化水素、フッ化水素ピリジニウム塩等を例示することができる。 Nitrogen-containing fluorine such as N, N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, (2-chloro-1,1,2-trifluoroethyl) diethylamine, etc. Oxidizing agents; phosphorus-containing fluorinating agents such as triphenylphosphine difluoride and diphenylphosphine trifluoride; sulfur-containing fluorinating agents such as diethylaminosulfur trifluoride and bis (2-methoxyethyl) aminosulfur trifluoride; hydrogen fluoride And a pyridinium hydrogen fluoride salt.
　塩素化剤として（１－クロロ－２－メチル－１－プロペニル）ジメチルアミン等の含窒素塩素化剤；塩素／トリアリールホスフィン、Ｎ－クロロコハク酸イミド／トリアリールホスフィン、１，３－ジクロロ－５，５－ジメチルヒダントイン／トリアリールホスフィン、四塩化炭素／トリアリールホスフィン、塩素／亜リン酸トリアリール、Ｎ－クロロコハク酸イミド／亜リン酸トリアリール、１，３－ジクロロ－５，５－ジメチルヒダントイン／亜リン酸トリアリール、四塩化炭素／亜リン酸トリアリール、三塩化リン、五塩化リン、オキシ塩化リン等の含リン塩素化剤；Ｎ－クロロコハク酸イミド／ジメチルスルフィド、ｐ－トルエンスルホン酸クロリド、メタンスルホン酸クロリド、塩化チオニル等の含硫黄塩素化剤；塩素、塩化トリメチルシリル、塩化亜鉛、塩化チタン、塩化水素等を例示することができる。 Nitrogenous chlorinating agents such as (1-chloro-2-methyl-1-propenyl) dimethylamine as chlorinating agents; chlorine / triarylphosphine, N-chlorosuccinimide / triarylphosphine, 1,3-dichloro-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetrachloride / triarylphosphine, chlorine / triarylphosphite, N-chlorosuccinimide / triarylphosphite, 1,3-dichloro-5,5-dimethylhydantoin / Phosphorus chlorinating agents such as triaryl phosphite, carbon tetrachloride / triaryl phosphite, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride; N-chlorosuccinimide / dimethyl sulfide, p-toluenesulfonic acid Sulfur-containing chlorinating agents such as chloride, methanesulfonic acid chloride, thionyl chloride; chlorine, chloride Methylsilyl, zinc chloride, titanium chloride, may be exemplified hydrogen chloride and the like.
　臭素化剤として（１－ブロモ－２－メチル－１－プロペニル）ジメチルアミン等の含窒素臭素化剤；臭素／トリアリールホスフィン、Ｎ－ブロモコハク酸イミド／トリアリールホスフィン、１，３－ジブロモ－５，５－ジメチルヒダントイン／トリアリールホスフィン、四臭化炭素／トリアリールホスフィン、臭素／亜リン酸トリアリール、Ｎ－ブロモコハク酸イミド／亜リン酸トリアリール、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリアリール、四臭化炭素／亜リン酸トリアリール、三臭化リン、五臭化リン、オキシ臭化リン等の含リン臭素化剤；Ｎ－ブロモコハク酸イミド／ジメチルスルフィド、臭化チオニル等の含硫黄臭素化剤；臭素、臭化トリメチルシリル、臭化アルミニウム、臭化チタン、臭化水素等を例示することができる。 Nitrogen-containing brominating agents such as (1-bromo-2-methyl-1-propenyl) dimethylamine as brominating agents; bromine / triarylphosphine, N-bromosuccinimide / triarylphosphine, 1,3-dibromo-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetrabromide / triarylphosphine, bromine / triarylphosphite, N-bromosuccinimide / triarylphosphite, 1,3-dibromo-5,5-dimethyl Phosphorus-containing brominating agents such as hydantoin / triaryl phosphite, carbon tetrabromide / triaryl phosphite, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide; N-bromosuccinimide / dimethyl sulfide, Sulfur-containing brominating agents such as thionyl bromide; bromine, trimethylsilyl bromide, aluminum bromide, titanium bromide, hydrogen bromide, etc. It can Shimesuru.
　ヨウ素化剤として（１－ヨード－２－メチル－１－プロペニル）ジメチルアミン等の含窒素ヨウ素化剤；ヨウ素／トリアリールホスフィン、Ｎ－ヨードコハク酸イミド／トリアリールホスフィン、１，３－ジヨード－５，５－ジメチルヒダントイン／トリアリールホスフィン、四ヨウ化炭素／トリアリールホスフィン、ヨウ素／亜リン酸トリアリール、Ｎ－ヨードコハク酸イミド／亜リン酸トリアリール、１，３－ジヨード－５，５－ジメチルヒダントイン／亜リン酸トリアリール、四ヨウ化炭素／亜リン酸トリアリール等の含リンヨウ素化剤；Ｎ－ヨードコハク酸イミド／ジメチルスルフィド、ヨウ化チオニル等の含硫黄ヨウ素化剤；ヨウ素、ヨウ化トリメチルシリル、ヨウ化マグネシウム、ヨウ化亜鉛、ヨウ化水素等を例示することができる。 Nitrogen-containing iodinating agents such as (1-iodo-2-methyl-1-propenyl) dimethylamine as iodinating agents; iodine / triarylphosphine, N-iodosuccinimide / triarylphosphine, 1,3-diiodo-5 , 5-dimethylhydantoin / triarylphosphine, carbon tetraiodide / triarylphosphine, iodine / triaryl phosphite, N-iodosuccinimide / triaryl phosphite, 1,3-diiodo-5,5-dimethyl Phosphorus iodinating agents such as hydantoin / triaryl phosphite, carbon tetraiodide / triaryl phosphite; N-iodosuccinimide / dimethyl sulfide, sulfur iodinating agents such as thionyl iodide; iodine, iodination Examples include trimethylsilyl, magnesium iodide, zinc iodide, hydrogen iodide, etc. Kill.
