WO2016052353A1 - Procédé de production de composé difluoro géminal - Google Patents

Procédé de production de composé difluoro géminal Download PDF

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Publication number
WO2016052353A1
WO2016052353A1 PCT/JP2015/077175 JP2015077175W WO2016052353A1 WO 2016052353 A1 WO2016052353 A1 WO 2016052353A1 JP 2015077175 W JP2015077175 W JP 2015077175W WO 2016052353 A1 WO2016052353 A1 WO 2016052353A1
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WO
WIPO (PCT)
Prior art keywords
producing
compound
hydrogen fluoride
compound according
geminal difluoro
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PCT/JP2015/077175
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English (en)
Japanese (ja)
Inventor
昭裕 長屋
章一 近藤
準 武岡
智 中野
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日産化学工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 日産化学工業株式会社 filed Critical 日産化学工業株式会社
Priority to JP2016551988A priority Critical patent/JPWO2016052353A1/ja
Priority to CN201580052499.3A priority patent/CN106687431A/zh
Priority to KR1020177002861A priority patent/KR20170066310A/ko
Publication of WO2016052353A1 publication Critical patent/WO2016052353A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C07C17/42—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/02—Monocyclic aromatic halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/02—Monocyclic aromatic halogenated hydrocarbons
    • C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a novel method for producing a geminal difluoro compound using an oxime compound as a starting material.
  • a geminal difluoro compound having, as a partial structure, a group in which two fluorine atoms are substituted on one carbon atom is a compound useful as a pharmaceutical or agricultural chemical, or an intermediate thereof (Patent Document 1), and a method for producing these compounds As many reactions have been developed.
  • a typical example is a difluorination reaction of an oxime compound (Non-Patent Documents 1 to 3).
  • a method using iodine monofluoride (Non-patent Document 2) has been reported.
  • the iodine monofluoride used can only exist at a low temperature, and in the reaction, in order to generate iodine monofluoride in the system, pulverized iodine is added to the reaction solution, and fluorine / An operation for blowing nitrogen gas is required. Therefore, the use of iodine monofluoride has a problem of using special reaction conditions and a reaction apparatus (Non-Patent Documents 2 and 4).
  • Non-patent Document 3 A method using nitrosyltetrafluoroborate and a hydrogen fluoride-pyridine complex (Non-patent Document 3) has also been reported.
  • the target compound is obtained only in a low yield (Patent Document 2).
  • nitrosyltetrafluoroborate has a strong hygroscopic property, it is necessary to handle it under a dry inert gas when performing a difluorination reaction, and there is a problem that it is expensive (non-patent document). 5, 6). Therefore, a novel method for producing a geminal difluoro compound that is useful as an industrial production method with high yield without using these reagents has been desired.
  • An object of the present invention is to provide a method for producing a geminal difluoro compound with high yield, which does not require a special reaction apparatus or reaction conditions.
  • the present inventors have found a novel production method for producing a geminal difluoro compound in high yield by reacting a fluorinating agent with an oxime compound in the presence of an N-chloroimide compound,
  • the present invention has been completed. That is, the present invention is characterized by the following.
  • N-chloroimide compound is N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or trichloroisocyanuric acid
  • a method for producing a geminal difluoro compound [3] The method for producing a geminal difluoro compound according to the above [2], wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid.
  • the amount of the N-chloroimide compound is 0.1 to 100 equivalents per 1 equivalent of the oxime compound of the formula (1), according to any one of [1] to [3] above.
  • a method for producing a geminal difluoro compound [5] Geminal difluoro according to any one of [1] to [4] above, wherein the amount of the fluorinating agent used is 2 to 1000 equivalents relative to 1 equivalent of the oxime compound of formula (1). Compound production method. [6] The geminal difluoro according to any one of the above [1] to [5], wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or poly [4-vinylpyridinium poly (hydrogen fluoride)].
  • n- means normal
  • s- means secondary
  • t- means tertiary
  • (E) means E-form
  • (Z) means Z-form, which are used for describing chemical structures.
  • C 1-4 alkyl means a linear or branched alkyl having 1 to 4 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl is meant.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the geminal difluoro compound (compound) represented by formula (2) is reacted with the oxime compound (compound (1)) represented by formula (1) in the presence of an N-chloroimide compound. (2)) can be manufactured.
  • the N-chloroimide compound means an imide compound in which a nitrogen atom is chlorinated.
  • Examples of the N-chloroimide compound used in the present invention include N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid and the like.
  • a preferred N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid, and a more preferred N-chloroimide compound is trichloroisocyanuric acid.
  • N-chloroimide compounds may be used alone or in combination of two or more.
  • trichloroisocyanuric acid is known to be used as a pool disinfectant, deodorant and the like. Furthermore, trichloroisocyanuric acid is known to be a highly stable and inexpensive reagent (Organic Process Research and Development, 2002, Vol. 6, pages 384-393).
