JP5472638B2 - Process for producing 1- (substituted phenyl) -1-substituted silyl ethers, alcohols or ketones and intermediates - Google Patents

Description

  The present invention relates to a method for producing aromatic ketone compounds, substituted silyl ether compounds and 1- (substituted phenyl) -1-substituted alcohol compounds useful as intermediates for the production of functional materials such as medical and agricultural chemicals or electronic materials, and 1 -(Substituted phenyl) -2,2,2-trifluoroethanol compounds and substituted trimethylsilyl ether compounds.

Several methods for producing a substituted silyl ether compound or a 1- (substituted phenyl) -1-substituted alcohol compound using an aromatic aldehyde compound as a starting material are known (for example, Patent Documents 1 and 2, Non-Patent Document 1). ~ 12).
In addition, a method for producing an aromatic ketone compound using a 1- (substituted phenyl) -1-substituted alcohol compound as a raw material is also known (for example, Patent Documents 3 and 4, Non-Patent Documents 13 to 17).

Prior art documents

Japanese Patent Application Laid-Open No. 7-118188 German Patent Application Publication No. 3805534 US Patent Application No. 20051121616 German Patent Application Publication No. 4141435 US Patent Application No. 2004024386 International Publication No. 2007/074789 Pamphlet International Publication No. 2009/001942 Pamphlet

Chemical Communications, No. 24, 2575 (2006) Journal of Organic Chemistry, vol. 71, 6806 (2006) Synlett, No. 1, 112 (2006) Chemistry Letters, vol. 34, No. 1, 88 (2005) Organic Letters, vol. 7, No. 11, 2193 (2005) Combinatorial Chemistry and High Throughput Screening, Vol. 5, No. 3, 197 (2002) Tetrahedron Letters, vol. 40, No. 47, 8231 (1999) Bulletin of the Chemical Society of Japan, vol. 79, No. 7, 1133 (2006) Journal of Organic Chemistry, vol. 64, No. 8, 2873 (1999) Tetrahedron Letters, vol. 40, No. 11, 2065 (1999) Journal of Fluorine Chemistry, vol. 73, No. 1, 21 (1995) Journal of Organic Chemistry, vol. 56, No. 3, 984 (1999) Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 4, 1127 (2007) Journal of Organic Chemistry, vol. 69, No. 25, 8676 (2004) Bulletin of the Chemical Society of Japan, vol. 75, No. 2, 223 (2002) Tetrahedron Letters, vol. 41, No. 18, 3327 (2000) Journal of Organic Chemistry, vol. 64, No. 7, 2433 (1999) There are several methods for producing substituted silyl ether compounds or 1- (substituted phenyl) -1-substituted carbonyl compounds using benzoate compounds as starting materials. It is known (for example, Patent Literature 5 and Non-Patent Literature 9, 18 to 20). Bioorganic & Medicinal Chemistry Letters, vol.17, No.4, 1127 (2007) Bulletin of the Chemical Society of Japan, vol. 79, No. 7, 1133 (2006) Angewante Chemie, International Edition, vol. 37, No. 6, 820 (1998)

  The methods described in Patent Literature 2 and Non-Patent Literatures 9 to 12 using a fluorine compound as a catalyst have been conventionally known, but are not necessarily methods suitable for industrialization. In Patent Document 1, an organic base such as triethylamine is used, but if the amount used is a catalyst amount, the yield is low, which is not satisfactory as an industrial production method. Non-patent documents 1 to 7 all use materials and heavy metals that are difficult to obtain in large quantities, leading to an increase in manufacturing costs and waste, which is not satisfactory as an industrial production method. Non-Patent Document 8 also describes a method using a relatively inexpensive catalyst, but it is not satisfactory as an industrial production method because it requires a solvent that is difficult to recover.

  The method described in Patent Document 3 is not suitable for industrial production because a compound having a strong odor is by-produced after the reaction. The method described in Patent Document 4 is not satisfactory as an industrial production method because the yield of the product is not high. In the methods described in Patent Documents 13 to 17, materials and heavy metals that are difficult to obtain in large quantities are used, which leads to an increase in manufacturing costs and waste, and is not satisfactory as an industrial manufacturing method.

  Thus, in the existing method, a substituted silyl ether compound or a 1- (substituted phenyl) -1-substituted alcohol compound is produced using an aromatic aldehyde compound as a starting material without using an expensive reagent or heavy metal. The method is unknown and leaves room for improvement.

  In addition, there is a method for producing an aromatic ketone compound from a 1- (substituted phenyl) -1-substituted alcohol compound as a raw material in a low-polarity solvent that can be easily recovered without using reagents or heavy metals that are difficult to obtain in large quantities. It is not known and leaves room for improvement.

  Patent Document 5 shows only an example of synthesizing 2,2,2-trifluoro-1- (4-nitrophenyl) ethanone from methyl 4-nitrobenzoate, and the yield is moderate at 47%. It was difficult to generalize as an industrial production method. When the reaction is carried out at a relatively high temperature in a dimethoxyethane solvent as described in Patent Documents 6 and 7, trifluoromethyltrimethylsilane is considered to be produced by further reaction of the target trifluoroacetophenone with trifluoromethyltrimethylsilane. There was a problem that the yield of the target product was lowered because a relatively large amount of by-product containing two groups was produced. In the methods described in Non-Patent Documents 18 and 20, the reaction must be performed at an extremely low temperature of −78 ° C., which is not satisfactory as an industrial production method. In the method described in Non-Patent Document 19, a by-product is produced by further reacting the target carbonyl compound depending on the substrate, so it may be difficult to obtain the target carbonyl compound with high selectivity and high yield. It was. The method described in Non-Patent Document 9 uses cesium fluoride as a catalyst. However, the reaction does not proceed in a low-polar solvent commonly used in industry such as toluene, and the reaction substrate is used without a solvent. Since the risk of runaway reaction of adding cesium fluoride as a catalyst to the mixture as a solid is extremely high, it was not satisfactory as an industrial production method.

  As described above, in existing methods, a substituted silyl ether compound or a 1- (substituted phenyl) -1-substituted carbonyl compound using a benzoic acid ester compound as a starting material is used in an industrially low A method for producing a high yield and high selectivity in a polar solvent is not known except that the reaction is carried out at an extremely low temperature of −78 ° C., leaving room for improvement.

As a result of intensive studies in view of such circumstances, the present inventors have represented a substituted silyl ether compound or a 1- (substituted phenyl) -1-substituted alcohol compound as a starting material by using an aromatic aldehyde compound as a starting material. In a low-polarity solvent, in the presence or absence of a water-soluble solvent, the reaction was carried out using an easily available material such as potassium carbonate as a catalyst, and a method for producing in high yield was found, leading to the invention. It was.
In addition, an aromatic ketone compound made from a 1- (substituted phenyl) -1-substituted alcohol compound as a raw material, in a low polarity solvent typified by toluene, in the presence of an oxidation catalyst and an additive, such as hypochlorite A reaction was carried out using an oxidant to find a method for producing in a high yield, leading to the invention.
Further, a substituted silyl ether compound or a 1- (substituted phenyl) -1-substituted carbonyl compound is used as a starting material from a benzoate ester compound in a low polarity solvent typified by toluene at a temperature higher than −50 ° C. The present invention has been carried out to find a method of producing a product with high selectivity and high yield, leading to the invention.

［式中、Ｒ¹は、Ｃ₁〜Ｃ₆ハロアルキル又はＣ₃〜Ｃ₈ハロシクロアルキルを表し、
Ｘは、ハロゲン原子、シアノ、ニトロ、−ＳＦ₅、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₈シクロアルキル、Ｃ₁〜Ｃ₆アルケニル、Ｃ₁〜Ｃ₆アルキニル、シアノ（Ｃ₁〜Ｃ₆）アルキル、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルケニル、ヒドロキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₁〜Ｃ₆アルコキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₃〜Ｃ₈ハロシクロアルキル、−ＯＨ、−ＯＲ⁵、ベンジルオキシ、−ＮＨ₂、−Ｎ（Ｒ⁷）Ｒ⁶、−Ｓ（Ｏ）_rＲ⁵又はフェニルスルホニルオキシを表し、ｍが２以上を表すとき、各々のＸは互いに同一であっても又は互いに相異なっていてもよく、
Ｒ⁵は、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₄アルコキシ（Ｃ₁〜Ｃ₄）アルキル、Ｃ₁〜Ｃ₆ハロアルキル又はＣ₁〜Ｃ₃ハロアルコキシ（Ｃ₁〜Ｃ₃）ハロアルキルを表し、
Ｒ⁶は、Ｃ₁〜Ｃ₆アルキル、−ＣＨＯ、Ｃ₁〜Ｃ₆アルキルカルボニル、Ｃ₁〜Ｃ₆ハロアルキルカルボニル、Ｃ₁〜Ｃ₆アルコキシカルボニル、Ｃ₁〜Ｃ₆アルキルチオカルボニル、Ｃ₁〜Ｃ₆アルコキシチオカルボニル、Ｃ₁〜Ｃ₆アルキルジチオカルボニル、Ｃ₁〜Ｃ₆アルキルスルホニル又はＣ₁〜Ｃ₆ハロアルキルスルホニルを表し、
Ｒ⁷は、水素原子又はＣ₁〜Ｃ₆アルキルを表し、
ｍは、０〜５の整数を表し、
ｒは、０〜２の整数を表す。］ で表される１−（置換フェニル）−１−置換アルコール化合物を酸化触媒および添加物の存在下、酸化剤と反応させることによる式（２）：