　上記ハロゲン化剤で用いることのできるトリアリールホスフィンとしては、例えば、トリフェニルホスフィン、トリ（ｐ－トリル）ホスフィン、トリス（４－メトキシフェニル）ホスフィン、トリス（４－クロロフェニル）ホスフィン等を挙げることができる。収率が良い点で、トリフェニルホスフィンを用いることが好ましい。また、上記ハロゲン化剤で用いることのできる亜リン酸トリアリールとしては、例えば、亜リン酸トリフェニル、亜リン酸トリ（ｐ－トリル）、亜リン酸トリ（２，４－ジ－ｔ－ブチルフェニル）等を挙げることができる。収率が良い点で亜リン酸トリフェニル、亜リン酸トリ（ｐ－トリル）を用いることが好ましい。 Examples of the triarylphosphine that can be used in the halogenating agent include triphenylphosphine, tri (p-tolyl) phosphine, tris (4-methoxyphenyl) phosphine, and tris (4-chlorophenyl) phosphine. it can. Triphenylphosphine is preferably used from the viewpoint of good yield. Examples of the triaryl phosphite that can be used in the halogenating agent include triphenyl phosphite, tri (p-tolyl) phosphite, and tri (2,4-di-t-phosphite). Butylphenyl) and the like. From the viewpoint of good yield, it is preferable to use triphenyl phosphite and tri (p-tolyl) phosphite.
　塩素／トリアリールホスフィン、臭素／トリアリールホスフィン及びヨウ素／トリアリールホスフィンは、市販されているものを使用してもよいが、トリアリールホスフィンと塩素、臭素又はヨウ素からin situに形成されたもの、すなわち反応容器内で調製したものをそのまま使用してもよい。同様に、塩素／亜リン酸トリアリール、臭素／亜リン酸トリアリール及びヨウ素／亜リン酸トリアリールは、市販されているものを使用してもよいが、亜リン酸トリアリールと塩素、臭素又はヨウ素からin situに形成されたもの、すなわち反応容器内で調製したものをそのまま使用してもよい。 Chlorine / triarylphosphine, bromine / triarylphosphine and iodine / triarylphosphine may be commercially available, but are formed in situ from triarylphosphine and chlorine, bromine or iodine, That is, what was prepared in the reaction container may be used as it is. Similarly, commercially available chlorine / triaryl phosphites, bromine / triaryl phosphites and iodine / triaryl phosphites may be used, but triaryl phosphites and chlorine, bromine Or what was formed in-situ from iodine, ie, what was prepared in the reaction container, may be used as it is.
　ハロゲン化剤としては、含窒素ハロゲン化剤（すなわち、含窒素フッ素化剤、含窒素塩素化剤、含窒素臭素化剤、含窒素ヨウ素化剤）、含リンハロゲン化剤（すなわち、含リンフッ素化剤、含リン塩素化剤、含リン臭素化剤、含リンヨウ素化剤）及び含硫黄ハロゲン化剤（すなわち、含硫黄フッ素化剤、含硫黄塩素化剤、含硫黄臭素化剤、含硫黄ヨウ素化剤）からなる群より選択される少なくとも１種を用いることが好ましい。 Examples of the halogenating agent include a nitrogen-containing halogenating agent (that is, a nitrogen-containing fluorinating agent, a nitrogen-containing chlorinating agent, a nitrogen-containing brominating agent, a nitrogen-containing iodinating agent), and a phosphorus-containing halogenating agent (that is, phosphorus-containing fluorine-containing agent). Agent, phosphorus-containing chlorinating agent, phosphorus-containing brominating agent, phosphorus-containing iodinating agent) and sulfur-containing halogenating agent (that is, sulfur-containing fluorinating agent, sulfur-containing chlorinating agent, sulfur-containing brominating agent, sulfur-containing) It is preferable to use at least one selected from the group consisting of (iodinating agents).
　収率の点から、ハロゲン化剤が臭素化剤であり、Ｘが臭素原子である、一般式（２）の４－ハロセネシオ酸誘導体の製造方法が好ましい。 From the viewpoint of yield, a method for producing a 4-halosenecioic acid derivative of the general formula (2) in which the halogenating agent is a brominating agent and X is a bromine atom is preferred.
