JP2002338517A - METHOD OF PRODUCTION FOR gem-DIFLUORO COMPOUND - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method synthesizing a gem-difluoro compound having the objective gem-difluoro structure from an easily obtainable carbonyl compound in high yield. SOLUTION: This method produces the compound expressed by formula (2) in a selective ratio >=98% by reacting a compound expressed by formula (1) and a fluorinating agent in the presence of a Lewis acid catalyst. The selective ratio is defined as a ratio of the mass of the compound expressed by formula (2) to the total mass of the compound expressed by formula (2) and a compound expressed by formula (3). R<1> , R<2> and R<3> are each a monovalent group. Two groups selected from R<1> , R<2> and R<3> optionally form a bivalent organic group and the rest is a monovalent group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a gem- useful as an intermediate for medical and agricultural chemicals such as neurokinin antagonists.
The present invention relates to a method for producing difluoride with a high selectivity.

[0002]

_2. Description of the Related Art A reaction for converting a keto group (--C--CO--C--) of a compound having the keto group into --C--CF ₂ --C-- (hereinafter also referred to as deoxofluorination) is described. There are the following reports.

(1) A method of reacting 4-t-butylcyclohexanone with aminosulfur trifluoride as a fluorinating agent for several days to obtain 4-t-butyl-1,1-difluorocyclohexane. A method in which 4-t-butylcyclohexene is formed in an amount of 4% or more based on the total amount of t-butylcyclohexanone and 4-t-butylcyclohexene. In this method, it is described that the reaction time is reduced to 16 hours by adding a catalytic amount of HF. When the fluorinating agent is N-methyl-N-phenylsulfur trifluoride, the reaction time is 69 hours in the absence of BF ₃ .O (CH ₂ CH ₃ ) ₂ as a Lewis acid. On the other hand, in the presence of a Lewis acid, the reaction time is stated to be 16 hours. However, it is described that the reaction time is not shortened when the fluorinating agent is diethylaminosulfur trifluoride (hereinafter, referred to as DAST) (Japanese Patent Application Laid-Open No. 11-1).
71858).

(2) A compound having a keto group is reacted with N, N-bis (2-
Methoxyethyl) by amino trifluoride at room temperature for 16 hours, the method of obtaining a compound obtained by converting the keto group to CF ₂ in 81-98% yield. In addition, in the deoxofluorination of 4-t-butylcyclohexanone using the same fluorinating agent, 4-t-butylcyclohexene is produced at 16% of the total amount of 4-t-butylcyclohexanone and 4-t-butylcyclohexene. However, it is described that when the fluorinating agent is DAST, 33% of 4-t-butylcyclohexene is formed. It is also described that the reaction does not proceed at room temperature for some raw materials (J. Org. Chem. 1999, 6).
4,7048-7054. ).

[0005]

The conventional method has a problem that the reaction time is too long. Furthermore, in the deoxofluorination of 4-t-butylcyclohexanone, there is a problem that 4-t-butylcyclohexene as a by-product is present in an amount of 4% or more, and the proportion of the by-product increases when the reaction time is shortened. Was. Further, by-produced fluoroolefins such as 4-t-butylcyclohexene have a problem that they have a boiling point close to that of gem-difluoride and are difficult to separate by a distillation method. Also, in other separation methods, it is difficult to separate the fluoroolefin compound, and the separation operation is complicated and economical.

[0006] The present invention is a method for solving the above-mentioned problem, and it is intended to reduce the amount of gems from a compound having a carbonyl group in a short time while suppressing the formation of a fluoroolefin compound which is difficult to separate.
-To provide a method for producing difluoride.

[0007]

That is, the present invention provides a compound represented by the following formula (2) by reacting a compound represented by the following formula (1) with a fluorinating agent in the presence of a Lewis acid catalyst. A method for producing a gem-difluoride represented by the following formula (2), wherein a compound having a selectivity of 98% or more is produced. Here, the selectivity refers to the following formula (2) based on the total mass of the compound represented by the formula (2) and the compound represented by the following formula (3).
Is the proportion of the mass of the compound represented by the formula: R ¹ in the following formula,
R ² and R ³ each independently represent a monovalent group. Two groups selected from R ¹ , R ² and R ³ may together form a divalent organic group, and the remaining groups may be monovalent groups.