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表す。］で表される芳香族ケトン化合物の製造方法。That is, the present invention
[1] Formula (1):

[Wherein R ¹ represents C ₁ -C ₆ haloalkyl or C ₃ -C ₈ halocycloalkyl,
X is a halogen atom, cyano, nitro, —SF ₅ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, cyano (C ₁ -C ₆ ) Alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkenyl, hydroxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ ~C ₆₎ haloalkyl, C ₃ -C ₈ halocycloalkyl, -OH, -OR ^{5, _{benzyloxy, -NH 2, -N (R 7}} ) R 6, -S (O) r R 5 or Represents phenylsulfonyloxy, and when m represents 2 or more, each X may be the same as or different from each other;
R ⁵ represents C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₃ haloalkoxy (C ₁ -C ₃ ) haloalkyl. ,
R ⁶ is C ₁ -C ₆ alkyl, —CHO, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylthiocarbonyl, C ₁ -C ₆ alkoxythiocarbonyl, C ₁ -C ₆ alkyl dithio carbonyl, represents C ₁ -C ₆ alkylsulfonyl or C ₁ -C ₆ haloalkylsulfonyl,
R ⁷ represents a hydrogen atom or C ₁ -C ₆ alkyl,
m represents an integer of 0 to 5;
r represents an integer of 0-2. Formula (2) by reacting a 1- (substituted phenyl) -1-substituted alcohol compound represented by the following formula with an oxidizing agent in the presence of an oxidation catalyst and an additive:

[Wherein R ¹ , X and m represent the same meaning as described above. ] The manufacturing method of the aromatic ketone compound represented by this.

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表し、Ｒ²、Ｒ³およびＲ⁴は、Ｃ₁〜Ｃ₆アルキル又は芳香族基を表す。］ で表される置換シリルエーテル化合物を水を添加してまたは添加しないで、他の有機溶媒を添加してまたは添加しないで、酸および／またはフッ素源と反応させることによる前記式（１）：

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表す。］で表される１−（置換フェニル）−１−置換アルコール化合物の製造方法。[2] Formula (3):

[Wherein, R ¹ , X, and m represent the same meaning as described above, and R ² , R ^3, and R ⁴ represent C ₁ -C ₆ alkyl or an aromatic group. The above-described formula (1) is obtained by reacting the substituted silyl ether compound represented by the formula (1) with or without addition of water and with or without the addition of another organic solvent:

[Wherein R ¹ , X and m represent the same meaning as described above. ] The manufacturing method of 1- (substituted phenyl) -1-substituted alcohol compound represented by this.

［式中、Ｘ、ｍは前記と同様の意味を表す。］ で表される芳香族アルデヒド化合物と
式（５）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は前記と同様の意味を表す。］ で表される置換ケイ素化合物とを溶媒中反応させることによる前記式（３）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｘ、ｍは前記と同様の意味を表す。］で表される置換シリルエーテル化合物の製造方法。
〔４〕 溶媒が水に不溶な有機溶媒であることを特徴とする〔３〕記載の製造方法。
〔５〕 溶媒が水に可溶な有機溶媒であることを特徴とする〔３〕記載の製造方法。
〔６〕 溶媒が水に不溶な有機溶媒であり、水に可溶な有機溶媒を混合することを特徴とする〔３〕記載の製造方法。[3] Formula (4):

[Wherein, X and m represent the same meaning as described above. ] An aromatic aldehyde compound represented by the formula (5):

[Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above. The above formula (3) by reacting with a substituted silicon compound represented by the following formula:

[Wherein, R ¹ , R ² , R ³ , R ⁴ , X, m represent the same meaning as described above. ] The manufacturing method of the substituted silyl ether compound represented by this.
[4] The production method according to [3], wherein the solvent is an organic solvent insoluble in water.
[5] The method according to [3], wherein the solvent is an organic solvent soluble in water.
[6] The production method according to [3], wherein the solvent is an organic solvent insoluble in water and an organic solvent soluble in water is mixed.

［式中、Ｘ、ｍは前記と同様の意味を表す。］ で表される芳香族アルデヒド化合物と前記式（５）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は前記と同様の意味を表す。］ で表される置換ケイ素化合物とを溶媒中反応させ、次いで、水を添加してまたは添加しないで、他の有機溶媒を添加してまたは添加しないで、酸および／またはフッ素源と反応させることにより前記式（１）：

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表す。］ で表される１−（置換フェニル）−１−置換アルコール化合物を１工程で製造する方法。[7] Formula (4):

[Wherein, X and m represent the same meaning as described above. ] An aromatic aldehyde compound represented by the formula (5):

[Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above. And then reacting with the acid and / or fluorine source with or without the addition of water and with or without the addition of other organic solvents. According to the formula (1):

[Wherein R ¹ , X and m represent the same meaning as described above. ] The method to manufacture the 1- (substituted phenyl) -1-substituted alcohol compound represented by these by 1 process.

[8] A solution containing the compound represented by the formula (1) obtained by reacting the compound represented by the formula (4) with the compound represented by the formula (5) is used as a raw material [1. ] The manufacturing method of the aromatic ketone compound of description.

[9] X is a halogen atom, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy (C ₁ ~C ₆₎ haloalkyl, cyano (C ₁ ~C ₆₎ alkyl, C ₁ ~ C ₆ alkoxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ -C ₆ ) haloalkyl, C ₃ -C ₈ halocycloalkyl, —OH, —OR ⁵ , —NH ₂ or —N (R ⁷ ) R ⁶ and when m represents 2 or more, each X may be the same as or different from each other,
Production according to any one of [1] to [8], wherein R ⁶ represents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl or C ₁ -C ₆ alkoxycarbonyl. Method.

［式中、Ｙは、ハロゲン原子、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ又はＣ₁〜Ｃ₆ハロアルキルチオを表し、
Ｚは、塩素原子、臭素原子、よう素原子、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ又はＣ₁〜Ｃ₆ハロアルキルチオを表す。］ で表される１−（置換フェニル）−２，２，２−トリフルオロエタノール化合物。[10] Formula (6):

[Wherein Y represents a halogen atom, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ haloalkylthio;
Z represents a chlorine atom, a bromine atom, an iodine atom, C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ haloalkylthio. ] The 1- (substituted phenyl) -2,2,2-trifluoroethanol compound represented by these.

［式中、Ｚは前記と同様の意味を表し、
Ｗは、臭素原子、よう素原子、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ又はＣ₁〜Ｃ₆ハロアルキルチオを表す。］ で表される１−（置換フェニル）−２，２，２−トリフルオロエタノール化合物。[11] Formula (7):

[Wherein Z represents the same meaning as described above,
W represents a bromine atom, an iodine atom, C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ haloalkylthio. ] The 1- (substituted phenyl) -2,2,2-trifluoroethanol compound represented by these.

［式中、Ｙ¹は、ハロゲン原子、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ又はＣ₁〜Ｃ₆ハロアルキルチオを表し、Ｙ²は、ハロゲン原子、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ又はＣ₁〜Ｃ₆ハロアルキルチオを表し、Ｚは前記と同様の意味を表す。］ で表される１−（置換フェニル）−２，２，２−トリフルオロエタノール化合物。[12] Formula (8):

[Wherein Y ¹ represents a halogen atom, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ haloalkylthio, Y ² represents a halogen atom, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ haloalkylthio is represented, and Z represents the same meaning as described above. ] The 1- (substituted phenyl) -2,2,2-trifluoroethanol compound represented by these.

［式中、Ｙ、Ｚは前記と同様の意味を表す。］ で表される置換トリメチルシリルエーテル化合物。[13] Formula (9):

[Wherein Y and Z represent the same meaning as described above. ] The substituted trimethylsilyl ether compound represented by these.

［式中、Ｗ、Ｚは前記と同様の意味を表す。］ で表される置換トリメチルシリルエーテル化合物。[14] Formula (10):

[Wherein W and Z represent the same meaning as described above. ] The substituted trimethylsilyl ether compound represented by these.

［式中、Ｙ¹、Ｙ²、Ｚは前記と同様の意味を表す。］ で表される置換トリメチルシリルエーテル化合物。[15] Formula (11):

[Wherein Y ¹ , Y ² and Z represent the same meaning as described above. ] The substituted trimethylsilyl ether compound represented by these.