　臭素化剤の中でも、特に、臭素／トリアリールホスフィン、Ｎ－ブロモコハク酸イミド／トリアリールホスフィン、１，３－ジブロモ－５，５－ジメチルヒダントイン／トリアリールホスフィン、臭素／亜リン酸トリアリール、Ｎ－ブロモコハク酸イミド／亜リン酸トリアリール、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリアリール、三臭化リン、五臭化リン、オキシ臭化リンからなる群より選択される少なくとも１種の含リン臭素化剤を用いることが好ましい。さらに、臭素化剤としては、臭素／トリフェニルホスフィン、Ｎ－ブロモコハク酸イミド／トリフェニルホスフィン、１，３－ジブロモ－５，５－ジメチルヒダントイン／トリフェニルホスフィン、臭素／亜リン酸トリフェニル、Ｎ－ブロモコハク酸イミド／亜リン酸トリフェニル、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリフェニル、臭素／亜リン酸トリ（ｐ－トリル）、Ｎ－ブロモコハク酸イミド／亜リン酸トリ（ｐ－トリル）、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリ（ｐ－トリル）を用いることがより好ましい。 Among brominating agents, bromine / triarylphosphine, N-bromosuccinimide / triarylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triarylphosphine, bromine / triarylphosphite, N -Selected from the group consisting of bromosuccinimide / triaryl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triaryl phosphite, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide It is preferable to use at least one phosphorus-containing brominating agent. Further, brominating agents include bromine / triphenylphosphine, N-bromosuccinimide / triphenylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triphenylphosphine, bromine / triphenylphosphite, N -Bromosuccinimide / triphenyl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triphenyl phosphite, bromine / triphosphite (p-tolyl), N-bromosuccinimide / phosphorous It is more preferable to use tri (p-tolyl) acid, 1,3-dibromo-5,5-dimethylhydantoin / tri (p-tolyl) phosphite.
　アリルアルコール誘導体（１）とハロゲン化剤とのモル比は、１：１から１：５が好ましい。この中でも、収率が良い点で１：１から１：３がさらに好ましい。 The molar ratio of the allyl alcohol derivative (1) to the halogenating agent is preferably 1: 1 to 1: 5. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.
　工程１の反応では、収率向上のために塩基の存在下に反応を行うことができる。用いることのできる塩基としては、水素化ナトリウム、水素化カリウム、水素化カルシウム等の金属水素化物；イミダゾール、ピリジン、２，６－ルチジン、ｓ－コリジン等の芳香族アミン；Ｎ－メチルピロリジン、Ｎ－メチルピペリジン等の環状アミン；エチルジイソプロピルアミン、トリエチルアミン、トリブチルアミンを含むトリ（Ｃ１～Ｃ４アルキル）アミン等の脂肪族アミン；水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩等を例示することができる。収率が良い点で、芳香族アミン又は脂肪族アミンを用いることが好ましく、さらにピリジン又はトリ（Ｃ１～Ｃ４アルキル）アミンを用いることが好ましい。 In the reaction of Step 1, the reaction can be carried out in the presence of a base in order to improve the yield. Bases that can be used include metal hydrides such as sodium hydride, potassium hydride and calcium hydride; aromatic amines such as imidazole, pyridine, 2,6-lutidine and s-collidine; N-methylpyrrolidine, N A cyclic amine such as methylpiperidine; an aliphatic amine such as tri (C 1 -C 4 alkyl) amine including ethyldiisopropylamine, triethylamine and tributylamine; an inorganic salt such as sodium hydroxide, potassium hydroxide and potassium carbonate; It can be illustrated. From the viewpoint of good yield, it is preferable to use an aromatic amine or an aliphatic amine, and it is more preferable to use pyridine or tri (C 1 -C 4 alkyl) amine.
　塩基の使用量は、アリルアルコール誘導体（１）１モルに対して１～５モル程度用いることが好ましい。 The amount of base used is preferably about 1 to 5 moles per mole of allyl alcohol derivative (1).
　工程１の反応では、収率向上のために、使用するハロゲン化剤と同じハロゲン種のハロゲン化物を加えてもよい。ハロゲン化物としては、ハロゲン化物イオンを供給しうるものであれば特に限定はないが、フッ化水素酸、塩化水素酸、臭化水素酸、ヨウ化水素酸等のハロゲン化水素の水溶液；リチウム、ナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属又はアルカリ土類金属のハロゲン化物；亜鉛、銅等の遷移金属のハロゲン化物；脂肪族アミン、芳香族アミン等のアミン又はアンモニアのハロゲン化水素酸塩；第４級アンモニウム：ＮＲ″４ ＋（ここで、Ｒ″は、それぞれ独立して、炭素数１～６のアルキル基又はアリール基を意味する）のハロゲン化物等を例示することができる。したがって、具体的には、ハロゲン化剤としてフッ素化剤を用いる場合、ハロゲン化物としてフッ化リチウム、フッ化ナトリウム、フッ化カリウム、フッ化アンモニウム、フッ化テトラブチルアンモニウム等を例示することができる。ハロゲン化剤として塩素化剤を用いる場合、ハロゲン化物として塩化リチウム、塩化ナトリウム、塩化カリウム、塩化アンモニウム、塩化テトラブチルアンモニウム等を例示することができる。ハロゲン化剤として臭素化剤を用いる場合、ハロゲン化物として臭化リチウム、臭化ナトリウム、臭化カリウム、臭化アンモニウム、臭化テトラブチルアンモニウム等を例示することができる。ハロゲン化剤としてヨウ素化剤を用いる場合、ハロゲン化物としてヨウ化リチウム、ヨウ化ナトリウム、ヨウ化カリウム、ヨウ化リチウム、ヨウ化アンモニウム、ヨウ化テトラブチルアンモニウム等を例示することができる。アルカリ金属のハロゲン化物又は第４級アンモニウムのハロゲン化物が好ましく、リチウム、ナトリウム、カリウム又はテトラ（Ｃ１～Ｃ４アルキル）アンモニウムのハロゲン化物がより好ましい。 In the reaction of Step 1, a halide of the same halogen species as the halogenating agent to be used may be added to improve the yield. The halide is not particularly limited as long as it can supply halide ions, but an aqueous solution of hydrogen halide such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; lithium, Halogens of alkali metals or alkaline earth metals such as sodium, potassium, magnesium, calcium; halides of transition metals such as zinc and copper; amines such as aliphatic amines and aromatic amines or hydrohalides of ammonia; Examples thereof include halides of quaternary ammonium: NR ″ 4 + (wherein R ″ independently represents an alkyl group or aryl group having 1 to 6 carbon atoms). Therefore, specifically, when a fluorinating agent is used as the halogenating agent, examples of the halide include lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, and tetrabutylammonium fluoride. When a chlorinating agent is used as the halogenating agent, examples of the halide include lithium chloride, sodium chloride, potassium chloride, ammonium chloride, and tetrabutylammonium chloride. When a brominating agent is used as the halogenating agent, examples of the halide include lithium bromide, sodium bromide, potassium bromide, ammonium bromide, tetrabutylammonium bromide and the like. When an iodinating agent is used as the halogenating agent, examples of the halide include lithium iodide, sodium iodide, potassium iodide, lithium iodide, ammonium iodide, and tetrabutylammonium iodide. Alkali metal halides or quaternary ammonium halides are preferred, and lithium, sodium, potassium or tetra (C 1 -C 4 alkyl) ammonium halides are more preferred.
