TECHNICAL FIELD
[0001] The present invention relates to a method for producing fluoroamines.
BACKGROUND OF THE INVENTION
[0002] The applicant of the present patent application has disclosed a
dehydroxyfluorination reaction of an alcohol by a combination of sulfuryl fluoride
(SO2F2) and an organic base (according to need, it is conducted in the presence of a
salt or complex comprising an organic base and hydrogen fluoride) (Patent Publication
1). Furthermore, the applicant has also disclosed a method for producing an optically
active fluoroamine using this technique (Patent Publication 2).
[0003] In a dehydroxyfluorination reaction of an amino alcohol by a combination of
sulfuryl fluoride and an organic base, the selection of a protecting group of the amino
group is important. If nucleophilicity remains in the amino group protected by a
protecting group, there is caused a side reaction, such as 1,2-rearrangement due to the
involvement of an adjacent group (Japanese Patent Application Publication 2009-
286779), an intermolecular nucleophilic attack against a fluorosulfuric acid ester as an
intermediate, etc. Patent Publications 1 and 2 disclose phthaloyl group and
benzylidene group as protecting groups of amino groups. These protecting groups,
however, can be applied only to primary amines and cannot be applied to secondary
amines.
PRIOR ART PUBLICATIONS
PATENT PUBLICATIONS
[0004] Patent Publication 1: Japanese Patent Application Publication 2006-290870
Patent Publication 2: Japanese Patent Application Publication 2009-227596
SUMMARY OF THE INVENTION
[0005] Under such condition, there is a demand for a preferable amino group's
protecting group, which hardly causes side reactions in a dehydroxyfluorination
reaction of an amino alcohol by a combination of sulfuryl fluoride and an organic base.

[0006] The present inventors have examined the above dehydroxyfluorination reaction
with respect to amino alcohols protected with typical amino group's protecting groups
[benzyl (Bn) group, tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group,
and acetyl (Ac) group], but the target reaction did almost not proceed (see Comparative
Examples 1-4). In amino groups protected with Boc group, Cbz group and Ac group,
their nucleophilicity is considered to be sufficiently suppressed, but only this
advantageous effect could not make them become preferable amino group's protecting
groups in a dehydroxyfluorination reaction.
[0007] On the other hand, in amino alcohols protected with methanesulfonyl group,
benzenesulfonyl group and paratolunesulfonyl group, it was found that desired
dehydroxyfluorination reactions proceeded well. It was, however, not possible to
achieve deprotection of these protecting groups without side reactions. Therefore, it
was not possible to complete the invention from the viewpoint of a method for
producing fluoroamines.
[0008] Under such condition, as a result of an eager study, the present inventors have
found a useful method for producing fluoroamines and have reached the present
invention.
[0009] That is, the present invention includes [Invention 1] to [Invention 12] and
provides a method for producing fluoroamines.
[0010] [Invention 1]
A method for producing a protected fluoroamine represented by the general
formula [2]:

[in the formula, R represents an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group, each of R2 independently represents a
hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a

substituted aromatic ring group, m represents an integer of 2, 3 or 4, n represents an
integer of 4, 6 or 8, and P1 represents an ortho-, meta- or para-nitrobenzenesulfonyl
group.]
comprising a dehydroxyfluorination step of reacting a protected amino alcohol
represented by the general formula [1]:

[in the formula, R1, R2, m, n and P1 are the same as those of the above formula [2].]
with sulfuryl fluoride (SO2F2) in the presence of an organic base.
[0011] [Invention 2]
The method of Invention 1, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
[0012] [Inventions]
A method for producing a fluoroamine represented by the general formula [4]:

[in the formula, R1 represents an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group, each of R independently represents a
hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a
substituted aromatic ring group, m represents an integer of 2, 3 or 4, and n represents
an integer of 4, 6 or 8.]
comprising an amino group protecting step of converting an amino alcohol
represented by the general formula [3]:


[in the formula, R1, R2, m and n are the same as those of the formula [4].]
to a protected amino alcohol represented by the general formula [1]:

[in the formula, R1, R2, m and n are the same as those of the formula [4]. P1 represents
an ortho-, meta- or para-nitrobenzenesulfonyl group.]
by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [2]:

[in the formula, R , R", m, n and P are the same as those of the general formula [1].]
by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the presence
of an organic base, and
a deprotection step of deprotecting a protecting group of an amino group of the
protected fluoroamine.
[0013] [Invention 4]
The method of Invention 3, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
[0014] [lnvention5]
A method for producing a protected fluoroamine represented by the general
formula [6]:


[in the formula, R"' represents an alkyl group or a substituted alkyl group, each of R
independently represents a hydrogen atom, an alkyl group or a substituted alkyl group,
x represents an integer of 2 or 3, y represents an integer of 4 or 6, and P represents an
ortho- or para-nitrobenzenesulfonyl group.]
comprising a dehydroxyfluorination step of reacting a protected amino alcohol
represented by the general formula [5]:

[in the formula, R3, R4, x, y and P" are the same as those of the formula [6].]
with sulfuryl fluoride (SO2F2) in the presence of an organic base.
[0015] [Invention 6]
The method of Invention 5, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of an organic base and
hydrogen fluoride.
[0016] [Invention?]
A method for producing a fluoroamine represented by the general formula [8]:

[in the formula, R3 represents an alkyl group or a substituted alkyl group, each of R4
independently represents a hydrogen atom, an alkyl group or a substituted alkyl group,
x represents an integer of 2 or 3, and y represents an integer of 4 or 6.]
comprising an amino group protecting step of converting an amino alcohol
represented by the general formula [7]:


[in the formula, R3, R4, x and y are the same as those of the above general formula [8].]
to a protected amino alcohol represented by the general formula [5]:

[in the formula, R3, R4, x and y are the same as those of the general formula [8]. P
represents an ortho- or para-nitrobenzenesulfonyl group.]
by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [6]:

[in the formula, R3, R4, x, y and P2 are the same as those of the above formula [5].]
by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the presence
of an organic base, and
a deprotection step of deprotecting a protecting group of an amino group of the
protected fluoroamine.
[0017] [Invention8]
The method of Invention 7, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
[0018] [Invention9]
A method for producing a protected fluoroamine represented by the general
formula [10]:


[in the formula, Me represents a methyl group]
comprising a dehydroxyfluorination step of reacting a protected amino alcohol
represented by the general formula [9]:

with sulfuryl fluoride (SO2F2) in the presence of an organic base.
[0019] [Invention 10]
The method of Invention 9, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
[0020] [Invention 11]
A method for producing a fluoroamine represented by the general formula [12]:

I in the formula, Me represents a methyl group]
comprising an amino group protecting step of converting an amino alcohol represented
by the general formula [11]:

to a protected amino alcohol represented by the general formula [9]:


by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [10]:

by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the presence
of an organic base, and
a deprotection step of deprotecting a protecting group of an amino group of the
protected fluoroamine.
[0021] [Invention 12]
The method of Invention 11, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
ADVANTAGEOUS EFFECT OF THE INVENTION
[0022] According to a preferred mode of the present invention, it is possible to
provide a preferable amino group's protecting group, which hardly causes side
reactions in a dehydroxyfluorination reaction of an amino alcohol by a combination of
sulfuryl fluoride and an organic base. Furthermore, according to a preferred mode of
the present invention, although an amino group and a hydroxyl group exist together in
the amino alcohol as the raw material substrate, it is possible to selectively protect only
the amino group in the amino group protecting step. Furthermore, according to a
preferred mode of the present invention, it is possible in the deprotection step to

achieve deprotection without side reactions by mild reaction conditions. Finally,
according to a preferred mode of the present invention, it is possible to obtain the
fluoroamine with a high purity and a good yield.
DETAILED EXPLANATION
[0023] A method for producing a fluoroamine of the present invention is explained in
detail.
[0024] A preferable method for producing a fluoroamine of the present invention
comprises three steps of an amino group protecting step of protecting an amino group
of an amino alcohol represented by the general formula [3] with a nitrobenzenesulfonyl
group, a dehydroxyfluorination step of reacting a protected amino alcohol represented
by the general formula [1] with sulfuryl fluoride in the presence of an organic base,
and a deprotection step of deprotecting a protecting group of an amino group of a
protected fluoroamine represented by the general formula [2].
[0025] 1. Amino group protecting step
Firstly, the amino group protecting step is specifically explained.
[0026] R1 of an amino alcohol represented by the general formula [3] represents an
alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic
ring group. The alkyl group is of C1-18 straight-chain or branched chain or cyclic (in
case that the number of carbon atoms is at least three). The aromatic ring groups are
C1-18 aromatic hydrocarbon groups, such as phenyl group, naphthyl group and anthryl
group, or hetero atom (e.g., nitrogen atom, oxygen atom or sulfur atom) containing,
aromatic heterocyclic groups, such as pyrrolyl group (containing its nitrogen-
protecting groups), pyridyl group, furyl group, thienyl group, indolyl group (containing
its nitrogen-protecting groups), quinolyl group, benzofuryl group and benzothienyl
group. The substituted alkyl group and the substituted aromatic ring group have
substituents by an arbitrary number and an arbitrary combination on arbitrary carbon
atoms or nitrogen atoms of their alkyl group and aromatic ring group. Such
substituents are halogen atoms such as fluorine, chlorine and bromine, lower alkyl
groups such as methyl group, ethyl group and propyl group, lower haloalkyl groups
such as fluoromethyl group, chloromethyl group and bromomethyl group, lower

alkoxy groups such as methoxy group, ethoxy group and propoxy group, lower
haloalkoxy groups such as fluoromethoxy group, chloromethoxy group and
bromomethoxy group, cyano group, lower alkoxycarbonyl groups such as
methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, aromatic
ring groups such as phenyl group, naphthyl group, anthryl group, pyrrolyl group
(containing its nitrogen-protecting groups), pyridyl group, furyl group, thienyl group,
indolyl group (containing its nitrogen-protecting groups), quinolyl group, benzofuryl
group and benzothienyl group, carboxyl-protecting groups, amino-protecting groups,
hydroxyl-protecting groups, etc. In the present specification, "lower" means one being
C1-6, straight-chain or branched chain or cyclic (in the case of having at least three
carbon atoms). The aromatic ring groups of the above-mentioned "such substituents"
can also be replaced with halogen atoms, lower alkyl groups, lower haloalkyl groups,
lower alkoxy groups, lower haloalkoxy groups, cyano group, lower alkoxycarbonyl
groups, carboxyl-protecting groups, amino-protecting groups, hydroxyl-protecting
groups, etc. Furthermore, the protective groups of the pyrrolyl group, the indolyl
group, the carboxyl group, the amino group, and the hydroxyl group are protective
groups described in Protective Groups in Organic Synthesis, Third Edition, 1999, John
Wiley & Sons, Inc., etc. Of these, alkyl groups and substituted alkyl groups are
preferable, and methyl group is particularly preferable.
[0027] Each of R2 of an amino alcohol represented by the general formula [3]
independently represents a hydrogen atom, an alkyl group, a substituted alkyl group,
an aromatic ring group or a substituted aromatic ring group. The alkyl group, the
substituted alkyl group, the aromatic ring group and the substituted aromatic ring
group are the same as the alkyl group, the substituted alkyl group, the aromatic ring
group and the substituted aromatic ring group, which are mentioned in R1 of an amino
alcohol represented by the general formula [3]. In case that the carbon with R2
substituted therefor is an asymmetric carbon, it can take an arbitrary stereochemistry
(R form, S form or racemate). Furthermore, in case that a plurality of asymmetric
carbons exist, it can take an arbitrary stereochemical combination (for example, in case
that two asymmetric carbons exist, R,R form, R,S form, S,R form, S,S form or an
arbitrary diastereomeric mixture of these). Furthermore, two of R" of an amino alcohol

represented by the general formula [3] can directly take a ring structure by a covalent
bond with arbitrary carbon atoms together or with an interposal of a nitrogen atom [a
protected amino group is also included, the protective group is not limited to
nitrobenzenesulfonyl group, and it can take protective groups mentioned in the above-
mentioned book about protective groups], an oxygen atom, or a sulfur atom. Such ring
structures are also contained in the claims. Of these, hydrogen atoms, alkyl groups and
substituted alkyl groups are preferable, and hydrogen atoms are particularly preferable.
[0028] In an amino alcohol represented by the general formula [3], m represents an
integer of 2, 3 or 4. Of these, integers of 2 and 3 are preferable, and an integer of 2 is
particularly preferable.
[0029] In an amino alcohol represented by the general formula [3], n represents an
integer of 4, 6 or 8. Of these, integers of 4 and 6 are preferable, and an integer of 4 is
particularly preferable. The relationship between integers m and n is that, when m is
an integer of 2, n takes an integer of 4; when m is an integer of 3, n takes an integer of
6; and when m is an integer of 4, n takes an integer of 8.
[0030] Of amino alcohols represented by the general formula [3], amino alcohols
represented by the general formula [7] are preferable, and an amino alcohol
represented by the general formula [11] is particularly preferable. As to amino
alcohols represented by the general formula [7], most of them are on the market, and
they are easily available in a large scale. As to an amino alcohol represented by the
general formula [11], a fluoroamine represented by the general formula [12] obtainable
from this is important as intermediate of medicines and agricultural chemicals.
[0031] An amino alcohol represented by the general formula [3] can also be used in
the form of a salt prepared together with an inorganic acid, such as hydrogen chloride,
hydrogen bromide and sulfuric acid, or an organic acid, such as oxalic acid, phthalic
acid and p-toluenesulfuric acid.
[0032] The amino group protecting step can be conducted by using an ordinary
method [e.g., the above-mentioned book about protective groups, such as "Jikken
Kagaku Koza 5th Edition" edited by the Chemical Society of Japan (MARUZEN Co.,
Ltd.)] in organic syntheses. Specifically, it is possible to produce a protected amino

alcohol represented by the general formula [1] by reacting an amino alcohol
represented by the general formula [3] with a nitrobenzenesulfonyl halide represented
by the general formula [13]:

[in the formula, nitro group is substituted therefor at ortho, meta or para-position, and
X represents a halogen atom]
in the presence of a base.
[0033] R1, R2, m and n in the general formula [1] are the same as R1, R2, m and n in
the general formula [3]. P1 in the general formula [1] represents ortho-, meta- or para-
nitrobenzenesulfonyl group.
[0034] Nitro group of a nitrobenzenesulfonyl halide represented by the general
formula [13] is substituted therefor at ortho, meta or para position. Of these, ortho and
para positions are preferable, and ortho position is particularly preferable.
[0035] X of a nitrobenzenesulfonyl halide represented by the general formula [13]
represents a halogen atom. The halogen atom is the same as the halogen atom
mentioned in "such substituents" of R1 of an amino alcohol represented by the general
formula [3]. Of all, chlorine and bromine are preferable, and chlorine is particularly
preferable.
[0036] Of nitrobenzenesulfonyl halides represented by the general formula [13],
ortho- and para-nitrobenzenesulfonyl chlorides are preferable, and ortho-
nitrobenzenesulfonyl chloride is particularly preferable. Ortho- and para-
nitrobenzenesulfonyl chlorides are on the market and easily available. Ortho-
nitrobenzenesulfonyl chloride has a lower price and is preferable for the production in
a large scale.
[0037] As to the usage of the nitrobenzenesulfonyl halide represented by the general
formula [13], it suffices to use 0.7 mol or greater, preferably 0.8-5 mol, particularly

preferably 0.9-3 mol, relative to 1 mol of the amino alcohol represented by the general
formula [3].
[0038] The base refers to inorganic bases, such as lithium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, cesium hydrogencarbonate, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium
hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, and organic
bases, such as triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-
butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,5-
diazabicyclo[4.3.0]non-5-ene and l,8-diazabicyclo[5.4.0]undec-7-ene. Of these,
organic bases are preferable, and triethylamine, diisopropylethylamine, pyridine, 2,6-
lutidine, 2,4.6-collidine, 4-dimethylaminopyridine, and l,8-diazabicyclo[5.4.0]undec-
7-en'e are particularly preferable. These bases can be used singly or in combination.
[0039] As to usage of the base, it suffices to use 0.35 mol or greater, preferably 0.4-20
mol, particularly preferably 0.45-15 mol, relative to 1 mol of the amino alcohol
represented by the general formula [3]. In the case of using the amino alcohol
represented by the general formula [3] in the form of a salt prepared together with an
inorganic acid or an organic acid, it is added by taking into account usage of the base
necessary for neutralizing the acid, and it is convenient to continuously conduct
neutralization of the acid and protection of the amino group in the same reaction
system. The base used for neutralizing the acid is the same as the above-mentioned
salt.
[0040] The timing of adding the base is not particularly limited. In some cases, good
results are obtained by adding the amino alcohol represented by the general formula
[3] and the nitrobenzenesulfonyl halide represented by the general formula [13] and
finally adding the base.
[0041] The reaction solvent is selected from aliphatic hydrocarbon series such as n-
hexane and n-heptane, aromatic hydrocarbon series such as toluene and xylene,
halogen series such as methylene chloride and 1,2-dichloroethane, ether series such as
tetrahydrofuran and tert-butyl methyl ether, ester series such as ethyl acetate and n-
butyl acetate, amide series such as N,N-dimethylformamide, l-methyl-2-pyrrolidinone,

N,N-dimethylacetamide and l,3-dimethyl-2-imidazolidinone, nitrile series such as
acetonitrile and propionitrile, dimethylsulfoxide, water, etc. Of these, n-heptane,
toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
acetonitrile. dimethylsulfoxide, and water are preferable, and toluene, methylene
chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, acetonitrile and
water are particularly preferable. These reaction solvents can be used singly or in
combination. In the case of using it in a combination with water, it is also possible to
conduct the reaction in a two-phase system.
[0042] As to usage of the reaction solvent, it suffices to use 0.05 L (liter) or greater,
preferably 0.1-20 L, particularly preferably 0.15-10 L, relative to 1 mol of the amino
alcohol represented by the general formula [3]. It is also possible to conduct the
present reaction in a neat condition without using the reaction solvent.
[0043] As to the reaction temperature, it suffices to conduct that in a range of-80 to
+200 °C, preferably -60 to +150 °C, particularly preferably -40 to +100 °C.
[0044] As to the reaction time, it suffices to conduct that in a range of 24 hours or
shorter. It depends on the raw material substrate, the reaction agent and the reaction
conditions. Therefore, it is preferable to monitor the condition of the reaction progress
by analytical means such as gas chromatography, liquid chromatography, or nuclear
magnetic resonance and judge the time when the decrease of the raw material substrate
has become almost not found as being the end point.
[0045 J It is possible to obtain a protected amino alcohol represented by the general
formula [1] by using an ordinary operation in organic syntheses as the post treatment.
According to need, the crude product can be purified to have a higher purity by
activated carbon treatment, fractional distillation, recrystallization, column
chromatography, or the like. In particular, a salt of an amino alcohol represented by
the general formula [3] and an inorganic acid, and halide ions derived from the
nitrobenzenesulfonyl halide represented by the general formula [13] may cause
impurities as by-products (see Japanese Patent Application Publication 2010-163422).
In such case, washing with water of an organic layer containing the target product, a
short column, etc. are effective.

[0046] 2. Dehydroxyfluorination step
Next, the dehydroxyfluorination step is specifically explained.
[0047] In the dehydroxyfluorination step, it is possible to produce a protected
fluoroamine represented by the general formula [2] by reacting an amino alcohol
represented by the general formula [1] with sulfuryl fluoride in the presence of an
organic base.
[0048] R1, R2, m, n and P1 in the general formula [2] are the same as R1, R2, m, n and
P1 in the general formula [1].
[0049] As to usage of the sulfuryl fluoride, it suffices to use 0.7 mol or greater,
preferably 0.8-20 mol, particularly preferably 0.9-15 mol, relative to 1 mol of a
protected amino alcohol represented by the general formula [1].
[0050] The organic base is the same as the organic bases mentioned as the base of the
amino group protecting step. It is, however, not limited to these, and it is also possible
to use organic bases generally used in organic syntheses. In particular, triethylamine,
diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, and
l,8-diazabicyclo[5.4.0]undec-7-ene are preferable, and triethylamine,
diisopropylethylamine, tri-n-butylamine, pyridine, and l,8-diazabicyclo[5.4.0]undec-7-
ene are particularly preferable. These organic bases can be used singly or in
combination.
[0051] As to usage of the organic base, it suffices to use 0.7 mol or greater, preferably
0.8-20 mol, particularly preferably 0.9-15 mol, relative to 1 mol of the protected amino
alcohol represented by the general formula [1].
[0052] The organic base of the salt or complex comprising the organic base and
hydrogen fluoride is the same as the organic base mentioned in the
dehydroxyfluorination step. Preferable and particularly preferable organic bases are
the same as those. These organic bases of the salt or complex comprising an organic
base and hydrogen fluoride can be used singly or in combination.
[0053] It suffices that the molar ratio of the organic base of the salt or complex
comprising the organic base and hydrogen fluoride to hydrogen fluoride is used in a