［式中、Ｒ⁸は、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルケニル、Ｃ₁〜Ｃ₆アルキニル、Ｃ₃〜Ｃ₈シクロアルキル、Ｃ₁〜Ｃ₆ハロアルキル、Ｃ₁〜Ｃ₆ハロアルケニル、ヒドロキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₁〜Ｃ₆アルコキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₁〜Ｃ₆ハロアルコキシ（Ｃ₁〜Ｃ₆）ハロアルキル、Ｃ₃〜Ｃ₈ハロシクロアルキル又は芳香族基を表し、Ｘ、ｍは前記と同様の意味を表す。］ で表される安息香酸エステル化合物を式（５）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は前記と同様の意味を表す。］ で表される置換ケイ素化合物と反応させることによる式（１３）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｘ、ｍは前記と同様の意味を表す。］ で表される置換シリルエーテル化合物の製造方法。[16] Formula (12):

[Wherein R ⁸ represents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo. alkenyl, hydroxy (C ₁ ~C ₆₎ haloalkyl, C ₁ -C ₆ alkoxy (C ₁ ~C ₆₎ haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ ~C ₆₎ haloalkyl, C ₃ -C ₈ Haroshikuro Represents an alkyl or aromatic group, and X and m represent the same meaning as described above. A benzoic acid ester compound represented by the formula (5):

[Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above. ] Formula (13) by making it react with the substituted silicon compound represented by these:

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , X, m represent the same meaning as described above. ] The manufacturing method of the substituted silyl ether compound represented by these.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｘ、ｍは前記と同様の意味を表す。］ で表される置換シリルエーテル化合物を反応させることによる式（２）：

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表す。］ で表される１−（置換フェニル）−１−置換カルボニル化合物の製造方法。[17] Formula (13):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , X, m represent the same meaning as described above. ] Formula (2) by making the substituted silyl ether compound represented by these react:

[Wherein R ¹ , X and m represent the same meaning as described above. ] The manufacturing method of 1- (substituted phenyl) -1-substituted carbonyl compound represented by these.

［式中、Ｒ⁸、Ｘ、ｍは前記と同様の意味を表す。］ で表される安息香酸エステル化合物と式（５）：

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は前記と同様の意味を表す。］ で表される置換ケイ素化合物とを反応させること、及び該反応への添加剤として、トリメチルアミン、トリエチルアミン又はトリ−ｎ−ブチルアミンを使用することを含む、式（２）：

［式中、Ｒ¹、Ｘ、ｍは前記と同様の意味を表す。］ で表される１−（置換フェニル）−
１−置換カルボニル化合物を１工程で製造する製造方法。特に、該製造方法のうち、式（５）及び式（２）中のＲ _１ がトリフルオロメチル基を表すところの製造方法。 [18] Formula (12):

[Wherein R ⁸ , X and m represent the same meaning as described above. And a benzoic acid ester compound represented by the formula (5):

[Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above. And using trimethylamine, triethylamine, or tri-n-butylamine as an additive to the reaction , with a substituted silicon compound represented by formula (2):

[Wherein R ¹ , X and m represent the same meaning as described above. 1- (substituted phenyl)-
A production method for producing a 1-substituted carbonyl compound in one step. In particular, among the production methods, the production method in which R ₁ in formula (5) and formula (2) represents a trifluoromethyl group.

[19] Any of [16] to [18], wherein an aliphatic hydrocarbon optionally substituted with halogen, an aromatic hydrocarbon optionally substituted with halogen, or a mixed solvent containing at least one of them is used as a solvent. The manufacturing method as described in.
[20] The production method according to any one of [16] to [19], wherein the reaction is performed at a temperature higher than −50 ° C.

According to the production method of the present invention, aromatic ketone compounds such as 1- (substituted phenyl) -1-substituted carbonyl compounds, substituted silyl ether compounds, or the like useful for the synthesis of intermediates for the production of functional materials such as medical pesticides or electronic materials Using 1- (substituted phenyl) -1-substituted alcohol compound as a starting material, 1- (substituted phenyl) -1-substituted alcohol compound, aromatic aldehyde compound, substituted silicon compound or substituted silyl ether compound, and benzoate compound Appropriate selection of reagents such as catalysts, and in high-yield, high-selectivity while suppressing the formation of by-products containing two trifluoromethyl groups in industrially easy-to-use solvents such as toluene Can be manufactured and thereby provide a useful method for industrial production.

  The compound represented by the general formula (1), (3), (6) to (11) or (13) described in the present application has an optically active substance resulting from the presence of one or more asymmetric carbon atoms. However, the compounds described herein include all optically active forms or racemates.

  Among the compounds described in the present application, those which can be converted into acid addition salts according to a conventional method are, for example, hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, nitric acid , Inorganic acid salts such as sulfuric acid, phosphoric acid, chloric acid, perchloric acid, sulfonic acid salts such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid , Salt of carboxylic acid such as propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, citric acid or glutamic acid, It can be a salt of an amino acid such as aspartic acid.

  Alternatively, among the compounds described in the present application, those which can be converted into a metal salt according to a conventional method include, for example, alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as calcium, barium and magnesium, or aluminum The salt of

  Alternatively, among the compounds described in the present application, those that can be converted into an amine salt according to a conventional method are, for example, ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, benzylamine, aniline, dimethylamine, diethylamine, It can be a salt of dipropylamine, dibutylamine, dipentylamine, pyrrolidine, piperidine, piperazine, morpholine, dibenzylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, tribenzylamine and the like.

  Next, specific examples of each substituent shown in the present specification are shown below. Here, n- represents normal, i- represents iso, s- represents secondary, and t- represents tertiary, and Ph represents phenyl.

  Examples of the halogen atom in the compounds described in the present application include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the present specification, the notation “halo” also represents these halogen atoms.

The notation of C _a -C _b alkyl in the present specification represents a linear or branched hydrocarbon group comprising _a to _b carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group, Specific examples include 1,3-dimethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, etc., and each is selected within the range of the designated number of carbon atoms.

The notation of C _a -C _b cycloalkyl in the present specification represents a cyclic hydrocarbon group having _a to _b carbon atoms, and forms a monocyclic or complex ring structure having 3 to 6 members. I can do it. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms. For example, cyclopropyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2- Specific examples include methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo [2.2.1] heptan-2-yl group, and the like. Each of which is selected for each specified number of carbon atoms.

  Specific examples of the notation of the aromatic group in the present specification include a phenyl group, a naphthyl group, and an anthryl group.

In the present specification, C _a -C _b haloalkyl is a linear or branched chain having _a to _b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. Represents a hydrocarbon group, and when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl Group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl Group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2 -Fluoroethyl group, 2,2,2-trichloroethyl group, 2 Bromo-2,2-difluoroethyl group, 2-bromo-2-chloro-2-fluoroethyl group, 2-bromo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, penta Fluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1,1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2- Trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropyl group, 2-chloro-2-fluoropropyl group, 2,3-dichloropropyl group, 2-bromo-3-fluoropropyl group, 3-bromo-2-chloropropyl group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 3-butyl Mo-3,3-difluoropropyl group, 2,2,3,3-tetrafluoropropyl group, 2-chloro-3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoro Propyl group, 1,1,2,3,3,3-hexafluoropropyl group, heptafluoropropyl group, 2,3-dichloro-1,1,2,3,3-pentafluoropropyl group, 2-fluoro- 1-methylethyl group, 2-chloro-1-methylethyl group, 2-bromo-1-methylethyl group, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl group, 1,2,2 , 2-tetrafluoro-1- (trifluoromethyl) ethyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3, 4,4,4-hexafluoro Butyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, 1,1,2,2,3,3 , 4,4-octafluorobutyl group, nonafluorobutyl group, 4-chloro-1,1,2,2,3,3,4,4-octafluorobutyl group, 2-fluoro-2-methylpropyl group, 1,2,2,3,3,3-hexafluoro-1- (trifluoromethyl) propyl group, 2-chloro-1,1-dimethylethyl group, 2-bromo-1,1-dimethylethyl group, 5 Specific examples include -chloro-2,2,3,4,4,5,5-heptafluoropentyl group, tridecafluorohexyl group, and the like, and each is selected within the range of the designated number of carbon atoms.

In the present specification, cyano (C _a -C _b ) alkyl is represented by a straight or branched chain having _a to _b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a cyano group. Represents a chain-like alkyl group, for example, cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group, 2-cyanopropyl group, 3-cyanopropyl group, 2-cyanobutyl group and the like. Selected in the range of the number of carbon atoms.

In the present specification, C _a -C _b halocycloalkyl represents a cyclic hydrocarbon group having _a to _b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. And can form monocyclic or complex ring structures from 3 to 6-membered rings. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the substitution with a halogen atom may be a ring structure part, a side chain part, They may be both, and when they are substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methyl Cyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group , 4- (trifluoromethyl) cyclohexyl group and the like can be mentioned as specific examples, and each is selected within the range of the designated number of carbon atoms.

