WO2001066509A1 - PROCEDE DE PRODUCTION D'α,α-DIFLUORO-β-CETOESTER - Google Patents

PROCEDE DE PRODUCTION D'α,α-DIFLUORO-β-CETOESTER Download PDF

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Publication number
WO2001066509A1
WO2001066509A1 PCT/JP2001/001103 JP0101103W WO0166509A1 WO 2001066509 A1 WO2001066509 A1 WO 2001066509A1 JP 0101103 W JP0101103 W JP 0101103W WO 0166509 A1 WO0166509 A1 WO 0166509A1
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Prior art keywords
group
general formula
difluoro
represented
ketoester
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PCT/JP2001/001103
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English (en)
Japanese (ja)
Inventor
Katsuhiko Iseki
Yoshichika Kuroki
Yuko Sakamaki
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Daikin Industries Ltd.
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Application filed by Daikin Industries Ltd. filed Critical Daikin Industries Ltd.
Publication of WO2001066509A1 publication Critical patent/WO2001066509A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/46—Preparation of carboxylic acid esters from ketenes or polyketenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

Definitions

  • the present invention relates to a method for producing a difluoro /?-Ketoester useful as a physiologically active substance such as a medicine or a pesticide, and a method for producing difluoroketene silyl acetal useful as a synthetic intermediate thereof. Also, the present invention relates to a method for producing optically active aniline, difluoro-5-hydroxy ester.
  • a compound obtained by replacing a hydrogen atom with a fluorine atom from a known compound having a function or a physiological activity has a function or a physiological activity enhanced by a specific electronic effect of the fluorine atom, Alternatively, it is known to exhibit new functions and physiological activities.
  • fluorinated building blocks having a structure similar to the raw materials of known compounds have been designed [“Fluorine Physiologically Active Substances in the 1990s”, supervised by Nobuo Ishikawa, published by CMC (1991), Latest Trends in Materials ”edited by Masaaki Yamabe and Hitoshi Matsuo, published by CMC (1994)].
  • H H-difluoro /?-Ketoester. It is known primarily as an important synthetic intermediate for making pharmaceuticals and pesticides.
  • a method of oxidizing a di-difluoro /?-Hydroxy ester corresponding to a target product, a method of fluorinating a keto ester, and the like are known.
  • the present invention has been made in order to improve the above circumstances, and its object is to collect a thiophene, a thiofluoride mono /?-Ketoester and a derivative thereof, and a synthetic intermediate thereof by a general method.
  • An object is to provide a method for efficiently synthesizing.
  • the method of the present invention for producing a monodifluoro-5-ketoester comprises an acid halide represented by the following general formula [1] and a difluoroketene silyl acetal represented by the following general formula [2]. And non-catalytic conditions or metal-based The reaction is carried out in the presence of a catalyst to obtain a fluorinated / fluoroketoester represented by the following general formula [3].
  • R 1 represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyloxy group
  • R 2 represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group or an alkynyl group
  • R 3 , R 4 and R 5 are the same or different groups
  • an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group or an aralkyloxy group which may form a cyclic group together with each other.
  • the present invention is characterized in that a difluoroketene silyl acetal represented by the following general formula [2] is produced using a difluoroacetic acid ester represented by the general formula [4], zinc and trialkyl halosilane.
  • R 2 represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group or an alkynyl group
  • R 3 , R 4 and R 5 are the same as each other.
  • X 2 represents a chlorine atom, a bromine atom or an iodine atom (the same applies hereinafter).
  • the method for producing the mono- or mono-difluoro-hydroxy ester of the present invention is as follows.
  • An acid halide represented by the formula [1] and a difluoroketene silyl acetal represented by the following general formula [2] are reacted under non-catalytic conditions or with a metal.
  • the reaction is carried out in the presence of a catalyst to obtain a difluoro /?-Ketoester represented by the following general formula [3].
  • the di-difluoro- ⁇ -ketoester is subjected to asymmetric reaction using a hydrogenation catalyst. It is characterized in that it is converted into an optically active compound represented by the following general formula [5] by hydrogenation reaction.
  • R 1 is an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyl
  • R 2 represents an alkyl group, an aralkyl group, an aralkyl group, an alkenyl group or an alkynyl group
  • R 3 , R 4 and R 5 represent the same or different groups
  • An alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group or an aralkyloxy group which may form a cyclic group together with each other.
  • X 1 Represents a halogen atom
  • * C represents a chiral carbon atom.
  • the acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [2] are reacted under non-catalytic conditions or in the presence of a metal-based catalyst. Because of the reaction, it is possible to mass-produce para-difluoro-5-ketoester, which is useful, for example, as an intermediate for pharmaceuticals and agricultural chemicals in higher yields than in the case of conventional techniques, and to broaden the selection range of substrates to be used. can do.
  • difluoroketene silyl acetate can serve as an intermediate for the synthesis of di-difluoro-/-keto-esters. It can be produced efficiently using the difluoroacetate represented by the formula [4], zinc and trialkylhalosilane.
  • difluoroketene silyl acetal produced in this way can be reacted with the acid halide to form the dihydroketene silyl acetal in situ without isolation and purification.
  • difluoroketene silyl acetal can be used in the system without isolation in the process of obtaining the desired product without isolation, and not only does not cause any problem, but also greatly contributes to the efficiency of the process.
  • an optically active substance can be further produced from the above-mentioned difluoro- / di-ketoester.
  • an asymmetric hydrogenation reaction is carried out in the presence of a hydrogenated catalyst using the above-mentioned difluoro-/?-Ketoester to obtain optically-enriched difluoro-/?-Hydroxyester. It can be mass-produced efficiently.
  • the alkyl group (or alkyl) represented by the general formula [1], [2], [3] or [4] has a linear, branched or cyclic structure.
  • An alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group, which may have a heteroatom or a halogen atom and may have a substituent and has 1 to 30 carbon atoms; Or a cycloalkyl group having an equivalent number of carbon atoms.