range of from 100:1 to 1:100, preferably from 50:1 to 1:50, particularly preferably
from 25:1 to 1:25. It is convenient to use a complex comprising 1 mol of triethylamine
and 3 mol of hydrogen fluoride or a complex comprising ~30 % (-10 mol %) of
pyridine and ~70 % (~90 mol %) of hydrogen fluoride, which is on sale from Aldrich
(Catalogue of 2009-2010).
[0054] As to usage in the case of using a salt or complex comprising an organic base
and hydrogen fluoride, it suffices to use fluoride ions (F~) by 0.05 mol or greater,
preferably 0.07-30 mol, particularly preferably 0.09-15 mol, relative to 1 mol of the
protected amino alcohol represented by the general formula [1].
(0055] The reaction solvent is the same as the reaction solvent except water, which is
mentioned in the amino group protecting step. Preferable and particularly preferable
reaction solvents are also the same (naturally water is excluded). These reaction
solvents can be used singly or in combination.
[0056] As to usage of the reaction solvent, it suffices to use 0.05 L or greater,
preferably 0.1-20 L, particularly preferably 0.15-10 L, relative to 1 mol of the
protected amino alcohol represented by the general formula [1]. The present reaction
can also be conducted in a neat condition without using the reaction solvent.
[0057] As to the reaction temperature, it suffices to conduct that in a range of-50 to
+200 °C, preferably -40 to +150 °C, particularly preferably -30 to +100 °C.
[0058] As to the reaction time, it suffices to conduct that in a range of 48 hours or
shorter. It depends on the raw material substrate, the reaction agent and the reaction
conditions.. Therefore, it is preferable to monitor the condition of the reaction progress
by analytical means such as gas chromatography, liquid chromatography, or nuclear
magnetic resonance and judge the time when the decrease of the raw material substrate
has become almost not found as being the end point.
[0059] It is possible to obtain a protected fluoroamine represented by the general
formula [2] by using an ordinary operation in organic syntheses as the post treatment.
According to need, the crude product can be purified to have a higher purity by
activated carbon treatment, fractional distillation, recrystallization, column
chromatography, or the like. The dehydroxyfluorination reaction of the present step

progresses by a bimolecular nucleophilic substitution (SN2) reaction. Therefore, in
case that the raw material substrate is an optically active alcohol, the target product is
obtained as an optically active fluoride with an inverse stereochemistry. In particular,
in the case of an optically active secondary alcohol, the reaction progresses with a high
inversion rate.
[0060] 3. Deprotection step
At last, the deprotection step is specifically explained.
[0061] The deprotection step can be conducted by using an ordinary method (e.g., the
above-mentioned book about protective groups, such as "Jikken Kagaku Koza 5n
Edition" edited by the Chemical Society of Japan (MARUZEN Co., Ltd.)] in organic
syntheses. Specifically, it is possible to produce a fluoroamine represented by the
general formula [4] by reacting a protected fluoroamine represented by the general
formula [2] with a thiol represented by the general formula [14]:
R5-SH [14]
[in the formula, R3 represents an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group]
in the presence of a base.
[0062] R1, R2, m and n in the general formula [4] are the same as R1, R2, m and n in
the general formula [3].
[0063] R3 of a thiol represented by the general formula [14] represents an alkyl group,
a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group.
The alkyl group, the substituted alkyl group, the aromatic ring group and the
substituted aromatic ring group are the same as the alkyl group, the substituted alkyl
group, the aromatic ring group and the substituted aromatic ring group mentioned in R1
of an amino alcohol represented by the general formula [3]. Of these, an alkyl group
and an aromatic ring group are preferable, and phenyl group is particularly preferable.
Thiophenol has a high reactivity and is on the market as an industrial chemical.

[0064] As to usage of a thiol represented by the general formula [14], it suffices to use
0.7 mol or greater, preferably 0.8-20 mol, 0.9-15 mol, relative to 1 mol of a protected
fluoroamine represented by the general formula [2].
[0065] The base is the same as the base mentioned in the amino group protecting step.
Above all, inorganic bases are preferable, and lithium carbonate, sodium carbonate,
potassium carbonate and cesium carbonate are particularly preferable. These bases can
be used singly or in combination. In general organic syntheses, in the case of using a
nitrobenzenesulfonyl group as the protecting group of amino group, an organic base of
1,8-diazabicyclo[5.4.0]undec-7-ene is frequently used as the base of the deprotection.
In the deprotection step of the present invention, however, it is possible to select mild
reaction conditions by using an inorganic base. With this, it is possible to achieve the
deprotection with a good yield and no side reaction (a preferable mode of the present
invention).
[0066] As to usage of the base, it suffices to use 0.35 mol or greater, preferably 0.4-20
mol, particularly preferably 0.45-15 mol, relative to 1 mol of the protected fluoroamine
represented by the general formula [2].
[0067] The reaction solvent is the same as the reaction solvent mentioned in the amino
group protecting step. Above all, n-heptane, toluene, methylene chloride,
tetrahydrofuran, N,N-dimethylformamide, l-methyl-2-pyrrolidinone, N,N-
dimethylacetamide, l,3-dimethyl-2-imidazolidinone, acetonitrile, and
dimethylsulfoxide are preferable, and tetrahydrofuran, N,N-dimethylformamide, 1-
methyl-2-pyrrolidinone, N,N-dimethylacetamide, l,3-dimethyl-2-imidazolidinone,
acetonitrile, and dimethylsulfoxide are particularly preferable. These reaction solvents
can be used singly or in combination.
[0068] As to usage of the reaction solvent, it suffices to use 0.05 L or greater,
preferably 0.1-20 L, particularly preferably 0.15-10 L, relative to 1 mol of the
protected fluoroamine represented by the general formula [2]. It is also possible to
conduct the present reaction in a neat condition without using the reaction solvent.
[0069] As to the reaction temperature, it suffices to conduct that in a range of-50 to
+100 °C, preferably -40 to +90 °C, particularly preferably -30 to +80 °C.