  • the amount of the N-chloroimide compound used is preferably 0.1 equivalents to 100 equivalents, more preferably 0.5 equivalents to 30 equivalents, still more preferably 1 equivalents to 15 equivalents, relative to compound (1). It is.
  • fluorinating agent used in the present invention examples include hydrogen fluoride-pyridine complex, poly [4-vinylpyridinium poly (hydrogen fluoride)], and the like.
  • a preferred fluorinating agent is a hydrogen fluoride-pyridine complex.
  • hydrogen fluoride can also be used.
  • Poly [4-vinylpyridinium poly (hydrogen fluoride)] is a compound composed of a polymer of a pyridine derivative and hydrogen fluoride (Synlett, 1990, pp. 267-269).
  • the amount of the fluorinating agent used in the present invention can be 2 to 1000 equivalents relative to 1 equivalent of the oxime compound represented by the formula (1).
  • the equivalent amount is more preferably 5 to 200 equivalents.
  • the compound (1) used in the present invention means any one of the oxime compounds represented by the formula (1a) or the formula (1b), or a mixture of the formula (1a) and the formula (1b).
  • the oxime compound represented by the formula (1a) has the stereochemical structure of (E), and the oxime compound represented by the formula (1b) has the stereochemical structure of (Z).
  • the compound which is the stereochemistry of (E) and the compound which is the stereochemistry of (Z) are geometric isomers of each other and in many cases they can be isolated.
  • isomerization to a thermodynamically stable isomer can be performed by fractional recrystallization, hydrochloric acid treatment or the like.
  • an oxime compound for example, a condensation reaction of a carbonyl compound and hydroxylamine can be mentioned, and an oxime compound can be produced according to a method described in known literature (Comprehensive Organic Functional Group Transformations II, 2005, volume 3, pages 451-467).
  • the solvent used in the present invention is not particularly limited as long as the reaction is not hindered, and examples thereof include the following.
  • Alcohol solvents eg, methanol, ethanol, 2-propanol
  • halogen-containing hydrocarbon solvents eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene
  • aromatic Group halogenated hydrocarbon solvents eg, chlorobenzene, dichlorobenzene
  • aromatic hydrocarbon solvents eg, benzene, toluene, xylene
  • aliphatic hydrocarbon solvents eg, hexane, heptane
  • amine solvents eg, Triethylamine, N, N-dibutylbutan-1-amine, 2-methyl-N, N-bis (2-methylbutyl) -1-butanamine,
  • halogen-containing hydrocarbon solvents amine solvents, pyridine solvents or ether solvents
  • halogen-containing hydrocarbon solvents more preferred are dichloromethane and chloroform.
  • the amount of the solvent that can be used in the production method of the present invention is preferably 0 to 1000 times, more preferably 1 to 100 times the oxime compound represented by the formula (1). More preferably, it is 5 to 50 times by weight.
  • the reaction temperature is not particularly limited but is preferably from ⁇ 78 ° C. to the reflux temperature of the reaction mixture, more preferably from ⁇ 60 ° C. to 50 ° C., still more preferably from ⁇ 40 ° C. to 30 ° C.
  • the temperature is 0 ° C. until about 7 hours from the start of the reaction, and thereafter, at 20 ° C.-30 ° C. for 3-21 hours.
  • the total reaction time is within about 28 hours, preferably 3 to 21 hours.
  • hydrogen fluoride is used as the fluorinating agent, it is within about 20 hours, preferably 1 to 5 hours.
  • Proton nuclear magnetic resonance ( 1 H NMR) in Examples is carried out in deuterated chloroform using JNM-ECP300 manufactured by JEOL or JNM-ECX300 manufactured by JEOL.
  • the chemical shift was represented by a ⁇ value (ppm) when tetramethylsilane was used as an internal standard (0.0 ppm).
  • the fluorine nuclear magnetic resonance ( 19 F NMR) of the example was measured in deuterated chloroform solvent using JNM-ECX300 manufactured by JEOL, and the chemical shift was determined using hexafluorobenzene as an internal standard (-162.2 ppm). ) Value (ppm).
  • Synthesis example 1 Production of 1- (1,1-difluoroethyl) -4-bromobenzene After replacing the inside of a reaction vessel made of a resin of tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (abbreviated as PFA) with nitrogen gas, hydrogen fluoride-pyridine complex (10.0 g, [63.8% Hydrogen fluoride): 36.2% (pyridine)], 318.8 mmol as hydrogen fluoride, manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C.
  • PFA tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer
  • reaction vessel was charged with 1,3-dichloro-5,5-dimethylhydantoin (4.60 g, 23.35 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol).
  • dichloromethane 30.0 g was added sequentially and the reaction mixture was stirred at 0 ° C. for 7 h. Furthermore, after raising the reaction temperature to 20 ° C., the mixture was stirred at the same temperature for 3 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated.
  • the reaction vessel was cooled with a dry ice-methanol-water bath, and hydrogen fluoride was distilled off under reduced pressure.
  • chloroform and water were added to the reaction vessel and the mixture was stirred and separated, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution.
  • the quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 51%.
  • the geminal difluoro compound obtained by the present invention is used in a wide range of fields as a production intermediate for medical and agricultural chemicals.
  • the entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2014-199055 filed on September 29, 2014 are incorporated herein as the disclosure of the specification of the present invention. Is.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

