JPH09268146A - Method for producing optically active fluorine-containing hydroxy compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and efficiently obtain an optically active fluorine containing hydroxy compound which is useful as an intermediate for medicines and the like in high yield of asymmetric reduction by hydrogenating a readily available fluorine-containing ketone compound in the presence of a heterogeneous catalyst. SOLUTION: (A) A fluorine containing ketone compound of the formula; CHn F3-n -CO-R (n is 0, 1, 2; R is an alkyl, a haloalkyl, an acyl, an aralkyl, an aryl) is hydrogenated in the presence of (B) a nickel catalyst supporting an optically active compound to give (C) an optically active fluorine-containing hydroxy compound of the formula: CHn F3-n -CH*H(OH)-R. The component B preferably carries an optically active hydroxy acid or amino acid, particularly optically active tartaric acid. The amount of the optically active compound to be carried by the nickel; catalyst ids preferably 0.3-3 times the weight of the nickel component in the nickel catalyst.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active fluorine-containing hydroxy compound, which is important as an intermediate for medicines, agricultural chemicals and liquid crystal substances.

[0002]

2. Description of the Related Art Conventionally, the following methods are known as methods for obtaining optically active fluorine-containing hydroxy compounds. (1) A method of optically resolving a racemate of a fluorine-containing hydroxy compound using a microorganism or an enzyme (JP-A-3-254)
694, Asahi Glass Foundation Research Report 1990 Volume 56 311
Page, Japanese Patent Publication No. 7-16437). (2) A method of optically resolving a racemate of a fluorine-containing hydroxy compound using a diastereoisomeric salt (Japanese Patent Publication No.
-6556).

(3) A method in which a microorganism or an enzyme is allowed to act on a fluorinated keto compound to stereoselectively reduce it (Journal of the Chemical Society of Japan, 1983, p. 1363). (4) A method of reacting an optically active fluorine-containing epoxy compound with a nucleophile (J.Org.Chem., 1995, Vol. 60, 41, JP-A-2).
-174735). (5) A method of carrying out an aldol reaction of a fluorinated aldehyde compound using a homogeneous asymmetric catalyst soluble in a solvent.

[0004]

However, (1),
The racemic form of the fluorine-containing hydroxy compound to which the method (3) can be applied is limited to a specific compound, and there is a problem that a great deal of labor is required to search for effective microorganisms and enzymes.
In addition, most of the operations are in an aqueous solution, which requires labor for extraction and is not suitable for large-scale production.

The method (2) requires a complicated operation and also needs to have an applicable functional group other than a hydroxyl group in the structure of the fluorine-containing hydroxy compound.

When the raw material is obtained by natural product extraction by the method (4), there is a problem that the optical purity of the product depends on the raw material. Further, when obtained by synthesis, there is a problem that the number of steps increases.

In the method (5), the fluorine-containing aldehyde compound is expensive, and the hydrogenation reaction of the compound is difficult to proceed due to the unique reactivity of the carbonyl group. However, there is a problem that the temperature control is complicated. In addition, there is a problem that the desired optical yield cannot be obtained because the asymmetric ligand of the catalyst is decomposed by the reaction under high temperature conditions. Furthermore, the homogeneous catalyst has a problem that it is difficult to recover it after the reaction is completed, and the catalytic metal remains in the product.

As described above, no satisfactory method has been known as a conventional method for producing an optically active fluorine-containing hydroxy compound.

[0009]

The present invention has been made for the purpose of solving the above problems, and provides an optically active fluorine-containing hydroxy compound, which is important as an intermediate for pharmaceuticals, agricultural chemicals, liquid crystal substances, etc. To provide a simple and efficient method for producing a simple and efficient method.

As a result of various studies on the method for producing an optically active fluorine-containing hydroxy compound, the present inventors selected a compound that is easily available as a raw material, and hydrogenated it in the presence of a specific catalyst called a heterogeneous catalyst. It was found that when the reaction is carried out, the asymmetric reduction reaction of the fluorine-containing keto compound proceeds at a high yield, and the target fluorine-containing hydroxy compound can be produced more easily and efficiently than before.

That is, according to the present invention, the fluorine-containing keto compound represented by the formula 1 is subjected to a hydrogenation reaction in the presence of a nickel catalyst carrying an optically active compound to give an optically active fluorine-containing hydroxy compound represented by the formula 2. A method for producing an optically active fluorine-containing hydroxy compound is provided. _{CH n F 3-n -CO-} R ··· Equation _{1, CH n F 3-n} -C * H (OH) -R ··· Equation 2.

