Technical Field
[0001.] The present invention relates to a method for industrial production of a
β-fluoroalcohol.
Background Art
[0002.] β-fluoroalcohols can be produced by reduction of corresponding
α-fluoroesters. For such reduction reactions, it is often to use stoichiometric
amounts of hydride reducing agents such as lithium aluminum hydride (see Patent
Document 1 and Scheme 1). However, the processes for producing
β-fluoroalcohols with the use of stoichiometric amounts of hydride reducing agents
are not suitable for mass-scale production due to the facts that: the reducing agents
are expensive and require caution in handling; and the after-treatment of the
resulting reaction products requires complicated operations and causes large
amounts of wastes.

[0003.] On the other hand, there have been reported processes for producing
alcohols by reaction of esters with hydrogen gas (H2) in the presence of ruthenium
catalysts (see Patent Documents 2 to 4 and Non-Patent Document 1).
Prior Art Documents
Patent Documents
[0004.] Patent Document 1: Japanese Laid-Open Patent Publication No.
2006-083163
Patent Document 2: International Application Publication No.
2006/106484
Patent Document 3: U.S. Patent No. 7,569,735
Patent Document 4: Japanese Laid-Open Patent Publication No.
2010-037329

Non-Patent Documents
[0005.] Non-Patent Document 1: Adv. Synth. Catal. (Germany), 2010, vol. 352, p.
92-96.
Summary of the Invention
Problems to be Solved by the Invention
[0006.] The processes for producing P-fiuoroalcohols by reaction of
α-fluoroesters with hydrogen gas in the presence of ruthenium catalysts provide
solutions to all of the problems in the use of stoichiometric amounts of hydride
reducing agents, but result in high cost because these processes require a high
hydrogen pressure of the order of 5 MPa and thus need to be industrially performed
in high-pressure gas production facilities.
[0007.] It is accordingly an object of the present invention to find out a catalyst
(or catalyst precursor) capable of reducing a hydrogen pressure in the reduction
reaction of an a-fluoroester with hydrogen and thereby provide a method for
industrial production of a β-fluoroaclohol by reduction of an a-fluoroester with
hydrogen by the use of such a catalyst.
Means for Solving the Problems
[0008.] The present inventors have made extensive researches in view of the
above problems and, as a result, have found that: a ruthenium complex of the
general formula [2], notably a ruthenium complex of the general formula [4], is
capable of dramatically reducing a hydrogen pressure in the hydrogen reduction
reaction of an a-fluoroester.

In the general formula [2], R each independently represent a hydrogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group or a substituted

aromatic ring group; Ar each independently represent an aromatic ring group or a
substituted aromatic ring group; X each independently represent a ligand having a
formal charge of-1 or 0 (with the proviso that the sum of formal charges of three X
is -2); and n each independently represent an integer of 1 or 2.

In the formula [4], Ph represent a phenyl group.
Even in the case of using the above ruthenium complex, the hydrogen reduction of
an ester having no fluorine atom at its a-position needs a hydrogen pressure of 4 to
5 MPa (see Comparative Example 2 explained later). On the other hand, the
hydrogen reduction of an α-fluoroester needs a hydrogen pressure of about 5 MPa
even in the case of using any other ruthenium complex analogous to the above
ruthenium complex (see Comparative Example 1 explained later as well as Example
26 of Patent Document 4). As a matter of course, there remains a need to set a high
hydrogen pressure in the hydrogen reduction using an ester having no fluorine atom
at its a-position in combination with the other analogous ruthenium complex. It is
possible to obtain a dramatic effect (dramatic reduction of hydrogen pressure in
reduction reaction) only by the combined use of the ruthenium complex of the
general formula [2], notably ruthenium complex of the general formula [4], and the
a-fluoroester.
[0009.] In this way, the present inventors have found useful techniques for
industrial production of β-fluoroalcohols. The present invention is based on these
findings.
[0010.] Namely, the present invention provides a method for producing a
P-fluoroalcohol according to Inventive Aspects 1 to 8.
[0011.] [Inventive Aspect 1 ]
A method for producing a P-fluoroalcohol of the general formula [3],
comprising: performing a reaction of an a-fluoroester of the general formula [1]
with hydrogen gas (H2) in the presence of a ruthenium complex of the general

formula [2]

where R1 and R2 each independently represent a hydrogen atom, a halogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic
ring group, an alkoxycarbonyl group or a substituted alkoxycarbonyl group; and R3
represents an alkyl group or a substituted alkyl group

where R each independently represent a hydrogen atom, an alkyl group, a
substituted alkyl group, an aromatic ring group or a substituted aromatic ring group;
Ar each independently represent an aromatic ring group or a substituted aromatic
ring group; X each independently represent a ligand having a formal charge of-1 or
0 (with the proviso that the sum of formal charges of three X is -2); and n each
independently represent an integer of 1 or 2