In the present specification, C _a -C _b alkenyl is a linear or branched chain composed of _a to _b carbon atoms and has one or more double bonds in the molecule. Represents a saturated hydrocarbon group, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2 -Pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl Specific examples include 2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group, 3,7-dimethyl-2,6-octadienyl group, and the like, each selected within the range of the specified number of carbon atoms. Is done.

In the present specification, C _a -C _b haloalkenyl is represented by a linear or branched chain in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and the number of carbon atoms is ab. And an unsaturated hydrocarbon group having one or more double bonds in the molecule. At this time, when substituted with two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, 2,2-dichlorovinyl group, 2-fluoro-2-propenyl group, 2-chloro-2-propenyl group, 3-chloro-2-propenyl group, 2-bromo-2-propenyl group, 3-bromo-2 -Propenyl group, 3,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl group, 3,3-dichloro-2-propenyl group, 2,3-dibromo-2-propenyl group, 2, 3,3-trifluoro-2-propenyl group, 2,3,3-trichloro-2-propenyl group, 1- (trifluoromethyl) ethenyl group, 3-chloro-2-butenyl group, 3-bromo-2- Butenyl group, 4,4-difluoro-3-butenyl group, 3,4,4-trifluoro-3-butenyl group, 3-chloro-4,4,4-trifluoro-2-butenyl group, 3-bromo- 2-methyl- - propenyl group, etc. As a specific example, it may be selected from the range of the specified number of carbon atoms.

In the present specification, C _a -C _b alkynyl is a linear or branched chain composed of _a to _b carbon atoms and has one or more triple bonds in the molecule. Represents a hydrocarbon group, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1, Specific examples include a 1-dimethyl-2-propynyl group, a 2-hexynyl group, and the like, and each is selected within the range of the designated number of carbon atoms.

The notation of C _a -C _b alkoxy in the present specification represents an alkyl-O— group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, methoxy group, ethoxy group, n-propyloxy group, Specific examples include i-propyloxy group, n-butyloxy group, i-butyloxy group, s-butyloxy group, t-butyloxy group, n-pentyloxy group, n-hexyloxy group and the like. It is selected in the range of the number of atoms.

The notation of C _a -C _b haloalkoxy in the present specification represents a haloalkyl-O— group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, difluoromethoxy group, trifluoromethoxy group, chlorodifluoro Methoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2, -tetrafluoroethoxy group, 2-chloro-1 , 1,2-trifluoroethoxy group, 2-bromo-1,1,2-trifluoroethoxy group, pentafluoroethoxy group, 2,2-dichloro-1,1,2-trifluoroethoxy group, 2,2 , 2-trichloro-1,1-difluoroethoxy group, 2-bromo-1,1,2,2-tetrafluoroethoxy group, 2,2,3,3-tetrafur Ropropyloxy group, 1,1,2,3,3,3-hexafluoropropyloxy group, 2,2,2-trifluoro-1- (trifluoromethyl) ethoxy group, heptafluoropropyloxy group, 2- Specific examples include a bromo-1,1,2,3,3,3-hexafluoropropyloxy group and the like, which are selected in the range of the respective designated number of carbon atoms.

The notation of C _a -C _b alkylsulfonyl in the present specification represents an alkyl-SO ₂ -group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, methylsulfonyl group, ethylsulfonyl group, n- Specific examples include propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group and the like. Each of which is selected for each specified number of carbon atoms.

The notation of C _a -C _b haloalkylsulfonyl in the present specification represents a haloalkyl-SO ₂ — group having the above-mentioned meaning consisting of _a to _b carbon atoms, such as a difluoromethylsulfonyl group or a trifluoromethylsulfonyl group. Chlorodifluoromethylsulfonyl group, bromodifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-tetrafluoroethylsulfonyl group, 2-chloro-1,1,2-trimethyl Specific examples include a fluoroethylsulfonyl group, a 2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group, and the like, and each is selected within the range of the designated number of carbon atoms.

The notation of C _a -C _b alkylcarbonyl in the present specification represents an alkyl-C (O) -group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, acetyl group, propionyl group, butyryl group. , Isobutyryl group, valeryl group, isovaleryl group, 2-methylbutanoyl group, pivaloyl group, hexanoyl group, heptanoyl group, and the like, and specific examples thereof are selected within the range of the number of carbon atoms designated.

The notation of C _a -C _b haloalkylcarbonyl in the present specification represents a haloalkyl-C (O) — group having the above-mentioned meaning consisting of _a to _b carbon atoms, such as a fluoroacetyl group, a chloroacetyl group, Difluoroacetyl group, dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl group, bromodifluoroacetyl group, trichloroacetyl group, pentafluoropropionyl group, heptafluorobutanoyl group, 3-chloro-2,2-dimethylpropanoyl group Etc. are given as specific examples, and each is selected within the range of the designated number of carbon atoms.

The notation of C _a -C _b alkoxycarbonyl in the present specification represents an alkyl-O—C (O) — group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, methoxycarbonyl group, ethoxycarbonyl Group, n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, t-butoxycarbonyl group, etc. Selected.

The notation of C _a -C _b alkylthiocarbonyl in the present specification represents an alkyl-S—C (O) — group having the above-mentioned meaning comprising _a to _b carbon atoms, for example, methylthio-C (O) -Group, ethylthio-C (O)-group, n-propylthio-C (O)-group, i-propylthio-C (O)-group, n-butylthio-C (O)-group, i-butylthio-C Specific examples include (O) -group, t-butylthio-C (O) -group and the like, and each is selected within the range of the number of carbon atoms designated.

In the present specification, the expression C _a -C _b alkoxythiocarbonyl represents an alkyl-O—C (S) — group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, methoxy-C (S ) -Group, ethoxy-C (S) -group, n-propyloxy-C (S) -group, i-propyloxy-C (S) -group, etc. Selected in a range of numbers.

The notation of C _a -C _b alkyldithiocarbonyl in the present specification represents an alkyl-S—C (S) — group having the above-mentioned meaning consisting of _a to _b carbon atoms, for example, methylthio-C (S ) -Group, ethylthio-C (S) -group, n-propylthio-C (S) -group, i-propylthio-C (S) -group and the like. Selected by range.

C _a -C _b alkoxy (C _d -C _e ) alkyl, hydroxy (C _d -C _e ) haloalkyl, C _a -C _b alkoxy (C _d -C _e ) haloalkyl or C _a -C _b halo herein The notation such as alkoxy (C _d -C _e ) haloalkyl represents a hydrogen atom or halogen bonded to a carbon atom by any C _a -C _b alkoxy group, C _a -C _b haloalkoxy group or hydroxyl group, respectively, as defined above. Represents a haloalkyl group having the above-mentioned meaning, wherein the number of carbon atoms is optionally substituted, and is, for example, 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl group , Difluoro (methoxy) methyl group, 2,2,2-trifluoro-1-methoxy-1- (trifluoromethyl) ethyl group, difluoro (2,2,2-trifluoroethoxy) ) Methyl group, 2,2,2-trifluoro-1- (2,2,2-trifluoroethoxy) -1- (trifluoromethyl) ethyl group, 3- (1,2-dichloro-1,2, Specific examples include 2-trifluoroethoxy) -1,1,2,2,3,3-hexafluoropropyl group and the like, and each is selected within the range of the designated number of carbon atoms.

In the compounds described in the present, the substituents represented by X, preferably a halogen atom, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy (C ₁ ~C ₆₎ haloalkyl, cyano (C ₁ ~C ₆₎ alkyl, C ₁ -C ₆ alkoxy (C ₁ ~C ₆₎ haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ ~C ₆₎ haloalkyl, C ₃ -C ₈ halocycloalkyl, - OH, —OR ⁵ , —NH ₂ and —N (R ⁷ ) R ⁶ , more preferably fluorine atom, chlorine atom, bromine atom, iodine atom, cyano, methyl, trifluoromethyl, pentafluoroethyl, tri Fluoromethoxy, difluoromethoxy, bromodifluoromethoxy, trifluoromethylthio, chlorodifluoromethylthio and bromodifluoromethylthio At this time, when m representing the number of substituents represented by X represents an integer of 2 or more, each X may be the same as or different from each other.
In the compounds described in the present application, m representing the number of substituents represented by X preferably includes 1, 2 and 3.
In the compounds described in the present application, the position of the substituent represented by X preferably includes a meta position and a para position with respect to the bonding position with the carbon to which R ¹ is bonded.

In the compounds described in the present application, the substituent represented by R ¹ preferably includes C _{1 to} C ₄ haloalkyl, more preferably difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl, and trifluoromethyl. Very particular preference is given to chlorodifluoromethyl and trifluoromethyl.

In the compounds described in the present application, the substituent represented by R ² is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl or phenyl, more preferably Includes methyl, ethyl and t-butyl.

In the compounds described in the present application, the substituent represented by R ³ is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl or phenyl, more preferably Includes methyl, ethyl and t-butyl.

In the compounds described in the present application, the substituent represented by R ⁴ is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl or phenyl, more preferably Includes methyl, ethyl and t-butyl.