In the formulas 1 and 2, n represents 0, 1 or 2, and R represents an alkyl group, a haloalkyl group, an acyl group, an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group or an aralkyl group. , Aryl group, or haloaryl group, and * means optically active carbon.

The fluorine-containing keto compound represented by the formula 1 of the present invention is a known or well-known compound and is easily available. The fluorine-containing keto compound represented by the formula 1 is a compound containing at least one fluorine atom, and n is 0, 1, or 2
It is preferable that n is 0 from the viewpoint of easy availability.

R is an alkyl group, a haloalkyl group, an acyl group, an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an aryl group,
An aralkyl group or a haloaryl group is shown, and an alkoxycarbonylalkyl group is preferable.

The alkyl group is preferably an alkyl group having 1 to 8 carbon atoms. The alkyl group is preferably a linear or branched alkyl group, and particularly preferably a linear alkyl group. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like.

The haloalkyl group is a group in which one or more hydrogen atoms of the above alkyl group are substituted with a halogen atom, and the halogen atom is preferably a chlorine atom or a fluorine atom. The haloalkyl group preferably has 1 to 8 carbon atoms, and a linear or branched haloalkyl group is preferable, and a linear haloalkyl group is particularly preferable. Examples of the haloalkyl group include chloromethyl, fluoromethyl, 2-chloroethyl, 2-fluoroethyl and the like.

The acyl group is preferably a group represented by --CO--R '(R' represents a hydrogen atom or an alkyl group), and when R'is an alkyl group, a preferred embodiment is the above alkyl group. Is the same as. Specific examples of the acyl group include a formyl group, an acetyl group, a propionyl group and a butyryl group, and a propionyl group is preferable.

The acylalkyl group is-(CH ₂ ) _m --C
O-R '(R' is a hydrogen atom or an alkyl group, m is 1
Shows an integer of ~ 8. ) Is preferable, and when R ′ is an alkyl group, a preferred embodiment is the same as the above alkyl group. As the acylalkyl group, a propionylmethyl group is preferable.

The alkoxycarbonyl group is --CO--O.
It is a group represented by R ′ (R ′ represents the above alkyl group), and a preferred embodiment of R ′ is the same as the alkyl group. The alkoxycarbonyl group is preferably an ethoxycarbonyl group.

The alkoxycarbonylalkyl group is-
A group represented by (CH ₂ ) _m CO-OR '(R' is an alkyl group, m is an integer of 1 to 8) is preferable, and R '
The preferred embodiment of is the same as the alkyl group. The alkoxycarbonylalkyl group is preferably a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a methoxycarbonylethyl group or an ethoxycarbonylethyl group.

As the aryl group, a phenyl group, a tolyl group, a biphenylyl group, a naphthyl group and the like are preferable. A phenylmethyl group is preferred as the aralkyl group.

The haloaryl group is a group in which one or more hydrogen atoms in the aryl group are substituted with a halogen atom, and the halogen atom is preferably a fluorine atom or a chlorine atom. As the haloaryl group, a 4-chlorophenyl group,
A 4-fluorophenyl group is preferred.

Specific examples of the fluorine-containing keto compound represented by the formula 1 in the present invention include ketocarboxylic acid esters represented by each ester shown in Chemical formula 1 and ketones represented by each ketone shown in Chemical formula 2. And the like, 4,
Ethyl 4,4-trifluoro-3-oxobutyrate is preferred.

[0024]

Embedded image CF ₃ COCH ₂ COOCH ₂ CH ₃ (ethyl 4,4,4-trifluoro-3-oxobutyrate), CF ₃ COCH ₂ COOCH ₃ (methyl 4,4,4-trifluoro-3-oxobutyrate) _{), CF 3 COCH (CH 3} ) COOCH 2 CH 3 (4,4,4- _{trifluoro-2-methyl-3-oxobutyrate), CHF 2 COCH 2 COOCH 2} CH 3 (4,4- difluoro -3 - ethyl oxo _{acid), CH 2 FCOCH 2 COOCH 2} CH 3 (4- fluoro-3-oxobutyrate).

[0025]

Embedded image CF ₃ COCH ₂ CH ₃ (1,1,1-trifluoro-2-butanone), CF ₃ COCH ₂ CH ₂ CH ₃ (1,1,1-trifluoro-2-pentanone), CF _{3 COCH 2 CH 2 CH 2 CH 3} (1,1,1- trifluoro-2-hexanone).

In the present invention, the fluorine-containing keto compound represented by the formula 1 is hydrogenated in the presence of a nickel catalyst carrying an optically active compound.

