JP4523324B2 - Method for producing alcohol derivative having perfluoroalkyl group - Google Patents

Description

  The present invention relates to a method for producing an alcohol derivative having a perfluoroalkyl group useful for an intermediate such as medical and agricultural chemicals.

  Fluoroalkyl compounds typified by alcohols having a perfluoroalkyl group are extremely useful compounds as intermediates for pharmaceuticals, agricultural chemicals and the like.

  As a method for producing these compounds, conventionally, a perfluoroalkyl anion is generated by using a metal such as copper or zinc in a perfluoroalkyl halide such as perfluoroalkyl iodine or perfluoroalkyl bromine, or using tetrakis diethylaminoethylene or the like. A method for producing an alcohol derivative having a perfluoroalkyl group by reacting with a carbonyl compound is known (Non-Patent Document 1, Non-Patent Document 2).

  However, in these methods, many perfluoroalkyl halides have a low boiling point, and in addition to being difficult to handle, methods using metals have problems in terms of waste.

  On the other hand, as a method for solving the above problems, a method has been developed in which a perfluoroalkylsilane and a corresponding carbonyl compound are reacted using a fluoride ion source typified by tetrabutylammonium fluoride (Non-patent Document 3). Non-Patent Document 4).

  However, these methods are not easy to handle because the fluoride ion source represented by tetrabutylammonium fluoride is expensive and has high hygroscopicity.

  Furthermore, it is very difficult to synthesize optically active perfluoroalkyl alcohol derivatives by these methods.

  In order to improve these problems, a method of reacting perfluoroalkylsilanes and corresponding carbonyl compounds using a Lewis base has been developed (Patent Document 1).

However, even in this method, it has been reported that the yield is greatly reduced unless an aprotic polar solvent is used.
J. et al. Chem. Soc. Perkin Trans. , 1,1951 (1990) Org. Lett. , 3, 4241 (2001) J. et al. Am. Chem. Soc. , 111, 393 (1989) J. et al. Org. Chem. , 56, 984 (1991) JP 07-118188 A

  Accordingly, the problem to be solved by the present invention is to provide a production method that can be applied to a low-polar solvent using an inexpensive and easy-to-handle catalyst and can be applied to the synthesis of an optically active perfluoroalkyl alcohol derivative. It is.

  In view of such a current situation, the present inventors have conducted intensive studies. As a result, the inventors have found a method for producing perfluoroalkyl alcohol derivatives inexpensively and safely from carbonyl compounds corresponding to perfluoroalkylsilanes and that the method can be applied to the synthesis of optically active perfluoroalkyl alcohol derivatives.

That is, the present invention relates to the general formula (1)
R ¹ COR ² (1)
(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, An aralkyl group, an alkynyl group, an aryl group, an alkoxy group or an aryloxy group, wherein R ¹ and R ² are combined to form a part of a cyclic structure with or without a heteroatom. May be good.)
A carbonyl compound represented by the general formula (2)
R _F SiR ³ R ⁴ R ⁵ (2)
(In the formula, R _F is a perfluoroalkyl group, and R ³ , R ⁴ or R ⁵ represents the same or different substituted or unsubstituted alkyl group or aryl group.)
Perfluoroalkylsilanes represented by general formula (3)
R ⁶ R ⁷ R ⁸ R ⁹ NX (3)
(Wherein R ⁶ , R ⁷ , R ⁸ or R ⁹ represent the same or different substituted or unsubstituted alkyl group or aryl group, and X represents Cl, Br or I. R ⁶ , R ⁷ , R ⁸ and R ⁹ may be combined to form part of the cyclic structure with or without heteroatoms.)
And the general formula (4)
MF (4)
(In the formula, M represents K, Na, Li, Ca _1/2 or Mg _1/2 .)
(5), characterized by reacting with a fluoride represented by formula (5)
R _F C (OH) R ¹ R ² (5)
(Wherein R ¹ , R ² and R _F are as defined above)
It relates to a method for producing an alcohol derivative having a perfluoroalkyl group represented by the formula:

  Furthermore, the present invention relates to a method for producing an optically active substance of an alcohol derivative having a perfluoroalkyl group using an optically active substance in an ammonium salt.

  Conventionally, when producing a perfluoroalkyl alcohol derivative, there are problems in that an expensive substrate is required, a large amount of waste is generated, and the substrate is unstable, so that it is not easy to handle. However, according to the present invention, an inexpensive and easy-to-handle catalyst can be used, and a low-polar solvent can be produced. In addition, an optically active perfluoroalkyl alcohol derivative can be produced by using an optically active ammonium salt.