  • Examples of the aryl group (or aryl) shown in each of the above general formulas include a phenyl group which may have a substituent, a naphthyl group, an anthryl group, a heterocyclic aromatic group having a hetero atom or a halogen atom, and the like. Can be exemplified.
  • Examples of the substituent include an alkyl group having 1 to 10 carbon atoms which may be branched, an alkoxy group, an amino group and the like.
  • Examples of the aralkyl group (or aralkyl) include a benzyl group, a p-methylbenzyl group, a naphthylmethyl group, a furfuryl group, and a polyphenyl group.
  • alkenyl group examples include a vinyl group,? -Styryl group, 1-probenyl group, 1-butenyl group, 1-hexenyl group, 1-decenyl group, cyclohexenyl group, aryl group, Examples thereof include a cinnamyl group, a 2-butenyl group and a 2-decenyl group.
  • alkynyl group examples include an ethynyl group, a phenylethynyl group, and a 2-propyl group.
  • the solvent used in each of the production methods of the present invention is not particularly limited, but preferred are 1,3-dimethyl-2-imidazolidinone (DMI), acetonitrile, tetrahydrofuran (THF), dimethylformamid Non-protonic solvents such as amide (DMF) and dimethoxetane (DME).
  • DMI 1,3-dimethyl-2-imidazolidinone
  • THF tetrahydrofuran
  • DME dimethylformamid Non-protonic solvents
  • the reaction proceeds even under non-catalytic conditions, but the reaction rate is extremely slow.
  • a metal catalyst it is preferable to use a metal catalyst.
  • the term “metal-based catalyst” as used herein means not only a metal catalyst but also a metal compound catalyst.
  • a transition metal catalyst is preferable.
  • Specific examples include, for example, cuprous chloride, cupric chloride, tetrakis (triphenylphosphine) palladium (0), and among them, cuprous chloride is preferable.
  • the amount of the metal-based catalyst used in the present invention can be appropriately selected from the range of 0.0001 to 100 equivalents to the acid halide, and among them, 0.1 to 2.0 equivalents. A range is preferred.
  • the reaction temperature in the production method of the present invention can be appropriately selected from the range of —100X; to 200 ° C., and is preferably in the range of 0 ° C. to 100 ° C.
  • difluoroketene silyl acetal produced by this method can be isolated and purified alone, but as described above, in the step of producing a-difluoro-/-ketoester, It is preferable to use it as is without purification.
  • the present invention it is possible to efficiently and efficiently produce not only H, H-difluoro-/-ketoester but also H, H-difluoro-/-H-hydroxy ester which is particularly rich in optical activity. That is, the acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [2] are reacted under non-catalytic conditions, preferably in the presence of the metal-based catalyst. The reaction is carried out below to synthesize the di- and di-fluoro-ketoesters represented by the general formula [3], and the 5-ketoester is subjected to an asymmetric hydrogenation reaction using a hydrogenation catalyst. Then, the target substance can be efficiently obtained in a large amount.
  • the acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [2] are reacted under non-catalytic conditions, preferably in the presence of the metal-based catalyst
  • the hydrogenation catalyst is replaced by Even if 0.001 to 10 mol% is used, the reaction proceeds.
  • the amount of the hydrogenation catalyst used is more preferably 0.01 to 1 mol%, for example, 0.1 mol% or around 0.1 mol%.
  • a metal complex represented by the general formula [6] is preferably used.
  • M represents a metal atom
  • L represents an optically active phosphine ligand
  • the metal atom is Ru, Rh, Pd, Ir or Ni
  • the ligand (optically active phosphine ligand) combined therewith is (R) or (S) —BI NAP, (R) or (S) —T ol—BI NAP, (R) or (S) —Xy l—BI NAP, (R, R) or (S, S) —Me—D uphos, (R , R) or (S, S) —Me—BPE, (R, R) or
  • the ketoester of the general formula [3] can be efficiently synthesized, and the hydroxyester of the general formula [5] can be synthesized from the ketoester in a large amount even with a small amount of a catalyst. It is possible to obtain highly selective difluoro-1-hydroxy ester.
  • the hydroxy ester of the general formula [5] obtained by the production method of the present invention is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.
  • the reaction solvent is not particularly limited, but alcohols, particularly Me OH (methyl alcohol), Et 0 H (Ethyl alcohol) is preferred.
  • the reaction temperature may be between 0 ° C. and 200 ° C., with around 100 ° C. being particularly preferred.
  • the pressure may be from 1 to: L 50 atm, but is especially preferred around lOOatm.
  • the fjij nil-acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [1] are used under non-catalytic conditions or in the presence of a gold-based catalyst. Therefore, it is possible to produce a large amount of Nakawa Takahi, a difluoro-5-ketoester at a high yield, for example, as a cross-linking agent for pharmaceuticals.
  • the difluoroketene silyl acetate represented by the general formula [2] can be produced from difluoro w steep ester represented by the general formula [4], lead and trialkylhalosilane. Further, the acetal can be supplied in a form that is efficiently preferable for the production process of the above-mentioned di-difluoro-/-ketoester and does not require separation and purification.
  • Method 1 The target compound was obtained in the same manner as in Example 1 except that benzoyl-cuff light was used instead of dodecanoic acid-cure light (369 mg, 90% yield) .
  • Method 2 In a suspension of zinc dust (654 mg, 10 mmo1) in acetonitrile (2.5 ml), add 1,2-promoen (0.06 ml) and trimethylsilyl chloride (0.06 ml) at 40 ° C and stirred for 10 minutes. At the same temperature, trimethylsilyl chloride (1.27 ml, 10 mmo1) was further added, and ethyl bromodifluoroacetate (0.64 ml) was added. 1, 5. Ommol) was added dropwise. After stirring at the same temperature for 20 minutes, the supernatant of the suspension was added to a previously prepared suspension of cuprous chloride (495 ml, 5.0 mmol) in DMI (5 ml).
  • the desired compound was obtained in the same manner as in Example 1 except that cyclohexanecarbonyl chloride was used instead of dodecanoic acid chloride [341 mg, 81% yield].
  • the desired compound was obtained in the same manner as in Example 1 except that acetyl chloride was used instead of dodecanoic acid chloride [161 mg, 54% yield].
  • the analytical data of this target compound is shown below.
  • the desired compound was obtained in the same manner as in Example 1 except that tert-butylacetylacetyl chloride was used instead of dodecanoic acid octalide [272 mg, 68% yield].
  • the desired compound was obtained in the same manner as in Example 1 except that 2-furoyl chloride was used instead of dodecanoic acid chloride [23 mg, 59% yield].
  • the desired compound was obtained in the same manner as in Example 1 except that benzyloxyacetyl chloride was used instead of dodecanoic acid cuprate [3 13 mg, 64% yield].