where R1 and R2 have the same definitions as in the general formula [1].
[0012.] [Inventive Aspect 2]
The method according to Inventive Aspect 1, wherein the reaction is
performed in the presence of a base.
[0013.] [Inventive Aspect 3]
A method for producing a β-fluoroalcohol of the general formula [3],
comprising: performing a reaction of an a-fluoroester of the general formula [1]
with hydrogen gas (H2) in the presence of a ruthenium complex of the general

formula [4] and a base

where R1 and R2 each independently represent a hydrogen atom, a halogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic
ring group, an alkoxycarbonyl group or a substituted alkoxycarbonyl group; and R
represents an alkyl group or a substituted alkyl group

where Ph represent a phenyl group

where R1 and R2 have the same definitions as in the general formula [1].
[0014.] [Inventive Aspect 4]
The method according to any one of Inventive Aspects 1 to 3, wherein the
a-fluoroester of the general formula [1] is an a-fluoroester of the general formula
[5]; and wherein the β-fluoroalcohol of the general formula [3] is a β-fluoroalcohol
of the general formula [6]

where R4 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an
aromatic ring group or a substituted aromatic ring group; and R5 represents an alkyl
group

where R has the same definition as in the general formula [5].

[0015.] [Inventive Aspect 5]
The method according to any one of Inventive Aspects 1 to 3, wherein the
α-fluoroester of the general formula [1] is an α-fluoroester of the general formula
[7]; and wherein the β-fluoroalcohol of the general formula [3] is a β-fluoroalcohol
of the general formula [8]

where Me represents a methyl group

[0016.] [Inventive Aspect 6]
The method according to any one of Inventive Aspects 1 to 5, wherein the
reaction is performed at a hydrogen pressure of 3 MPa or lower.
[0017.] [Inventive Aspect 7]
The method according to any one of Inventive Aspects 1 to 5, wherein the
reaction is performed at a hydrogen pressure of 2 MPa or lower.
[0018.] [Inventive Aspect 8]
The method according to any one of Inventive Aspects 1 to 5, wherein the
reaction is performed at a hydrogen pressure of 1 MPa or lower.
[0019.] In the present invention, the hydrogen pressure can preferably be set to 1
MPa or lower in the production of the β-fluoroalcohol by hydrogen reduction of the
a-fluoroester at a hydrogen pressure of 1 MPa or lower. This eliminates the need
to utilize a high-pressure gas production facility for the industrial production of the
β-fluoroalcohol. The amount of the catalyst used can also be reduced to a
significantly low level (e.g. to a substrate/catalyst ratio of 20,000) as compared to
the substrate/catalyst ratio (of e.g. 1,000) in conventional reduction of
α-fluoroalcohol. It is possible by these reductions in hydrogen pressure and
catalyst amount to largely reduce the production cost of the p-fluoroalcohol.
Further, the reduction reaction is inert to unsaturated bonds (such as carbon-carbon

double bond) in the present invention so that it is a preferred embodiment of the
present invention to carry out the reduction reaction in a functional-group-selective
manner (see Examples 7 and 8 explained later).
Detailed Description of the Embodiments
[0020.] Hereinafter, the industrial production method of β-fluoroalcohol
according to the present invention will be described in detail below. It is
understood that: the scope of the present invention is not limited to the following
examples; and various modifications and variations can be made to the following
examples without departing from the scope of the present invention. All of the
publications cited in the present specification, such as prior art documents and patent
documents e.g. published patents and patent applications, are herein incorporated by
reference. In the following description, the specific structures of the general
formulas [1] to [8] are as indicated above.
[0021.] In the present invention, the β-fluoroalcohol of the general formula [3] is
produced by reaction of the α-fluoroester of the general formula [1] with hydrogen
gas in the presence of the ruthenium complex of the general formula [2].
[0022.] In the α-fluoroester of the general formula [1], R and R each
independently represent a hydrogen atom, a halogen atom, an alkyl group, a
substituted alkyl group, an aromatic ring group, a substituted aromatic ring group, an
alkoxycarbonyl group or a substituted alkoxycarbonyl group. Examples of the
halogen atom are fluorine, chlorine, bromine and iodine. Examples of the alkyl
group are those of 1 to 18 carbon atoms having a straight-chain structure, a branched
structure or a cyclic structure (in the case of 3 or more carbons). Examples of the
aromatic ring group are those of 1 to 18 carbon atoms, such as: aromatic
hydrocarbon groups as typified by phenyl, naphthyl and anthryl; and aromatic
heterocyclic groups containing heteroatoms e.g. as nitrogen, oxygen or sulfur as
typified by pyrrolyl (including nitrogen-protected form), pyridyl, furyl, thienyl,
indolyl (including nitrogen-protected form), quinolyl, benzofuryl and benzothienyl.
Examples of alkyl (R) of the alkoxycarbonyl group (ROCO) are the same as those of
the above alkyl group. Examples of the substituted alkyl group, the substituted
aromatic ring group and the substituted alkoxycarbonyl group are those obtained by