[0070] As to the reaction time, it suffices to conduct that in a range of 36 hours or
shorter. It depends on the raw material substrate, the reaction agent and the reaction
conditions. Therefore, it is preferable to monitor the condition of the reaction progress
by analytical means such as gas chromatography, liquid chromatography, or nuclear
magnetic resonance and judge the time when the decrease of the raw material substrate
has become almost not found as being the end point.
[0071] It is possible to obtain a fluoroamine represented by the general formula [4] by
using an ordinary operation in organic syntheses as the post treatment. According to
need, the crude product can be purified to have a higher purity by activated carbon
treatment, fractional distillation, recrystallization, column chromatography, or the like.
In case that the target product has a low boiling point, it is convenient to conduct a
direct recovery distillation of the reaction-terminated liquid. Furthermore, the target
product can also be obtained in the form of a salt prepared together with an inorganic
acid, such as hydrogen chloride, hydrogen bromide, and sulfuric acid, or an organic
acid, such as oxalic acid, phthalic acid and p-toluenesulfonic acid.
[0072] [Examples]
Embodiments of the present invention are specifically explained by examples,
but the present invention is not limited to these examples. Comparative Examples 1-4
show the results in the case of using protecting groups of the amino group, which are
different from that of the present invention.
Example 1
[0073] To 30.0 raL (0.752 L/mol) of methylene chloride, 3.00 g (39.9 mmol, 1.00 eq)
of amino alcohol represented by the following formula:

and 29.0 g (287 mmol, 7.19 eq) of triethylamine were added for their dissolution,
followed by adding 8.89 g (40.1 mmol, 1.01 eq) of ortho-nitrobenzenesulfonyl chloride
at 0 °C and then stirring at room temperature for 1 hour. To the reaction-terminated

liquid, 40.0 mL of water was added, followed by extraction with 80.0 mL of ethyl
acetate. The recovered aqueous layer was re-extracted with 80.0 mL of ethyl acetate.
The recovered organic layers were combined, followed by drying with anhydrous
sodium sulfate, concentration under reduced pressure, vacuum drying, and purifying
by a column chromatography (silica gel/ethyl acetate : n-hexane = 2 : 1), thereby
obtaining 7.93 g of a protected amino alcohol (a purified product) represented by the
following formula.

Yield was 76 %. Gas chromatography purity was 95.8 %. 1H-NMR is shown as
follows.
[0074] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 1.97
(br, 1H), 3.00 (s, 3H), 3.42 (m, 2H), 3.80 (m, 2H), 7.84 (Ar, 4H).
[0075] A stainless steel (SUS), pressure-proof, reaction container was charged with
5.93 g (22.8 mmol, 1.00 eq) of the above-obtained protected amino alcohol, 23.0 mL
(1.01 L/mol) of acetonitrile, 4.95 g (38.3 mmol, 1.68 eq) of diisopropylethylamine, and
1.43 g (7.56 mmol, 0.332 eq) of diisopropylethylamine trihydrofluoride for their
dissolution, followed by immersion in a coolant bath of-78 °C, bubbling of 6.30 g
(61.7 mmol, 2.71 eq) of sulfuryl fluoride from a cylinder, and stirring at room
temperature for four hours. To the reaction-terminated liquid, a potassium carbonate
aqueous solution (prepared from 3.00 g (21.7 mmol, 0.952 eq) of potassium carbonate
and 30.0 mL of water) was added, followed by extraction with 60.0 mL of ethyl
acetate. The recovered organic layer was dried with anhydrous sodium sulfate,
followed by concentration under reduced pressure, vacuum drying, and purifying with
a short column (silica gel/ethyl acetate : n-hexane = 2 : 1), thereby obtaining 5.55 g of
a protected fluoroamine (a purified product) represented by the following formula.


Yield was 93 %. The purified product was in the form of crystals. Gas
chromatography purity was 98.0 %. 1H and 19F-NMR are shown in the following.
[0076] 'H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), 8 ppm; 3.03
(s, 311), 3.61 (m, 2H), 4.62 (m, 2H), 7.83 (Ar, 4H).
[0077] 19F-NMR (standard substance: C6F6, deuterated solvent: CDC13), 8 ppm;
-58.84 (m, IF).
[0078] To 20.0 mL (2.03 L/mol) of N,N-dimethylformamide, 2.58 g (9.84 mmol, 1.00
eq) of the above-obtained protected fluoroamine (a purified product) and 4.09 g (29.6
mmol/3.01 eq) of potassium carbonate were added, followed by adding 2.69 g (24.4
mmol, 2.48 eq) of thiophenol at 0 °C and stirring at the same temperature for 1 hour.
The reaction-terminated liquid was subjected to a direct recovery distillation, thereby
obtaining 987 mg of a fluoroamine (a crude product) represented by the following
formula.

From l9F-NMR analysis of the crude product, quantity was determined by an internal
standard method (internal standard substance: a,a,a-trifluorotoluene). With this, the
target product was contained by 622 mg. The remaining 365 mg was of N,N-
dimethylformamide. Yield was 82 %. Gas chromatography purity except N,N-
diinethylformamide was 94.2 %. 1H and l9F-NMR are shown in the following.
[0079] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDCl3), δ ppm; 2.48
(s, 3H), 2.87 (m, 2H), 4.54 (m, 2H), and no assignment of the amino proton.

[0080] 19F-NMR (standard substance: C6F6, deuterated solvent: CDC13), δ ppm;
-61.95 (m, 1F).
Example 2
[0081] To 2.20 L (1.03 L/mol) of acetonitrile, 180 g (2.40 mol, 1.13 eq) of an amino
alcohol represented by the following formula:

and 241 g (2.38 mol, 1.12 eq) of triethylamine were added for their dissolution,
followed by adding 473 g (2.13 mol, 1.00 eq) of ortho-nitrobenzenesulfonyl chloride at
0 °C and stirring at room temperature all night. After the termination of the reaction,
the precipitated salt of triethylamine and hydrogen chloride was removed by filtration,
followed by washing the salt by using 1.00 L of ethyl acetate. The filtrate and the
washing liquid were combined together, followed by concentration under reduced
pressure to reduce the volume to about 1/3, adding 1.00 L of water, and extraction with
1.50 L of ethyl acetate. The aqueous layer was re-extracted two times with 500 mL of
ethyl acetate. The organic layers were combined together, and then a concentration
under reduced pressure was conducted. After the concentration, a further
concentration under reduced pressure was conducted by adding 200 mL of toluene,
thereby obtaining 533 g of a protected amino alcohol represented by the following
formula.

Yield was 96 %. Gas chromatography purity was 92.0 %.

