JP5170987B2 - Novel fluorine-containing unsaturated silyl ether compound and method for producing fluorine-containing unsaturated alcohol derivative using the compound as an intermediate - Google Patents

Description

  The present invention relates to a novel fluorine-containing unsaturated silyl ether compound and a method for producing a fluorine-containing unsaturated alcohol derivative having the compound as an intermediate.

  Fluorine-containing unsaturated alcohol derivatives are important synthetic intermediates in the fields of medicine and agricultural chemicals.

  General formula (2)

Wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group, and R ² is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group or an aralkyl. A group, an alkynyl group, an aryl group, an alkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, wherein R ¹ and R ² are combined to form a hetero atom or not. A part of the ring structure may be formed.)
Examples of the method for producing the fluorine-containing unsaturated alcohol derivative represented by the following include the following methods.

That is,
(1) A method in which 2-bromo-3,3,3-trifluoropropene is lithiated with normal butyl lithium and then reacted with an aldehyde to hydrolyze the reaction solution (Non-patent Document 1).
(2) A method in which an aldehyde compound, 2-bromo-3,3,3-trifluoropropene and tin are reacted in a dimethylformamide or pyridine-tetrahydrofuran solvent in the presence of a copper chloride catalyst to hydrolyze the reaction solution (non-patented) Reference 2),
(3) A method of reducing 2-trifluoromethyl-1-buten-3-one obtained by reacting 2-trifluoromethylpropenoic acid with methyllithium and chlorotrimethylsilane with yeast (Non-patent Document 3),
(4) A method in which a microorganism is allowed to act on an α, β-unsaturated ketone having a fluorinated aliphatic group to selectively convert it into an unsaturated alcohol (Non-patent Document 4) is known.

  However, in the method (1), it is necessary to carry out the reaction at an extremely low temperature of minus 90 ° C., and there is a problem in producing it safely and easily on an industrial scale.

  In the method (2), it is necessary to use a large amount of tin, and the by-product generated in a large amount after the reaction must be removed.

  In the method (3), 2-bromo-3,3,3-trifluoropropene must be reacted with magnesium to obtain 2-trifluoromethylpropenoic acid as a raw material, and the reaction becomes multistage, The yield was low due to the yeast action. In the method (4), the reaction time is as long as 2 days, and the carbon-carbon double bond is also reduced when the aging time is further extended, so that the yield of the target compound is lowered. There was a point.

  As a method for producing a compound other than the fluorine-containing unsaturated alcohol derivative represented by the general formula (2), a method for introducing a perfluoroalkyl group using a perfluoroalkylmethylsilane to a carbonyl compound is known ( Patent Document 1). However, there have been no reported examples of introducing a trifluoropropenyl group using a vinylsilane compound with respect to a carbonyl compound.

Therefore, production of a fluorine-containing unsaturated alcohol derivative represented by the general formula (2), which can introduce a trifluoropropenyl group directly into a safe, easy and inexpensive aldehyde compound and can be efficiently produced on an industrial scale. A method was desired.
German Patent No. 3805534 J. Org. Chem., 33 (1), 280 (1967) J. Chem. Soc., Chem. Commun., 3, 289 (1994) J. Fluorine Chem., 29 (4), 431 (1985) Chem. Lett., 587 (1985)

  The present invention has been made to solve the above-mentioned problems, and its purpose is to react a carbonyl compound with a vinylsilane compound to introduce a trifluoropropenyl group directly into a safe, easy and inexpensive carbonyl compound. It is possible to provide a method for producing a fluorine-containing unsaturated alcohol derivative represented by the general formula (2) that can be produced efficiently on an industrial scale.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a fluorine-containing unsaturated silyl ether obtained by reacting a carbonyl compound with a vinylsilane compound in the presence of a Lewis base catalyst in an aprotic solvent. To find out that a fluorine-containing unsaturated alcohol derivative represented by the general formula (2) can be obtained by directly desilylating or purifying and separating a reaction solution containing a compound and then completing the present invention. It came.