substitution of any number of and any combination of substituents onto any of
carbon or nitrogen atoms of the above alkyl, aromatic ring and alkoxycarbonyl
groups. As such substituent groups, there can be used: halogen atoms such as
fluorine, chlorine and bromine; lower alkyl groups such as methyl, ethyl and propyl;
lower haloalkyl groups such as fluoromethyl, chloromethyl and bromomethyl; lower
alkoxy groups such as methoxy, ethoxy and propoxy; lower haloalkoxy groups such
as fluoromethoxy, chloromethoxy and bromomethoxy; cyano group; lower
alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; aromatic ring groups such as phenyl, naphthyl, anthryl, pyrrolyl
(including nitrogen-protected form), pyridyl, furyl, thienyl, indolyl (including
nitrogen-protected form), quinolyl, benzofuryl and benzothienyl; carboxyl group;
protected carboxyl groups; amino group; protected amino groups; hydroxyl group;
and protected hydroxyl groups. The substituted alkyl group may be one obtained
by substitution of an arbitrary carbon-carbon single bond or bonds of the alkyl group
with any number of and any combination of carbon-carbon double bonds and
carbon-carbon triple bonds. (The alkyl group with such an unsaturated bond may
naturally have any of the above substituent groups. In the present specification, the
alkyl group with the unsaturated bond is also categorized in the substituted alkyl
group.) Depending on the kind of the substituent group, the substituent group itself
may be involved in a side reaction. However, the side reaction can be minimized
by the adoption of suitable reaction conditions. In the present specification, the
term "lower" means that the group to which the term is attached is a group of 1 to 6
carbon atoms having a straight-chain structure, a branched structure or a cyclic
structure (in the case of 3 or more carbons). The aromatic ring groups described
above as "such substituent groups" may further be substituted with a halogen atom,
a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower
haloalkoxy group, a cyano group, a lower alkoxycarbonyl group, a carboxyl group, a
protected carboxyl group, an amino group, a protected amino group, a hydroxyl
group, a protected hydroxyl group etc. As the protecting groups of the pyrrolyl,
indolyl, carboxyl, amino and hydroxyl groups, there can be used those described in
"Protective Groups in Organic Synthesis", Third Edition, 1999, John Wiley & Sons,
Inc. Among others, it is preferable that: either one of R1 and R2 is a fluorine atom;

and the other of R1 and R2 is a hydrogen atom, an alkyl group, a substituted alkyl
group, an aromatic ring group or a substituted aromatic ring group, more preferably
a hydrogen atom.
[0023.] Further, R3 represents an alkyl group or a substituted alkyl group in the
α-fluoroester of the general formula [1]. Examples of the alkyl and substituted
alkyl groups as R3 are the same as those of R1 and R2 in the α-fluoroester of the
general formula [1]. Among others, alkyl is preferred. Particularly preferred is
methyl.
[0024.] The a-fiuoroester of the general formula [5] is one preferred example of
the α-fluoroester of the general formula [1]. Among others, the α-fluoroester of
the general formula [7] is a particularly preferred example. The α-fluoroester of
the general formula [5] is relatively readily available on a mass scale. The
α-fluoroester of the general formula [7] is particularly preferred because the
β-fluoroalcohol of the general formula [8] obtained from the α-fluoroester of the
general formula [7] is important as an intermediate for pharmaceutical and
agrichemical products.
[0025.] In the case where the α-fluoroester of the general formula [1] has an
asymmetric carbon atom at its a-position, the asymmetric carbon atom can be in any
configuration (R-configuration, S-configuration or racemic configuration). When
the optically active substance is used as the raw substrate material, the configuration
of the target compound can be maintained, with almost no deterioration in optical
purity, by the adoption of suitable reaction conditions (e.g. by "reacting in the
absence of a base" as will be explained later or "slowly dropping the raw substrate
material" as will be explained later in Example 12).
[0026.] It is feasible to use a-fluorolactone as the raw substrate material in the
present invention. Not only a-fluorolactone, but also any other compound capable
of being converted to the target α-fluoroester by the action of the base or reaction
solvent and then subjected to reduction reaction in the reaction system, are herein
included in the scope of the present invention.
[0027.] In the ruthenium complex of the general formula [2], R each