[0008]

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[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the following, a compound represented by the formula (1) is described as a compound (1). The same applies to other compounds. Further, the pressure in this specification is described in absolute pressure.

In the present specification, a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. An organic group refers to a group that requires a carbon atom. The monovalent group refers to a group having one bond, and may be a monovalent organic group or a monovalent atom. The divalent organic group refers to an organic group having two bonds.

When R ¹ , R ² and R ³ are each a monovalent atom, a hydrogen atom and a fluorine atom are preferred. R
^1, if R ^2, and R ³ is a monovalent organic group, respectively,
These groups are selected from monovalent groups which are not changed by the reaction in the present invention, and the following groups are preferred.

That is, a monovalent aliphatic saturated hydrocarbon group,
A group (r ¹ ) selected from a monovalent aliphatic saturated hydrocarbon group substituted with a valent aromatic hydrocarbon group and / or a monovalent heterocyclic group, a monovalent aromatic hydrocarbon group, and a monovalent heterocyclic group. A group wherein an etheric oxygen atom, a thioetheric sulfur atom, or a substituted nitrogen atom is inserted between carbon-carbon bonds of the selected group (r ¹ ). A group in which an etheric oxygen atom, a thioetheric sulfur atom, or a substituted nitrogen atom is bonded to the bonding terminal of the selected group (r ¹ ). In a monovalent aromatic hydrocarbon group, a monovalent aliphatic hydrocarbon group substituted with a monovalent aromatic hydrocarbon group and / or a monovalent heterocyclic group, and a monovalent heterocyclic group, each of A group in which one or more atoms have been substituted with a substituent (r ² ).

As the substituent (r ² ), an alkyl group,
Cycloalkyl groups and monovalent aromatic hydrocarbon groups are preferred.
The substituent (r ² ) includes a fluorine atom, an alkoxyl group, an alkyl-substituted amino group, a cycloalkyl-substituted amino group, an aryloxy group, an aryl-substituted amino group,
^{_{-NO 2, -CN, -COOR a,}} -CONR b R c, -S
A group selected from O ₂ NR ^b R ^c , —S (O) R ^a , —S (O) ₂ R ^a , and —C (OR ^a ) ₃ (hereinafter, the selected groups are collectively referred to as a substituent (r ³ ) is also preferred.

Here, R ^a , R ^b , and R ^c are each independently an alkyl group having 1 to 20 carbon atoms (eg, a methyl group, an ethyl group, a 2-propyl group, a tert-butyl group, etc.); A cycloalkyl group having 3 to 8 carbon atoms (such as a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group);
An alkyl group substituted with at least one aryl group (eg, benzyl group, phenethyl group, trityl group, etc.) and an alkyl group substituted with at least one monovalent heterocyclic group (eg, 2-pyridylmethyl group, etc.) An aryl group (eg, phenyl group), a substituted aryl group (eg, 3-chlorophenyl group, 4-methylphenyl group, 2,3-dimethoxyphenyl group, 2-nitrophenyl group, 4-aminophenyl group, etc.), or fluoroalkyl group having 1 to 20 carbon atoms _{(e.g., -CF 3, -CF 2 CF 3} , -CH 2 C
It is F _3, etc.) and the like.

When R ¹ , R ² , and R ³ are each a monovalent organic group, an alkyl group, a cycloalkyl group, a phenyl group, an alkyl-substituted phenyl group, an alkyl-substituted monovalent heterocyclic group, and a benzyl group Or a group in which at least one hydrogen atom in the selected group is substituted with the substituent (r ³ ).

Further, ² selected from R ¹ , R ² and R ³
When one and the other form a divalent organic group (in this case, the remaining one group is a monovalent group, and is preferably a hydrogen atom, a fluorine atom, or a monovalent organic group). Hydrocarbon group, etheric oxygen atom (-O-)-containing divalent saturated hydrocarbon group, thioetheric sulfur atom (-S-)-containing 2
A divalent organic group selected from a valent saturated hydrocarbon group and a -NH-containing divalent saturated hydrocarbon group, or one or more hydrogen atoms bonded to carbon atoms in the selected divalent organic group are the substituents A group substituted with (r ³ ) is preferred. Examples of the divalent organic group, an alkylene group is preferably substituted by an alkylene group or a substituent (r ^3), - (C
H ₂ ) _n — (where n is an integer of 1 or more) or a group in which one of the hydrogen atoms in the group is substituted with —COOR ⁶ . A compound containing a —COOR ⁶ group, in particular, the following compound (1a) has the advantage that the formation of fluoroolefin is remarkably suppressed and the reaction time is short. It is thought to be due to acting on.