　ハロゲン化物の使用量は、アリルアルコール誘導体（１）１モルに対して０．０１～５モル程度用いることが好ましい。 The amount of halide used is preferably about 0.01 to 5 moles per mole of allyl alcohol derivative (1).
　工程１の反応で用いることのできる溶媒としては、反応を阻害しない溶媒であれば良い。具体的には、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン、メチル－ｔｅｒｔ－ブチルエーテル、１，２－ジメトキシエタン、シクロペンチルメチルエーテル等のエーテル系溶媒；ヘキサン、ペンタン、シクロヘキサン等の炭化水素系溶媒；ベンゼン、トルエン、キシレン、メシチレン等の芳香族炭化水素系溶媒；クロロベンゼン、ジクロロベンゼン、トリクロロベンゼン等のハロゲン化芳香族炭化水素溶媒；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリドン、１，３－ジメチル－３，４，５，６－テトラヒドロ－２（１Ｈ）－ピリミジノン等のアミド系溶媒；メタノール、エタノール等のアルコール系溶媒；ジメチルスルホキシド、水等を例示することができる。これらの溶媒のうち２種類以上を混合して用いても差し支えない。この中でも、収率が良い点で、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素溶媒を用いることが好ましい。 As a solvent that can be used in the reaction of Step 1, any solvent that does not inhibit the reaction may be used. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether; hydrocarbon solvents such as hexane, pentane, cyclohexane; Aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene; halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene; N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1, Examples thereof include amide solvents such as 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide and water. Two or more of these solvents may be mixed and used. Among these, it is preferable to use a halogenated aromatic hydrocarbon solvent such as chlorobenzene or dichlorobenzene in terms of a good yield.
　反応温度は、特に限定はないが、通常、－７８℃から１８０℃の範囲から適宜選ばれた温度で行うことができる。反応速度の観点から、１０℃超から１３０℃の範囲が好ましく、室温（約２０℃）から１００℃の範囲がより好ましい。 The reaction temperature is not particularly limited, but it can usually be carried out at a temperature appropriately selected from the range of −78 ° C. to 180 ° C. From the viewpoint of reaction rate, a range of more than 10 ° C to 130 ° C is preferable, and a range of room temperature (about 20 ° C) to 100 ° C is more preferable.
　反応後の溶液から目的物を単離する方法は、特に限定はない。例えば、溶媒抽出、カラムクロマトグラフィー、分取薄層クロマトグラフィー、分取液体クロマトグラフィー、再結晶または昇華等の汎用的な方法で目的物を得ることができる。 The method for isolating the target product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.
　工程２は、アリルアルコール誘導体（１）を、１０℃以下の温度でハロゲン化剤と反応させ、アリルハライド誘導体（３）を製造する工程である。ハロゲン化剤、塩基、溶媒等の反応条件及びその好ましい実施態様は、温度条件及びハロゲン化物を添加しない点を除いて、工程１に準ずる。 Step 2 is a step of producing the allyl halide derivative (3) by reacting the allyl alcohol derivative (1) with a halogenating agent at a temperature of 10 ° C. or lower. Reaction conditions such as a halogenating agent, a base, a solvent, and preferred embodiments thereof are the same as in Step 1, except that temperature conditions and a halide are not added.
　工程２の反応後の溶液から目的物を単離する方法にもまた、特に限定はない。例えば、溶媒抽出、カラムクロマトグラフィー、分取薄層クロマトグラフィー、分取液体クロマトグラフィー等の汎用的な方法で目的物を得ることができる。 There is also no particular limitation on the method for isolating the target product from the solution after the reaction in Step 2. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography or the like.