In the compounds described in the present application, the substituent represented by R ⁵ preferably includes C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy (C ₁ -C ₆ ) haloalkyl, more preferably trifluoro. Examples thereof include methyl and difluoromethyl.

In the compounds described in the present application, the substituent represented by R ⁶ is preferably C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, and C ₁ -C ₆ alkoxycarbonyl. More preferred are methyl, acetyl, propionyl, trifluoroacetyl, methoxycarbonyl and ethoxycarbonyl.

In the compounds described in the present application, the substituent represented by R ⁷ preferably includes a hydrogen atom and methyl.

In the compounds described in the present application, the substituent represented by R ⁸ preferably includes C ₁ -C ₄ alkyl, and more preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Examples include butyl, t-butyl or phenyl, and very preferably methyl and ethyl.

  In the compounds described in the present application, examples of r representing the number of oxygen atoms on the sulfur atom include 0, 1, and 2.

  The solvent that can be used in the reaction of the present invention is not particularly limited as long as it is inert to the reaction. For example, it may be substituted with a halogen atom such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, or mesitylene. Aromatic hydrocarbons or fats that may be substituted with halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane Group hydrocarbons, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, ethers such as dimethoxyethane, nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate and butyl acetate, methanol, Such as ethanol Examples include alcohols, amines such as triethylamine, tributylamine, pyridine, nitromethane, nitroethane, N, N-dimethylformamide, dimethyl sulfoxide, water, supercritical fluid, etc., preferably toluene, chlorobenzene, n-hexane, n- Heptane, cyclohexane, methylene chloride, 1,2-dichloroethane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, dimethoxyethane, acetonitrile, propionitrile, ethyl acetate, methanol, nitromethane, N, N-dimethylformamide or dimethyl Sulphoxide, particularly preferably toluene for the preparation of (2) from (1) and toluene, methanol, N, N-dimethylphenol for the preparation of (1) from (3). In the case where (3) is produced from (4) and (5), it is toluene, N, N-dimethylformamide or dimethyl sulfoxide, and is one step from (4) and (5). In the case of producing (1), toluene, methanol, N, N-dimethylformamide or dimethyl sulfoxide. These may be used singly or as a mixture of two or more. For the production of (13) from (12) and (5), toluene, chlorobenzene, n-hexane, n -Heptane, cyclohexane, cyclopentyl methyl ether, t-butyl methyl ether or dimethoxyethane, for the preparation of (2) from (13), toluene, chlorobenzene, n-hexane, n-heptane, cyclohexane, cyclopentyl methyl ether, t-butyl methyl ether, dimethoxyethane, acetonitrile, methanol or ethanol, and when (2) is produced from (12) and (5) in one step, toluene, chlorobenzene, n-hexane, n-heptane, Cyclohexane, cyclopentyl methyl ether, t-butyl Ether, dimethoxyethane, acetonitrile, methanol or ethanol. These may be used singly or in combination of two or more. For example, a mixed solvent of toluene and cyclopentyl methyl ether, t-butyl methyl ether, or dimethoxyethane is preferable from the viewpoint of avoiding a cryogenic reaction such as −78 ° C.

  Although the usage-amount of such a solvent is not specifically limited, It is 0.01-50 weight normally with respect to an aromatic ketone compound or a substituted silyl ether compound, 1- (substituted phenyl) -1-substituted alcohol compound, or an aromatic ester compound. Parts, preferably 0.05 to 25 parts by weight, particularly preferably 0.1 to 10 parts by weight.

Examples of the catalyst that can be used in the reaction of the present invention include sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, barium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, acetic acid. Sodium, potassium acetate, lithium acetate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, potassium tert-butoxide, cinchonidine, trimethylamine-N-oxide, tri-t-butylphosphine, tri-n-butyl Phosphine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, acetic acid tetra-n-butylammonium, hydrogen sulfate tetra-n-butylammonium, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, p- toluene Examples include sulfonic acid, formic acid or acetic acid, preferably potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, lithium acetate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, tetra-n-butylammonium chloride, tetra-n. -Butylammonium bromide, acetic acid tetra-n-butylammonium, hydrochloric acid, sulfuric acid or acetic acid. These may be used singly or in combination of two or more.

  The amount of such a catalyst used is not particularly limited. For example, when used as a hydrolysis catalyst as in the production of (1) from (3), with respect to 1 part by weight of the substituted silyl ether compound, Usually, it is 0.1 to 10 parts by weight. For example, in the case of using as an addition reaction catalyst as in the production of (3) from (4) and (5), 1 mol of the aromatic aldehyde compound is used. On the other hand, it is usually 0.001-1 mole, preferably 0.005-0.5 mole, particularly preferably 0.005-0.1 mole.

  Examples of the oxidation catalyst that can be used in the reaction of the present invention include 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl, 2-azaadamantane-N-oxyl, 1 -Methyl-2-azaadamantane-N-oxyl, 1,3-dimethyl-2-azaadamantane-N-oxyl and the like, and preferably 2,2,6,6-tetramethylpiperidine-1-oxyl, for example 2-azaadamantane-N-oxyl.

  The amount of the oxidation catalyst used is not particularly limited, but is usually 0 to 0.1 times mol, preferably 0.00005 to 1 mol per 1 mol or 1 part by weight of 1- (substituted phenyl) -1-substituted alcohol compound. It is 0.05 times mole.

  Additives that can be used in the reaction of the present invention include tetra-n-butylammonium fluoride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, acetic acid tetra-n-butylammonium, hydrogen sulfate tetra-n- Butyl ammonium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bromide, potassium bromide, barium hydroxide, calcium hydroxide, barium carbonate, calcium carbonate, sodium acetate, Potassium acetate, lithium acetate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, potassium tert-butoxide, hydrochloric acid, trimethylamine, triethylamine, tri-n-butylamine, cinchonidine, trime Examples include tilamine-N-oxide, tri-t-butylphosphine, tri-n-butylphosphine, or cesium fluoride, preferably tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, hydrogen sulfate Tetra-n-butylammonium, potassium carbonate, sodium bicarbonate, sodium bromide, potassium bromide, sodium carbonate, sodium acetate, potassium acetate, lithium acetate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, hydrochloric acid, trimethylamine, Triethylamine, tri-n-butylamine, tetra-n-butylammonium fluoride, tetra-n-butylammonium acetate or cesium fluoride. These may be used singly or in combination of two or more. As the additive used for the production of (13) from (12) and (5), for example, tetra-n-butylammonium fluoride or cesium fluoride is particularly preferable among the above-mentioned additives.

As the additive used for the production of (2) from (13), for example, hydrochloric acid, trimethylamine, triethylamine or tri-n-butylamine is preferable.
The amount of such additives used is not particularly limited, but for additives other than potassium carbonate, sodium hydrogen carbonate, sodium bromide and potassium bromide, 1 mol or 1- (substituted phenyl) -1-substituted alcohol compound is used. It is usually 0.00001 to 0.1 times mol, preferably 0.00005 to 0.05 times mol for parts by weight or 1 mol of the aromatic ester compound. About sodium bromide and potassium bromide Is usually 0.01 to 0.5 times mol, preferably 0.05 to 0.3 times mol, per mol of 1- (substituted phenyl) -1-substituted alcohol compound, potassium carbonate and hydrogen carbonate Sodium may be used in a solid state, but is preferably 0.5 to 5 parts by weight as a 1 to 15% by weight aqueous solution.

Examples of the oxidizing agent that can be used in the reaction of the present invention include perchloric acid or its salt, chloric acid or its salt, chlorous acid or its salt, hypochlorous acid or its salt, bromic acid or its salt, bromine Examples include acids or salts thereof, hypobromite or salts thereof, periodic acid or salts thereof, and examples of the salts include alkali metals (lithium, sodium and potassium) or alkaline earth metals (calcium and magnesium). Preferably, sodium perchlorate, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium bromate, sodium bromite, sodium hypobromite or potassium hypobromite Particularly preferred are sodium hypochlorite, potassium hypochlorite, calcium hypochlorite or sodium hypobromite. These may be used singly or in combination of two or more.
Although the usage-amount of such an oxidizing agent is not specifically limited, It is 1-2 times mole normally with respect to 1 mol of 1- (substituted phenyl) -1-substituted alcohol compounds, Preferably it is 1-1.5 times mole.
Such an oxidizing agent is preferably used in the form of an aqueous solution containing a predetermined amount.

Examples of water-soluble organic solvents that can be used in the reaction of the present invention include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, and N, N ′. -Dimethylethyleneurea, hexamethylphosphoric triamide, acetonitrile, propionitrile, methanol, ethanol or the like can be mentioned, and dimethyl sulfoxide, N, N-dimethylformamide or methanol is preferable. These may be used singly or in combination of two or more.
The amount of such an organic solvent soluble in water is usually 0.01 to 10 parts by weight, preferably 0.01 to 5 parts by weight, particularly preferably 0. 0 parts by weight based on 1 part by weight of the aromatic aldehyde compound. 1 to 4 parts by weight.