independently represent a hydrogen atom, an alkyl group, a substituted alkyl group,
an aromatic ring group or a substituted aromatic ring group. Examples of the alkyl,
substituted alkyl, aromatic ring and substituted aromatic ring groups as R are the
same as those of R1 and R2 in the α-fluoroester of the general formula [1]. Two
vicinal R (except hydrogen atoms) may form a cyclic structure by covalent bond of
carbon atoms through or without a nitrogen atom, an oxygen atom or a sulfur atom.
It is preferable that all of eight R are hydrogen (each of two n is 1)
[0028.] Ar each independently represent an aromatic ring group or a substituted
aromatic ring group in the ruthenium complex of the general formula [2].
Examples of the aromatic ring or substituted aromatic ring groups as Ar are the same
as those of R1 and R2 in the α-fluoroester of the general formula [1]. It is
preferable that all of four Ar are phenyl.
[0029.] X each independently represent a ligand having a formal charge of -1 or 0
with the proviso that the sum of formal charges of three X is -2 (the formal charge of
Ru is +2) in the ruthenium complex of the general formula [2]. Examples of the
ligand having a formal charge of-1 or 0 are: ligands described in "Hegedus:
Transition Metals in the Synthesis of Complex Organic Molecules (written by L. S.
Hegedus, Second Edition, translated by Shinji Murai, p. 4-9, Tokyo Kagaku Dojin,
2001)" and in "Organic Chemistry for Graduate Students Vol. II: Molecular
Structure & Reaction/Organic Metal Chemistry (Ryoji Noyori et al., p. 389-390,
Tokyo Kagaku Dojin, 1999)" etc.; BH4_; and R6C02-. (Herein, R6 represents a
hydrogen atom, an alkyl group or a substituted alkyl group. Examples of the alkyl
and substituted alkyl groups as R6 are the same as those of R1 and R2 in the
α-fluoroester of the general formula [1].) Among others, it is preferable that the
three ligands are hydrogen, chlorine and carbon monoxide, respectively.
[0030.] The reaction can be performed in the absence of the base in the case
where at least one of three X ligands is BH4 in the ruthenium complex of the general
formula [2]. (As a matter of course, it is alternatively feasible to perform the
reaction in the presence of the base). Among others, it is preferable to use the
ruthenium complex of the general formula [4] in which the Clligand has been
replaced by BH4(H-BH3) (see International Application Publication No.

2011/048727).
[0031.] Further, n each independently represent an integer of 1 or 2 in the
ruthenium complex of the general formula [2]. In the case where n is 1, a nitrogen
atom and a phosphorus atom are bonded to each other via two carbon atoms in the
ruthenium complex. In the case where n is 2, a nitrogen atom and a phosphorus
atom are bonded to each other via three carbon atoms in the ruthenium complex. It
is preferable that each of both two n is 2.
[0032.] In the ruthenium complex of the general formula [4], Ph represent a
phenyl group.
[0033.] The ruthenium complex of the general formula [4] is one preferred
example of the ruthenium complex of the general formula [2]. As the ruthenium
complex of the general formula [4], there can be used a commercially available
product "Ru-MACHO™" (manufactured by Takasago International Corporation).
[0034.] It is feasible to prepare the ruthenium complex of the general formula [2]
in a similar manner to that for preparation of Ru-MACHO™. Water or an organic
solvent such as toluene may be contained in the ruthenium complex. It suffices
that the purity of the ruthenium complex is 70% or higher. The purity of the
ruthenium complex is preferably 80% or higher, more preferably 90% or higher.
[0035.] It suffices to use the ruthenium complex of the general formula [2] in an
amount of 0.000001 mol or more per 1 mol of the α-fluoroester of the general
formula [1]. The amount of the ruthenium complex of the general formula [2] used
is preferably 0.00001 to 0.005 mol, more preferably 0.00002 to 0.002 mol, per 1 mol
of the α-fluoroester of the general formula [1],
[0036.] Examples of the base usable in the reaction are: alkali metal
hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate
and potassium hydrogencarbonate; alkali metal carbonates such as lithium carbonate,
sodium carbonate and potassium carbonate; alkali metal hydroxides such as lithium
hydroxide, sodium hydroxide and potassium hydroxide; tetraalkyl ammonium
hydroxides such as tetramethyl ammonium hydroxide, tetraethyl ammonium
hydroxide, tetra-n-propyl ammonium hydroxide and tetra-butyl ammonium

hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide,
potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide,
lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium
tert-butoxide, sodium tert-butoxide and potassium tert-butoxide; organic bases such
as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and
l,8-diazabicyclo[5.4.0]undec-7-ene; alkali metal bis(trialkylsilyl)amides such as
lithium bis(trialkylsilyl)amide, sodium bis(trialkylsilyl)amide and potassium
bis(trialkylsilyl)amide; and alkali metal borohydrides such as lithium borohydride,
sodium borohydride and potassium borohydrode. Among others, alkali metal
alkoxides are preferred. Particularly preferred are lithium methoxide, sodium
methoxide and potassium methoxide.
[0037.] It suffices to use the base in an amount of 0.001 mol or more per 1 mol of
the α-fluoroester of the general formula [1]. The amount of the base used is
preferably 0.005 to 5 mol, more preferably 0.01 to 3 mol, per 1 mol of the
α-fluoroester of the general formula [1].
[0038.] As it is assumed that the true catalytic active species is derived from the
ruthenium catalyst of the general formula [2] optionally in the presence of the base,
the case where the catalytic active species (including isolated form) is prepared in
advance and used in the reduction reaction is included in the scope of the present
invention.
[0039.] It suffices to use the hydrogen gas in an amount of 2 mol or more per 1
mol of the α-fluoroester of the general formula [1]. The hydrogen gas is preferably
used in a large excessive amount, more preferably in a large excessive amount under
the following pressurized conditions.
[0040.] There is no particular limitation on the hydrogen pressure. The
hydrogen pressure is preferably 3 to 0.001 MPa, more preferably 2 to 0.01 MPa. It
is particularly preferred that the hydrogen pressure is 1 MPa or lower in order to
maximize the effects of the present invention.
[0041.] Examples of the reaction solvent usable in the reaction are: aliphatic
hydrocarbon solvents such as n-hexane and n-heptane; aromatic hydrocarbon
solvents such as toluene and xylene; halogenated solvents such as methylene