The optically active compound in the nickel catalyst carrying the optically active compound is not particularly limited as long as it is a compound capable of exhibiting optical activity, and it is a compound having one or more asymmetric carbons in the molecule or an axially asymmetric compound. Compounds and the like,
Compounds having one or more asymmetric carbons are preferred. The supported amount of the optically active compound is not particularly limited, and is usually preferably 0.3 to 3 times the weight of the nickel component of the nickel catalyst.

The optically active compound is preferably an optically active substance of oxyacid (D-form or L-form) or an optically active form of amino acid (D-form or L-form), and particularly, an optically active form of tartaric acid or an optically active form of lactic acid. , An optically active substance of malic acid, an optically active substance of valine, an optically active substance of leucine and an optically active substance of glutamic acid are preferable, and an optically active substance of tartaric acid is particularly preferable.

Examples of the nickel catalyst include known or well-known nickel-containing catalysts that can be used in the hydrogenation reaction. Raney nickel catalysts or reduced nickel catalysts are preferable, and Raney nickel catalysts are particularly preferable.

As a method for preparing the nickel catalyst treated with the optically active compound of the present invention, a known method can be adopted. For example, according to the method of Izumi et al. Described in JP-B-60-14616, the optically active substance is used. It can be prepared by immersing the nickel catalyst in an aqueous solvent containing

The amount of the catalyst is preferably 0.01 to 0.5 part by weight, more preferably 0.05 to 0.3 part by weight, based on 1 part by weight of the fluorine-containing keto compound represented by the formula 1. .

The hydrogen source in the hydrogenation reaction of the present invention is not particularly limited as long as it can be a hydrogen source in the hydrogenation reaction, and hydrogen, formic acid, formate salts, formate esters and the like are preferable, and hydrogen gas is particularly preferable. Further, it may be a compound capable of generating a hydrogen source in the reaction system. When hydrogen gas is used in the hydrogenation reaction, the amount thereof is preferably 1 to 200 mol, based on 1 mol of the fluorine-containing keto compound represented by Formula 1.

The hydrogenation reaction occurs selectively from one direction of the carbonyl group in the fluorine-containing keto compound represented by the formula 1, the carbonyl group is reduced to a hydroxyl group, and the carbon atom bonded to the carbonyl group is changed. Hydrogen is added in a specific orientation and the carbon atom becomes an asymmetric carbon atom.

A solvent may be present in the hydrogenation reaction of the present invention. The solvent may be one or two selected from ethers, esters, alcohols and water.
A mixed solvent of at least one species is preferred. As the solvent, tetrahydrofuran, methyl propionate and ethyl propionate are particularly preferable. The amount of the solvent is preferably 0.5 to 100 parts by weight, and practically 1 to 20 parts by weight with respect to 1 part by weight of the fluorine-containing keto compound represented by Formula 1.

The reaction temperature of the hydrogenation reaction is 10 to 150 ° C.
Is preferable, and 50 to 120 ° C. is particularly preferable. The initial hydrogen pressure when carrying out the hydrogenation reaction using hydrogen gas is 1
˜200 kg / cm ² is preferable, and 1 to 120 kg / cm ² is particularly preferable from a practical viewpoint such as reaction rate. The reaction time can be appropriately changed depending on the structure of the fluorinated keto compound and the like, and is usually about 10 minutes to 48 hours.

The product obtained by the hydrogenation reaction is usually purified to remove the catalyst, by-products and the like and have a high purity. The purification treatment method is not particularly limited, but a method of separating and recovering the catalyst by a method such as filtration or adsorption to a magnet and then distilling off the solvent as appropriate can be employed.

The object compound of the present invention is an optically active fluorine-containing hydroxy compound represented by the formula 2, and specific examples thereof include (S) or (R) -4,4,4-trifluoro-.
Ethyl 3-hydroxybutyrate, (S) or (R) -4,
Methyl 4,4-trifluoro-3-hydroxybutyrate,
(S) or (R) -4,4,4-trifluoro-2-
Ethyl methyl-3-hydroxybutyrate, (S) or (R) -4,4-difluoro-3-hydroxybutyrate, (S) or (R) -4-fluoro-3-hydroxybutyrate, (S) or (R) -1,1,1-trifluoro-2-hydroxybutane, (S) or (R)
-1,1,1-trifluoro-2-hydroxypentane, (S) or (R) -1,1,1-trifluoro-
2-hydroxyhexane etc. are mentioned.

[0038]

The mechanism by which the hydrogenation reaction of the present invention proceeds in a selective orientation is not clear, but it is considered as follows. That is, the optically active substance is adsorbed at the active sites on the surface of the catalyst treated with the optically active compound. When a hydrogenation reaction is carried out using this, when the raw material fluorine-containing keto compound approaches the active site, the carbonyl group surface becomes selective due to the effect of the optically active substance. As a result, the hydrogenation reaction proceeds selectively from a specific orientation, and as a result, the R- or S-configuration fluorine-containing hydroxy compound, which is one of the antipodes, is predominantly produced.