That is, the present invention relates to the following (1) to (5).
(1) General formula (1)

(Wherein R ¹ represents a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group , or an unsubstituted or substituted alkyl group substituted with a substituent selected from the group consisting of an acyloxy group, A hydrogen atom, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group, and R ² is selected from the group consisting of a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group and an acyloxy group. substituted with a substituent or unsubstituted alkyl group, a hydrogen atom, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an alkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group. Note R ¹ and R ² are combined, and a hetero atom is interposed or not A ¹ , A ^2, and A ³ may be independent of each other, and may be the same or different, and may be a linear or branched group that may have a hydrogen atom or a substituent. Represents an alkyl group having 1 to 4 carbon atoms.)
A fluorine-containing unsaturated silyl ether compound represented by the formula:

(2) General formula (3) in the presence of a Lewis base catalyst in an aprotic solvent
R ¹ COR ² (3)
Wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group, and R ² is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group or an aralkyl. A group, an alkynyl group, an aryl group, an alkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, wherein R ¹ and R ² are combined to form a ring with or without a heteroatom. Part of the structure may be formed.)
And a carbonyl compound represented by the general formula (4)

(In the formula, A ¹ , A ² and A ³ are each independently the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms which may have a substituent. .)
Is reacted with a vinylsilane compound represented by the general formula (1)

(Wherein R ¹ , R ² , A ¹ , A ² and A ³ are the same as defined above.)
Wherein the reaction solution containing the fluorine-containing unsaturated silyl ether compound is directly desilylated or purified and separated, followed by desilylation (2)

(Wherein R ¹ and R ² are the same as defined above)
The manufacturing method of the fluorine-containing unsaturated alcohol derivative shown by these.

(3) The carbonyl compound represented by the general formula (3) is an aldehyde, and the general formula
The method for producing a fluorine-containing unsaturated alcohol derivative according to (2) above, wherein the vinylsilane compound represented by (4) is (1-trifluoromethylvinyl) trimethylsilane.

(4) The aprotic solvent is at least one selected from the group consisting of N-methyl-2-pyrrolidone, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide. The manufacturing method of the fluorine-containing unsaturated alcohol compound as described in said (2) or (3).

(5) The fluorine-containing unsaturated alcohol compound according to any one of (2) to (4), wherein the Lewis base catalyst is an organic amine compound, an alkali metal fluoride, an alkali metal carbonate, or an ammonium salt. Production method.

  Conventionally, in order to produce the fluorine-containing unsaturated alcohol derivative represented by the general formula (2), a reaction at an ultra-low temperature is necessary, a large amount of heavy metal used, and a large amount of heavy metal waste is generated, There were problems such as a multi-step reaction process and a low yield. Compared with the conventional method, the production method in the present invention can safely and easily introduce a trifluoropropenyl group directly into an inexpensive carbonyl compound, and is efficiently represented by the general formula (2) on an industrial scale. It is possible to obtain a fluorine-containing unsaturated alcohol derivative, and its industrial utility value is high.

  Hereinafter, the present invention will be described in detail. The present invention relates to a method for producing a fluorine-containing unsaturated alcohol derivative represented by the general formula (2), wherein a carbonyl compound is reacted with a vinylsilane compound in the presence of a Lewis base catalyst in an aprotic solvent, In the production method, the reaction liquid containing the fluorine-containing unsaturated silyl ether compound represented by the formula (1) is directly desilylated or purified and separated, followed by desilylation.

  The fluorine-containing unsaturated silyl ether compound represented by the general formula (1) is a novel compound and is useful as an intermediate for producing the fluorine-containing unsaturated alcohol derivative represented by the general formula (2).