In the present invention, the compound (1) includes R
¹ is a hydrogen atom, and R ² and R ³ are taken together to form -COOR ⁶
The compound (1a) in which a tetramethylene group substituted with is formed is preferred. The gem-difluoride (2), which is the target compound of the present invention, includes the compound (1a)
The following compound (2a) corresponding to is preferred, and compound (3a) is preferred as compound (3).

[0018]

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Here, R⁶Is R^aIs the same group as
An alkyl group having 1 to 20 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms
Alkyl group substituted with a kill group or one or more aryl groups
A group, an alkyl group substituted with one or more monovalent heterocyclic groups,
An aryl group, a substituted aryl group, or a group having 1 to 20 carbon atoms
A fluoroalkyl group, an alkyl having 1 to 20 carbon atoms
Or a cycloalkyl group having 3 to 8 carbon atoms is preferred.
Methyl, ethyl, phenyl, benzyl,
Propyl group, isopropyl group, butyl group, tert-butyl
Group, hexyl group, cyclohexyl group, substituted phenyl group
Is particularly preferred. R ⁶Is methyl or ethyl
The product (1a) is a known compound, and is commercially available or
Is a compound obtainable by a known production method. other
Compound (1a) can be derived from a known compound.

The starting material in the present invention is the compound (1).
The method for obtaining the compound (1) is not particularly limited, and is preferably a known compound or a compound produced by a known method.

In the present invention, the compound (1) having a ketone group is reacted with a fluorinating agent in the presence of a Lewis acid catalyst.

The following examples are given as Lewis acids. However, X represents a halogen atom, and when X is 2 or more, X may be the same halogen atom or different halogen atoms, and part of X is an alkyl group. Is also good. When X is an alkyl group, it is preferably an alkyl group having 1 to 9 carbon atoms.

Alkali metal halides (eg, M ^a
A compound represented by X. However, M ^a represents an alkali metal atom. ), Alkaline earth metal halides (e.g.,
A compound represented by M ^b X ₂ . Here, ^Mb represents an alkaline earth metal atom. ), Transition metal halides (e.g.,
A compound represented by M ^c X _j . Here, ^Mc represents a j-valent transition metal atom, and j represents an integer of 2 to 6. Transition metal atoms refer to elements from element 21 to element 30, element 39 to element 48, element 57 to element 80, and element 89 or more. ), Halogenated silanes (eg, Si
A compound represented by X _4. ), Germanium halide,
Boron halide (for example, a compound represented by BX ₃ ), aluminum halide (for example, AlX ₃
A compound represented by the formula: ).

Gallium halide, indium halide, thallium halide, tin halide (for example,
A compound represented by M ^d X _k . Here, ^Md represents a k-valent tin atom, and k represents an integer of 2 to 4. ), Lead halide (e.g., a compound represented by M ^e X _p. However, M ^e represents a p Atainamari atoms, p is an integer of 2-6.), Halogenated bismuth (e.g., M ^f a compound represented by X _q.
Here, M ^f represents a q-valent bismuth atom, and q represents an integer of 2 to 6. ), Antimony halide, tellurium halide, selenium halide, and germanium halide.

As the Lewis acid, trivalent antimony trihalide, pentavalent antimony pentahalide, trivalent aluminum trihalide, trivalent chromium trihalide,
It is particularly preferably at least one selected from divalent calcium dihalide, trivalent boron trihalide, divalent magnesium dihalide, divalent beryllium dihalide or trivalent rubidium trihalide, and trivalent trihalide. Antimony and pentavalent antimony pentahalide are particularly preferred.
Antimony chloride is preferred.

The amount of the Lewis acid is 0.1 to the fluorinating agent.
The molar amount is preferably from 01 to 10.0 times, and particularly preferably from 0.1 to 2.0 times.