chloride and 1,2-dichloroethane; ether solvents such as diethyl ether,
1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran,
tert-butyl methyl ether, diisopropyl ether, diethylene glycol dimethyl ether and
anisole; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, tert-butanol, n-pentanol, n-hexanol and cyclohexanol; amide solvents
such as N,N-dimethylformamide and l,3-dimethyl-2-imidazolidinone; nitrile
solvents such as acetonitrile and propionitrile; and dimethyl sulfoxide. Among
others, ether solvents and alcohol solvents are preferred. Alcohol solvents are
more preferred as the reaction solvent. These reaction solvents can be used solely
or in combination of two or more thereof. It is particularly preferable to use
methanol, which is easy to separate by fractional distillation, for production of the
β-fluoroalcohol of the general formula [8] as the preferred target compound.
[0042.] It suffices to use the reaction solvent in an amount of 0.01 L (liter) or
more per 1 mol of the α-fluoroester of the general formula [1]. The amount of the
reaction solvent used is preferably 0.03 to 10 L, more preferably 0.05 to 7 L, per 1
mol of the α-fluoroester of the general formula [1]. The reaction can alternatively
be performed under neat conditions without the use of the reaction solvent.
[0043.] It suffices that the reaction temperature is +150°C or lower. The
reaction temperature is preferably +125 to -50°C, more preferably +100 to -25°C.
[0044.] Further, it suffices that the reaction time is 72 hours or less. As the
reaction time varies depending on the raw substrate material and reaction conditions,
it is preferable to determine the time at which there is seen almost no decrease of the
raw substrate material as the end of the reaction while monitoring the progress of the
reaction by any analytical means such as gas chromatography, liquid
chromatography or nuclear magnetic resonance.
[0045.] The β-fluoroalcohol of the general formula [3] can be obtained by any
ordinary post treatment operation for organic synthesis. In the case where R1
and/or R is alkoxycarbonyl or substituted alkoxycarbonyl in the α-fluoroester of the
general formula [1], the reaction product may be in the form of a diol or triol (see
Example 11). This reaction is also included in the scope of the present invention.
Further, the crude product can be purified to a high purity, as needed, by activated

carbon treatment, fractional distillation, recrystallization, column chromatography or
the like. It is convenient to directly subject the reaction completed solution to
distillation recovery operation in the case where the target compound has a low
boiling point. In the case where the reaction is performed in the presence of the
base, the target compound of relatively high acidity tends to form a salt or complex
with the base used and remain in the distillation residue during distillation recovery
operation. In such a case, the target compound can be obtained with high yield by
neutralizing the reaction completed solution with an organic acid such as formic acid,
acetic acid, citric acid, oxalic acid, benzoic acid, methanesulfonic acid or
paratoluenesulfonic acid or an inorganic acid such as hydrogen chloride, hydrogen
bromide, nitric acid or sulfuric acid in advance, and then, subjecting the neutralized
reaction completed solution to distillation recovery operation (including recovery by
washing the distillation residue with an organic solvent such as diisopropyl ether).
Examples
[0046.] The present invention will be described in more detail below by way of
the following examples. It should be noted that the following examples are
illustrative and are not intended to limit the present invention thereto. In the
present invention, α-fluoroesters can be produced as the raw substrate material in
similar manners with reference to publicly known disclosures. (As a matter of
course, it is feasible to use commercially available α-fluoroesters as the raw
substrate material.) In particular, the raw substrate materials of the following
Examples 7 and 8 can be produced with high yield by ordinary organic synthesis
processes. For example, it is convenient to produce the α-fluoroester by the
following steps: 1) Reformatsky reaction of bromodifiuoroacetic acid ethyl ester and
propionaldehyde or acetoaldehyde; 2) conversion of a hydroxyl group (-OH) to a
trifluoromethanesulfonyl group (-OSO2CF3); and 3) elimination of a
trifluoromethanesulfonic acid by a strong base. (The raw substrate material of the
following Example 13 is the reaction product of the above step 1.) In the following
description, the abbreviations "Me", "Ph", and "Et" refer to methyl, phenyl and
ethyl, respectively.

[0047.] [Example 1]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 4.4 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 5.2 mg (purity:
94.2%; 8.0 μmol, 0.0002 eq) of ruthenium complex of the following formula, 540
mg (10 mmol, 0.25 eq) of sodium methoxide and 40 mL (1.0 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 40°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
each 100%.

