JP2009242270A - Method for producing 4-perfluoroisopropylaniline - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for highly selectively and efficiently producing a 4-perfluoroisopropylaniline from an inexpensive raw material. <P>SOLUTION: Aminoaryl-containing fluoroalcohol is reacted with sulfuryl fluoride (SO<SB>2</SB>F<SB>2</SB>) in the coexistence of an organic base or "a salt or complex comprising an organic base and hydrogen fluoride" in the presence of an organic solvent. A nitrile is particularly desirable as the organic solvent, and a tertiary amine is particularly desirable as the organic base. It is possible to produce the objective product of the formula while markedly suppressing the formation of by-producs. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

    The present invention relates to an industrial production method of 4-perfluoroisopropylanilines useful as an intermediate for pharmaceuticals and agricultural chemicals.

    Conventionally known 4-perfluoroisopropylanilines represented by the formula [2]

In Expression [2], R ¹ and R ² are the same or different hydrogen atom, an alkyl group having 1 to 10 carbon atoms, the number 3-8 cycloalkyl group, -COR ⁷ (wherein the carbon, R ⁷ is a hydrogen atom , An alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group or a substituted phenyl group) and COOR ⁸ (wherein R ⁸ represents a group selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a phenyl group. R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different hydrogen atom, halogen atom, hydroxyl group, nitro group, alkyl group having 1 to 10 carbon atoms, haloalkyl group having 1 to 10 carbon atoms, 1 to 1 carbon atoms. 10 alkoxy groups, alkylthio groups having 1 to 10 carbon atoms, —N (R ⁹ ) (R ¹⁰ ) (wherein R ⁹ and R ¹⁰ are the same or different hydrogen atoms, alkyl groups having 1 to 10 carbon atoms, carbon atoms) A cycloalkyl group having a number of 3 to 8 or a phenyl group, R ⁹ and R ¹⁰ may be combined to form an alkylene group having a carbon number of 3 to 6),-(R ')-N ( R ⁹ ) (R ¹⁰ ) (wherein R ′ represents an alkylene group having 1 to 6 carbon atoms, and R ⁹ and R ^{10 have} the same meaning as described above), and a group selected from the group consisting of phenyl groups To express.

Any ^{two of} R ¹ , R ² , R ³ and R ⁵ can be combined to form an alkylene group having 2 to 4 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶ can be formed. Among them, two adjacent groups can be combined to form an alkylene group having 3 to 5 carbon atoms. ]
Examples of the production method include the following A) to C).

  A) A method in which aniline is reacted with 2-halogenated perisopropyl in the presence of a radical reaction initiator to replace the 4-position of aniline with a perisopropyl group (Patent Documents 1 and 2).

[In the above reaction formula, the meanings of R ^{1 to} R ⁶ are the same as those in the formula [1]. ]
B) A method in which halogenated benzenes and 2-iodoheptafluoropropane are used as raw materials and coupled in the presence of metallic copper (Patent Document 3, Non-Patent Document 1, and Non-Patent Document 2).

[In the above reaction formula, the meanings of R ^{1 to} R ⁶ are the same as those in the formula [1]. ]
C) 2-phenyl-1,1,1,3,3,3-hexafluoro-2-propanol obtained by reacting a phenyl Grignard reagent with hexafluoroacetone using a fluorinating agent such as sulfur tetrafluoride And then dehydroxylating and nitrating with a mixed acid and further reducing the nitro group to obtain anilines (Patent Document 4).

  On the other hand, perfluoroisopropylanilines are described as intermediates for medicines, agricultural chemicals, chemicals, etc., for example, phthalamide derivatives having a perfluoroisopropyl group on the benzene ring are useful as insecticides in agriculture and horticulture. (Patent Document 5).

In addition, the reaction which reacts perfluoroalkanesulfonyl fluoride with the compound which has a hydroxyl group, and produces dehydroxyfluorination is already known (nonpatent literature 3, patent documents 6, etc.), and has a hydroxyl group. A reaction in which a compound is reacted with sulfuryl fluoride (SO ₂ F ₂ ) to obtain a corresponding fluorinated product is also known (Patent Document 7). However, no dehydroxylation fluorination of fluoroalcohols containing aryl groups containing amino groups has been known.
JP 2001-122836 A JP 2003-335735 A German Published Patent No. 2606982 Canadian Patent Specification No. 1,022,573 Japanese translation of publication No. 2005-529963 JP 2004-323518 A JP 2006-290870 A Tetrahedron, 25, 5921 (1969) Bull. Chem. Soc. Jpn. , 65.141 (1992). Organic Letters, Vol. 6, No. 9 (2004), 1465-1468.