The fluorinating agent is preferably selected from known fluorinating agents capable of fluorinating a carbonyl group. The following compounds (4), (5), (6) and (7) , The following compound (8), the following compound (9), IF ₃ , IF ₅ , or IF _{7, and the} like, and the compound (4), IF ₃ , IF ₅ , or IF ₇ is preferable. Compound (4) which is excellent in safety, easy to handle and easily available is particularly preferred.

[0028]

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Wherein R ^{7 to} R ²⁰ are each independently an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkyl group substituted with at least one aryl group,
An alkyl group, an aryl group, a substituted aryl group, or a fluoroalkyl group having 1 to 20 carbon atoms substituted with one or more heterocyclic groups.

As the compound (4), DAST, N, N
-Bis (2-methoxyethyl) aminosulfur trifluoride, N, N-bis (phenyl) aminosulfur trifluoride, N, N-bis (4-methylphenyl)
Aminosulfur trifluoride, N, N-bis (4-
Methoxyphenyl) aminosulfur trifluoride,
N-2-methoxyethyl-N-phenylaminosulfur trifluoride and N-methyl-N-phenylaminosulfur trifluoride are particularly preferred. When compound (4) is used as the fluorinating agent, it is preferable to use only one of compound (4).

As the compound (5), diethyl mono (2
-Chloro-1,1,2-trifluoroethyl) amine is preferred. As the compound (6), diethyl mono (1,
1,2,2-tetrafluoroethyl) amine is preferred. When compound (5) or compound (6) is used as the fluorinating agent, two or more of each compound may be used.

As the compound (7), diethyl mono (1,1,2,3,3,3-hexafluoropropyl)
Amines are preferred. As the compound (8), diethyl (hexafluoro-1-propenyl) amine is preferable. When compound (7) and compound (8) are used, R
^It is preferred to use a 1: 1 (molar ratio) mixture of both compounds wherein ¹³ and R ¹⁵ and R ¹⁴ and R ¹⁶ are identical. As the compound (9), tetra (n-butyl) ammonium fluoride is preferable.

The amount of the fluorinating agent is preferably 0.1 to 100 times the molar amount of the compound (1),
A 10-fold molar amount is particularly preferred.

When reacting compound (1) with a fluorinating agent in the presence of a Lewis acid catalyst, a solvent may be present. As the solvent, it is preferable to use one or more solvents inert in the reaction of the present invention. Examples of solvents include
Toluene, xylene, benzene, cyclohexane, n-
Hydrocarbon solvents such as hexane, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, carbon tetrachloride and chloroform; ether solvents such as diethyl ether, diisopropyl ether, methyl-tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane And nitrile solvents such as acetonitrile, dimethyl sulfoxide, water and the like. Among these, toluene, xylene,
Hydrocarbon solvents such as benzene, dichloromethane, cyclohexane and n-hexane are preferred.

The amount of the solvent used is 0.5 to 2 per gram of the compound (1) for reasons such as ease of post-treatment.
00 ml is preferable, and particularly preferably 1 to 50 ml.

The reaction temperature is preferably from the freezing point of the solvent to less than the boiling point, and particularly preferably from -78 ° C to + 100 ° C. The reaction pressure is preferably from atmospheric pressure to 10 kPa (gauge pressure), particularly preferably from atmospheric pressure to 0.3 kPa (gauge pressure). The reaction time is usually preferably from 0.1 to 12 hours, particularly preferably from 0.5 to 8 hours. In general, the selectivity tends to increase as the reaction time becomes longer. However, in the method of the present invention, the selectivity is improved even when the reaction time is short, and the compound (3), which is a by-product monofluoro compound, can be obtained. The target product (2), which is also a difluoro compound, is preferentially generated. The compound (3) may have an E-form and a Z-form, but the concept of the compound (3) in the present invention includes all of the E-form only, the Z-form only, and the mixture of the E-form and the Z-form. Is included.

In the method of the present invention, compound (2) is formed with a selectivity of 98% or more. The selectivity is the ratio of the mass of the compound (2) to the total mass of the compound (2) and the compound (3), and the selectivity is preferably 99% or more,
In particular, substantially 100% (ie a selectivity of substantially 1%)
00% means that the compound (3) is not substantially formed in the product. ) Is preferred. The selectivity is a value determined by analyzing the product by gas chromatography or the like.