The reaction completed solution was directly subjected to distillation so that the
target compound was recovered in the form of a methanol solution thereof. It was
confirmed by 19F-NMR quantitative analysis of the methanol solution according to
internal standard method (internal standard material: α,α,α-trifluorotoluene) that 3.0
g of the target compound was contained. The yield of the target compound was
thus 91%. For reference purposes, the reaction procedure and reaction results of
the present example are indicated in the following scheme.


[0048.] [Example 2]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 53 g (480 mmol, 1 eq) of ct-fluoroester of the following formula, 15 mg (purity:
94.2%; 24 μmol, 0.00005 eq) of ruthenium complex of the following formula, 8.4 g
(120 mmol, 0.25 eq) of potassium methoxide and 240 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 40°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
100% and 97.6%, respectively.

For reference purposes, the reaction procedure and reaction results of the present
example are indicated in the following scheme.


The above reaction operation was repeated five times to obtain the reaction
completed solution equivalent to 2.4 mol of α-fluoroester. The reaction completed
solution was admixed with 36 g (600 mmol, 0.25 eq) of acetic acid. The admixed
solution was directly subjected to distillation (oil bath temperature: 55°C, vacuum
degree: ~1.5 kPa) so that the target compound was recovered in the form of a
methanol solution thereof. The distillation residue (i.e. the solid matter containing
the target compound and potassium acetate) was washed by stirring with 200 mL of
diisopropyl ether and filtered out. The resulting solid matter was further washed
with 200 mL of diisopropyl ether. The target compound was thus recovered in the
form of a diisopropyl ether solution thereof. The above recovered solutions were
combined and subjected to distillation separation (theoretical plate number: 20,
distillation temperature: 92°C, atmospheric pressure), thereby yielding 158 g of
β-fluoroalcohol of the above formula. The yield of β-fluoroalcohol was 80%.
The gas chromatographic purity of β-fluoroalcohol was 99.6%. The water content
of β-fluoroalcohol was 0.05%.
[0049.] [Example 3]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 4.2 g (40 mmol, 1 eq, optical purity 98.4%ee) of α-fluoroester of the following
formula, 5.2 mg (purity: 94.2%; 8.0 μmol, 0.0002 eq) of ruthenium complex of the
following formula, 700 mg (10 mmol, 0.25 eq) of potassium methoxide and 20 mL
(0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred for 9 hours at 36°C. It was
confirmed by gas chromatographic analysis of the reaction completed solution that
the conversion rate and the selectivity of β-fluoroalcohol of the following formula
were 100% and 90.4%, respectively. Further, the optical purity of β-fluoroalcohol
was 66.2%ee.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0050.] [Example 4]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 5.0 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 10 mg (purity:
94.2%; 16 μmol, 0.0004 eq) of ruthenium complex of the following formula, 700
mg (10 mmol, 0.25 eq) of potassium methoxide and 20 mL (0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 37°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
92% and 98.9%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0051.] [Example 5]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 4.8 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 13 mg (purity:
94.2%; 20 μmol, 0.0005 eq) of ruthenium complex of the following formula, 540
mg (10 mmol, 0.25 eq) of sodium methoxide and 20 mL (0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
98% and 84.2%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0052.] [Example 6]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 4.0 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 4.3 mg (purity:
94.2%; 6.7 μmol, 0.0003 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.25 eq) of sodium methoxide and 10 mL (0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 40°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
100% and 98.2%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0053.] [Example 7]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 74 g (450 mmol, 1 eq) of α-fluoroester (E-configuration:Z-configuration =
95:5) of the following formula, 120 mg (purity: 94.2%; 180 μmol, 0.0004 eq) of
ruthenium complex of the following formula, 6.1 g (110 mmol, 0.25 eq) of sodium

methoxide and 230 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol
(E-configuration:Z-configuration = 95:5) of the following formula were 100% and
99.3%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

The above reaction operation was repeated twice to obtain the reaction completed
solution equivalent to 490 mmol of α-fiuoroester. The reaction completed solution
was admixed with 7.4 g (120 mmol, 0.25 eq) of acetic acid. The admixed solution

