JP2019127449A - Manufacturing method of optically active 1-chloro-3,3-difluoro isopropyl alcohol - Google Patents

Abstract

To provide a manufacturing method of optically active 1-chloro-3,3-difluoro isopropyl alcohol in an industrially possible condition.SOLUTION: Optically active 1-chloro-3,3-difluoro isopropyl alcohol can be manufactured easily by asymmetry hydrogenation reaction of 1-chloro-3,3-difluoro-2-propanone in an industrially possible condition with specified ruthenium-catalyst and hydrogen donating substances such as formic acid, formate or hydrogen (H).SELECTED DRAWING: None

Description

  The present invention relates to a method for producing optically active 1-chloro-3,3-difluoroisopropyl alcohol.

  Optically active fluorine-containing isopropyl alcohol is an important compound as various medical and agricultural chemicals intermediates. As a general method for producing optically active fluorine-containing alkyl isopropyl alcohol, Patent Document 1 discloses a method for producing optically active 1,1-difluoroisopropyl alcohol by asymmetric hydrogenation of 1,1-difluoroacetones. 1 discloses asymmetric hydrogenation of 2,2-difluoroacetophenone.

  Also, as an example of asymmetric hydrogenation of ketones having a chloromethyl group, a method for producing optically active chloromethyl alcohol or arylchloromethyl alcohol by asymmetric hydrogenation of alkyl chloromethyl ketone or aryl chloromethyl ketone has been reported. (Non-Patent Documents 2, 3, and 4).

  On the other hand, optically active 1-chloro-3,3-difluoroisopropyl alcohol can be efficiently obtained by performing asymmetric hydrogenation on 1-chloro-3,3-difluoro-2-propanone, which is a starting material of the present invention. The manufacturing method to obtain is not known so far.

JP 2012-006888 A

Tetrahedoron 2011, No. 67, p. 5642-5650. J. Fluorine Chem. 2007, No. 128, p. 844-850. Org. Lett. 2007, No. 9, p. 255-257. J. Am. Chem. Soc. 2011, 133, p. 14960-14963.

  An object of the present invention is to provide an industrial production method of optically active 1-chloro-3,3-difluoroisopropyl alcohol.

  According to the methods described in Patent Document 1 and Non-Patent Documents 1 to 4, optically active fluorinated isopropyl alcohol can be produced. Therefore, with regard to the preparation of optically active 1-chloro-3,3-difluoroisopropyl alcohol, which is the subject of the present invention, it was initially anticipated that these prior arts could be easily prepared by reference.

  However, actually, referring to the methods described in Patent Document 1, Non-Patent Document 1 and Non-Patent Document 4, the inventors show the following formula for 1-chloro-3, 3-difluoro-2-propanone. When the asymmetric hydrogenation reaction was examined using a catalyst, it was not possible to produce the target compound (1-chloro-3,3-difluoroisopropyl alcohol) with high optical purity (the following formula; Comparative Example 4 described later) -6, where ee is an abbreviation for enantiometric excess).

  Thus, it has been found that it is difficult to produce optically active 1-chloro-3,3-difluoroisopropyl alcohol under the conditions disclosed in the prior art.

  An object of the present invention is to provide a method for producing optically active 1-chloro-3,3-difluoroisopropyl alcohol under industrially practicable conditions.

  The present inventors diligently studied based on the problems described above. As a result, the inventors have found that the selectivity in the asymmetric hydrogenation reaction varies greatly depending on the type of starting material.

  That is, when screening is started by performing asymmetric hydrogenation reaction on 1-chloro-3,3-difluoro-2-propanone using a catalyst described in Patent Document 1 and Non-patent Document 4, optical purity can be obtained. Is 1.0 to 9.3% ee, and the optical purity is low in all cases (Comparative Examples 1 to 4 described later), while 1-chloro-3,3,3-trifluoro is used as a comparison control. When the same asymmetric hydrogenation reaction was carried out using the same catalyst for -2-propanone, surprisingly, the optical purity was 56.9 to 93.0% ee, giving relatively high optical purity. (Comparative Examples 7 to 10).

  This result is presumed that some factor of the substrate works by changing the difluoromethyl group of the starting material to the trifluoromethyl group, which affects the optical purity.