　工程３は、アリルハライド誘導体（３）を、１０℃超の温度でハロゲン化物と反応させ、４－ハロセネシオ酸誘導体（２）を製造する工程である。使用することのできるハロゲン化物は、工程１に挙げたハロゲン化物に準ずる。ハロゲン化物の使用量は、アリルハライド誘導体（３）１モルに対して０．０１～５モル程度用いることが好ましい。
　使用することのできる反応溶媒は、工程１に挙げた溶媒に準ずるが、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒を用いることが好ましい。反応温度は、１０℃超から１８０℃の範囲から適宜選ばれた温度で行うことができる。室温（約２０℃）から１００℃の範囲がより好ましい。 Step 3 is a step in which the allyl halide derivative (3) is reacted with a halide at a temperature higher than 10 ° C. to produce the 4-halosenecioic acid derivative (2). The halide that can be used is in accordance with the halide listed in Step 1. The amount of halide used is preferably about 0.01 to 5 moles per mole of allyl halide derivative (3).
The reaction solvent that can be used is the same as the solvent listed in Step 1, but an amide solvent such as N, N-dimethylformamide, N-methyl-2-pyrrolidone is preferably used. The reaction temperature can be carried out at a temperature appropriately selected from the range of more than 10 ° C. to 180 ° C. A range from room temperature (about 20 ° C.) to 100 ° C. is more preferable.
　以下、実施例により本発明をさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではない。以下の実施例で純度測定に用いたガスクロマトグラフ（ＧＣ）及びその測定条件を示す。 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The gas chromatograph (GC) used for purity measurement and the measurement conditions are shown in the following examples.
装置：ＧＣ－２０１０（（株）島津製作所）
カラム：ＵＬＴＲＡ１（アジレント・テクノロジー）
２５ｍ×Ｉ．Ｄ．０．３２ｍｍ、０．５２μｍｄｆ
カラム温度：１００℃→［１０℃／ｍｉｎ］→２８０℃
インジェクション温度：３００℃
キャリヤーガス：ヘリウムガス
検出器：水素炎イオン化検出器（ＦＩＤ） Equipment: GC-2010 (Shimadzu Corporation)
Column: ULTRA1 (Agilent Technology)
25 m × I. D. 0.32mm, 0.52μmdf
Column temperature: 100 ° C. → [10 ° C./min]→280° C.
Injection temperature: 300 ° C
Carrier gas: Helium gas detector: Hydrogen flame ionization detector (FID)
　また、実施例で単離した化合物のＮＭＲスペクトルの測定条件は、以下のとおりである。 In addition, the measurement conditions of the NMR spectrum of the compound isolated in the examples are as follows.
装置：ＡＶＡＮＣＥ　４００（ブルカー（株））
化合物と重クロロホルム（Cambrige Isotope Laboratories, Inc.製、０．０５％ＴＭＳ含有）とを混合した溶液を調製し、１Ｈ－ＮＭＲ測定を行った。 Device: AVANCE 400 (Bruker)
A solution in which the compound was mixed with deuterated chloroform (Cambrige Isotope Laboratories, Inc., containing 0.05% TMS) was prepared, and 1 H-NMR measurement was performed.
［実施例１］　４－ブロモセネシオ酸エチルの製造
　クロロベンゼン １０ｍＬ中に亜リン酸トリフェニル ２．８ｇ（９ｍｍｏｌ）を加え、５℃以下に冷却し、臭素 １．４ｇ（９ｍｍｏｌ）を滴下した。３０分反応後，２－ヒドロキシ－３－メチル－３－ブテン酸エチル１ｇ（７ｍｍｏｌ）、トリエチルアミン ０．９ｇ（９ｍｍｏｌ）、クロロベンゼン ２ｍＬの混合液を滴下した。滴下終了後８０℃にて１時間反応を行い、反応率をＧＣで確認すると目的とする4－ブロモセネシオ酸エチルが９４％（Ｅ体＋Ｚ体の混合物）であった。
　反応液に水を２０ｍＬ加え、有機層を分取したのち、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン；１／２）にて精製すると、４－ブロモセネシオ酸エチルを８６％（Ｅ体＋Ｚ体の混合物）の収率で得ることができた。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）Ｅ体δ： ５．９６（１Ｈ，ｓ），４．１８（２Ｈ，ｑ，Ｊ＝８．０Ｈｚ），３．９４（２Ｈ，ｓ），２．２８（３Ｈ，ｓ），１．２９（３Ｈ，ｔ，Ｊ＝８．０Ｈｚ），Ｚ体；δ：５．７８（１Ｈ，ｓ），４．５６（２Ｈ，ｓ），４．１８（２Ｈ，ｑ，Ｊ＝８．０Ｈｚ），２．０５（３Ｈ，ｓ），１．２９（３Ｈ，ｔ，Ｊ＝８．０Ｈｚ）． [Example 1] Production of ethyl 4-bromosenecioate In 10 mL of chlorobenzene, 2.8 g (9 mmol) of triphenyl phosphite was added and cooled to 5 ° C or lower, and 1.4 g (9 mmol) of bromine was added dropwise. After the reaction for 30 minutes, a mixed solution of ethyl 2-hydroxy-3-methyl-3-butenoate 1 g (7 mmol), triethylamine 0.9 g (9 mmol) and chlorobenzene 2 mL was added dropwise. After completion of the dropwise addition, the reaction was carried out at 80 ° C. for 1 hour, and the reaction rate was confirmed by GC. As a result, the desired ethyl 4-bromosenecioate was 94% (mixture of E form + Z form).