[0082] A stainless steel (SUS), pressure-proof, reaction container was charged with
533 g (2.05 mol, 1.00 eq) of the above-obtained protected amino alcohol, 500 mL
(0.244 L/mol) of acetonitrile, 329 g (2.55 mol, 1.24 eq) of diisopropylethylamine, and
39.7 g (0.210 mol, 0.102 eq) of diisopropylethylamine trihydrofluoride for their
dissolution, followed by immersion in an iced bath, bubbling of 246 g (2.41 mol, 1.18
eq) of sulfuryl fluoride from a cylinder, and stirring at room temperature for 2.5 hours.
After the reaction-terminated liquid was concentrated under reduced pressure, 500 mL
of ethyl acetate and 500 mL of water were added. The generated crystals were isolated
by filtration, followed by adding 1.00 L of ethyl acetate and 500 mL of water to the
filtrate to conduct a separation into two layers. The obtained organic layer was washed
with 1.00 L of water two times and then 500 mL of a brine containing 50.0 g of sodium
chloride. After concentration under reduced pressure, a reprecipitation was conducted
by 1.20 L of ethyl acetate and 1.20 L of n-heptane, followed by a combination with the
previously isolated crystals and conducting a vacuum drying, thereby obtaining 517 g
of a protected fluoroamine represented by the following formula:

in the form of crystals. Yield was 96%. Gas chromatography purity was 98.0 %.
[0083] To 300 mL (0.987 L/mol) of l,3-dimethyl-2-imidazolidinone, 79.6 g (304
mmol, 1.00 eq) of the above-obtained protected fluoroamine, 53.7 g (487 mmol, 1.60
eq) of thiophenol and 82.2 g (595 mmol, 1.96 eq) of potassium carbonate were added
at 0 °C, followed by stirring at room temperature for 3 hours. The reaction-terminated
liquid was subjected to a direct recovery distillation, thereby obtaining 21.4 g of a
fluoroamine (a crude product) represented by the following formula.


Yield was 91 %. Gas chromatography purity was 92.7 %.
Example 3
[0084] To 53.0 mL (0.987 L/mol) of acetonitrile, 5.12 g (57.4 mmol, 1.07 eq) of an

and 5.66 g (55.9 mmol, 1.04 eq) of triethylamine were added for their dissolution,
followed by adding 11.9 g (53.7 mmol, 1.00 eq) of ortho-nitrobenzenesulfonyl chloride
at 0 °C and stirring at room temperature all night. After the termination of the reaction,
100 mL of ethyl acetate and 30.0 mL of water were added to conduct a separation into
two layers. The aqueous layer was re-extracted two times with 30.0 mL of ethyl
acetate, followed by combining the organic layers together and passing the organic
layer through a silica gel column in a small amount, and conducting a concentration
under reduced pressure, thereby obtaining 13.2 g of a protected amino alcohol
represented by the following formula.

Yield was 90 %. Gas chromatography purity was 99.0 %. 1H-NMR is shown as
follows.
[0085] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 1.82
(m, 2H), 2.65 (br, 1H), 2.93 (s, 3H), 3.38 (m, 2H), 3.70 (m, 2H), 7.60-7.70 (Ar, 3H),
7.96 (Ar, 1H).
[0086] A stainless steel (SUS), pressure-proof, reaction container was charged with
2.91 g (10.6 mmol, 1.00 eq) of the above-obtained protected amino alcohol, 11.0 mL
(1.04 L/mol) of acetonitrile, 1.65 g (12.8 mmol, 1.21 eq) of diisopropylethylamine, and

200 mg (1.06 mniol, 0.100 eq) of diisopropylethylamine trihydrofluoride for their
dissolution, followed by bubbling of 4.60 g (45.1 mmol, 4.25 eq) of sulfuryl fluoride
from a cylinder and stirring at room temperature for 3.5 hours. To the reaction-
terminated liquid, a potassium carbonate aqueous solution [prepared from 830 mg
(6.01 mmol, 0.567 eq) of potassium carbonate and 10.0 mL of water] was added,
followed by extraction with 40.0 mL of ethyl acetate. The organic layer was washed
with 20.0 mL of water and 20.0 mL of brine, followed by drying with anhydrous
sodium sulfate. This was concentrated under reduced pressure, followed by
purification with a short column (silica gel/ethyl acetate : n-hexane = 2 : 1), thereby
obtaining 2.52 g of a protected fluoroamine (a crude product) represented by the
following formula.

Yield was 86 %. Gas chromatography purity was 98.8 %. 1H- and 19F-NMR are
shown in the following.
[0087] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 1.95-
2.06 (m, 2H), 2.94 (s, 3H), 3.39 (m, 2H), 4.46 (m, 1H), 4.58 (m, 1H), 7.60-7.70 (Ar,
3H),7.99(Ar, 1H).
[0088] l9F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), δ ppm;
-59.85 (m, 1F).
[0089] To 8.50 mL (1.0 L/mol) of l,3-dimethyl-2-imidazolidinone, 2.34 g (8.47
mmol, 1.00 eq) of the above-obtained protected fluoroamine and 2.28 g (16.5 mmol,
1.95 eq) of potassium carbonate were added, followed by adding 1.50 g (13.6 mmol,
1.61 eq) of thiophenol at 0 °C and stirring at room temperature for three days. The
reaction-terminated liquid was subjected to a direct recovery distillation, thereby
obtaining 750 mg of a fluoroamine (a crude product) represented by the following
formula.


Yield was 97 %. Gas chromatography purity was 84.7 %. 1H- and 19F-NMR are
shown in the following.
[0090] 'H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 2.00
(m, 2H), 2.46 (s, 3H), 2.75 (m, 2H), 4.48 (m, 1H), 4.59 (m, 1H), and no assignment of
the amino proton.
[0091] l9F-NMR (standard substance: C6F6, deuterated solvent: CDC13), δ ppm;
-59.82 (m, 1F).
Example 4
[0092] To 50.0 mL (0.998 L/mol) of acetonitrile, 5.70 g (55.3 mmol, 1.10 eq) of
valinol and 5.52 g (54.6 mmol, 1.09 eq) of triethylamine were added for their
dissolution, followed by adding 11.1 g (50.1 mmol, 1.00 eq) of ortho-
nitrobenzenesulfonyl chloride at 0 °C and stirring at room temperature all night. After
the termination of the reaction, 40.0 mL of ethyl acetate and 20.0 mL of water were
added to conduct a separation into two layers. The aqueous layer was re-extracted two
times with 30.0 mL of ethyl acetate, followed by combining the organic layers together
and passing the organic layer through a silica gel column in a small amount, and
conducting a concentration under reduced pressure. The obtained concentrate was
dissolved in 50.0 mL of acetonitrile and 50.0 mL of N,N-dimethylformamide, followed
by adding 10.9 g (76.8 mmol, 1.53 eq) of iodomethane and 2.39 g (59.8 mmol, 1.19
eq) of 60 % sodium hydride and stirring at 50 °C for three hours. After the termination
of the reaction, 300 mL of ethyl acetate and 40.0 mL of water were added to conduct a
separation into two layers. The aqueous layer was re-extracted with 40.0 mL of ethyl
acetate. The organic layers were combined together, followed by passing the organic
layer through a silica gel column in a small amount and conducting a concentration
under reduced pressure, thereby obtaining 10.9 g of a protected amino alcohol
represented by the following formula.