  Therefore, the inventors of the present invention conducted intensive studies to find that 1-chloro-3,3-difluoro-2-propanone was not effectively reduced in the reduction reaction using formic acid, formate or hydrogen as a hydrogen donating substance. A catalyst capable of homohydrogenation was found. As a result, it has been found that optically active 1-chloro-3,3-difluoroisopropyl alcohol can be produced under industrially adoptable reaction conditions, and the present invention has been completed.

  In the present invention, the operation is not burdened and the scale-up is easy. Superiority as an industrial manufacturing method.

That is, the present invention provides a method for producing optically active 1-chloro-3,3-difluoroisopropyl alcohol described in the following [Invention 1]-[Invention 9].
[Invention 1]
General formula [1]:

[Wherein, R represents a straight chain having 1 to 18 carbon atoms, a branched chain having 3 to 18 carbon atoms, a cyclic, unsubstituted or substituted alkyl group having 3 to 18 carbon atoms,
Or a C6-C18 unsubstituted or substituted aromatic ring group.
n is 1 or 2, * represents an asymmetric carbon, and Ph represents a phenyl group. ]
In the presence of a ruthenium catalyst represented by and a hydrogen donating substance,
Formula [2]:

By the asymmetric hydrogenation reaction of 1-chloro-3,3-difluoro-2-propanone represented by the formula [3]:

[In the formula, * represents an asymmetric carbon. ]
A process for producing optically active 1-chloro-3,3-difluoroisopropyl alcohol represented by
[Invention 2]
The method according to invention 1, wherein R of the ruthenium catalyst represented by the general formula [1] is a methyl group, an ethyl group, a propyl group, an isopropyl group, a p-tolyl group, a phenyl group or a naphthyl group.
[Invention 3]
The method according to invention 1 or 2, wherein R of the ruthenium catalyst represented by the general formula [1] is a p-tolyl group or a methyl group, and n is 1.
[Invention 4]
Any of inventions 1 to 3, wherein the hydrogen-donating substance is hydrogen (H ₂ ), formic acid (HCO ₂ H) or a salt of formic acid and an inorganic base, a salt of formic acid and an organic base, cyclohexadiene or phosphorous acid The method described in.
[Invention 5]
The method according to invention 4, wherein the salt of formic acid and an inorganic base is an alkali metal salt of formic acid, an alkaline earth metal salt of formic acid or an ammonium salt of formic acid.
[Invention 6]
Organic bases in salts of formic acid and organic bases are trimethylamine, triethylamine, tri-n-butylamine, n-propylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,3-lutidine, 2,4-lutidine, 2 , 3,4-collidine, 2,4,5-collidine, 2,4,6-collidine, 2,5,6-collidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0] undeca The production method according to invention 4, which is at least one selected from the group consisting of -7-ene.
[Invention 7]
Any one of inventions 1 to 6, wherein the asymmetric hydrogenation reaction is performed using at least one solvent selected from the group consisting of hydrocarbon, ether, nitrile, amide, ester, halogen, and alcohol. The method described in.
[Invention 8]
The method according to any one of Inventions 1 to 7, wherein a phase transfer catalyst is added to carry out an asymmetric hydrogenation reaction.
[Invention 9]
Phase transfer catalysts include tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, tetrabutyl ammonium hydroxide, tetramethyl ammonium fluoride, tetramethyl ammonium chloride, tetramethyl ammonium bromide, tetra Methyl ammonium iodide, tetramethyl ammonium hydroxide, benzyl trimethyl ammonium fluoride, benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium bromide, benzyl trimethyl ammonium iodide, benzyl trimethyl ammonium hydroxide, tetraethyl ammonium fluoride, tetraethyl ammonium chloride, tetraethyl ammonium chloride At least one member selected from the group consisting of bromide, tetraethylammonium iodide, tetraethylammonium hydroxide, tetrapropylammonium fluoride, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide and tetrapropylammonium hydroxide The method according to claim 8.

  The present invention exhibits an effect that optically active 1-chloro-3,3-difluoroisopropyl alcohol can be produced under industrially practicable conditions.

  Hereinafter, the present invention will be described in detail. Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments, and can be appropriately carried out based on the ordinary knowledge of the person skilled in the art within the scope of the present invention. can do.