In the general formulas (1), (2) and (3), the alkyl group represented by R ¹ is an alkyl group having 1 to 20 carbon atoms which may be branched or a cycloalkyl having 3 to 20 carbon atoms. Group is preferable, and an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable. The alkyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, and an acyloxy group. The alkenyl group represented by R ¹ is preferably an alkenyl group having 2 to 20 carbon atoms which may be branched or a cycloalkenyl group having 3 to 20 carbon atoms, and an alkenyl group having 2 to 10 carbon atoms or carbon number. Is more preferably a cycloalkenyl group of 3 to 10. Examples of the alkenyl group include vinyl group, 1-propenyl group, 1-butenyl group, 1-hexenyl group, cyclohexenyl group, allyl group and the like. The alkenyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, an acyloxy group. Examples of the aralkyl group represented by R ¹ include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, furfuryl group, An α-phenethyl group and the like can be mentioned. Examples of the alkynyl group represented by R ¹ include ethynyl group, phenylethynyl group, 2-propynyl group and the like. The aryl group represented by R ¹ is preferably an aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. The aryl group may be substituted with a substituent such as an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, an alkoxy group, or an acyloxy group.

In the general formulas (1), (2), and (3), the alkyl group represented by R ² may be an alkyl group having 1 to 20 carbon atoms or a cycloalkyl having 3 to 20 carbon atoms. Group is preferable, and an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable. The alkyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, and an acyloxy group. The alkenyl group represented by R ² is preferably an alkenyl group having 2 to 20 carbon atoms which may be branched or a cycloalkenyl group having 3 to 20 carbon atoms, and an alkenyl group having 2 to 10 carbon atoms or carbon number. Is more preferably a cycloalkenyl group of 3 to 10. Examples of the alkenyl group include vinyl group, 1-propenyl group, 1-butenyl group, 1-hexenyl group, cyclohexenyl group, allyl group and the like. The alkenyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, an acyloxy group. Examples of the aralkyl group represented by R ² include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, furfuryl group, An α-phenethyl group and the like can be mentioned. Examples of the alkynyl group represented by R ² include ethynyl group, phenylethynyl group, 2-propynyl group and the like. The aryl group represented by R ² is preferably an aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. The aryl group may be substituted with a substituent such as an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, an alkoxy group, or an acyloxy group. The alkoxy group represented by R ² is preferably an alkoxy group having 1 to 20 carbon atoms, and more preferably an alkoxy group having 1 to 10 carbon atoms. In the case of an alkoxy group, it may be substituted with the same substituent as in the case of the above alkyl group. The aryloxy group represented by R ² is preferably an aryloxy group having 1 to 20 carbon atoms, and more preferably an aryloxy group having 1 to 10 carbon atoms. In the case of an aryloxy group, it may be substituted with the same substituent as in the case of the above aryl group. The acyl group represented by R ² is preferably an acyl group having 1 to 20 carbon atoms, and more preferably an acyl group having 1 to 10 carbon atoms. Although not particularly limited, examples include formyl group, acetyl group, malonyl group, benzoyl group, cinnamoyl group and the like. The alkoxycarbonyl group represented by R ² is preferably an alkoxycarbonyl group having 2 to 20 carbon atoms, and more preferably an alkoxycarbonyl group having 2 to 10 carbon atoms. In the case of an alkoxycarbonyl group, it may be substituted with the same substituent as in the case of the above alkoxy group. The aryloxycarbonyl group represented by R ² is preferably an aryloxycarbonyl group having 7 to 20 carbon atoms, and more preferably an aryloxycarbonyl group having 7 to 15 carbon atoms. In the case of an aryloxycarbonyl group, it may be substituted with the same substituent as in the case of the above aryloxy group.

In the general formulas (1), (2), and (3), R ¹ and R ² may be combined to form a part of a cyclic structure with or without hetero atoms.

In the general formulas (1) and (4), A ¹ , A ² and A ³ are each independently the same or different, and may be a linear or branched carbon atom which may have a hydrogen atom or a substituent. 1 to 4 alkyl groups are represented. Examples of the alkyl group include, but are not limited to, methyl group, ethyl group, n-propyl group, n-butyl group, tert-butyl group and the like.

  Examples of the fluorine-containing unsaturated silyl ether compound represented by the general formula (1) include 2-trifluoromethyl-3-trimethylsiloxy-1-butene, 2-trifluoromethyl-3-trimethylsiloxy-1-pentene, 2 -Trifluoromethyl-3-trimethylsiloxy-1-hexene, 2-trifluoromethyl-3-trimethylsiloxy-1-heptene, 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene, 3- (4-methoxyphenyl) -2-trifluoromethyl-3-trimethylsiloxy-1-propene, 3- (4-chlorophenyl) -2-trifluoromethyl-3-trimethylsiloxy-1-propene, and the like.