Yield was 72 %. Gas chromatography purity was 92.0 %. 'H-NMR is shown as
follows.
[0093] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 0.83
(d, 3H), 0.96 (d, 3H), 1.77 (m, 1H), 1.97 (m, 1H), 2.93 (s, 3H), 3.57 (m, 2H), 3.85 (m,
1H), 7.60-7.70 (Ar, 3H), 8.05 (Ar, 1H).
[0094] A stainless steel (SUS), pressure-proof, reaction container was charged with
3.33 g (11.0 mmol, 1.00 eq) of the above-obtained protected amino alcohol, 11.0 mL
(1.00 L/mol) of acetonitrile, 1.76 g (13.6 mmol, 1.24 eq) of diisopropylethylamine, and
200 mg (1.06 mmol, 0.0964 eq) of diisopropylethylamine trihydrofluoride for their
dissolution, followed by bubbling of 4.00 g (39.2 mmol, 3.56 eq) of sulfuryl fluoride at
0 °C from a cylinder and stirring at room temperature for three hours. To the reaction-
terminated liquid, a potassium carbonate aqueous solution [prepared from 820 mg
(5.93 mmol, 0.539 eq) of potassium carbonate and 20.0 mL of water] was added,
followed by extraction with 30.0 mL of ethyl acetate. The organic layer was washed
two times with 20.0 mL of water, followed by drying with anhydrous sodium sulfate.
After a concentration under reduced pressure, a purification was conducted with a
short column (silica gel/ethyl acetate : n-hexane =1:1), thereby obtaining 3.26 g of a
protected fluoroamine represented by the following formula.


Yield was 97 %. Gas chromatography purity was 86.7 %. 1H- and l9F-NMR are
shown in the following.
[0095] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 0.92
(d, 3H), 1.04 (d, 3H), 2.04 (m, 1H), 2.97 (s, 3H), 3.72 (m, 1H), 4.49-4.71 (m, 2H),
7.60-7.70 (Ar, 3H), 8.00 (Ar, 1H).
[0096] l9F-NMR (standard substance: C6F6, deuterated solvent: CDC13), 5 ppm;
-66.71 (m, IF).
[0097] To 10.0 raL (0.935 L/mol) of l,3-dimethyl-2-imidazolidinone, 3.26 g (10.7
mmol, 1.00 eq) of the above-obtained protected fluoroamine and 2.66 g (19.2 mmol,
1.79 eq) of potassium carbonate were added, followed by adding 1.68 g (15.2 mmol,
1.42 eq) of thiophenol at 0 °C and stirring at room temperature all night. The reaction-
terminated liquid was subjected to a direct recovery distillation, thereby obtaining 790
mg of a fluoroamine (a crude product) represented by the following formula.

Yield was 62 %. Gas chromatography purity was 74.4 %. 1H- and l9F-NMR are
shown in the following.
[0098] 1H-NMR (standard substance: Me4Si, deuterated solvent: CDC13), δ ppm; 0.96
(m, 6H), 1.88 (m, 1H), 2.48 (m, 4H), 4.30-4.60 (m, 2H), and no assignment of the
amino proton.
[0099] l9F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), δ ppm;
-67.57 (m, 1F).
[0100] [Comparative Example 1]
A stainless steel (SUS), pressure-proof reaction container was charged with 2.95
g (17.9 mmol, 1.00 eq) of a Bn-protected amino alcohol represented by the following
formula:


20.0 mL (1.12 L/mol) of acetonitrile, 7.06 g (54.6 mmol, 3.05 eq) of
diisopropylethylamine and 3.36 g (17.8 mmol, 0.994 eq) of diisopropylethylamine
trihydrofluoride for their dissolution, followed by immersion in a coolant bath of-78
°C, bubbling of 3.50 g (34.3 mmol, 1.92 eq) of sulfuryl fluoride from a cylinder, and
stirring at room temperature for four hours. To the reaction-terminated liquid, a
potassium carbonate aqueous solution [prepared from 15.0 g (109 mmol, 6.09 eq) of
potassium carbonate and 30.0 mL of water] was added, followed by extraction with
60.0 mL of ethyl acetate. The recovered organic layer was dried with anhydrous
sodium sulfate, followed by concentration under reduced pressure, and vacuum drying,
thereby obtaining 3.36 g of a Bn-protected fluoroamine (a crude product) represented
by the following formula.

From 19F-NMR analysis of the crude product, quantity was determined by an internal
standard method (internal standard substance: a,a,a-trifiuorotoluene). With this, the
existence of the target product was confirmed, but it was contained by only 150 mg
even at the maximum. Yield was less than 5 %.
[0101] [Comparative Example 2]
A stainless steel (SUS), pressure-proof, reaction vessel was charged with 1.74 g
(9.93 mmol, 1.00 eq) of a Boc-protected amino alcohol represented by the following
formula:


10.0 mL (1.01 L/mol) of acetonitrile, 1.57 g (12.1 mmol, 1.22 eq) of
diisopropylethylamine, and 205 mg (1.08 mmol, 0.109 eq) of diisopropylethylamine
trihydrofluoride for their dissolution, followed by immersion in a coolant bath of-78
°C, bubbling of 2.00 g (19.6 mmol, 1.97 eq) of sulfuryl fluoride from a cylinder, and
stirring at room temperature for three hours. To the reaction-terminated liquid, a
potassium carbonate aqueous solution (prepared from 300 mg (2.17 mmol, 0.219 eq)
of potassium carbonate and 20.0 mL of water) was added, followed by extraction with
30.0 mL of ethyl acetate. The recovered organic layer was washed with 20.0 mL of
water, followed by drying with anhydrous sodium sulfate, concentration under reduced
pressure, and vacuum drying, thereby obtaining 1.12 g of a Boc-protected fluoroamine
(a crude product) represented by the following formula.

From l9F-NMR analysis of the crude product, quantity was determined by an internal
standard method (internal standard substance: a,a,a-trifluorotoluene). With this, the
existence of the target product was confirmed, but it was contained by only 88.0 mg
even at the maximum. Yield was less than 5 %.
[0102] [Comparative Example 3]
A stainless steel (SUS), pressure-proof, reaction vessel was charged with 2.12 g
(10.1 mmol, 1.00 eq) of a Cbz-protected amino alcohol represented by the following
formula:

10.0 mL (0.990 L/mol) of acetonitrile, 1.58 g (12.2 mmol, 1.21 eq) of
diisopropylethylamine, and 187 mg (988 μumol, 0.0978 eq) of diisopropylethylamine
trihydrofluoride for their dissolution, followed by immersion in a coolant bath of-78
°C, bubbling of 5.00 g (49.0 mmol, 4.85 eq) of sulfuryl fluoride from a cylinder, and

stirring at room temperature for three hours and thirty minutes. To the reaction-
terminated liquid, a potassium carbonate aqueous solution (prepared from 390 mg
(2.82 mmol, 0.279 eq) of potassium carbonate and 20.0 mL of water) was added,
followed by extraction with 30.0 mL of ethyl acetate. The recovered organic layer was
washed with 20.0 mL of water, followed by drying with anhydrous sodium sulfate,
concentration under reduced pressure, and vacuum drying, thereby obtaining 1.69 g of
a Cbz-protected fiuoroamine (a crude product) represented by the following formula.