  Hereinafter, the present invention will be described in detail.

  The alkyl group in the general formula (1) means an optionally branched alkyl group having 1 to 20 carbon atoms or a cycloalkyl group having 3 to 20 carbon atoms, and the alkyl group optionally represents a halogen atom. , A cyano group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, an acyloxy group and the like may be substituted.

  In addition, the alkenyl group in the general formula (1) means an alkenyl group having 1 to 20 carbon atoms which may be branched or a cycloalkenyl group having 3 to 20 carbon atoms, a vinyl group, 1- A propenyl group, 1-butenyl group, 1-hexenyl group, cyclohexenyl group, allyl group, etc. can be illustrated.

  Examples of the aralkyl group in the general formula (1) include a benzyl group, a pentafluorobenzyl group, a p-methylbenzyl group, a p-nitrobenzyl group, and a naphthylmethyl group.

  Examples of the alkynyl group in the general formula (1) include ethynyl group, phenylethynyl group, 2-propynyl group and the like.

  The aryl group in the general formula (1) means an aromatic group having 6 to 20 carbon atoms, and the aryl group may optionally be an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, or an alkoxy group. , An aryloxy group, an acyloxy group and the like may be substituted.

  Moreover, the alkoxy group in the said General formula (1) means a C1-C20 alkoxy group, and the alkoxy group may be substituted by the same substituent as the case of said alkyl group.

  In addition, the aryloxy group in the general formula (1) means an aryloxy group having 6 to 20 carbon atoms, and the aryloxy group may be substituted with the same substituent as in the above aryl group. Good.

Examples of the cyclic structure that can be formed by combining R ¹ and R ² in the general formula (1) include monocyclic, bicyclic, or higher polycyclic structures having 3 to 20 members. Can be shown. These cyclic structures may have a hetero atom.

  Examples of the carbonyl compound represented by the general formula (1) include acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, hexaaldehyde, isobutyraldehyde, trimethylacetaldehyde, cyclopentanecarboxaldehyde, cyclohexanecarboxaldehyde, acrolein, 3 -Butyn-2-one, benzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 2-benzenesulfonylbenzaldehyde, 2-benzenesulfinylbenzaldehyde, 4-chlorobenzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, acetone, 2-butanone 2-pentanone, 3-pentanone, acetophenone, propiophenone, methyl acetate, ethyl acetate, It can be exemplified acids such as phenyl.

  The perfluoroalkyl group in the general formula (2) is preferably an alkyl group or a cycloalkyl group having 1 to 10 carbon atoms, which may be branched by substituting hydrogen with fluorine.

  The alkyl group in the general formulas (2) and (3) is preferably an alkyl group having 1 to 20 carbon atoms, which may be branched, or a cycloalkyl group having 3 to 20 carbon atoms. It may be substituted with a halogen atom or the like.

  The aryl group in the general formulas (2) and (3) is preferably an aromatic group having 6 to 20 carbon atoms, and the aryl group is optionally substituted with a substituent such as an alkyl group or a halogen atom. Also good.

Examples of the cyclic structure that can be formed by combining R ⁶ , R ⁷ , R ⁸ and R ⁹ in the general formula (3) include monocyclic, bicyclic, or The above polycyclic structure can be shown. These cyclic structures may have a hetero atom.

  Examples of the perfluoroalkylsilanes of the general formula (2) include trifluoromethyltrimethylsilane, pentafluoroethyltrimethylsilane, and heptafluoropropyltrimethylsilane, and the amount used is particularly limited as long as it is more than the theoretical amount relative to the carbonyl compound. However, it is preferably 1 to 10 mol, more preferably 1.1 to 2 mol, per 1 mol of the carbonyl compound.

  Examples of the ammonium salt of the general formula (3) include tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetra Examples include butylammonium iodide, N-benzylcinchonium bromide, N- (4-methoxybenzyl) cinchonium bromide and N- (4-trifluoromethylbenzyl) cinchonium bromide, and the amount used is a carbonyl compound. However, it is preferably 0.01 to 10 moles per mole of the carbonyl compound. , More preferably from 0.1 to 0.3 mol.

  The fluoride of the general formula (4) is potassium fluoride, sodium fluoride, lithium fluoride, calcium fluoride or magnesium fluoride, and the amount used is not particularly limited with respect to the carbonyl compound. The amount is preferably 0.01 to 10 mol, more preferably 0.1 to 0.3 mol, per 1 mol of the carbonyl compound.

  The reaction of the present invention is carried out in a low polarity organic solvent or a mixed solvent of a low polarity organic solvent and water.