  1-chloro-3,3-difluoro-2-propanone represented by the formula [2] is a known compound and can be produced, for example, by the method described in JP-A-2017-8006.

In the ruthenium catalyst represented by the general formula [1], * represents an asymmetric carbon, R is linear having 1 to 18 carbon atoms, branched having 3 to 18 carbon atoms, cyclic having 3 to 18 carbon atoms, Unsubstituted or substituted alkyl group,
Or a C6-C18 unsubstituted or substituted aromatic ring group.

  Among the R in the ruthenium catalyst represented by the formula [1], linear, branched and cyclic unsubstituted alkyl groups are preferably those having 1 to 10 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, n-octyl group, Examples include n-decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.

  Among R of the ruthenium catalyst represented by the formula [1], an unsubstituted aromatic ring group having 6 to 10 carbon atoms is preferable. Specifically, a phenyl group, a naphthyl group and the like are preferable.

  Among the above-mentioned R, the substituent in each of a substituted alkyl group (corresponding to a linear, branched and cyclic substituted alkyl group) and a substituted aromatic ring group is a halogen atom, an aromatic ring group, an alkoxy group, a haloalkoxy Group, cyano group, nitro group, alkoxycarbonyl group and the like. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, 1-butyl group, 2-butyl group, isobutyl group, tert-butyl group, 1-cyclohexyl group, benzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 1- Phenylethyl group, 2-phenylethyl group, phenyl group, naphthyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl Group, 3-fluorophenyl group, 4-fluorophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group Group and the like.

  Among R in the ruthenium catalyst represented by the formula [1], methyl group, ethyl group, n-propyl group, isopropyl group, p-tolyl group (4-methylphenyl group), phenyl group, 2,4,6- A trimethylphenyl group, a 2,4,6-triisopropylphenyl group, a 2,3,4,5,6-pentafluorophenyl group and a naphthyl group are preferable, and a methyl group, a p-tolyl group and a 2,4,6-trimethyl group are preferable. Phenyl and 2,4,6-triisopropylphenyl are particularly preferred.

  n represents 1 or 2, particularly preferably 1. Furthermore, a combination of the aforementioned R is a p-tolyl group or a methyl group and n is 1 is very preferable.

  Since there are two asymmetric carbons of the ruthenium catalyst represented by the general formula [1], enantiomers {(R, R form), (S, S form)} exist. In the present invention, the configuration of the desired product (1-chloro-3,3-difluoroisopropyl alcohol) differs depending on the configuration of the ruthenium catalyst. For example, in order to obtain R-form 1-chloro-3,3-difluoroisopropyl alcohol (the stereochemistry of asymmetric carbon is in "R" configuration), a ruthenium catalyst of (S, S) form is required as a configuration. Conversely, in order to obtain a product of S form, an (R, R) form of ruthenium catalyst is required.

  In addition, although the ruthenium catalyst represented by General formula [1] is well-known and it is also possible to utilize what is marketed, For example, Organometallics 2014, No. 33, p. 5517-5524. Those skilled in the art can also synthesize them based on the methods described in the literature.

  The amount of ruthenium catalyst represented by the general formula [1] is the molar ratio of 1-chloro-3,3-difluoro-2-propanone represented by the formula [2] to the molar ratio of the catalyst, “S S / C can be used in a range of 10 to 10,000 when representing / C (S is a substrate (Substrate), C is a catalyst (Catalyst)).

  It is preferable to use in the range of 10-5,000 from a viewpoint of reaction efficiency or economical efficiency, and 50-2,000 are further more preferable.

In the present invention, an optically active 1-chloro-3,3-difluoroisopropyl alcohol is produced by performing an asymmetric hydrogenation reaction in the presence of a ruthenium catalyst represented by the general formula [1] and a hydrogen donating substance. . The hydrogen donating substance used here can be used without particular limitation as long as it is a substance which can supply a hydrogen atom in the asymmetric hydrogenation reaction. For example, hydrogen gas, formic acid (HCO ₂ H) or a salt of formic acid and an inorganic base, a salt of formic acid and an organic base, a salt of formic acid and ammonia, cyclohexadiene, phosphorous acid, or the like.