  In the method A), it is necessary to prepare 2-halogenated perisopropyl beforehand. In this method, the desired product cannot be obtained in a satisfactory yield except when an expensive iodide is used as 2-halogenated perisopropyl.

  The method B) is disadvantageous for industrial mass production in that it is necessary to prepare halogenated benzenes in advance and that a copper equivalent or more is required as a catalyst.

In the method C), it is necessary to use a large amount of a reagent that is not easy to handle, such as sulfur tetrafluoride as a fluorinating agent, and it is not necessarily industrially advantageous. Furthermore, when this dehydroxylation fluorination reaction using sulfur tetrafluoride is applied to an aminoaryl group-containing fluoroalcohol, in addition to the desired 4-perfluoroisopropylaniline, undesired byproducts are present. It has been found that a significant amount is generated. In particular, when the substituent at the 4-position is —NH ₂ , the —NH ₂ group reacts with a perfluoroisopropyl group to produce “dimer A” or “dimer B” represented by the following formula:

Is generated in a considerable amount, and the yield of the target product is greatly reduced (see the reference example described later) (in this specification, a chemical species having a perfluoroisopropyl group at the right end is similar to this). “Dimer A”, a chemical species whose right end is a 2-hydroxyhexafluoroisopropyl group is referred to as “Dimer B”).

  As described above, all known methods for producing 4-perfluoroisopropylanilines useful as intermediates for pharmaceuticals and agricultural chemicals are suitable for obtaining a desired product on a small scale, but as a large-scale production method, It was not satisfactory enough.

  Therefore, the present inventors have made extensive studies in view of the above problems, and as a result, aminoaryl group-containing fluoroalcohols represented by the formula [1].

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) to give 4-perfluoroisopropylanilines represented by the formula [2]

When an organic base or “a salt or complex comprising an organic base and hydrogen fluoride” is allowed to coexist in the presence of an organic solvent, dehydroxylation fluorination reaction occurs at a high selectivity, and is represented by the formula [2]. It was found that 4-perfluoroisopropylanilines were obtained (in the formula [1] and the formula [2], the meanings of R ¹ to R ⁶ are the same as above).

That is, the present invention reacts the aminoaryl group-containing fluoroalcohol represented by the formula [1] with sulfuryl fluoride (SO ₂ F ₂ ) to produce 4-perfluoroisopropyl represented by the formula [2]. 4-perfluoroisopropyl represented by the formula [2], wherein an aniline is produced by coexisting an organic base or a “salt or complex comprising an organic base and hydrogen fluoride” in the presence of an organic solvent. This is a method for producing anilines.

In the case where both R ¹ and R ² are hydrogen atoms (that is, when the 4-position substituent is —NH ₂ ), the compound represented by the formula [1] according to the above method C) Instead of “a fluoroalcohol having an amino group-free aryl group” as a raw material, this is reacted with perfluoroalkanesulfonyl fluoride (RfSO ₂ F) to replace the hydroxyl group with fluorine. It is also envisaged that the aryl group is nitrated and then reduced (see formula below).

  However, when “fluoroalcohol having an amino group-free aryl group” was used as a raw material, it was found that dehydroxyl fluorination with perfluoroalkanesulfonyl fluoride hardly progressed (the above formula).

In addition, regarding the above-mentioned dehydroxyl fluorination of aminoaryl group-containing fluoroalcohols using sulfur tetrafluoride, a considerable amount of by-products such as the above-mentioned “dimerized product” is generated. Is it possible to successfully obtain the corresponding target product even if an attempt is made to fluorinate the aminoaryl group-containing fluoroalcohol represented by the formula [1] using sulfuryl fluoride (SO ₂ F ₂ )? It was unclear.

  However, the present inventor used the conventionally known sulfuryl fluoride as a fluorinating agent and applied it to the aminoaryl group-containing fluoroalcohol represented by the formula [1]. We obtained practically and industrially advantageous knowledge that the target product was obtained with high selectivity and high yield.