  Examples of the low polarity organic solvent used include halogenated hydrocarbons such as dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, dimethyl ether, diethyl ether, 1, Ethers such as 4-dioxane or tetrahydrofuran, and aromatic hydrocarbons such as benzene, toluene or xylene. These low polar organic solvents may be used alone or in combination of two or more. Of these, chloroform, dichloromethane, tetrahydrofuran or toluene is preferred.

  The solvent of the present invention may be a mixed solvent by adding water to the above low-polar organic solvent at an arbitrary ratio.

  Although reaction temperature is not specifically limited, Usually, it is -80-100 degreeC, More preferably, it is -40-60 degreeC.

  The stirring speed is appropriately selected so that stirring is sufficiently performed.

  The reaction time is not particularly limited, but the reaction is usually completed in 1 to 24 hours.

  As the hydrolysis method, any conditions capable of eliminating the silyl group can be selected. Acid hydrolysis using hydrochloric acid, sulfuric acid, etc., alkaline hydrolysis using sodium hydroxide, potassium hydroxide, etc. can be used. Can be mentioned.

  A desired reaction product can be obtained from this reaction solution by a conventional method.

  The product of the present invention is an alcohol derivative having a perfluoroalkyl group represented by the general formula (5). For example, 1,1,1-trifluoro-2-propanol, 3,3,4,4,4 -Pentafluoro-2-butanol, 3,3,4,4,5,5,5-heptafluoro-2-pentanol, 1,1,1-trifluoro-2-butanol, 1,1,1,2 , 2-pentafluoro-3-pentanol, 4,4,5,5,6,6,6-heptafluoro-3-hexanol, 1,1,1-trifluoro-2-pentanol, 1,1, 1-trifluoro-2-hexanol, 1,1,1-trifluoro-2-heptanol, 1,1,1-trifluoro-3-methyl-2-butanol, 1,1,1-trifluoro-3, 3-dimethyl-2-butanol, -Cyclopentyl-2,2,2-trifluoro-1-ethanol, 1-cyclohexyl-2,2,2-trifluoro-1-ethanol, 1,1,1-trifluoro-3-buten-2-ol, 1,1,1-trifluoro-3-butyn-2-ol, 2,2,2-trifluoro-1-phenyl-1-ethanol, 2,2,2-trifluoro-1- (4-nitrophenyl) ) -1-ethanol, 2,2,2-trifluoro-1- (4-methoxyphenyl) -1-ethanol, 1- (2-benzenesulfonylphenyl) -2,2,2-trifluoro-1-ethanol 1- (2-benzenesulfinylphenyl) -2,2,2-trifluoro-1-ethanol, 2,2,2-trifluoro-1- (4-chlorophenyl) -1-ethanol, 2,2 2-trifluoro-1-benzyl-1-ethanol, 1,1,1-trifluoro-3-phenyl-2-butanol, 1,1,1-trifluoro-2-methyl-2-propanol, 1,1 , 1-trifluoro-2-methyl-2-butanol, 1,1,1-trifluoro-2-methyl-2-pentanol, 1,1,1-trifluoro-2-ethyl-2-butanol, 1,1,1-trifluoro-2-phenyl-2-propanol, 1,1,1-trifluoro-2-phenyl-2-butanol, 1,1,1-trifluoro-2-methoxy-2-propanol, Examples include 1,1,1-trifluoro-2-ethoxy-2-propanol and 1,1,1-trifluoro-2-phenoxy-2-propanol.

  Furthermore, when an optically active substance is used for the ammonium salt of the general formula (3), an optically active alcohol derivative can be obtained.

EXAMPLES Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.

  Moreover, the optical purity was measured using DAICEL CHIRALPAK AD-H and OD-H (hexane / isopropanol = 99/1).

Add potassium fluoride (6.5 mg, 0.11 mmol), tetrabutylammonium bromide (36.1 mg, 0.11 mmol), and benzaldehyde (39.6 mg, 0.37 mmol) to a capped test tube and dissolve in tetrahydrofuran (1 ml). And trifluoromethyltrimethylsilane (0.11 ml, 0.75 mmol) was added. After confirming the completion of the reaction by TLC, water was added. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained product was dissolved in tetrahydrofuran (2 ml), 6N aqueous hydrochloric acid solution (1 ml) was added, and the mixture was stirred at room temperature for 2 hours. After extraction with ethyl acetate, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (SiO ₂ 17.3 g, hexane: ethyl acetate = 70: 30) to obtain 2,2,2-trifluoro-1-phenylethanol (59.1 mg, 90%).
¹ H-NMR (CDCl ₃ , TMS): δ2.58 (b, 1H), 5.02 (q, 1H), 7.3-7.5 (m, 5H); ¹⁹ F-NMR (CDC1 ₃ , CFC1 ₃ ): δ- 78.9