  Examples of salts of formic acid and inorganic bases include alkali metal salts and alkaline earth metal salts of formic acid. The term "alkali metal" as used herein refers to lithium, sodium, potassium, rubidium, cesium and the like, and the term "alkaline earth metal" refers to magnesium, calcium, strontium, barium and the like. Inorganic bases in formic acid and inorganic bases are carbonates or hydrogencarbonates of alkali metals, carbonates of alkaline earth metals, etc. Specific compounds of these are lithium carbonate, lithium hydrogencarbonate, potassium carbonate, And potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate and calcium carbonate.

  On the other hand, organic bases in salts of formic acid and organic bases are trimethylamine, triethylamine, tri-n-butylamine, n-propylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,3-lutidine, 2,4-lutidine , 2,3,4-collidine, 2,4,5-collidine, 2,4,6-collidine, 2,5,6-collidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0 ] Undec-7-ene etc. are mentioned.

  Among them, hydrogen gas, a salt of formic acid with an inorganic base, a salt of formic acid with an organic base, and a salt of formic acid with ammonia from the viewpoint of easy separation from the product as a hydrogen donating substance. It is preferable to use it.

  Specific examples of preferable hydrogen donating substances include hydrogen gas, lithium formate, sodium formate, potassium formate, cesium formate, magnesium formate, calcium formate, formic acid / trimethylamine (here, "/" in "formic acid / trimethylamine") The description means a "salt" of formic acid and an organic base (in this case, representing trimethylamine), hereinafter the same as in the present specification), formic acid / triethylamine, formic acid / tri-n-propylamine, formic acid / N, N-diisopropylethylamine, formic acid / 1,8-diazabicyclo [5.4.0] undec-7-ene, ammonium formate and the like.

  Among these, hydrogen gas, potassium formate, sodium formate, formic acid / trimethylamine, formic acid / triethylamine, and ammonium formate are preferable, and potassium formate, sodium formate, and formic acid / triethylamine are particularly preferable. These hydrogen donating substances may be used alone or in combination of two or more.

  The amount of the hydrogen donating substance used in the present invention is 1 to 20 equivalents, preferably 1 to 15 equivalents to 1-chloro-3,3-difluoro-2-propanone represented by the formula [2]. It is an equivalent, particularly preferably 2 to 10 equivalents.

  When the asymmetric hydrogenation reaction is performed using hydrogen gas as the hydrogen donating substance, the pressure of hydrogen is not particularly limited as long as it is under a hydrogen atmosphere. Usually, the reaction proceeds at 0.1 MPa or more (absolute pressure, hereinafter the same in the present specification), but it is preferable to adjust while observing the progress of the asymmetric hydrogenation reaction. In consideration of the economics and the like in manufacturing on an industrial scale, the pressure range is usually 1.0 to 15.0 MPa, preferably 1.0 to 10.0 MPa, particularly preferably 1.0 to 5.0 MPa. Good to do.

  As the solvent used in this reaction, any solvent can be used so long as it can dissolve the ruthenium catalyst and the hydrogen donating substance represented by the general formula [1], for example, water, hydrocarbon solvents, ether solvents Preferred are nitrile solvents, amide solvents, ester solvents, halogen solvents and alcohol solvents. Specific compounds include benzene, toluene, xylene, chlorobenzene, benzotrifluoride, 1,3-difluorobenzene, diethyl ether, diisopropyl ether, dibutyl ether, dibutyl ether, t-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, acetonitrile, dimethylformamide Methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, n -Hexanol, cyclohexanol and the like, toluene, xylene, chlorobenzene, 1,3-difluorobenzene, benzotrifluoride, Ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, methyl acetate, ethyl acetate, propyl acetate, dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, 1,3 -Difluorobenzene, benzotrifluoride, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-propanol are particularly preferred. These solvents may be used alone or in combination.

  In the present invention, if necessary, a phase transfer catalyst can be added to carry out the asymmetric hydrogenation reaction. Specific examples of the phase transfer catalyst used are tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, tetrabutyl ammonium hydroxide, tetramethyl ammonium fluoride, tetramethyl ammonium chloride, tetramethyl Ammonium bromide, tetramethylammonium iodide, tetramethylammonium hydroxide, benzyltrimethylammonium fluoride, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltrimethylammonium hydroxide, tetraethylammonium fluoride, tetraethylammonium Chloride, tetrae Le ammonium bromide, tetraethylammonium iodide, tetraethylammonium hydroxide, tetrapropylammonium fluoride, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetrapropylammonium hydroxide and the like. Among these, you may use 1 type or in combination of 2 or more types.