was directly subjected to distillation (oil bath temperature: ~63°C, vacuum degree:
~1.6 kPa) so that the target compound was recovered in the form of a methanol
solution thereof. The distillation residue (i.e. the solid matter containing the target
compound and sodium acetate) was washed by stirring with 240 mL of diisopropyl
ether and filtered out. The resulting solid matter was further washed with a small
amount of diisopropyl ether. The target compound was thus recovered in the form
of a diisopropyl ether solution thereof. The above recovered solutions were
combined and subjected to distillation separation (theoretical plate number: 4,
distillation temperature: 60°C, 3.0 to 2.6 kPa), thereby yielding 46 g of
β-fluoroalcohol of the above formula. The yield of β-fluoroalcohol was 77%.
The gas chromatographic purity of β-fluoroalcohol was 99.6%. The 1H- and
19F-NMR measurement results of β-fluoroalcohol are indicated below.
[E-configuration]
1H-NMR (reference material: Me4Si, deuterated solvent: CDC13) δ ppm; 1.80 (m,
3H), 3.72 (m, 2H), 5.63 (m, 1H), 6.19 (m, 1H). The proton of OH group was
unidentified.
19F-NMR (reference material: C6F6, deuterated solvent: CDCl3) δ ppm; 55.96 (m,
2F).
[Z-configuration]
1H-NMR (reference material: Me4Si, deuterated solvent: CDCl3) δ ppm; 1.86 (m,
3H), 3.72 (m, 2H), 5.51 (m, 1H), 5.96 (m, 1H). The proton of OH group was
unidentified.
19F-NMR (reference material: C6F6, deuterated solvent: CDCl3) δ ppm; 59.57 (m,
2F).
[0054.] [Example 8]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 38 g (250 mmol, 1 eq) of α-fluoroester of the following formula, 64 mg (purity:
94.2%; 100 μmol, 0.0004 eq) of ruthenium complex of the following formula, 3.4 g
(63 mmol, 0.25 eq) of sodium methoxide and 250 mL (0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed
by 19F-NMR analysis of the reaction completed solution that the conversion rate and
the selectivity of β-fluoroalcohol of the following formula were 100% and 98.0%,
respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

The above reaction operation was repeated twice to obtain the reaction completed
solution equivalent to 470 mmol of α-fluoroester. The reaction completed solution
was admixed with 7.1 g (120 mmol, 0.25 eq) of acetic acid and an appropriate
amount of methoquinone (polymerization inhibitor). The admixed solution was
directly subjected to distillation (oil bath temperature: ~63°C, vacuum degree: -7.9
kPa) so that the target compound was recovered in the form of a methanol solution

thereof. The distillation residue (i.e. the solid matter containing the target
compound and sodium acetate) was washed by stirring with 400 mL of diisopropyl
ether and filtered out. The resulting solid matter was further washed with a small
amount of diisopropyl ether. The target compound was thus recovered in the form
of a diisopropyl ether solution thereof. The above recovered solutions were
combined and subjected to distillation separation (theoretical plate number: 4,
distillation temperature: 57 to 62°C, 13 to 12 kPa), thereby yielding 40 g of
β-fluoroalcohol of the above formula. The yield of β-fluoroalcohol was 78%.
The gas chromatographic purity of β-fluoroalcohol was 98.9%. The lH- and
19F-NMR measurement results of β-fluoroalcohol are indicated below.
1H-NMR (reference material: Me4Si, deuterated solvent: CDCl3) δ ppm; 2.21 (br,
1H), 3.81 (t, 2H), 5.55 (d, 1H), 5.74 (m, 1H), 5.97 (m, 1H).
19F-NMR (reference material: C6F6, deuterated solvent: CD3OD) δ ppm; 55.44 (m,
2F).
[0055.] [Example 9]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 6.0 g (30 mmol, 1 eq) of α-fluoroester of the following formula, 6.5 mg (purity:
94.2%; 10 μmol, 0.0003 eq) of ruthenium complex of the following formula, 406
mg (7.5 mmol, 0.25 eq) of sodium methoxide and 15 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were

100% and 98.2%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0056.] [Example 10]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 6.4 g (30 mmol, 1 eq) of α-fiuoroester of the following formula, 6.5 mg (purity:
94.2%; 10 μmol, 0.0003 eq) of ruthenium complex of the following formula, 406
mg (7.5 mmol, 0.25 eq) of sodium methoxide and 15 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the

conversion rate and the selectivity of p-fiuoroalcohol of the following formula were
98.0% and 98.0%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

The 1H- and 19F-NMR measurement results of β-fluoroalcohol are indicated below.
1H-NMR (reference material: Me4Si, deuterated solvent: CDCl3) δ ppm; 1.90 (br,
1H), 2.52 (t, 3H), 4.06 (t, 2H), 7.29 (m, 2H), 7.39 (dd, 1H) 7.54 (d, 1H).
19F-NMR (reference material: C6F6, deuterated solvent: CDCl3) δ ppm; 57.04 (t, 2F).
[0057.] [Example 11]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 3.6 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 4.3 mg (purity:
94.2%; 6.7 μmol, 0.0003 eq) of ruthenium complex of the following formula, 162
mg (3.0 mmol, 0.15 eq) of sodium methoxide and 20 mL (1.0 L/mol) of methanol.



The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
99.6% and 74.2%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0058.] [Example 12]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 77 mg (purity: 94.2%; 0.12 mmol, 0.0003 eq) of ruthenium complex of the
following formula, 1.6 g (30 mmol, 0.06 eq) of sodium methoxide and 240 mL (0.5
L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. Into the
resulting solution inside the reaction vessel, a mixed solution of 51 g (480 mmol, 1
eq, optical purity: 97.3%ee) of α-fluoroester of the following formula in 240 mL
(0.5 L/mol) of methanol was dropped over 14 hours at 36°C.