Examples of the fluorine-containing unsaturated alcohol derivative represented by the general formula (2) include 3-trifluoromethyl-3-buten-2-ol, 2-trifluoromethyl-1-penten-3-ol, and 2-trifluoro. Methyl-1-hexen-3-ol, 2-trifluoromethyl-1-hepten-3-ol, 1-phenyl-2-trifluoromethyl-2-propen-1-ol, 1- (4-methoxyphenyl) 2-trifluoromethyl-2-propen-1-ol, 1- (4-chlorophenyl) -2-trifluoromethyl-2-propen-1-ol, and the like.

Examples of the carbonyl compound represented by the general formula (3) include acetaldehyde, propionaldehyde, valeraldehyde, hexaaldehyde, isobutyraldehyde, trimethylacetaldehyde, cyclopentanecarboxaldehyde, cyclohexanecarboxaldehyde, acrolein, 3-butyl-2- ON, benzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 2-benzenesulfonylaldehyde, 2-benzenesulfinylaldehyde, 4-chlorobenzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, acetone, 2-butanone, 2-pentanone, 3-pentanone, acetophenone, propiophenone, methyl acetate, ethyl acetate, phenyl acetate, diacetyl, methyl pyruvate And ethyl pyruvate.


The Lewis base catalyst of the present invention is not particularly limited as long as it is a Lewis base that gives an electron pair to form a chemical bond with the partner, but is preferably an organic amine compound, metal fluoride, metal carbonate or ammonium salt, and an alkali metal fluoride. More preferred are fluorides, alkali metal carbonates and ammonium salt fluorides. As the catalyst, a normal commercial product can be used directly, and the catalyst can be used evenly dissolved in a solvent or partially dissolved. The alkyl metal fluoride is preferably cesium fluoride or potassium fluoride, and more preferably cesium fluoride or potassium fluoride produced by a spray drying method having a large specific surface area from the viewpoint of dissolution in a solvent and dispersibility. The organic amine compound is preferably diethylamine, triethylamine, di-n-butylamine, tri-n-butylamine, pyridine, or N, N-dimethylaniline. The alkali metal carbonate is preferably potassium carbonate or sodium carbonate, more preferably potassium carbonate. preferable. The ammonium salt fluoride is preferably tetrabutylammonium fluoride.

  The reaction of the present invention must be carried out in a solvent that does not participate in the reaction, and an aprotic solvent is preferred. Protic solvents are not preferred because they are involved in the reaction. Specific examples of the aprotic solvent include N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether, hexamethyl. Examples thereof include phosphoric acid triamide. At this time, the concept of the aprotic solvent includes heptane, hexane, xylene, toluene, chloroform, dichloromethane, diisopropyl ether, and acetonitrile. Among them, N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, because the reaction yield is high and easy to handle and industrially obtain. Chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile are preferred, and N-methyl-2-pyrrolidone, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide are more preferred. These can be used alone or in combination of two or more.

  The reagent used in the present invention can be introduced according to any conventional method, and the catalyst can be charged into a mixture comprising a carbonyl compound, a vinylsilane compound and a solvent. Moreover, a carbonyl compound and a vinyl silane compound can also be thrown into the mixture which consists of a solvent and a catalyst simultaneously or as a mixture. It is also possible to put the carbonyl compound into a ternary mixture consisting of a solvent, a catalyst and a vinyl silane compound, or to put the vinyl silane compound into a ternary mixture consisting of a solvent, a catalyst and a carbonyl compound.

  The amount of the reagent used in the present invention is preferably 0.1 to 10 mol of vinylsilane compound, more preferably 0.5 to 2 mol, relative to 1 mol of carbonyl compound. Moreover, it is preferable that a Lewis base catalyst is 0.005-2 mol with respect to 1 mol of carbonyl compounds, More preferably, it is 0.02-0.2 mol. Although the amount of solvent is not particularly limited, 1 to 100 g of solvent is preferable and 1 to 20 g is more preferable with respect to 1 g of carbonyl compound to be used.