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un halogénure d'acide représenté par la formule générale [1], est mis en réaction avec un difluorocétène silyle acétal représenté par la formule générale [2], de préférence, en présence d'un catalyseur de métal de transition, afin d'obtenir un α,α-difluoro-β-cétoester représenté par la formule générale [3]. Selon les besoins, le β-cétoester est soumis à une réaction d'hydrogénation asymétrique à l'aide d'un catalyseur d'hydrogénation, afin d'induire le α,α-difluoro-β-hydroxyester actif sur le plan optique correspondant. Formule générale [1] Formule générale [2] Formule générale [3] (Dans ces formules générales, R?1, R2, R3, R4, et R5¿ sont chacun représentés, par exemple, par un alkyle et X1 représente un halogéno.) le procédé de l'invention permet de produire en masse du α,α-difluoro-β-cétoester à des rendements élevés. L'invention concerne également un procédé de production de difluorocétène silyle acétal pouvant s'utiliser comme intermédiaire dans ce procédé, et un procédé permettant de produire en masse de façon efficace du α,α-difluoro-β-hydroxyester actif sur le plan optique à partir du β-cétoester.
PCT/JP2001/001103 2000-03-07 2001-02-15 PROCEDE DE PRODUCTION D'α,α-DIFLUORO-β-CETOESTER WO2001066509A1 (fr)