Potassium fluoride (6.5 mg, 0.11 mmol), tetrabutylammonium bromide (36.1 mg, 0.11 mmol), 4-nitrobenzaldehyde (56.4 mg, 0.37 mmol) are added to a capped test tube and dissolved in tetrahydrofuran (1 ml). Cool to −10 ° C. and add trifluoromethyltrimethylsilane (0.11 ml, 0.75 mmol). The reaction solution was treated in the same manner as in Example 1 to obtain 2,2,2-trifluoro-1- (4-nitrophenyl) ethanol (50.1 mg, 61%).
¹ H-NMR (CDCl ₃ , TMS): δ 2.78 (b, 1H), 5.18 (q, 1H), 7.68 (d, 2H), 8.26 (d, 2H); ¹⁹ F-NMR (CDC1 ₃ , CFC1 ₃ ): δ-78.O

  Add potassium fluoride (6.5 mg, 0.11 mmol), tetrabutylammonium bromide (36.1 mg, 0.11 mmol), 4-nitrobenzaldehyde (56.4 mg, 0.37 mmol) to a capped test tube, dissolve in dichloromethane (3 ml), Cool to −10 ° C. and add trifluoromethyltrimethylsilane (0.11 ml, 0.75 mmol). The reaction solution was treated in the same manner as in Example 1 to obtain 2,2,2-trifluoro-1- (4-nitrophenyl) ethanol (66.0 mg, 80%).

Potassium fluoride (2.6 mg, 0.044 mmol), tetrabutylammonium bromide (14.2 mg, 0.044 mmol), 4-methoxybenzaldehyde (20.0 mg, 0.15 mmol) were added to a capped test tube, and dissolved in tetrahydrofuran (1 ml). Cool to −10 ° C. and add trifluoromethyltrimethylsilane (0.11 ml, 0.75 mmol). The reaction solution was treated in the same manner as in Example 1 to obtain 2,2,2-trifluoro-1- (4-methoxyphenyl) ethanol (58.3 mg, 90%).
¹ H-NMR (CDCl ₃ , TMS): δ3.3 (b, 1H), 3.83 (s, 3H), 4.98 (q, 1H), 6.9-7.0 (m, 2H), 7.3-7.5 (m, 2H ); ¹⁹ F-NMR (CDC1 ₃ , CFC1 ₃ ): δ-79.O

  In a capped test tube, potassium fluoride (3.5 mg, 0.060 mmol), N- (4-trifluoromethylbenzyl) cinchonium bromide (31.8 mg, 0.060 mmol), 4-nitrobenzaldehyde (30.0 mg, 0.20 mmol). In addition, it was dissolved in dichloromethane (3 ml), cooled to −10 ° C., and trifluoromethyltrimethylsilane (0.035 ml, 0.24 mmol) was added. The reaction solution was treated in the same manner as in Example 1 to obtain 2,2,2-trifluoro-1- (4-nitrophenyl) ethanol (26.9 mg, 61%, 6% ee).

In a capped test tube, potassium fluoride (1.4 mg, 0.024 mmol), N- (4-trifluoromethylbenzyl) cinconium bromide (13.0 mg, 0.024 mmol), 2-benzenesulfonylbenzaldehyde (20.0 mg, 0.081 mmol) Was dissolved in dichloromethane (3 ml), cooled to −10 ° C., and trifluoromethyltrimethylsilane (0.015 ml, 0.10 mmol) was added. The reaction solution was treated in the same manner as in Example 1 to obtain 1- (2-benzenesulfonylphenyl) -2,2,2-trifluoroethanol (17.9 mg, 70%, 9% ee).
¹ H-NMR (CDCl ₃ , TMS): δ 3.28 (s, 1H), 6.17 (q, 1H), 7.52-8.15 (m, 9H); ¹⁹ F-NMR (CDC1 ₃ , CFC1 ₃ ): δ- 75.6