  The trifluoropropenylation reaction of the present invention is possible at a reaction temperature of -20 ° C to 120 ° C. The reactor can be either an open-air reactor or a closed reactor such as an autoclave. The reaction pressure can be either atmospheric pressure or pressurized.

  In the purification method of the fluorine-containing unsaturated silyl ether compound represented by the general formula (1), the trifluoropropenylation reaction-terminated liquid can be directly purified by distillation. The residue liquid after distillation purification can be directly recycled as a solvent for the trifluoropropenylation reaction, or can be recycled as a reaction solvent by purifying the residue liquid. For purification, a column chromatography method or a preparative thin layer chromatography method can be applied. As the adsorbent, for example, silica gel, alumina or the like can be selected. As the developing solvent, for example, hexane / ethyl acetate (0/100 to 100/0), hexane / diisopropyl ether (0/100 to 100/0), or the like can be used.

  The resulting fluorine-containing unsaturated silyl ether compound is desilylated to obtain a fluorine-containing unsaturated alcohol derivative represented by the above general formula (2).

  Alternatively, the trifluoropropenylation reaction solution can be directly desilylated to obtain the fluorine-containing unsaturated alcohol derivative represented by the general formula (2). The purification method of the fluorine-containing unsaturated alcohol derivative after direct desilylation can be directly purified by distillation after desilylation. The residue liquid after distillation purification can be directly used as a solvent for the trifluoromethylation reaction, or can be recycled as a reaction solvent after the residue liquid is purified.

  In the desilylation reaction, any conditions capable of eliminating the silyl group can be selected. Acid hydrolysis using hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, sodium hydroxide, potassium hydroxide, etc. Examples include alkali hydrolysis used.

The fluorine-containing unsaturated alcohol derivative represented by the above general formula (2) obtained by desilylation can be isolated and purified from the reaction solution by a general method, for example, solvent extraction from the reaction solution, drying, After concentration, examples include distillation purification, purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, crystallization, recrystallization, and the like.
Examples Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention is not limited to the following examples.

In a 100 mL flask equipped with a reflux condenser, a thermometer, and a stirrer, 15 g of N-methyl-2-pyrrolidone (hereinafter abbreviated as “NMP”), 1.0 g (9.4 mmol) of benzaldehyde, (1-trifluoromethylvinyl) ) 1.9 g (11 mmol) of trimethylsilane was added. 68 mg (0.45 mmol) of cesium fluoride was added and reacted at a reaction temperature of 50 ° C. for 37 hours. ^{As a} result of quantitative analysis by ¹⁹ F-NMR internal standard method, 1.5 g (5.4 mmol) of 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene, 1-phenyl-2-trifluoromethyl- 18 g of a reaction solution containing 0.65 g (3.2 mmol) of 2-propen-1-ol was obtained (yield 91%).

  27 g of water was added to 18 g of the obtained reaction solution, and extracted 3 times with 16 g of diisopropyl ether, and then washed twice with 20 g of water. After drying over 1.0 g of magnesium sulfate, the filtrate was filtered and the solvent was distilled off. The solvent was distilled off to obtain 2.1 g of product. Of these, 0.90 g was purified by preparative thin layer chromatography (PLC plate silica gel, MERCK, developing solvent chloroform) to give 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene 0.31 g (1.1 mmol) was obtained. Among them, 110 mg (0.4 mmol) was dissolved in 3.5 g of diisopropyl ether, 2.0 g of 10% aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 27 hours. The aqueous layer was removed and washed 3 times with 5.0 g of water. After adding 7.3 g of diisopropyl ether and drying with 0.7 g of magnesium sulfate, the mixture was filtered and the filtrate was evaporated to give 80 mg of colorless liquid 1-phenyl-2-trifluoromethyl-2-propen-1-ol ( 0.4 mmol) was obtained.