In addition, among the aminoaryl group-containing fluoroalcohols represented by the formula [1], when R ^{1 to} R ⁶ are alcohols having specific substituents (for details, refer to Examples described later), the hydroxyl group is markedly dehydroxylated. Fluorination progressed, and the target product was obtained with high selectivity.

  In addition, when the aminoaryl group-containing fluoroalcohol represented by the formula [1] is used as a starting material, the present invention provides a specific “organic base” or a specific “organic base and fluoride in the presence of a specific organic solvent. There is also a finding that by reacting under “suitable reaction conditions” such as coexistence of a “salt or complex comprising hydrogen”, dehydroxylation fluorination proceeds particularly well, and the target product can be produced in a higher yield. Obtained.

  According to the present invention, it is not necessary to use an expensive reagent such as the method A) and B), and it is not necessary to use a large amount of difficult-to-handle reagent such as the method C). Furthermore, compared to the method C), the production of the “dimer” and other by-products can be remarkably suppressed, and the desired 4-perfluoroisopropylaniline can be produced with higher selectivity. In addition, the purification operation after the reaction was greatly reduced.

  In addition, the applicant of the present invention converts the aminoaryl group-containing fluoroalcohol represented by the formula [1] in the presence of an organic base or a “salt or complex composed of an organic base and hydrogen fluoride” in a perfluoroalkanesulfonyl fluoride. A method for producing 4-perfluoroisopropylaniline represented by the formula [2] using a process has already been filed (Japanese Patent Application No. 2007-326140). In the present invention, perfluoroalkanesulfonyl fluoride used in this method can be replaced with sulfuryl fluoride and reacted under more suitable reaction conditions, so that it can be supplied more easily than conventional production methods. It became. This is a very excellent method for efficiently producing the target product on an industrial scale.

  The present invention makes it possible to produce the desired 4-perfluoroisopropylanilines using sulfuryl fluoride, which is inexpensive and suitable for handling a large amount, while greatly suppressing the production of by-products. There is an effect.

  Hereinafter, the present invention will be described in detail. The present invention provides a sulfuryl fluoride containing an aminoaryl group-containing fluoroalcohol represented by the formula [1] in the presence of an organic base or a “salt or complex comprising an organic base and hydrogen fluoride” in the presence of an organic solvent. To produce a 4-perfluoroisopropylaniline represented by the formula [2] by causing a dehydroxylation fluorination reaction.

In the aminoaryl group-containing fluoroalcohol represented by the formula [1] used in the present invention, R ¹ and R ² are the same or different, and are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 3 carbon atoms. ˜8 cycloalkyl group, —COR ⁷ (wherein R ⁷ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or phenyl. A group or a substituted phenyl group.) And COOR ⁸ (wherein R ⁸ represents an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a phenyl group). Represents a selected group.

R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an alkyl group having 1 to 10 carbon atoms, or a haloalkyl group having 1 to 10 carbon atoms. , An alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, —N (R ⁹ ) (R ¹⁰ ) (wherein R ⁹ and R ¹⁰ are the same or different, a hydrogen atom, An alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group, R ⁹ and R ¹⁰ can be combined to form an alkylene group having 3 to 6 carbon atoms. ), — (R ′) — N (R ⁹ ) (R ¹⁰ ) (wherein R ′ represents an alkylene group having 1 to 6 carbon atoms, R ⁹ and R ^{10 have} the same meanings as described above), and phenyl Represents a group selected from the group consisting of groups.

Any two groups out of R ¹ , R ² , R ³ and R ⁵ can be combined to form an alkylene group having 2 to 4 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶ can be formed. Among them, two adjacent groups can be combined to form an alkylene group having 3 to 5 carbon atoms.

Of these, R ¹ and R ² are preferably hydrogen or an alkyl group having 1 to 6 carbon atoms (more preferably a methyl group or an ethyl group), and R ^{3 to} R ⁶ are also hydrogen or alkyl having 1 to 6 carbon atoms. A group (a methyl group or an ethyl group is more preferred) is preferred.

For example, as also shown in this example, among the alcohols, R ¹ and R ² are hydrogen, and R ^{3 to} R ⁶ are hydrogen or a methyl group, which is one of particularly preferable ones.