In a capped test tube, potassium fluoride (1.5 mg, 0.026 mmol), N- (4-trifluoromethylbenzyl) cinchonium bromide (13.9 mg, 0.026 mmol), 2-benzenesulfinylbenzaldehyde (20.0 mg, 0.087 mmol) Was dissolved in dichloromethane (3 ml), cooled to −10 ° C., and trifluoromethyltrimethylsilane (0.015 ml, 0.10 mmol) was added. The reaction solution was treated in the same manner as in Example 1 to obtain 1- (2-benzenesulfinylphenyl) -2,2,2-trifluoroethanol (20.9 mg, 74%, 42% de).
¹ H-NMR (CDCl ₃ , TMS): δ 2.45 (brs, 1H), 5.72 (q, 1H), 7.2-8.0 (m, 9H); ¹⁹ F-NMR (CDC1 ₃ , CFC1 ₃ ): δ- 76.5, -77.4

Comparative Example 1

  Add potassium fluoride (6.5 mg, 0.11 mmol) and benzaldehyde (39.6 mg, 0.37 mmol) to a capped test tube, dissolve in tetrahydrofuran (1 ml), cool to −10 ° C., and add trifluoromethyltrimethylsilane (0.11 ml). 0.75 mmol) was added. The reaction solution was treated in the same manner as in Example 1, but 2,2,2-trifluoro-1-phenylethanol, the target product, was not obtained.

Comparative Example 2

  Add tetrabutylammonium bromide (36.1 mg, 0.11 mmol) and benzaldehyde (39.6 mg, 0.37 mmol) to a capped test tube, dissolve in tetrahydrofuran (1 ml), cool to −10 ° C., and add trifluoromethyltrimethylsilane (0.11 ml, 0.75 mmol) was added. The reaction solution was treated in the same manner as in Example 1, but 2,2,2-trifluoro-1-phenylethanol, the target product, was not obtained.

  Conventionally, when producing a perfluoroalkyl alcohol derivative, there are problems in that an expensive substrate is required, a large amount of waste is generated, and the substrate is unstable, so that it is not easy to handle. However, according to the present invention, an inexpensive and easy-to-handle catalyst can be used, and a low-polar solvent can be produced. In addition, an optically active perfluoroalkyl alcohol derivative can be produced by using an optically active ammonium salt. For this reason, an efficient perfluoroalkyl alcohol derivative can be produced, the production cost can be reduced, and the economic effect is great.

Claims (7)

General formula (1)
R ¹ COR ² (1)
(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, An aralkyl group, an alkynyl group, an aryl group, an alkoxy group or an aryloxy group, wherein R ¹ and R ² are combined to form a part of a cyclic structure with or without a heteroatom. May be good.)
A carbonyl compound represented by the general formula (2)
R _F SiR ³ R ⁴ R ⁵ (2)
(In the formula, R _F is a perfluoroalkyl group, and R ³ , R ⁴ or R ⁵ represents the same or different substituted or unsubstituted alkyl group or aryl group.)
Perfluoroalkylsilanes represented by general formula (3)
R ⁶ R ⁷ R ⁸ R ⁹ NX (3)
(Wherein R ⁶ , R ⁷ , R ⁸ or R ⁹ represent the same or different substituted or unsubstituted alkyl group or aryl group, and X represents Cl, Br or I. R ⁶ , R ⁷ , R ⁸ and R ⁹ may be combined to form part of the cyclic structure with or without heteroatoms.)
And the general formula (4)
MF (4)
(In the formula, M represents K, Na, Li, Ca _1/2 or Mg _1/2 .)
Wherein the fluoride represented by the general formula (5) is reacted in a low polar organic solvent or a mixed solvent of a low polar organic solvent and water.
R _F C (OH) R ¹ R ² (5)
(Wherein R ¹ , R ² and R _F are as defined above)
The manufacturing method of the alcohol derivative which has the perfluoroalkyl group represented by these. The method according to claim 1, wherein the perfluoroalkylsilane represented by the general formula (2) is trifluoromethyltrimethylsilane. The production method according to claim 1 or 2, wherein the ammonium salt represented by the general formula (3) is tetrabutylammonium bromide, and the fluoride represented by the general formula (4) is potassium fluoride. The low polarity organic solvent is dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, benzene, toluene and The production method according to claim 3 , wherein the production method is at least one selected from the group consisting of xylene. The low polarity organic solvent is dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, benzene, toluene and The production method according to claim 1, wherein the production method is at least one selected from the group consisting of xylene . Ammonium salt represented by the general formula (3) is an optically active form, the formula (5) alcohol derivatives having perfluoroalkyl groups represented by the claims 1, 2 or 5 is an optically active substance The manufacturing method of any one of Claims. The ammonium salt represented by the general formula (3) is N- (4-trifluoromethylbenzyl) cinconium bromide, and the alcohol derivative having a perfluoroalkyl group represented by the general formula (5) is optically active. The manufacturing method according to any one of claims 1, 2, 5 and 6 .