Analytical value of 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene
¹ H-NMR (CDCl ₃ , internal reference TMS) δ 0.06 (s, 9H), 5.35 (s, 1H), 5.69 (m, 1H), 5.84 (m, 1H), 7. 27-7.37 (m, 5H)
¹⁹ F-NMR (CDCl ₃ , internal reference CFCl ₃ ) δ-65.3 (s, CF ₃ )
Mass spectrum (m / z) 274

1-phenyl-2-trifluoromethyl-2-propen-1-ol analytical value
¹ H-NMR (CDCl ₃ , internal reference TMS) δ 2.16 (brd, 1H), 5.43 (brd, 1H), 5.80 (m, 1H), 5.93 (m, 1H), 7. 30-7.40 (m, 5H)
¹⁹ F-NMR (CDCl ₃ , internal reference CFCl ₃ ) δ-65.7 (s, CF ₃ )
Mass spectrum (m / z) 202

To a 100 mL flask equipped with a reflux condenser, thermometer, and stirrer, 14 g of NMP, 1.1 g (10 mmol) of benzaldehyde, and 2.0 g (12 mmol) of (1-trifluoromethylvinyl) trimethylsilane were added. 70 mg (0.51 mmol) of potassium carbonate was added and reacted at a reaction temperature of 50 ° C. for 120 hours. ^When quantitative analysis was performed by ¹⁹ F-NMR internal standard method, 0.55 g (2.0 mmol) of 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene, 1-phenyl-2-trifluoromethyl- A reaction solution containing 0.95 g (4.7 mmol) of 2-propen-1-ol was obtained (yield 67%).

  In a 100 mL flask equipped with a reflux condenser, a thermometer, and a stirrer, 18 g of tetrahydrofuran (hereinafter abbreviated as “THF”), 1.1 g (10 mmol) of benzaldehyde, 2.2 g of (1-trifluoromethylvinyl) trimethylsilane (13 mmol) ) Was added. 1.5 mL (1.5 mmol) of a THF solution (1M) of tetrabutylammonium fluoride was added and reacted at a reaction temperature of 50 ° C. for 120 hours. 10 g of a 10% hydrochloric acid aqueous solution was added, and the mixture was stirred at room temperature for 24 hours. 30 g of water was added, extracted 3 times with 20 g of diisopropyl ether, and washed twice with 20 g of water. The organic layer was evaporated to obtain a product containing 0.57 g (2.8 mmol) of 1-phenyl-2-trifluoromethyl-2-propen-1-ol as a colorless liquid (yield 28%).

To a 100 mL flask equipped with a reflux condenser, a thermometer, and a stirrer, 14 g of NMP, 1.4 g (10 mmol) of p-chlorobenzaldehyde, and 2.0 g (12 mmol) of (1-trifluoromethylvinyl) trimethylsilane were added. Potassium fluoride (spray-dried product) 12 mg (0.20 mmol) was added and reacted at a reaction temperature of 50 ° C. for 166 hours. ^The quantitative analysis by ¹⁹ F-NMR internal standard method revealed that 1.5 g (4.8 mmol) of 3- (4-chlorophenyl) -2-trifluoromethyl-3-trimethylsiloxy-1-propene, 1- (4-chlorophenyl) 17 g of reaction solution containing 0.70 g (3.0 mmol) of 2-trifluoromethyl-2-propen-1-ol was obtained (yield 78%).

  30 g of water was added to 17 g of the obtained reaction solution and extracted 3 times with 15 g of diisopropyl ether, and then washed twice with 20 g of water. The organic layer was evaporated to give 2.3 g of product. Of these, 0.90 g was purified by preparative thin layer chromatography (PLC plate silica gel, MERCK, developing solvent chloroform) to give 3- (4-chlorophenyl) -2-trifluoromethyl-3-trimethylsiloxy-1- 0.11 g of propene was obtained. Of these, 63 mg (0.21 mmol) was dissolved in 2.0 g of diisopropyl ether, 1.5 g of a 10% aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 27 hours. The aqueous layer was removed and washed 3 times with 5.0 g of water. After adding 7.3 g of diisopropyl ether and drying with 0.7 g of magnesium sulfate, the mixture was filtered and the filtrate was evaporated to give 1- (4-chlorophenyl) -2-trifluoromethyl-2-propen-1-ol 40 mg. (0.17 mmol) was obtained.