  These aminoaryl group-containing fluoroalcohols as raw materials are disclosed in, for example, Am. Chem. Soc. 87, p. Each compound can be produced according to the method described in 2410 (1965).

  The amount of sulfuryl fluoride used in the present invention is preferably at least equimolar with respect to the raw material aminoaryl group-containing fluoroalcohol in terms of economy. However, since it is wasted if it is used too much, it is preferably 10 molar equivalents or less, more preferably 2 molar equivalents or less.

The organic base used in this reaction is trimethylamine, triethylamine [(C ₂ H ₅ ) ₃ N], diisopropylethylamine (((CH ₃ ) ₂ CH) ₂ N (C ₂ H ₅ )), tripropylamine, tributylamine Secondary amines such as diisopropylamine (((CH ₃ ) ₂ CH) ₂ NH), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6- Lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4, Nitrogen-containing aromatic heterocyclic compounds such as 5-collidine, 3,5,6-collidine, pyrrolidine, 2-methylpyrrolidine, piperidine, 2-methylpiperidine, morpholine, 2-methylmorpholine, 1,8-diaza Cyclo [5.4.0] nitrogen-containing cyclic compounds such as undec-7-ene (DBU). Among these, tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, secondary amines such as diisopropylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, Nitrogen-containing aromatic heterocyclic compounds such as 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 3,5,6-collidine, etc. are preferable, trimethylamine, triethylamine, diisopropylethylamine, tripropylamine Tertiary amines such as tributylamine are more preferable.

  Although there is no restriction | limiting in particular as the usage-amount of an organic base, It is preferable from a yield surface to use 1 mol equivalent or more with respect to 1 mol of aminoaryl group containing fluoroalcohols. Although there is no restriction | limiting in an upper limit, Usually, 20 molar equivalent or less is preferable, and especially 10 molar equivalent or less is preferable from the surface of economical efficiency.

Examples of the organic base of the “salt or complex comprising an organic base and hydrogen fluoride” that can be used together with the organic base include trimethylamine, triethylamine [(C ₂ H ₅ ) ₃ N], diisopropylethylamine (((CH ₃ ) ₂ CH) ₂ N (C ₂ H ₅ )), tertiary amines such as tripropylamine and tributylamine, secondary amines such as diisopropylamine (((CH ₃ ) ₂ CH) ₂ NH), pyridine, 2, 3 -Lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2 , 5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine and the like nitrogen-containing aromatic heterocyclic compounds, pyrrolidine, 2-methylpyrrolidine, piperidy , 2-methylpiperidine, morpholine, 2-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) nitrogen-containing cyclic compounds of the like. Among these, tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, secondary amines such as diisopropylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, Nitrogen-containing aromatic heterocyclic compounds such as 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 3,5,6-collidine, etc. are preferable, trimethylamine, triethylamine, diisopropylethylamine, tripropylamine Tertiary amines such as tributylamine are more preferable.

  The present invention can be carried out in the presence of these organic bases, but using a “salt or complex comprising an organic base and hydrogen fluoride” instead of the organic base or together with the organic base. You can also. In order to obtain a higher yield, it is more preferable to carry out the reaction of the present invention in the presence of “a salt or complex comprising an organic base and hydrogen fluoride”.

  The molar ratio of the organic base and hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” is in the range of 100: 1 to 1: 100, and usually in the range of 50: 1 to 1:50. The range of 25: 1 to 1:25 is particularly preferable. Furthermore, “complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride” commercially available from Aldrich (2003-2004 general catalog), and “pyridine 30% (-10 mol%) and hydrogen fluoride˜70 It is very convenient to use “complex consisting of% (˜90 mol%)”.

  In the present invention, the above organic base and hydrogen fluoride can be added separately at the above-mentioned ratio to form a “salt or complex comprising an organic base and hydrogen fluoride” in the reaction system.

The amount of the “salt or complex comprising an organic base and hydrogen fluoride” is not particularly limited, but 0.3 mol or more as a fluorine anion (F ⁻ ) per 1 molar equivalent of an aminoaryl group-containing fluoroalcohol. What is necessary is just to use, and 0.5-50 mol is preferable normally, and 0.7-25 mol is especially more preferable.