From 19F-NMR analysis of the crude product, quantity was determined by an internal
standard method (internal standard substance: a,a,a-trifluorotoluene). With this, the
existence of the target product was confirmed, but it was contained by only 107 mg
even at the maximum. Yield was less than 5 %.
[0103] [Comparative Example 4]
A stainless steel (SUS), pressure-proof, reaction vessel was charged with 1.19 g
(10.2 mmol, 1.00 eq) of a Ac-protected amino alcohol represented by the following
formula:

10.0 mL (0.980 L/mol) of acetonitrile, 1.57 g (12.1 mmol, 1.19 eq) of
diisopropylethylamine, and 199 mg (1.05 mmol, 0.103 eq) of diisopropylethylamine
trihydrofluoride for their dissolution, followed by immersion in a coolant bath of-78
°C, bubbling of 3.40 g (33.3 mmol, 3.26 eq) of sulfuryl fluoride from a cylinder, and
stirring at room temperature for four hours. To the reaction-terminated liquid, a
potassium carbonate aqueous solution (prepared from 320 mg (2.32 mmol, 0.227 eq)
of potassium carbonate and 20.0 mL of water) was added, followed by extraction with
30.0 mL of ethyl acetate. The recovered organic layer was washed with 20.0 mL of

water, followed by drying with anhydrous sodium sulfate, concentration under reduced
pressure, and vacuum drying, thereby obtaining 575 mg of a Ac-protected fluoroamine
(a crude product) represented by the following formula.

From 19F-NMR analysis of the crude product, quantity was determined by an internal
standard method (internal standard substance: α,α,α-trifluorotoluene). With this, the
existence of the target product was confirmed, but it was contained by only 61.0 mg
even at the maximum. Yield was less than 5 %.
INDUSTRIAL APPLICABILITY
[0104] A fluoroamine, which is the target of the present invention, can be used as an
intermediate of medicines and agricultural chemicals.

WE CLAIM:
1. A method for producing a protected fluoroamine represented by the general
formula [2]:

[in the formula, R1 represents an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group, each of R independently represents
a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group
or a substituted aromatic ring group, m represents an integer of 2, 3 or 4, n
represents an integer of 4, 6 or 8, and P1 represents an ortho-, meta- or para-
nitrobenzenesulfonyl group.]
comprising a dehydroxyfluorination step of reacting a protected amino
alcohol represented by the general formula [1]:

in the formula, R1,R% m, n and P1 are the same as those of the above formula [2]]
with sulfuryl fluoride (SO2F2) in the presence of an organic base.
2. The method as claimed in claim 1, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
3. A method for producing a fluoroamine represented by the general formula [4]:


[in the formula, R1 represents an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group, each of R2 independently represents
a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group
or a substituted aromatic ring group, m represents an integer of 2, 3 or 4, and n
represents an integer of 4, 6 or 8.]
comprising an amino group protecting step of converting an amino alcohol
represented by the general formula [3]:

[in the formula, R1, R2, m and n are the same as those of the formula [4].]
to a protected amino alcohol represented by the general formula [1]:

[in the formula, R1 , R2, m and n are the same as those of the formula [4]. P
represents an ortho-, meta- or para-nitrobenzenesulfonyl group.]
by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl
group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [2]:

[in the formula, R1, R2, m, n and P1 are the same as those of the general formula [1].]
by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the
presence of an organic base, and

a deprotection step of deprotecting a protecting group of an amino group of
the protected fluoroamine.
4. The method as claimed in claim 3, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
5. A method for producing a protected fluoroamine represented by the general
formula [6]:

[in the formula, R3 represents an alkyl group or a substituted alkyl group, each of R4
independently represents a hydrogen atom, an alkyl group or a substituted alkyl
group, x represents an integer of 2 or 3, y represents an integer of 4 or 6, and P
represents an ortho- or para-nitrobenzenesulfonyl group.]
comprising a dehydroxyfluorination step of reacting a protected amino alcohol
represented by the general formula [5]:

[in the formula, R3, R4, x, y and P2 are the same as those of the formula [6].]
with sulfuryl fluoride (SO2F2) in the presence of an organic base.
6. The method as claimed in claim 5, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.

7. A method for producing a fluoroamine represented by the general formula [8]:

[in the formula, R3 represents an alkyl group or a substituted alkyl group, each of R
independently represents a hydrogen atom, an alkyl group or a substituted alkyl
group, x represents an integer of 2 or 3, and y represents an integer of 4 or 6.]
comprising an amino group protecting step of converting an amino alcohol
represented by the general formula [7]:

[in the formula, R3 , R4, x and y are the same as those of the above general formula
[8].]
to a protected amino alcohol represented by the general formula [5]:

[in the formula, R3, R4, x and y are the same as those of the general formula [8]. P2
represents an ortho- or para-nitrobenzenesulfonyl group.]
by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl
group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [6]:


[in the formula, R3, R4, x, y and P2 are the same as those of the above formula [5].]
by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the
presence of an organic base, and
a deprotection step of deprotecting a protecting group of an amino group of
the protected fluoroamine.
8. The method as claimed in claim 7, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.
9. A method for producing a protected fluoroamine represented by the general
formula [10]:

[in the formula, Me represents a methyl group]
comprising a dehydroxyfluorination step of reacting a protected amino alcohol
represented by the general formula [9]:

with sulfuryl fluoride (SO2F2) in the presence of an organic base.
10. The method as claimed in claim 9, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.

11. A method for producing a fluoroamine represented by the general formula
[12]:

[in the formula, Me represents a methyl group]
comprising an amino group protecting step of converting an amino alcohol
represented by the general formula [11]:

to a protected amino alcohol represented by the general formula [9]:

by protecting an amino group of the amino alcohol with a nitrobenzenesulfonyl
group,
a dehydroxyfluorination step of converting the protected amino alcohol to a
protected fluoroamine represented by the general formula [10]:


by reacting the protected amino alcohol with sulfuryl fluoride (SO2F2) in the
presence of an organic base, and
a deprotection step of deprotecting a protecting group of an amino group of
the protected fluoroamine.
12. The method as claimed in claim 11, which is characterized by that the
dehydroxyfluorination step is conducted in the presence of a salt or complex
comprising an organic base and hydrogen fluoride.