Analytical value of 3- (4-chlorophenyl) -2-trifluoromethyl-3-trimethylsiloxy-1-propene
¹ H-NMR (CDCl ₃ , internal reference TMS) δ 0.07 (s, 9H), 5.31 (s, 1H), 5.70 (m, 1H), 5.85 (m, 1H), 7. 26-7.34 (m, 4H)
¹⁹ F-NMR (CDCl ₃ , internal reference CFCl ₃ ) δ-65.2 (s, CF ₃ )
Mass spectrum (m / z) 308

1- (4-Chlorophenyl) -2-trifluoromethyl-2-propen-1-ol analytical value
¹ H-NMR (CDCl ₃ , internal reference TMS) δ 2.16 (brd, 1H), 5.43 (brd, 1H), 5.80 (m, 1H), 5.94 (m, 1H), 7. 28-7.38 (m, 4H)
¹⁹ F-NMR (CDCl ₃ , internal reference CFCl ₃ ) δ-65.7 (s, CF ₃ )
Mass spectrum (m / z) 236

To a 100 mL flask equipped with a reflux condenser, a thermometer, and a stirrer, 14 g of NMP, 0.72 g (10 mmol) of n-butyraldehyde, and 2.0 g (12 mmol) of (1-trifluoromethylvinyl) trimethylsilane were added. Potassium fluoride (spray-dried product) 12 mg (0.20 mmol) was added and reacted at a reaction temperature of 50 ° C. for 166 hours. ^{As a} result of quantitative analysis by ¹⁹ F-NMR internal standard method, 0.76 g (3.2 mmol) of 2-trifluoromethyl-3-trimethylsiloxy-1-hexene, 2-trifluoromethyl-1-hexen-3-ol 0 A reaction solution containing .49 g (2.9 mmol) was obtained (yield 61%).

To a 100 mL flask equipped with a reflux condenser, a thermometer, and a stirrer, 14 g of NMP, 1.4 g (10 mmol) of p-methoxybenzaldehyde, and 2.0 g (12 mmol) of (1-trifluoromethylvinyl) trimethylsilane were added. Potassium fluoride (spray-dried product) 12 mg (0.20 mmol) was added and reacted at a reaction temperature of 50 ° C. for 166 hours. Quantitative analysis by ¹⁹ F-NMR internal standard method revealed that 3- (4-methoxyphenyl) -2-trifluoromethyl-3-trimethylsiloxy-1-propene 1.4 g (4.5 mmol), 1- (4- A reaction solution containing 0.53 g (2.3 mmol) of methoxyphenyl) -2-trifluoromethyl-2-propen-1-ol was obtained (yield 68%).

To a 2 L flask equipped with a reflux condenser, a thermometer, and a stirrer, 1350 g of NMP, 100 g (0.95 mol) of benzaldehyde, and 190 g (1.1 mol) of (1-trifluoromethylvinyl) trimethylsilane were added. Cesium fluoride (7.1 g, 47 mmol) was added and reacted at a reaction temperature of 50 ° C. for 18 hours. Quantitative analysis by ¹⁹ F-NMR internal standard method revealed that 137 g (0.50 mol) of 3-phenyl-2-trifluoromethyl-3-trimethylsiloxy-1-propene, 1-phenyl-2-trifluoromethyl-2- 1647 g of reaction liquid containing 75 g (0.37 mol) of propen-1-ol was obtained (yield 92%).
100 g of 10% hydrochloric acid aqueous solution was added and stirred at room temperature for 18 hours. To the obtained reaction solution, 2000 g of water was added and extracted twice with 700 g of diisopropyl ether, and then washed twice with 500 g of water. After drying over 50 g of magnesium sulfate, the filtrate was filtered and the solvent was distilled off. The solvent was distilled off to obtain 190 g of product. Under reduced pressure, precision distillation and purification were performed to obtain 114 g (0.56 mol) of 1-phenyl-2-trifluoromethyl-2-propen-1-ol as a colorless liquid. Boiling point 98-100 ° C. (2 kPa).