  Further, in the present invention, dehydroxyfluorination proceeds well by carrying out the reaction in the presence of an organic solvent. Here, the organic solvent means an inert organic compound that does not directly participate in the reaction of the present invention. Reaction solvents include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, halogens such as methylene chloride, chloroform and 1,2-dichloroethane. Hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, tert-butyl methyl ether, esters such as ethyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc. Examples include amides, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide.

  Among them, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide are preferable. Nitriles such as acetonitrile and propionitrile are more preferable. These reaction solvents can be used alone or in combination.

  In the present invention, when an organic solvent is not present in the reaction system, dehydroxylation fluorination is less likely to proceed as compared with the case where an organic solvent is present, and the conversion rate is reduced (see Comparative Example 1 described later). In the present invention, by adding an organic solvent, the dehydroxylation fluorination reaction proceeds dramatically, and the target product can be obtained satisfactorily with high selectivity.

  Although there is no restriction | limiting in particular as the usage-amount of a reaction solvent, 0.1 L (liter) or more should just be used with respect to 1 mol of aminoaryl group containing fluoroalcohol, Usually, 0.1-20 L is preferable, and especially 0 .1 to 10 L is more preferable.

  The temperature condition is not particularly limited, but may be performed in the range of −100 to + 100 ° C., usually −90 to + 90 ° C., and more preferably −80 to + 80 ° C.

  The pressure condition is not particularly limited, but may be performed, for example, in the range of normal pressure (0.1 MPa (absolute pressure reference, hereinafter the same)) to 2 MPa. In this case, 0.1 MPa to 1.5 MPa is preferable. In particular, 0.1 MPa to 1 MPa is more preferable.

  As shown in the examples described later, after adding the aminoaryl group-containing fluoroalcohol to the pressure-resistant reaction vessel, the pressure is reduced under conditions for degassing of inert gas (air, nitrogen) in the pressure-resistant reaction vessel, and organic After adding a base or a “salt or complex comprising an organic base and hydrogen fluoride” and sulfuryl fluoride, the reaction can be carried out with the container sealed.

  Examples of the reaction vessel used for the reaction include a pressure-resistant reaction vessel lined with Monel, Hastelloy, nickel, or a fluorine resin such as these metals, polytetrafluoroethylene, and perfluoropolyether resin.

  The reaction time is not particularly limited, but may be in the range of 0.1 to 72 hours, and varies depending on the substrate and reaction conditions. Therefore, the reaction proceeds by an analytical means such as gas chromatography, liquid chromatography, or NMR. It is preferable that the end point is the time when the raw material is almost disappeared by tracking the situation.

  The “preferred reaction conditions” for producing 4-perfluoroisopropylaniline, which is the object of the present invention, will be described below.

  For the aminoaryl group-containing fluoroalcohol represented by the formula [1], the organic solvent is particularly preferably a nitrile such as acetonitrile or propionitrile, and the amount of the organic solvent used is 0 with respect to 1 mol of the alcohol. 0.1 to 10 L, tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tributylamine and the like are particularly suitable as the organic base, and the amount of the organic base used is 10 mol with respect to 1 mol of the alcohols. The target product can be obtained with a high selectivity and a high yield by reacting at a reaction temperature of -80 to + 80 ° C. and a reaction temperature of 0.1 MPa to 1 MPa within 24 hours.

  There is no particular limitation on the post-treatment, but usually the reaction-terminated solution is poured into water or an aqueous solution of an alkali metal inorganic base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate), and an organic solvent ( For example, a crude product can be obtained by extraction with toluene, mesitylene, methylene chloride, ethyl acetate or the like.

If necessary, it can be purified to a higher chemical purity by activated carbon treatment, distillation, recrystallization and the like.
[Example]
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.

Here, “%” of the composition analysis value means “mol%” of the composition obtained by measuring the reaction mixture with a nuclear magnetic resonance analyzer (NMR, unless otherwise specified, the measurement nucleus is ¹⁹ F). Or gas chromatography (GC, unless otherwise stated, represents “area%” of the composition obtained by measurement with a detector.