In the method of the present invention, the fact that the amount of the compound (3) in the product can be reduced means that not only the labor of the purification step can be omitted, but also the loss of the target compound (2) in the purification step can be prevented. This has the advantage of increasing the yield of compound (2). Further, the compound (2) and the compound (3) are compounds that are difficult to separate by distillation, so that the compound (2) can be obtained with high purity.

The reaction product containing the compound (2) may be subjected to a usual post-treatment if necessary. The obtained compound (2) may be used as it is, or may be derivatized according to the purpose. For example, in the compound (2a), the following compound (2b) can be obtained with high purity by converting the ester moiety into a carboxylic acid by hydrolysis.

[0040]

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[0041]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto. [Example 1] N, N-bis (2-methoxyethyl) aminosulfur trifluoride (39 g, 0.176 mol)
Was added to dichloromethane (100 ml) and cooled to 0 ° C. Antimony trichloride (4.
42 g, 0.019 mol), and the mixture was stirred for 2 hours under atmospheric pressure. Next, ethyl 4-oxocyclohexanecarboxylate (20 g, 0.118 mol) was added dropwise. After the completion of the dropwise addition, the temperature was raised to room temperature (25 ° C.).
Stirred for hours. The reaction was stopped by adding this solution to an aqueous sodium hydrogen carbonate suspension (50 g, 200 ml). As a result of analyzing the product by gas chromatography, formation of ethyl 4-fluoro-3-cyclohexenecarboxylate was not recognized.

Extraction was performed by adding dichloromethane to the aqueous solution. Next, the dichloromethane layer was washed with saturated saline,
The dichloromethane layer was dried with magnesium sulfate. Next, the dichloromethane layer was concentrated and distilled under reduced pressure to obtain ethyl 4,4-difluorocyclohexanecarboxylate in a yield of 52.7% (12.4 g).

[0043]

According to the method of the present invention, gem-difluoride can be produced from a compound having a carbonyl group while suppressing formation of a fluoroolefin compound which is difficult to separate.
The method of the present invention is economically advantageous because it does not require any special operation, and can end the reaction in a short time without the need for separating the product, and as an industrial production method. Is an efficient method that can be adopted.

Continued on the front page F term (reference) 4H006 AA02 AC30 BA13 BA37 BA67 BE90 BJ20 BM20 BM71 BS20 4H039 CA50 CD40

Claims (7)

[Claims] A compound represented by the following formula (2) is reacted with a fluorinating agent in the presence of a Lewis acid catalyst to give a compound represented by the following formula (2) at a selectivity of 98% or more: A method for producing gem-difluoride represented by the following formula (2): Here, the selectivity is a ratio of the mass of the compound represented by the following formula (2) to the total mass of the compound represented by the formula (2) and the compound represented by the following formula (3). R ¹ , R ² and R ³ are each independently 1
Represents a valence group. ² selected from R ¹ , R ² and R ³
The two groups together form a divalent organic group, and the remaining groups may be monovalent groups. Embedded image 2. The method according to claim 1, wherein the compound represented by the formula (3) is not substantially produced. 3. The method according to claim 1, wherein the fluorinating agent is at least one selected from the compounds represented by the following formula (4), IF ₃ , IF ₅ and IF ₇ . However, R ⁷ and R ⁸ in the following formula each independently represent a monovalent group. Embedded image 4. A Lewis acid comprising an alkali metal halide, an alkaline earth metal halide, a transition metal halide, a silane halide, a germanium halide, a boron halide, an aluminum halide, a gallium halide,
4. The method according to claim 1, which is at least one selected from indium halide, thallium halide, tin halide, lead halide, bismuth halide, antimony halide, tellurium halide, and selenium halide. Manufacturing method. 5. The method according to claim 4, wherein the Lewis acid is antimony trichloride or antimony pentachloride. 6. A compound represented by the formula (1):
Wherein R ⁶ represents a monovalent group, and the compound represented by the formula (2) is a compound represented by the following formula (2a), and represented by the formula (3) The production method according to any one of claims 1 to 5, wherein the compound is a compound represented by the following formula (3a). Embedded image 7. The method according to claim 1, wherein the reaction time is 0.1 to 12 hours.