20 mL of water was added to the reaction solution, and the organic layer was separated and purified by silica gel column chromatography (ethyl acetate / hexane; 1/2) to obtain 86% of ethyl 4-bromosenecioate (E-form + Z-form). Mixture).
1 H-NMR (400 MHz, CDCl 3 ) E-form δ: 5.96 (1H, s), 4.18 (2H, q, J = 8.0 Hz), 3.94 (2H, s), 2.28 (3H, s), 1.29 (3H, t, J = 8.0 Hz), Z body; δ: 5.78 (1H, s), 4.56 (2H, s), 4.18 (2H, q, J = 8.0 Hz), 2.05 (3H, s), 1.29 (3H, t, J = 8.0 Hz).
［実施例２－１２］
　実施例２～１２の反応を、実施例１と同様の方法で実施した。なお、実施例１１～１２では、ハロゲン化物を２－ヒドロキシ－３－メチル－３－ブテン酸エチルに対し、それぞれ１．３当量使用した。表１に実施例で用いた臭素化剤、塩基、ハロゲン化物、反応温度、反応時間、目的物の生成率（％）を示す。 [Example 2-12]
The reactions of Examples 2 to 12 were carried out in the same manner as in Example 1. In Examples 11 to 12, 1.3 equivalents of each halide was used with respect to ethyl 2-hydroxy-3-methyl-3-butenoate. Table 1 shows the brominating agent, base, halide, reaction temperature, reaction time, and production rate (%) of the target product used in the examples.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
［実施例１３］　４－ヨードセネシオ酸エチルの製造
　クロロベンゼン １０ｍＬ中に亜リン酸トリフェニル ２．８ｇ（９ｍｍｏｌ）を加え、５℃以下に冷却し、ヨウ素 ２．３ｇ（９ｍｍｏｌ）を添加した。３０分反応後、２－ヒドロキシ－３－メチル－３－ブテン酸エチル１ｇ（７ｍｍｏｌ）、トリエチルアミン ０．９ｇ（９ｍｍｏｌ）、クロロベンゼン ２ｍＬの混合液を滴下した。滴下終了後６０℃にて１時間反応を行い、反応率をＧＣで確認すると目的とする４－ヨードセネシオ酸エチルが３０％（Ｅ体＋Ｚ体の混合物）であった。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）Ｅ体；δ：６．００（１Ｈ，ｓ），４．２１－４．１３（２Ｈ，ｍ），３．９３（２Ｈ，ｓ），２．３２（３Ｈ，ｓ），１．３１－１．２４（３Ｈ，ｍ），Ｚ体；δ：５．７３（１Ｈ，ｓ），４．５２（２Ｈ，ｓ），４．２１－４．１３（２Ｈ，ｍ），２．０８（３Ｈ，ｓ），１．３１－１．２４（３Ｈ，ｍ）． [Example 13] Production of ethyl 4-iodosenecioate In 10 mL of chlorobenzene, 2.8 g (9 mmol) of triphenyl phosphite was added, cooled to 5 ° C or lower, and 2.3 g (9 mmol) of iodine was added. After reacting for 30 minutes, a mixed solution of 1 g (7 mmol) of ethyl 2-hydroxy-3-methyl-3-butenoate, 0.9 g (9 mmol) of triethylamine and 2 mL of chlorobenzene was added dropwise. After completion of the dropwise addition, the reaction was carried out at 60 ° C. for 1 hour, and the reaction rate was confirmed by GC.
1 H-NMR (400 MHz, CDCl 3 ) E isomer; δ: 6.00 (1H, s), 4.21-4.13 (2H, m), 3.93 (2H, s), 2.32 ( 3H, s), 1.31-1.24 (3H, m), Z form; δ: 5.73 (1H, s), 4.52 (2H, s), 4.21-4.13 (2H , M), 2.08 (3H, s), 1.31-1.24 (3H, m).
［実施例１４］　２－ブロモ－３－メチル－３－ブテン酸エチルの製造
　クロロベンゼン １０ｍＬ中に亜リン酸トリフェニル ２．８ｇ（９ｍｍｏｌ）を加え、５℃以下に冷却し、臭素 １．４ｇ（９ｍｍｏｌ）を滴下した。３０分反応後、２－ヒドロキシ－３－メチル－３－ブテン酸エチル１ｇ（７ｍｍｏｌ）、トリエチルアミン ０．９ｇ（９ｍｍｏｌ）、クロロベンゼン ２ｍＬの混合液を滴下した。滴下終了後、水 ２０ｍＬを加え、有機層を分取したのち、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン；１／２）にて精製すると、２－ブロモ－３－メチル－３－ブテン酸エチルを６９％（Ｅ体＋Ｚ体の混合物）の収率で得ることができた。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：５．２４（１Ｈ，ｓ），５．１０（１Ｈ，ｓ），４．９１（１Ｈ，ｓ），４．２４（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），１．９５（３Ｈ，ｓ），１．３０（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ）． [Example 14] Production of ethyl 2-bromo-3-methyl-3-butenoate Add 2.8 g (9 mmol) of triphenyl phosphite to 10 mL of chlorobenzene, cool to 5 ° C or lower, and then add 1.4 g of bromine ( 9 mmol) was added dropwise. After reacting for 30 minutes, a mixed solution of 1 g (7 mmol) of ethyl 2-hydroxy-3-methyl-3-butenoate, 0.9 g (9 mmol) of triethylamine and 2 mL of chlorobenzene was added dropwise. After completion of the dropwise addition, 20 mL of water was added, and the organic layer was separated and purified by silica gel column chromatography (ethyl acetate / hexane; 1/2) to obtain ethyl 2-bromo-3-methyl-3-butenoate. It was possible to obtain in a yield of 69% (mixture of E-form + Z-form).