This solution was stirred for 11 hours at the same temperature as above. It was
confirmed by gas chromatographic analysis of the reaction completed solution that
the conversion rate and the selectivity of β-fluoroalcohol of the following formula
were 98.5% and 98.8%, respectively. Further, the optical purity of β-fluoroalcohol
was 95.0%ee.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.


[0059.] [Example 13]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 3.6 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 6.5 mg (purity:
94.2%; 10 μmol, 0.0005 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.25 eq) of sodium methoxide and 10 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 2.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
100% and 99.6%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.


[0060.] [Comparative Example 1]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 5.0 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 30 mg (40
μmol, 0.001 eq) of ruthenium complex of the following formula, 1.1 g (9.8 mmol,
0.25 eq) of potassium tert-butoxide and 20 mL (0.5 L/mol) of tetrahydrofuran.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 3.8 MPa. The resulting
solution inside the reaction vessel was stirred all night at 100°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the
conversion rate and the selectivity of β-fluoroalcohol of the following formula were
100% and 93.8%, respectively.

It was impossible to obtain the same level results as those of Example 1 (conversion

rate: 100%, target compound selectivity: 100%) even by changing the ester moiety
of α-fluoroester to methyl ester, changing the base to sodium methoxide, changing
the reaction solvent to methanol, using double the amount of methanol, setting the
reaction temperature to 40°C or any combination thereof in Comparative Example 1.
For reference purposes, the reaction procedure and reaction results of the present
comparative example are indicated in the following scheme.

[0061.] [Comparative Example 2]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 3.0 g (40 mmol, 1 eq) of methyl acetate of the following formula, 5.2 mg
(purity: 94.2%, 8.0 μmol, 0.0002 eq) of ruthenium complex of the following formula,
700 mg (10 mmol, 0.25 eq) of potassium methoxide and 20 mL (0.5 L/mol) of
methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed
by gas chromatographic analysis of the reaction completed solution that the

conversion rate and the selectivity of β-fluoroalcohol of the following formula were
18% and 94.4%, respectively.

The reaction procedure and reaction results of the present comparative example are
indicated in the following scheme for reference purposes.

Industrial Applicability
[0062.] The β-fluoroalcohols produced by the production method according to
the present invention are usable as intermediates for pharmaceutical and
agrichemical products.

WE CLAIM:
1. A method for producing a p-fiuoroalcohol of the general formula [3],
comprising: performing a reaction of an α-fluoroester of the general formula [1]
with hydrogen gas (H2) in the presence of a ruthenium complex of the general
formula [2]

where R1 and R2 each independently represent a hydrogen atom, a halogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic
ring group, an alkoxycarbonyl group or a substituted alkoxycarbonyl group; and R
represents an alkyl group or a substituted alkyl group

where R each independently represent a hydrogen atom, an alkyl group, a
substituted alkyl group, an aromatic ring group or a substituted aromatic ring group;
Ar each independently represent an aromatic ring group or a substituted aromatic
ring group; X each independently represent a ligand having a formal charge of-1 or
0 (with the proviso that the sum of formal charges of three X is -2); and n each
independently represent an integer of 1 or 2

where R1 and R2 have the same definitions as in the general formula [1].
2. The method as claimed in claim 1, wherein the reaction is performed in
the presence of a base.

3. A method for producing a β-fluoroalcohol of the general formula [3],
comprising: performing a reaction of an α-fluoroester of the general formula [1]
with hydrogen gas (H2) in the presence of a ruthenium complex of the general
formula [4] and a base

where R1 and R2 each independently represent a hydrogen atom, a halogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic
ring group, an alkoxycarbonyl group or a substituted alkoxycarbonyl group; and R
represents an alkyl group or a substituted alkyl group

where Ph represent a phenyl group

where R1 and R2 have the same definitions as in the general formula [1].
4. The method as claimed in any one of claims 1 to 3, wherein the
α-fluoroester of the general formula [1] is an α-fluoroester of the general formula
[5]; and wherein the μ-fluoroalcohol of the general formula [3] is a β-fluoroalcohol
of the general formula [6]

where R4 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an
aromatic ring group or a substituted aromatic ring group; and R5 represents an alkyl

group

where R4 has the same definition as in the general formula [5].
5. The method as claimed in any one of claims 1 to 3, wherein the
α-fluoroester of the general formula [1] is an α-fluoroester of the general formula
[7]; and wherein the β-fiuoroalcohol of the general formula [3] is a β-fiuoroalcohol
of the general formula [8]

where Me represents a methyl group

6. The method as claimed in any one of claims 1 to 5, wherein the reaction
is performed at a hydrogen pressure of 3 MPa or lower.
7. The method as claimed in any one of claims 1 to 5, wherein the reaction
is performed at a hydrogen pressure of 2 MPa or lower.
8. The method as claimed in any one of claims 1 to 5, wherein the reaction
is performed at a hydrogen pressure of 1 MPa or lower.