  Examples of water-insoluble organic solvents that can be used in the reaction of the present invention include aromatic hydrocarbons that may be substituted with a halogen atom such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, or mesitylene, or n. Aliphatic hydrocarbons which may be substituted with halogen atoms such as -pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane, Preferred is toluene, chlorobenzene, n-hexane, n-heptane, cyclohexane, methylene chloride or 1,2-dichloroethane. These may be used singly or in combination of two or more.

  Examples of the acid that can be used in the reaction of the present invention include hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, and inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, chloric acid, and perchloric acid. And sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and organic acids such as formic acid and acetic acid.

  Examples of the fluorine source that can be used in the reaction of the present invention include tetrabutylammonium fluoride.

A reaction scheme according to the present invention is shown below.

The aromatic aldehyde compound represented by the formula (4), which is a starting material for carrying out the present invention, is commercially available or can be produced by a known method.
The substituted silicon compound represented by the formula (5), which is a starting material for carrying out the present invention, is commercially available or can be produced by a known method.
The aromatic ester compound represented by the formula (12), which is a starting material for carrying out the present invention, is commercially available or can be produced by a known method.

  In order to carry out the reaction according to the present invention, for example, a 1- (substituted phenyl) -1-substituted alcohol compound represented by the formula (1) in a reactor and a solvent represented by toluene, 2, 2, 6 Oxidation catalysts such as 1,6-tetramethylpiperidine-1-oxyl and 2-azaadamantane-N-oxyl, additives such as sodium bicarbonate or its aqueous solution and potassium bromide, and sodium hypochlorite -20 to 120 ° C., preferably −10 to 60 ° C., particularly preferably −5 to 10 ° C., usually 1 minute to 24 hours, preferably about 10 minutes to 10 hours with stirring. What is necessary is just to make it react.

  For example, in a reactor, a substituted silyl ether compound represented by the formula (3), toluene, N, N-dimethylformamide, dimethyl sulfoxide, a solvent typified by methanol, an acid typified by hydrochloric acid and / or a fluorine source The reaction is usually carried out at 0 to 120 ° C., preferably 10 to 80 ° C., usually 10 minutes to 96 hours, preferably 30 minutes to 72 hours with or without stirring with or without adding distilled water. .

  For example, an aromatic aldehyde compound represented by the formula (4) and a substituted silicon compound represented by the formula (5), toluene, N, N-dimethylformamide, a solvent typified by dimethyl sulfoxide, potassium carbonate, Sodium acetate, tetra-n-butylammonium bromide, a catalyst typified by tetra-n-butylammonium acetate are charged and, with stirring, usually −20 to 120 ° C., preferably −10 to 60 ° C., usually 1 minute to The reaction may be performed for 96 hours, preferably about 15 minutes to 72 hours.

  For example, an aromatic aldehyde compound represented by the formula (4) and a substituted silicon compound represented by the formula (5), toluene, N, N-dimethylformamide, a solvent typified by dimethyl sulfoxide, potassium carbonate, Sodium acetate, tetra-n-butylammonium bromide, a catalyst typified by tetra-n-butylammonium acetate are charged and, with stirring, usually −20 to 120 ° C., preferably −10 to 60 ° C., usually 1 minute to The reaction is allowed to proceed for 96 hours, preferably 15 minutes to 72 hours, and an additive typified by hydrochloric acid is added to the resulting reaction solution, with or without the addition of a solvent typified by methanol. The reaction may be performed at ˜120 ° C., preferably 10˜80 ° C., usually for 10 minutes to 96 hours, preferably about 30 minutes to 72 hours.

  For example, an aromatic aldehyde compound represented by the formula (4) and a substituted silicon compound represented by the formula (5), toluene, N, N-dimethylformamide, a solvent typified by dimethyl sulfoxide, potassium carbonate, Sodium acetate, tetra-n-butylammonium bromide, a catalyst typified by tetra-n-butylammonium acetate are charged and, with stirring, usually −20 to 120 ° C., preferably −10 to 60 ° C., usually 1 minute to The reaction is allowed to proceed for 96 hours, preferably about 15 minutes to 72 hours, and with or without the addition of water to the resulting reaction solution, it is soluble in other organic solvents, preferably the above-mentioned water represented by methanol. With or without the addition of an organic solvent, an acid typified by hydrochloric acid and / or a fluorine source is added, and with stirring, usually 0 to 120 ° C., preferably 10 to 80 The reaction is usually carried out for 10 minutes to 96 hours, preferably 30 minutes to 72 hours, and the reaction solution is extracted to obtain a solution containing the compound represented by formula (1). , 6,6-Tetramethylpiperidine-1-oxyl and oxidation catalyst represented by 2-azaadamantane-N-oxyl, sodium bicarbonate or its aqueous solution and additive represented by potassium bromide, sodium hypochlorite The oxidant typified by the formula (1) is charged, and under stirring, usually -20 to 120 ° C, preferably -10 to 60 ° C, particularly preferably -5 to 10 ° C, usually 1 minute to 24 hours, preferably 10 minutes to 10 It is sufficient to react for about an hour.

  For example, a benzoic acid ester compound represented by the formula (12) and a solvent typified by toluene and a substituted silicon compound represented by the formula (5) are charged into a reactor, and usually −50 to 120 ° C. with stirring. The catalyst is preferably added at a temperature of −30 to 60 ° C., particularly preferably −20 to 10 ° C. in a solution or solid state, and reacted.

  For example, a substituted silyl ether compound represented by the formula (3) and a solvent represented by toluene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, hydrochloric acid, triethylamine, tri-n-butylamine Additives to be added and usually reacted at 0 to 120 ° C., preferably 10 to 80 ° C. with stirring.

  For example, a benzoic acid ester compound represented by the formula (12) and a solvent typified by toluene and a substituted silicon compound represented by the formula (5) are charged into a reactor, and usually −50 to 120 ° C. with stirring. Preferably, at −30 to 60 ° C., particularly preferably at −20 to 10 ° C., the catalyst is added in a solution or solid state, and after the reaction, water is added, and a polar solvent typified by acetonitrile is added. What is necessary is just to cut | disconnect silyl ether.

Next, a specific example of a 1- (substituted phenyl) -1-substituted alcohol compound represented by the formula (1) that can be used as a starting material in Step C of the present invention and a starting material in Step B can be used. Although the specific example of the substituted silyl ether compound represented by Formula (3) is shown, this invention is not limited only to these.
In addition, the description of Me represents a methyl group.

Next, specific examples of 1- (substituted phenyl) -2,2,2-trifluoroethanol compounds represented by formulas (6) to (8), which are novel production intermediates of the present invention, and formula (9) Although the specific example of the substituted trimethylsilyl ether compound represented by-(11) is shown, this invention is not limited only to these.
In addition, the description of Me represents a methyl group.

  Examples of the present invention are shown below, but the present invention is not limited to these examples.

[Synthesis example]
[ Reference Example 1]
Synthesis of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone [ Reference Example 1-1]
1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol 0.49 g (2.0 mmol), toluene 2.45 g, 2,2,6,6-tetramethylpiperidine-1-oxyl 5 mg (0.022 mmol), potassium bromide 26 mg (0.22 mmol), and distilled water 0.25 g were charged and cooled to 0 ° C. Further, 1.5 ml of an aqueous sodium hypochlorite solution (manufactured by Junsei Chemical, about 2.2 mmol) was added dropwise so that the temperature of the reaction solution did not exceed 5 ° C. Furthermore, it stirred at 0 degreeC for 2.5 hours. To the reaction solution, 25 mg (0.2 mmol) of sodium sulfite was added and stirred at room temperature for 1 hour. The reaction solution was separated and extracted from the aqueous layer with 4.9 g of toluene. The organic layers were combined and washed with 0.5 ml of saturated brine to obtain 7.6 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. A small amount of this solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. The area percentage of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 97.3% ( Detection was carried out with a UV detector at a wavelength of 220 nm.

[ Reference Example 1-2]
0.25 g (1.0 mmol) of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol, 0.74 g of toluene, 10 μl of 2-azaadamantane-N-oxyl (0.01 mmol / ml of toluene) Solution, 0.0001 mmol), 0.74 g of 5% aqueous sodium hydrogen carbonate solution was charged, and cooled to 0 ° C. Further, 0.8 ml (about 1.1 mmol) of an aqueous sodium hypochlorite solution was added and stirred at 0 ° C. for 3 hours. To the reaction solution, 25 mg (0.2 mmol) of sodium sulfite was added and stirred at room temperature for 1 hour. The reaction solution was separated and extracted from the aqueous layer using 2.5 g of toluene. The organic layers were combined to obtain 3.4 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. When this solution was analyzed by a quantitative analysis method using high performance liquid chromatography, the content of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 0.24 g (yield 98%). ).