　L'invention concerne un nouveau procédé de production d'un composé difluoro géminal. Elle porte également sur un nouveau procédé de production pour l'obtention d'un composé difluoro géminal, représenté par la formule (2), avec un rendement élevé, par mise en réaction d'un composé représenté par la formule (1) avec un agent de fluoration, en présence d'un composé N-chloroimide. (Dans la formule, R1 indique un groupe alkyleC1-4 , X indique un atome d'halogène.)　
PCT/JP2015/077175 2014-09-29 2015-09-25 Procédé de production de composé difluoro géminal WO2016052353A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2016551988A JPWO2016052353A1 (ja) 2014-09-29 2015-09-25 ジェミナルジフルオロ化合物の製造方法
CN201580052499.3A CN106687431A (zh) 2014-09-29 2015-09-25 偕二氟化合物的制造方法
KR1020177002861A KR20170066310A (ko) 2014-09-29 2015-09-25 제미널 디플루오로 화합물의 제조 방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014199055 2014-09-29
JP2014-199055 2014-09-29

Publications (1)

Publication Number Publication Date
WO2016052353A1 true WO2016052353A1 (fr) 2016-04-07

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PCT/JP2015/077175 WO2016052353A1 (fr) 2014-09-29 2015-09-25 Procédé de production de composé difluoro géminal

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JP (1) JPWO2016052353A1 (fr)
KR (1) KR20170066310A (fr)
CN (1) CN106687431A (fr)
WO (1) WO2016052353A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08500366A (ja) * 1993-05-19 1996-01-16 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 部分的にふっ素化したベンゼン誘導体
WO2012139775A1 (fr) * 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Composés pyrrolosulfonamides pour la modulation de l'activité du récepteur orphelin gamma apparenté au récepteur nucléaire orphelin rar (ror-gamma, nr1f3) et pour le traitement de maladies inflammatoires chroniques et auto-immunes
JP2013180975A (ja) * 2012-03-01 2013-09-12 Central Glass Co Ltd α，α−ジフルオロ芳香族化合物の製造方法
JP2014510017A (ja) * 2010-12-07 2014-04-24 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１−ベンジルシクロアルキルカルボン酸およびその使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08500366A (ja) * 1993-05-19 1996-01-16 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 部分的にふっ素化したベンゼン誘導体
JP2014510017A (ja) * 2010-12-07 2014-04-24 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１−ベンジルシクロアルキルカルボン酸およびその使用
WO2012139775A1 (fr) * 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Composés pyrrolosulfonamides pour la modulation de l'activité du récepteur orphelin gamma apparenté au récepteur nucléaire orphelin rar (ror-gamma, nr1f3) et pour le traitement de maladies inflammatoires chroniques et auto-immunes
JP2013180975A (ja) * 2012-03-01 2013-09-12 Central Glass Co Ltd α，α−ジフルオロ芳香族化合物の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ROZEN S. ET AL.: "Conversion of the carbonyl group to CF2 using iodine monofluoride (IF", THE JOUNRAL OF ORGANIC CHEMISTRY, vol. 56, 1991, pages 4695 - 4700 *
YORK C. ET AL.: "Novel preparation of gem- difluorides from ketoximes with nitrosonium tetrafluoroborate and pyridinium", SYNLETT, vol. 6, 1994, pages 425 - 426 *

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JPWO2016052353A1 (ja) 2017-07-13
CN106687431A (zh) 2017-05-17
KR20170066310A (ko) 2017-06-14

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