  Production of 4-heptafluoroisopropyl-2-methylaniline

After adding 39 g (142 mmol) of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol to a 500 ml autoclave and depressurizing the reactor, , 73.4 g (568 mmol) of diisopropylethylamine and 64 g of acetonitrile were added under reduced pressure. After stirring the reaction mixture for 10 minutes at room temperature, 4.3 g (213 mmol) of hydrofluoric acid was added under ice cooling so that the temperature in the reactor was kept at 10 ° C. or lower, and 36 g (355 mmol) of sulfuryl fluoride was further added. Then, the mixture was stirred at room temperature for 25 hours. The progress of the reaction was followed by ¹⁹ F-NMR (conversion 93.0%).

From ¹⁹ F-NMR at the end of the reaction, the target product 4-heptafluoroisopropyl-2-methylaniline was 72.7%, and the starting material 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol is 7.0%, and "sulfonamide body" is 12.9% (sulfonamide body A is 9.8%, sulfonamide body B) 3.0%).

  After the reaction, the reaction solution was concentrated by gradually reducing the pressure to 127 hPa at 50 ° C. A 30% aqueous potassium hydroxide solution was gradually added to the concentrated residue for neutralization, followed by liquid separation. The separated organic layer was purified by distillation under reduced pressure to obtain 24 g of the desired product as a colorless oil. This compound had a boiling point of 76 ° C. at 670 Pa. The isolation yield was 62%.

  In the same apparatus and operation as in Example 1, 20.0 g of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol (73 .2 mmol) as a raw material under reduced pressure, 37.8 g (292.8 mmol) of diisopropylethylamine and 33.1 g of acetonitrile, 1.46 g (73.2 mmol) of hydrofluoric acid, 14.9 g (146.4 mmol) of sulfuryl fluoride ) And reacted at room temperature for 14 hours and at 50 ° C. for 3 hours (conversion rate 88%).

  After the reaction, 14.2 g of the desired product was obtained as a colorless oil by the same purification operation as in Example 1. The isolation yield was 70.3%.

  In the same apparatus and operation as in Example 1, 20.0 g of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol (73 2 mmol) and 37.8 g (292.8 mmol) 1,8-diazabicyclo [5,4,0] undec-7-ene 1.1 g (7.3 mmol) and acetonitrile 33.3 under reduced pressure. 1 g, 1.46 g (73.2 mmol) of hydrofluoric acid, and 14.9 g (146.4 mmol) of sulfuryl fluoride were added and reacted at room temperature for 13 hours and at 50 ° C. for 3 hours (conversion rate 89.3%) ).

From ¹⁹ F-NMR at the completion of the reaction, 77.0% of the target product 4-heptafluoroisopropyl-2-methylaniline was obtained, and the starting material, 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol is 10.7%, and "sulfonamide compound" is 11.3% (sulfonamide compound A is 4.5%, sulfonamide compound B) (In this embodiment, the final post-processing operation is not performed.)

  In the same apparatus and operation as in Example 1, 7.76 g of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol (28 .4 mmol) as a raw material under reduced pressure, 11.5 g (113.6 mmol) of diisopropylamine and 12.8 g of acetonitrile, 0.85 g (42.6 mmol) of hydrofluoric acid, 4.35 g (42.6 mmol) of sulfuryl fluoride For 20 hours at room temperature (conversion 95%).

From ¹⁹ F-NMR at the end of the reaction, the desired product 4-heptafluoroisopropyl-2-methylaniline was 66.3%, the starting material 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol is 5.5%, and "sulfonamide body" is 9.2% (sulfonamide body A is 1.8%, sulfonamide body B) (In this example, the final post-processing operation is not performed).

  In the same apparatus and operation as in Example 1, 39 g (142 mmol) of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropane-2-ol was added. As raw materials, 57.5 g (568 mmol) of triethylamine, 64 g of acetonitrile, 3.7 g (186 mmol) of hydrofluoric acid and 36 g (355 mmol) of sulfuryl fluoride were added under reduced pressure, and the mixture was reacted at room temperature for 20 hours (conversion rate) 91.7%).

From ¹⁹ F-NMR at the end of the reaction, the target product 4-heptafluoroisopropyl-2-methylaniline was 49.7%, and the starting material, 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol was 8.3%, and “sulfonamide body” was 37.4% (sulfonamide body A was 9.8%, sulfonamide body B) Was 25.6%).
After the reaction, 7.9 g of the desired product was obtained as a colorless oil by the same purification operation as in Example 1. The isolation yield was 20.31%.