[ Reference Example 1-3]
1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol 0.98 g (4.0 mmol), toluene 2.94 g, 2,2,6,6-tetramethylpiperidine-1-oxyl 9 mg (0.038 mmol) and 1.47 g of 5% aqueous sodium hydrogen carbonate solution were charged and cooled to 0 ° C. Furthermore, 3.6 ml (about 4.4 mmol) of an aqueous sodium hypochlorite solution was added, and the mixture was stirred at 0 ° C. for 2 hours. To the reaction solution was added 0.10 g (0.8 mmol) of sodium sulfite, and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated and extracted from the aqueous layer using 5.9 g of toluene. The organic layers were combined to obtain 8.1 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. When this solution was analyzed by a quantitative analysis method using high performance liquid chromatography, the content of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 0.95 g (yield 98%). ).

[ Reference Example 1-4]
A toluene solution containing 5.17 g of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone obtained by performing the same operation as in Reference Example 1-3 was concentrated under reduced pressure, and further reduced pressure Purified by distillation. As a fraction at 84 to 89 ° C. (14 mmHg), 4.68 g of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was obtained.

[ Reference Example 2]
Synthesis of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane 1.67 g, toluene 3 .81 g, 1.90 g of methanol, 0.76 g of distilled water, and 0.76 g of concentrated hydrochloric acid were added and stirred at 30 ° C. for 4 hours. Distilled water (3.8 g) and toluene (3.8 g) were added to the reaction solution to separate the layers. Further, the aqueous layer was extracted with 7.6 g of toluene. The organic layers were combined and concentrated under reduced pressure to obtain 0.81 g of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol (yield 79%).
¹ H-NMR (CDCl ₃ , Me ₄ Si, 400 MHz) δ7.41 (t, J = 1.8 Hz, 1H), 7.39 (bs, 2H), 4.96-5.0
6 (m, 1H), 2.66 (d, J = 4.4Hz, 1H).
Melting point: 48-49 ° C

[ Reference Example 3]
Synthesis of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane 3.5 g (20 mmol) of 3,5-dichlorobenzaldehyde, 10.5 g of toluene, 1.75 g of dimethyl sulfoxide, tri 3.41 g (24 mmol) of fluoromethyltrimethylsilane and 55 mg (0.4 mmol) of potassium carbonate were charged and stirred at room temperature for 7 hours. A small amount of the reaction solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was 98. 3% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peaks for toluene and dimethyl sulfoxide). To the reaction solution, 3.5 ml of cold distilled water was added and stirred at room temperature for 10 minutes. The reaction mixture was separated, and the organic layer was washed with saturated brine and concentrated under reduced pressure. 7.6 g of crude (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was obtained as a slightly yellow liquid. This was purified by distillation under reduced pressure, and 6.0 g of colorless liquid (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was obtained as a fraction at 116 to 118 ° C. (13 mmHg). (Yield 95%).
¹ H-NMR (CDCl ₃ , Me ₄ Si, 400 MHz) δ7.37 (t, J = 1.8 Hz, 1H), 7.32-7.36 (m, 2H), 4.85
(q, J = 6.4Hz, 1H), 0.15 (s, 9H).
¹³ C-NMR (CDCl ₃ , Me ₄ Si, 400 MHz) δ138.8, 136.1, 129.3, 126.0, 123.7 (q, ¹ J (C, F) = 282.7Hz), 72.2 (q, ² J (C, F ) = 32.8Hz), -0.36.

[ Reference Example 4]
Synthesis of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol in one step [ Reference Example 4-1]
3.75 g (10 mmol) of 3,5-dichlorobenzaldehyde, 7.0 g of toluene, 1.75 g of N, N-dimethylformamide, 1.71 g (12 mmol) of trifluoromethyltrimethylsilane, and 42 mg (0.30 mmol) of potassium carbonate. The mixture was stirred and stirred at room temperature for 20 hours. A small amount of the reaction solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was 98. 2% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peaks of toluene and N, N-dimethylformamide). Distilled water (1 ml) and concentrated hydrochloric acid (1 ml) were added to the reaction solution, followed by stirring at 60 ° C. for 2 hours and then at room temperature overnight. The reaction solution was separated and extracted from the aqueous layer using 7 g of toluene. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 7: 1 mixture of n-hexane: ethyl acetate) to give 1- (3,5-dichlorophenyl) -2,2,2-trifluoro as a white solid. 2.38 g of ethanol was obtained (yield 97%).

[ Reference Example 4-2]
Charged 0.70 g (4.0 mmol) of 3,5-dichlorobenzaldehyde, 1.4 g of dimethyl sulfoxide and 11 mg (0.08 mmol) of potassium carbonate, and heated to 30 ° C. 0.68 g (4.8 mmol) of trifluoromethyltrimethylsilane was added dropwise so that the temperature of the reaction solution did not exceed 35 ° C., and the mixture was stirred at 30 ° C. for 2 hours. Distilled water (0.4 ml) and concentrated hydrochloric acid (0.2 ml) were added to the reaction solution, and the mixture was stirred at 30 ° C. for 1 hour. The reaction solution was diluted with 4 ml of distilled water, and 10 ml of toluene was added for liquid separation. Further, the aqueous layer was extracted with 5 ml of toluene. The organic layers were combined to obtain 14.2 g of a solution containing 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol. When this solution was analyzed by a quantitative analysis method using high performance liquid chromatography, the content of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol was 0.91 g (yield) 93%).

[ Reference Example 5]
Synthesis of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone in one step [ Reference Example 5-1]
3.75 g (10 mmol) of 3,5-dichlorobenzaldehyde, 5.3 g of toluene, 1.71 g (12 mmol) of trifluoromethyltrimethylsilane, 0.16 g (0.5 mmol) of tetra-n-butylammonium bromide, 41 mg of sodium acetate ( 0.5 mmol), and stirred at 30 ° C. for 2 hours. A small amount of the reaction solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was 98. 2% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the toluene peak). Distilled water 0.88 g, concentrated hydrochloric acid 0.87 g, and methanol 2.6 g were added to the reaction solution, and the mixture was stirred at 30 ° C. for 3 hours. To the reaction solution, 5.3 g of distilled water and 5.3 g of toluene were added for liquid separation, and the aqueous layer was extracted with 10.5 g of toluene. The organic layers were combined to obtain 25.7 g of a solution containing 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol. A small amount of this solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol was 97.4%. (Detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peak of toluene.)
A part of the solvent of 25.7 g of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol solution was distilled off under reduced pressure to make the total amount 9.8 g. Further, 3.67 g of 5% aqueous sodium hydrogen carbonate solution and 15.6 mg (0.10 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl were added and cooled to 0 ° C. Subsequently, 8.8 ml of sodium hypochlorite aqueous solution was added so that it might not exceed 5 degreeC, and it stirred at 0 degreeC for 1.5 hours. Sodium sulfite (0.15 g, 1.2 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Concentrated hydrochloric acid (0.25 ml) was added to the reaction solution, the phases were separated, and the aqueous layer was extracted with 7.5 g of toluene. The organic layers were combined to obtain 17.1 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. When this solution was analyzed by a quantitative analysis method using high performance liquid chromatography, the content of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 2.26 g (yield: 92. 9%).

[ Reference Example 5-2]
3.75 g (10 mmol) of 3,5-dichlorobenzaldehyde, 5.3 g of toluene, 1.1 g of dimethyl sulfoxide and 28 mg (0.2 mmol) of potassium carbonate were charged and heated to 30 ° C. 1.71 g (12 mmol) of trifluoromethyltrimethylsilane was added dropwise so that the temperature of the reaction solution did not exceed 35 ° C., and the mixture was stirred at 30 ° C. for 3 hours. A small amount of the reaction solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was 98. 5% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peaks for toluene and dimethyl sulfoxide). Distilled water (0.88 g), concentrated hydrochloric acid (0.88 g), and methanol (2.1 g) were added to the reaction solution, and the mixture was stirred at 30 ° C. for 3 hours and then at room temperature overnight. The reaction solution was separated by adding 5.3 g of distilled water, and extracted from the aqueous layer with 10.5 g of toluene. The organic layers were combined to obtain 18.9 g of a solution containing 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol. A small amount of this solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. The area percentage of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol was 97.6%. (Detected with a UV detector at a wavelength of 220 nm. Calculations were made excluding the peaks for toluene and dimethyl sulfoxide.)
A portion of the 18.9 g solvent of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol solution was concentrated under reduced pressure to a total amount of 8.7 g. Further, 3.3 g of 5% aqueous sodium hydrogen carbonate solution and 13.6 mg (0.087 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl were added and cooled to 0 ° C. Subsequently, 10.7 ml of sodium hypochlorite aqueous solution was added so that it might not exceed 5 degreeC, and it stirred at 0 degreeC for 3 hours. Sodium sulfite (0.15 g, 1.2 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 0.25 ml of concentrated hydrochloric acid, and the mixture was separated, and extracted from the aqueous layer with 13 g of toluene. The organic layers were combined to obtain 21.7 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. When this solution was analyzed by quantitative analysis using high performance liquid chromatography, the content of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 2.35 g (yield 96. 7%).