1 H-NMR (400 MHz, CDCl 3 ) δ: 5.24 (1H, s), 5.10 (1H, s), 4.91 (1H, s), 4.24 (2H, q, J = 7) .2 Hz), 1.95 (3H, s), 1.30 (3H, t, J = 7.2 Hz).
［実施例１５］
　ＤＭＦ １ｍＬ中に、２－ブロモ－３－メチル－３－ブテン酸エチル５０ｍｇ（０．２ｍｍｏｌ）とＴＢＡＢ １５５ｍｇ（０．５ｍｍｏｌ）を加え、室温下で２４時間反応した。反応率をＧＣで確認すると目的とする４－ブロモセネシオ酸エチルが９５％（Ｅ体＋Ｚ体の混合物）であった。 [Example 15]
In 1 mL of DMF, 50 mg (0.2 mmol) of ethyl 2-bromo-3-methyl-3-butenoate and 155 mg (0.5 mmol) of TBAB were added and reacted at room temperature for 24 hours. When the reaction rate was confirmed by GC, the target ethyl 4-bromosenecioate was 95% (mixture of E-form and Z-form).
［実施例１６、１７］
　実施例１６、１７の反応は、実施例１５と同様の方法で実施した。表２に実施例で用いたハロゲン化物、溶媒、反応温度、反応時間、目的物の反応率（％）を示す。 [Examples 16 and 17]
The reactions of Examples 16 and 17 were carried out in the same manner as in Example 15. Table 2 shows the halide, solvent, reaction temperature, reaction time, and reaction rate (%) of the target product used in the examples.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
［比較例１］
　ＤＭＦ １ｍＬ中に、２－ブロモ－３－メチル－３－ブテン酸エチル５０ｍｇ（０．２ｍｍｏｌ）を加え、室温下で２４時間撹拌した。変化をＧＣで確認したが、４－ブロモセネシオ酸エチルは生成しなかった。 [Comparative Example 1]
50 mg (0.2 mmol) of ethyl 2-bromo-3-methyl-3-butenoate was added to 1 mL of DMF, and the mixture was stirred at room temperature for 24 hours. The change was confirmed by GC, but ethyl 4-bromosenecioate was not produced.

Claims (20)

  1. 　一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒは、保護基を表す）で示されるアリルアルコール誘導体を、ハロゲン化剤と反応させることを特徴とする、一般式（２）：
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒは、前記と同じ意味を表し、Ｘは、ハロゲン原子を表す）で示される４－ハロセネシオ酸誘導体の製造方法。     General formula (1):
    Figure JPOXMLDOC01-appb-C000001
     (Wherein R represents a protecting group), an allyl alcohol derivative represented by the general formula (2):
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R represents the same meaning as described above, and X represents a halogen atom).
  2. 　ハロゲン化剤が、含窒素ハロゲン化剤、含リンハロゲン化剤及び含硫黄ハロゲン化剤からなる群より選択される少なくとも１種である、請求項１に記載の製造方法。 The production method according to claim 1, wherein the halogenating agent is at least one selected from the group consisting of a nitrogen-containing halogenating agent, a phosphorus-containing halogenating agent and a sulfur-containing halogenating agent.
  3. 　ハロゲン化剤が、臭素化剤であり、Ｘが、臭素原子である、請求項１に記載の製造方法。 The production method according to claim 1, wherein the halogenating agent is a brominating agent and X is a bromine atom.
  4. 　臭素化剤が、臭素／トリアリールホスフィン、Ｎ－ブロモコハク酸イミド／トリアリールホスフィン、１，３－ジブロモ－５，５－ジメチルヒダントイン／トリアリールホスフィン、臭素／亜リン酸トリアリール、Ｎ－ブロモコハク酸イミド／亜リン酸トリアリール、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリアリール、三臭化リン、五臭化リン、オキシ臭化リンからなる群より選択される少なくとも１種の含リン臭素化剤である、請求項３に記載の製造方法。 Brominating agents are bromine / triarylphosphine, N-bromosuccinimide / triarylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triarylphosphine, bromine / triaryl phosphite, N-bromosuccinic acid At least one selected from the group consisting of imide / triaryl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triaryl phosphite, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide The production method according to claim 3, which is a seed phosphorus-containing brominating agent.
  5. 　トリアリールホスフィンが、トリフェニルホスフィン、トリ（ｐ－トリル）ホスフィン、トリス（４－メトキシフェニル）ホスフィン又はトリス（４－クロロフェニル）ホスフィンである、請求項４に記載の製造方法。 The production method according to claim 4, wherein the triarylphosphine is triphenylphosphine, tri (p-tolyl) phosphine, tris (4-methoxyphenyl) phosphine or tris (4-chlorophenyl) phosphine.
  6. 　トリアリールホスフィンが、トリフェニルホスフィンである、請求項４又は５に記載の製造方法。 The production method according to claim 4 or 5, wherein the triarylphosphine is triphenylphosphine.