  In the same apparatus and operation as in Example 1, 39 g (142 mmol) of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropane-2-ol was added. As raw materials, 73.4 g (568 mmol) of diisopropylethylamine, 64 g of acetonitrile, 8.5 g (426 mmol) of hydrofluoric acid, and 17 g (170 mmol) of sulfuryl fluoride were added under reduced pressure, and the mixture was reacted at 70 ° C. for 22 hours.

From ¹⁹ F-NMR at the end of the reaction, the desired product 4-heptafluoroisopropyl-2-methylaniline was 42.2%, the starting material 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol was 16.6%, and "sulfonamide body" was 34.1% (sulfonamide body A was 11.1%, sulfonamide body B) Was 23.0%).
[Comparative Example 1]
Production of 4-heptafluoroisopropyl-2-methylaniline

To a 100 ml autoclave was added 7.8 g (28.4 mmol) of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol to the reactor. Was reduced in pressure, and 29.4 g (227.3 mmol) of diisopropylethylamine was added. After stirring the reaction mixture for 10 minutes at room temperature, 0.9 g (42.6 mmol) of hydrofluoric acid was added under ice cooling so that the temperature in the reactor was kept at 10 ° C. or lower, and further, sulfuryl fluoride was added. After introducing 4 g (42.6 mmol), the mixture was stirred at room temperature for 21 hours (conversion rate: 11.3%).
From ¹⁹ F-NMR at the end of the reaction, the target product 4-heptafluoroisopropyl-2-methylaniline was 0.3%, and the starting material, 2- (4-amino-3-methylphenyl) -1,1,1, 3,3,3-hexafluoropropan-2-ol is 88.7%, and "sulfonamide body" is 11.0% (sulfonamide body A is 8.0%, sulfonamide body B) (In this comparative example, the final post-processing operation is not performed).
[Reference example]
10 g of 2- (4-amino-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol as in Example 1 was used as a raw material, and 15 g of SF ₄ in 100 ml of HF. Was added and reacted at 50-60 ° C. for 20 hours.

  The gas chromatograph composition at the end of the reaction was 33.7% of the target product 4-heptafluoroisopropyl-2-methylaniline, the raw material was not detected, and 66.7% of the “dimer” (dimer A, Total value of dimerized product B).

  That is, in the reference example, it was found that there were many by-products of the “dimer” and the yield of the target product was reduced.

Claims (3)

Aminoaryl group-containing fluoroalcohols represented by the formula [1]

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) to give 4-perfluoroisopropylanilines represented by the formula [2]

4-perfluoroisopropylaniline represented by the formula [2], wherein an organic base or a “salt or complex comprising an organic base and hydrogen fluoride” is allowed to coexist in the presence of an organic solvent. Manufacturing method.
[In the formula [1] and formula [2], R ¹ and R ² are the same or different hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, -COR ⁷ (wherein, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group or a substituted phenyl group.) And COOR ⁸ (Wherein, R ⁸ represents a group selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a phenyl group). R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different hydrogen atom, halogen atom, hydroxyl group, nitro group, alkyl group having 1 to 10 carbon atoms, haloalkyl group having 1 to 10 carbon atoms, carbon number 1 10 alkoxy group, an alkylthio group having 1 to 10 carbon ^{atoms, -N (R 9) (R} 10) ( wherein, R ⁹ and R ¹⁰ are the same or different hydrogen atom, an alkyl group having 1 to 10 carbon atoms Represents a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group, and R ⁹ and R ¹⁰ may be combined to form an alkylene group having 3 to 6 carbon atoms.), — (R ′) — N (R ⁹ ) (R ¹⁰ ) (wherein R ′ represents an alkylene group having 1 to 6 carbon atoms, R ⁹ and R ^{10 have} the same meanings as described above), and a group consisting of phenyl groups Represents a group.
Any ^{two of} R ¹ , R ² , R ³ and R ⁵ can be combined to form an alkylene group having 2 to 4 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶ can be formed. Among them, two adjacent groups can be combined to form an alkylene group having 3 to 5 carbon atoms. ] The method of claim 1 wherein the organic base is trimethylamine, triethylamine, diisopropylethylamine, or tributylamine. The method according to claim 1 or 2, wherein the organic solvent is ethyl acetate, butyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or propionitrile.