  The amount of the phase transfer catalyst to be added may be in the range of 0 to 10 equivalents based on 1 mole of 1-chloro-3,3-difluoro-2-propanone represented by the formula [2]. Preferably it is 0.01-8 equivalent, and 0.05-5 equivalent is especially preferable. The addition of a phase transfer catalyst can improve the reactivity (conversion rate) and enantioselectivity of 3-chloro-1,1-difluoro-2-propanone.

  Although the reaction temperature in the asymmetric hydrogenation reaction is not particularly limited, it is 70 ° C. or less considering the boiling point (56 ° C./11 kPa) of 1-chloro-3,3-difluoro-2-propanone represented by the formula [2]. The temperature is preferably 5 to 60 ° C., more preferably 10 to 50 ° C.

  With regard to the reaction container in the present invention, a pressure-resistant reaction container made of a material such as stainless steel (SUS), a tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) having corrosion resistance, a polytetrafluoroethylene (PTFE), etc. It is preferable to carry out the reaction using a pressure-resistant reaction vessel whose interior is lined with the above resin.

  The reaction time of the asymmetric hydrogenation reaction is not particularly limited, but usually, after the two raw materials are reacted, the end point when the raw materials are almost disappeared by means of gas chromatography, liquid chromatography, NMR, etc. It is preferable that

  Moreover, the present invention can improve the reactivity (conversion rate) and enantioselectivity of the ketone substrate by appropriately changing the acidity of the added hydrogen donating substance. Therefore, an acid or a base may be added to maintain an appropriate acidity as needed. The acid to be added is not particularly limited, and examples thereof include organic acids such as formic acid and acetic acid. Examples of the base include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, hydrogen carbonate. Inorganic bases such as sodium or organic bases such as triethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene can be mentioned. These acids or bases may be used alone or in combination of two or more.

  In the asymmetric hydrogenation reaction, the value (pH, hydrogen ion index) showing the degree of acidity / alkaticity in the reaction system may be 5.0 to 9.0, but the raw material 1-chloro-3, Since 3-difluoro-2-propanone is unstable under strongly basic conditions, it is particularly preferable to adjust in the range of 6.0 to 8.0.

  Purification of the reaction product can be optionally performed by a known method such as column chromatography, distillation, recrystallization, etc. However, a method of obtaining by distillation without extracting with a solvent is most preferable.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples. Here, "%" of the analysis value represents "area%" of the composition obtained by measurement by the gas chromatograph mass spectrometer. Also, the optical purity was measured by chiral gas chromatography.
Example 1
In a 20 ml glass 2-neck flask, the following formula:

Ruthenium catalyst (RuCl [(S, S) -C3-teth-Tsdpen]) (1.24 mg, 0.002 mmol, substrate / catalyst ratio (S / C) = 500) and a stirrer are put in the system. Were replaced with nitrogen. 2M sodium formate aqueous solution (2.5 mL, 5.0 mmol) adjusted to pH 7 by adding formic acid, 1-chloro-3,3-difluoro-2-propanone (128.5 mg, 1.0 mmol) And toluene (10 mL) were introduced. By stirring at 30 ° C. for 24 hours, the conversion rate was 99%, and it was converted to 1-chloro-3,3-difluoroisopropyl alcohol, and the optical purity was 74% ee. After the reaction, the aqueous layer was removed by separation into two layers, and the organic layer was distilled under reduced pressure to obtain the desired product. The NMR data of the desired product is shown below.
¹ H-NMR (heavy solvent: CD ₃ CN, reference material: tetramethylsilane), δ ppm: 3.67 (dq, 2H), 3.97 (m, 1H), 5.85 (dt, 1H), ¹⁹ F-NMR (deuterated solvent: CD ₃ CN, reference material: hexafluorobenzene set at −162.2 ppm), −130.5 (ddd, 1F), −128.6 (ddd, 1F).
[Example 2-9]
The following table shows the results of carrying out the hydrogenation reaction under the same reaction conditions as in Example 1 except that the ruthenium catalyst, the solvent and the hydrogen donating substance were changed.

Here, the structure of the ruthenium catalyst used in Examples 2 to 9 is shown below.