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JP2000-62046 2000-03-07
JP2000062046A JP2001247514A (ja) 2000-03-07 2000-03-07 α，α−ジフルオロ−β−ケトエステルの製造方法、及びジフルオロケテンシリルアセタールの製造方法、並びに光学活性なα，α−ジフルオロ−β−ヒドロキシエステルの製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960679B2 (en) 2003-04-25 2005-11-01 Shin-Etsu Chemical Co., Ltd. Preparation of silyl ketene acetal and disilyl ketene acetal
JP4781678B2 (ja) * 2005-01-06 2011-09-28 関東電化工業株式会社 含フッ素ケテンシリルアセタールを用いたβ−ケトエステルの製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120368A2 (fr) * 1983-03-09 1984-10-03 Daikin Kogyo Co., Ltd. Esters alpha-fluoroalkyliques d'acides carboxyliques et leur procédé de préparation
JPH0267250A (ja) * 1988-09-02 1990-03-07 Asahi Glass Co Ltd ２，２‐ジフルオロ‐３‐ヒドロキシカルボン酸誘導体の製造法
JPH11302226A (ja) * 1998-04-15 1999-11-02 Takasago Internatl Corp 光学活性アルコ−ルの製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120368A2 (fr) * 1983-03-09 1984-10-03 Daikin Kogyo Co., Ltd. Esters alpha-fluoroalkyliques d'acides carboxyliques et leur procédé de préparation
JPH0267250A (ja) * 1988-09-02 1990-03-07 Asahi Glass Co Ltd ２，２‐ジフルオロ‐３‐ヒドロキシカルボン酸誘導体の製造法
JPH11302226A (ja) * 1998-04-15 1999-11-02 Takasago Internatl Corp 光学活性アルコ−ルの製造方法

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