[0039]

[Examples] The present reaction will be specifically described below with reference to Examples, but the present invention is not limited to these Examples.

Reference Example 1: Preparation of Nickel Catalyst Supporting Optically Active Compound 25 g of Raney nickel alloy (Kawaken Fine Chemicals, aluminum content 50%) was added to 100 g of 20 wt% sodium hydroxide aqueous solution to such an extent that foaming occurred gently. Gradually added and stirred. After the foaming subsided, the mixture was heated at 100 ° C. for 1 hour and then washed with 100 ml of deionized water. An aqueous tartaric acid solution prepared by dissolving 4.5 g of L-tartaric acid and 19 g of sodium bromide in 150 ml of deionized water was added to the catalyst and heated at 90 ° C for 1.5 hours.
The tartaric acid aqueous solution was replaced, and the same operation was repeated 3 times. Next, it was washed with 100 ml of deionized exchanged water, subsequently washed with 50 ml of diethyl ether and then dried to obtain 25 g of Raney nickel catalyst treated with L-tartaric acid.

Example 1 700 mg of Raney nickel catalyst treated with L-tartaric acid prepared in Reference Example 1,
Ethyl 4,4-trifluoro-3-oxobutyrate 5.65
g and 50 ml of tetrahydrofuran were charged into a stainless steel autoclave, deaerated and then replaced with hydrogen, and reacted at an initial hydrogen pressure of 50 kg / cm ² and a temperature of 80 ° C. for 16 hours. The conversion rate was 89%.

After returning to room temperature, the catalyst was removed by a magnet, the solvent was distilled off, and vacuum distillation was carried out to obtain 4.48 g of ethyl 4,4,4-trifluoro-3-hydroxybutyrate (yield 7
8%).

When the optical purity was analyzed using a high performance liquid chromatography optical resolution column (chiral cell OD manufactured by Daicel Chemical Industries), it was confirmed that the S form was produced with an optical purity of 67% ee.

[Reference Example 2: Asymmetric hydrogenation reaction with homogeneous catalyst] [(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] ruthenium.2 which is a homogeneous catalyst Acetate] 100 mg and ethyl 4,4,4-trifluoro-3-oxobutyrate 3.68 g were added to ethanol 2
It was dissolved in 0 ml, charged into a stainless steel autoclave, degassed, then replaced with hydrogen, and the initial hydrogen pressure was 50 kg / c.
The reaction was carried out at m ² and a temperature of 80 ° C. for 24 hours, and a gas chromatography analysis was conducted. As a result, the conversion rate to ethyl 4,4,4-trifluoro-3-hydroxybutyrate was 1%.

[0045]

INDUSTRIAL APPLICABILITY According to the present invention, a fluorine-containing hydroxy compound, which is important as an intermediate for pharmaceuticals, agricultural chemicals and liquid crystal substances, can be obtained in a high yield from an easily available raw material by an efficient and simple method. be able to. Further, the obtained fluorine-containing hydroxy compound has a high yield in terms of optical purity. Furthermore, since the catalyst used is a solid, it can be easily recovered, and the operation for removing it from the product is also easy.

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Claims (4)

[Claims] 1. A fluorine-containing keto compound represented by formula 1 is hydrogenated in the presence of a nickel catalyst supporting an optically active compound to obtain an optically active fluorine-containing hydroxy compound represented by formula 2. A method for producing an optically active fluorine-containing hydroxy compound, which is characterized. However, in Expression 1 and Expression 2, n is
0, 1 or 2, R is an alkyl group, a haloalkyl group, an acyl group, an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an aralkyl group, an aryl group, or a haloaryl group, and * is an optically active carbon. Is shown. _{CH n F 3-n -CO-} R ··· Equation _{1, CH n F 3-n} -C * H (OH) -R ··· Equation 2. 2. The optically active fluorine-containing hydroxy compound according to claim 1, wherein the nickel catalyst carrying the optically active compound is a nickel catalyst carrying an optically active oxyacid or a nickel catalyst carrying an optically active amino acid. Production method. 3. The method for producing an optically active fluorine-containing hydroxy compound according to claim 1, wherein the nickel catalyst supporting an optically active compound is a nickel catalyst supporting an optically active substance of tartaric acid. 4. The method according to claim 1, 2 or 3, wherein R is an alkoxycarbonylalkyl group.