Comparative Examples 1 to 6
Ruthenium complex (0.008 mmol, substrate / catalyst ratio 700), potassium formate (0.967 g, 11.5 mmol), tetrabutylammonium bromide (TBAB) (0.181 g, 0. 1) in a 20 mL autoclave under an argon gas atmosphere. 56 mmol), water (0.56 mL), formic acid (0.63 mL, 16.7 mmol, 0.3 equivalents relative to the ketone used) and 1-chloro-3,3-difluoro-2-propanone hydrate (5.6 mmol) ) Was charged. The vessel was sealed and stirred at 30 ° C. for 21 hours. The measurement results of the conversion rate and optical purity for each ruthenium complex used are shown in the following table.

The structure of the ruthenium catalyst used is shown below.

[Comparative Examples 7 to 10]
1-Chloro-3,3,3-trifluoro-2-propanone is used instead of 1-chloro-3,3-difluoro-2-propanone of Comparative Example 1 and asymmetric hydrogenation is carried out under the same reaction conditions. The results of carrying out the reaction are shown in the following table.

  The optically active 1-chloro-3,3-difluoroisopropyl alcohol targeted in the present invention can be used as an intermediate for medical and agricultural chemicals.

Claims (9)

General formula [1]:

[Wherein, R represents a straight chain having 1 to 18 carbon atoms, a branched chain having 3 to 18 carbon atoms, a cyclic, unsubstituted or substituted alkyl group having 3 to 18 carbon atoms,
Or a C6-C18 unsubstituted or substituted aromatic ring group.
n is 1 or 2, * represents an asymmetric carbon, and Ph represents a phenyl group. ]
In the presence of a ruthenium catalyst represented by and a hydrogen donating substance,
Formula [2]:

The asymmetric hydrogenation reaction of 1-chloro-3,3-difluoro-2-propanone represented by the formula [3]:

[Wherein, * represents an asymmetric carbon. ]
And a method of producing optically active 1-chloro-3,3-difluoroisopropyl alcohol. The method according to claim 1, wherein R in the ruthenium catalyst represented by the general formula [1] is a methyl group, an ethyl group, a propyl group, an isopropyl group, a p-tolyl group, a phenyl group or a naphthyl group. The method according to claim 1 or 2, wherein R of the ruthenium catalyst represented by the general formula [1] is a p-tolyl group or a methyl group, and n is 1. The hydrogen-donating substance is hydrogen (H ₂ ), formic acid (HCO ₂ H) or a salt of formic acid and an inorganic base, a salt of formic acid and an organic base, cyclohexadiene or phosphorous acid. Production method described in. The method according to claim 4, wherein the salt of formic acid and the inorganic base is an alkali metal salt of formic acid, an alkaline earth metal salt of formic acid or an ammonium salt of formic acid. Organic bases in salts of formic acid and organic bases are trimethylamine, triethylamine, tri-n-butylamine, n-propylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,3-lutidine, 2,4-lutidine, 2 , 3,4-collidine, 2,4,5-collidine, 2,4,6-collidine, 2,5,6-collidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0] undeca The method according to claim 4, wherein the method is at least one selected from the group consisting of -7-ene. 7. The asymmetric hydrogenation reaction is carried out using at least one solvent selected from the group consisting of hydrocarbon type, ether type, nitrile type, amide type, ester type, halogen type and alcohol type. The manufacturing method of crab. The production method according to claim 1, wherein an asymmetric hydrogenation reaction is performed by adding a phase transfer catalyst. Phase transfer catalysts include tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, tetrabutyl ammonium hydroxide, tetramethyl ammonium fluoride, tetramethyl ammonium chloride, tetramethyl ammonium bromide, tetra Methyl ammonium iodide, tetramethyl ammonium hydroxide, benzyl trimethyl ammonium fluoride, benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium bromide, benzyl trimethyl ammonium iodide, benzyl trimethyl ammonium hydroxide, tetraethyl ammonium fluoride, tetraethyl ammonium chloride, tetraethyl ammonium chloride It is at least one selected from the group consisting of bromide, tetraethylammonium iodide, tetraethylammonium hydroxide, tetrapropylammonium fluoride, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide and tetrapropylammonium hydroxide. The manufacturing method according to claim 8.