To a 2 L flask equipped with a reflux condenser, a thermometer, and a stirrer, 1350 g of NMP, 68 g (0.94 mol) of n-butyraldehyde, and 190 g (1.1 mol) of (1-trifluoromethylvinyl) trimethylsilane were added. Cesium fluoride (7.1 g, 47 mmol) was added and reacted at a reaction temperature of 50 ° C. for 4 hours. ^{As a} result of quantitative analysis by ¹⁹ F-NMR internal standard method, 0.76 g (3.2 mmol) of 2-trifluoromethyl-3-trimethylsiloxy-1-hexene, 2-trifluoromethyl-1-hexen-3-ol 0 1590 g of a reaction solution containing .49 g (2.9 mmol) was obtained (58% yield). 100 g of 10% aqueous hydrochloric acid solution was added to 1120 g of the reaction solution, and the mixture was stirred at room temperature for 3 hours. To the obtained reaction solution, 1200 g of water was added and extracted twice with 600 g of diisopropyl ether, and then washed twice with 300 g of water. After drying with 30 g of magnesium sulfate, filtration was performed to distill off the filtrate. The solvent was distilled off to obtain 98 g of product. Under reduced pressure, precision distillation purification was performed to obtain 63 g (0.38 mol) of colorless liquid 2-trifluoromethyl-1-hexen-3-ol. Boiling point 68-70 ° C. (5 kPa).

  It is possible to safely and easily introduce a trifluoropropenyl group directly into an inexpensive carbonyl compound and to efficiently obtain a fluorine-containing unsaturated alcohol derivative represented by the general formula (2) on an industrial scale. Industrial utility value is high.

Claims (5)

General formula (1)

(Wherein R ¹ represents a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group , or an unsubstituted or substituted alkyl group substituted with a substituent selected from the group consisting of an acyloxy group, A hydrogen atom, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group, and R ² is selected from the group consisting of a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group and an acyloxy group. substituted with a substituent or unsubstituted alkyl group, a hydrogen atom, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an alkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group. Note R ¹ and R ² are combined to intervene or not interpose a heteroatom A ¹ , A ² and A ³ are each independently of each other, the same or different, and a linear or branched carbon which may have a hydrogen atom or a substituent. Represents an alkyl group of formulas 1 to 4.)
A fluorine-containing unsaturated silyl ether compound represented by the formula: General formula (3) in the presence of a Lewis base catalyst in an aprotic solvent
R ¹ COR ² (3)
Wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group, and R ² is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group or an aralkyl. A group, an alkynyl group, an aryl group, an alkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, wherein R ¹ and R ² are combined to form a ring with or without a heteroatom. Part of the structure may be formed.)
And a carbonyl compound represented by the general formula (4)

(In the formula, A ¹ , A ² and A ³ are each independently the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms which may have a substituent. .)
Is reacted with a vinylsilane compound represented by the general formula (1)

(Wherein R ¹ , R ² , A ¹ , A ² and A ³ are the same as defined above.)
Wherein the reaction solution containing the fluorine-containing unsaturated silyl ether compound is directly desilylated or purified and separated, followed by desilylation (2)

(Wherein R ¹ and R ² are the same as defined above)
The manufacturing method of the fluorine-containing unsaturated alcohol derivative shown by these.   The carbonyl compound represented by the general formula (3) is an aldehyde, and the vinylsilane compound represented by the general formula (4) is (1-trifluoromethylvinyl) trimethylsilane. Of producing a fluorine-containing unsaturated alcohol derivative.   3. The aprotic solvent is at least one selected from the group consisting of N-methyl-2-pyrrolidone, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide. Or the manufacturing method of the fluorine-containing unsaturated alcohol compound of 3.   The method for producing a fluorine-containing unsaturated alcohol compound according to any one of claims 2 to 4, wherein the Lewis base catalyst is an organic amine compound, an alkali metal fluoride, an alkali metal carbonate or an ammonium salt.