  7. 　亜リン酸トリアリールが、亜リン酸トリフェニル、亜リン酸トリ（ｐ－トリル）又は亜リン酸トリ（２，４－ジ－ｔ－ブチルフェニル）である、請求項４に記載の製造方法。 The process according to claim 4, wherein the triaryl phosphite is triphenyl phosphite, tri (p-tolyl) phosphite or tri (2,4-di-t-butylphenyl) phosphite. .
  8. 　亜リン酸トリアリールが、亜リン酸トリフェニルまたは亜リン酸トリ（ｐ－トリル）である、請求項４又は７に記載の製造方法。 The production method according to claim 4 or 7, wherein the triaryl phosphite is triphenyl phosphite or tri (p-tolyl) phosphite.
  9. 　臭素化剤が、臭素／トリフェニルホスフィン、Ｎ－ブロモコハク酸イミド／トリフェニルホスフィン、１，３－ジブロモ－５，５－ジメチルヒダントイン／トリフェニルホスフィン、臭素／亜リン酸トリフェニル、Ｎ－ブロモコハク酸イミド／亜リン酸トリフェニル、１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリフェニル、臭素／亜リン酸トリ（ｐ－トリル）、Ｎ－ブロモコハク酸イミド／亜リン酸トリ（ｐ－トリル）又は１，３－ジブロモ－５，５－ジメチルヒダントイン／亜リン酸トリ（ｐ－トリル）である、請求項４に記載の製造方法。 Brominating agents are bromine / triphenylphosphine, N-bromosuccinimide / triphenylphosphine, 1,3-dibromo-5,5-dimethylhydantoin / triphenylphosphine, bromine / triphenylphosphite, N-bromosuccinic acid Imido / triphenyl phosphite, 1,3-dibromo-5,5-dimethylhydantoin / triphenyl phosphite, bromine / triphosphite (p-tolyl), N-bromosuccinimide / triphosphite ( The production method according to claim 4, which is p-tolyl) or 1,3-dibromo-5,5-dimethylhydantoin / triphosphite (p-tolyl).
  10. 　さらに、塩基の存在下に反応を行うことを特徴とする、請求項１～９のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 9, wherein the reaction is further carried out in the presence of a base.
  11. 　塩基が、芳香族アミン又は脂肪族アミンである、請求項１０に記載の製造方法。 The production method according to claim 10, wherein the base is an aromatic amine or an aliphatic amine.
  12. 　芳香族アミンが、ピリジンである、請求項１１に記載の製造方法。 The production method according to claim 11, wherein the aromatic amine is pyridine.
  13. 　脂肪族アミンが、トリ（Ｃ１～Ｃ４アルキル）アミンである、請求項１１に記載の製造方法。 The production method according to claim 11, wherein the aliphatic amine is tri (C 1 -C 4 alkyl) amine.
  14. 　さらに、ハロゲン化物の存在下に反応を行うことを特徴とする、請求項１～１３のいずれかに記載の製造方法。 14. The production method according to claim 1, wherein the reaction is further performed in the presence of a halide.
  15. 　ハロゲン化物が、リチウム、ナトリウム又はカリウムのハロゲン化物である、請求項１４に記載の製造方法。 The production method according to claim 14, wherein the halide is a halide of lithium, sodium or potassium.
  16. 　ハロゲン化物が、第４級アンモニウムのハロゲン化物である、請求項１４に記載の製造方法。 The production method according to claim 14, wherein the halide is a quaternary ammonium halide.
  17. 　第４級アンモニウムのハロゲン化物が、ハロゲン化テトラ（Ｃ１～Ｃ４アルキル）アンモニウムである、請求項１６に記載の製造方法。 The process according to claim 16, wherein the quaternary ammonium halide is tetra (C 1 -C 4 alkyl) ammonium halide.
  18. 　一般式（１）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒは、保護基を表す）で示されるアリルアルコール誘導体を、１０℃以下の温度でハロゲン化剤と反応させることを特徴とする、一般式（３）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒは、前記と同じ意味を表し、Ｘは、ハロゲン原子を表す）で示されるアリルハライド誘導体の製造方法。     General formula (1):
    Figure JPOXMLDOC01-appb-C000003
     (Wherein R represents a protecting group), and an allyl alcohol derivative represented by the following general formula (3):
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R represents the same meaning as described above, and X represents a halogen atom).
  19. 　一般式（３）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒは、保護基を表し、Ｘは、ハロゲン原子を表す）で示されるアリルハライド誘導体を、１０℃超の温度でハロゲン化物と反応させることを特徴とする、一般式（２）：
    Figure JPOXMLDOC01-appb-C000006
     　（式中、Ｒ及びＸは、前記と同じ意味を表す）で示される４－ハロセネシオ酸誘導体の製造方法。     General formula (3):
    Figure JPOXMLDOC01-appb-C000005
     (Wherein R represents a protecting group and X represents a halogen atom), an allyl halide derivative represented by the general formula (2) is reacted with a halide at a temperature of more than 10 ° C. :
    Figure JPOXMLDOC01-appb-C000006
     (Wherein R and X represent the same meaning as described above).
  20. 　一般式（３）で示されるアリルハライド誘導体が、請求項１８に記載の製造方法により得られたものである、請求項１９に記載の製造方法。 The production method according to claim 19, wherein the allyl halide derivative represented by the general formula (3) is obtained by the production method according to claim 18.
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