[ Reference Example 5-3]
2.1 g (12 mmol) of 3,5-dichlorobenzaldehyde, 6.7 g of toluene, and 90 mg (0.3 mmol) of tetra-n-butylammonium acetate were charged and heated to 30 ° C. 1.90 g (13.4 mmol) of trifluoromethyltrimethylsilane was added dropwise so that the temperature of the reaction solution did not exceed 35 ° C., and the mixture was stirred at 30 ° C. for 1.5 hours. A small amount of the reaction solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of (1- (3,5-dichlorophenyl) -2,2,2-trifluoroethoxy) trimethylsilane was 97. 2% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the toluene peak). Distilled water (0.88 g), concentrated hydrochloric acid (0.88 g) and methanol (5.3 g) were added to the reaction mixture, and the mixture was stirred at 30 ° C. for 1 hour and then at room temperature overnight. Distilled water (10.5 g) and toluene (10.5 g) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with 10.5 g of toluene. The organic layers were combined, and toluene was partially distilled off under reduced pressure to obtain 4.2 g of a solution containing 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol. A small amount of this solution was taken, diluted with acetonitrile, and analyzed by high performance liquid chromatography. As a result, the area percentage of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol was 97.4%. (Detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peak of toluene.)
Toluene was added to 4.2 g of liquid 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanol to make the total amount 10.9 g. Further, 4.1 g of 5% aqueous sodium hydrogen carbonate solution and 17.1 mg (0.098 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl were added and cooled to 0 ° C. Subsequently, 9.8 ml of sodium hypochlorite aqueous solution was added so that it might not exceed 5 degreeC, and it stirred at 0 degreeC for 2 hours. Sodium sulfite (0.15 g, 1.2 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 0.3 ml of concentrated hydrochloric acid, and the mixture was separated, and extracted from the aqueous layer with 16.4 g of toluene. The organic layers were combined to obtain 28.5 g of a solution containing 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone. When this solution was analyzed by a quantitative analysis method using high performance liquid chromatography, the content of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 2.66 g (yield: 91. 1%).

Example 6
Synthesis of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone from 3,5-dichlorobenzoic acid methyl ester [ Reference Example 6-1]
3,5-Dichlorobenzoic acid methyl ester (3.075 g, 15 mmol), toluene (30 mL), and trifluoromethyltrimethylsilane (2.67 g, 18.75 mmol) were charged, and the mixture was cooled to -20 ° C. 90 μL (0.6 mol%) of a tetrahydrofuran solution of tetra-n-butylammonium fluoride having a concentration of 1M was dropped, and the mixture was stirred for 30 minutes while maintaining the temperature at −20 ° C. A small amount of the reaction solution was taken, diluted with water and acetonitrile, and analyzed by high performance liquid chromatography. (1- (3,5-dichlorophenyl) -2,2,2-trifluoro-1-methoxyethoxy) trimethylsilane The area percentage was 98.2% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the toluene peak). Distilled water (1.5 mL), concentrated hydrochloric acid (3 mL), and methanol (7 mL) were added to the reaction solution, and the mixture was stirred at 70 ° C. overnight. The reaction solution was separated and extracted from the aqueous layer with 10 mL of toluene. The organic layers were combined and the solvent was distilled off. Hexane 50mL was added, methanol was distilled off azeotropically using Dean Stark, and it distilled under reduced pressure, and obtained a 3.15g (78-82 degreeC / 20mmHg) fraction. A small amount of this was diluted with acetonitrile and analyzed by high performance liquid chromatography. The area percentage of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 99.9% (UV It was detected at a wavelength of 220 nm with a detector.)
(Yield 86.5%).

[Example 6-2]
3,5-dichlorobenzoic acid methyl ester 41.01 g (200 mmol), toluene 266 mL, dimethoxyethane 114 mL, and cesium fluoride 0.61 g (4 mmol) were charged and cooled to -20 ° C. 34.13 g (240 mmol) of trifluoromethyltrimethylsilane was added dropwise, and the mixture was stirred for 30 minutes while maintaining the temperature at −20 ° C. A small amount of the reaction solution was taken, diluted with water and acetonitrile, and analyzed by high performance liquid chromatography. (1- (3,5-dichlorophenyl) -2,2,2-trifluoro-1-methoxyethoxy) trimethylsilane The area percentage was 91.2% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the peak of toluene). Distilled water (31 mL) was added to the reaction solution to room temperature, followed by liquid separation. The organic layer was concentrated, 1.42 g (14 mmol) of triethylamine and 259 ml of methanol were added, and the mixture was stirred at 60 ° C. for 1 hour. After concentrating the reaction solution, 240 ml of heptane was added and methanol was distilled off azeotropically. The residue was distilled under reduced pressure to obtain 44.96 g (103 to 104 ° C./20 mmHg) fraction. A small amount of this was collected, diluted with acetonitrile, and analyzed by high performance liquid chromatography. The area percentage of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone was 99.4% (UV It was detected at a wavelength of 220 nm with a detector.)
(Yield 92.5%).

[ Reference Example 7]
Synthesis of (1- (3,5-dichlorophenyl) -2,2,2-trifluoro-1-methoxyethoxy) trimethylsilane 3,5-dichlorobenzoic acid methyl ester 0.4101 g (2 mmol), heptane 4.8 mL, Trifluoromethyltrimethylsilane 0.3697 g (2.6 mmol) was charged and cooled to 0 ° C. 40 μL of tetra-n-butylammonium fluoride in tetrahydrofuran having a concentration of 1M was dissolved in 0.2 mL of toluene, which was added dropwise, and stirred for 30 minutes while maintaining the temperature at 0 ° C. A small amount of the reaction solution was taken, diluted with water and acetonitrile, and analyzed by high performance liquid chromatography. (1- (3,5-dichlorophenyl) -2,2,2-trifluoro-1-methoxyethoxy) trimethylsilane The area percentage was 86.3% (detected with a UV detector at a wavelength of 220 nm. Calculation was performed excluding the toluene peak).

[ Reference Example 8]
Synthesis of 2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone 3- (trifluoromethyl) benzoic acid methyl ester 25.0 g (122.4 mmol), toluene 140 g, dimethoxyethane 60 g Then, 0.93 g (6.12 mmol) of cesium fluoride was charged and cooled to −20 ° C. 20.9 g (147.0 mmol) of trifluoromethyltrimethylsilane was added dropwise, and the mixture was stirred for 2 hours while keeping the temperature at -20 ° C. Distilled water (20 mL) was added to the reaction solution to room temperature, followed by liquid separation. The organic layer was concentrated, 120 g of methanol and 5 mL of 35% hydrochloric acid were added, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction solution was concentrated, 100 mL of hexane was added to azeotrope methanol. Distilling at normal pressure gave 27.1 g of 2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone (yield 91.4%).

  The production method of the present invention is useful as a production method for aromatic ketone compounds, substituted silyl ether compounds, and 1- (substituted phenyl) -1-substituted alcohol compounds, which are compounds useful as intermediates for agricultural chemicals, pharmaceuticals, and various chemicals. It is.

Claims (1)

Formula (12):

[Wherein R ⁸ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo. Alkenyl, hydroxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ -C ₆ ) haloalkyl, C ₃ -C ₈ halocyclo Represents an alkyl or aromatic group,
X is a halogen atom, cyano, nitro, —SF ₅ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkenyl, hydroxy (C ₁ -C ₆ ) haloalkyl, cyano (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) haloalkyl, C ₁ -C ₆ haloalkoxy (C ₁ -C ₆ ) haloalkyl, C ₃ -C ₈ halocycloalkyl, —OH, —OR ⁵ , benzyloxy, —NH ₂ , —N (R ⁷ ) R ⁶ , —S (O) _r R ⁵ or Represents phenylsulfonyloxy,
R ⁵ represents C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₃ haloalkoxy (C ₁ -C ₃ ) haloalkyl. ,
R ⁶ is C ₁ -C ₆ alkyl, —CHO, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylthiocarbonyl, C ₁ -C _{6 alkoxythiocarbonyl,} C 1 -C ₆ alkyl dithio _carbonyl, represents C 1 -C ₆ alkylsulfonyl or _C 1 -C ₆ haloalkylsulfonyl,
R ⁷ represents a hydrogen atom or C ₁ -C ₆ alkyl,
m represents an integer of 0 to 5;
r represents an integer of 0-2. A benzoic acid ester compound represented by the formula (5):

[Wherein R ¹ represents a trifluoromethyl group ,
R ² , R ³ and R ⁴ represent a C ₁ -C ₆ alkyl or aromatic group. And using trimethylamine, triethylamine or tri-n-butylamine as an additive to the reaction, formula (2):

[Wherein R ¹ , X and m represent the same meaning as described above. The manufacturing method which manufactures the 1- (substituted phenyl) -1-substituted carbonyl compound represented by this by 1 process.