Technical Field
The present invention relates to an industrial production process of an optically active
fluoroamine, which is important as an intermediate of pharmaceutical and agrichemical
products.
Background Art
An optically active fluoroamine, which is the target of the present invention, is an
important intermediate of pharmaceutical and agrichemical products. The direct production
of the optically active fluoroamine is generally conducted by dehydroxyfluorination of a
corresponding optically active amino alcohol in a protected amino form.
The present applicant has disclosed a process for producing an optically active
fluoroamine by dehydroxyfluorination of an alcohol with the combined use of sulfuryl
fluoride (SO2F2) and an organic base. This production process provides a target fluorinated
compound (phthaloyl-protected form) with a yield of 23% in the case of using as a raw
material an optically active amino alcohol of which the amino group (-NH2) has been
protected with a phthaloyl group (cf. Scheme 1: Patent Document 1).
[Chcm. 1]
Scheme 1

i-Pr: isopropyl
Et: ethyl
Further, there is known a process for dehydroxyfluorination of an optically active amino
alcohol in a protected amino form using a fluorination agent known as Deoxo-Fluor™ (cf.
Scheme 2: Non-Patent Document 1) or DAST (cf. Scheme 3: Non-Patent Document 2).

[Chem. 2]
Scheme 2

Ph: phenyl
Mc: methyl
Deoxo-Fluor™: (CH3OCH2CH2)2NSF3
[Chem. 3]
Scheme 3

Ph: phenyl
DAST: (CH3CH2)2NSF3
Patent Document 1: International Publication No. 2006/098444
(Japanese Laid-Open Patent Publication No. 2006-290870)
Non-Patent Document 1: Journal of Fluorine Chemistry (Netherlands), 2004,
Vol.125. P. 1869-1872
Non-Patent Document 2: Journal of American Chemical Society (US), 1982.
Vol.104. P.5836-5837
Summary of the Invention
It is an object of the present invention to provide an industrial production process of an
optically active fluoroamine.
It is known that the dehydroxyfluorination of the protected optically active amino
alcohol involves neighboring-group participation of a nitrogen atom even when the amino
group has been protected with a protecting group. For example, the dehydroxyfluorination

reaction of a substrate having the same 1,2-amino alcohol structure as that in the present
invention and containing a dibenzyl group as an amino protecting group cannot selectively
produce a target compound with a fluorine atom simply substituted on its hydroxyl-bonded
carbon atom and provides a rearranged form of the target compound as a main product (cf.
Schemes 2 and 3).
The dehydroxyfluorination reaction of Patent Document 1, in which the
phthaloyl-protected amino alcohol is dehydroxyfluorinated with sulfuryl fluoride, can limit
neighboring-group participation of a nitrogen atom and produce the target compound by a
relatively easy operation. The product yield is however merely 23% and is susceptible to
improvement. Further, the reaction system is placed under basic conditions by the addition
of hydrazine as a typical phthaloyl deprotecting agent. Jn such a basic reaction system, there
occurs a side reaction between the deprotected amino group (nucleophilic moiety) and
fluorine atom (electrophilic moiety) of the target compound. This results in a low
deprotection yield without being able to prevent the target compound from intramolecular
ring-closure to an aziridine, intermolecular polycondensation and hydrazine substitution etc.
In view of the above facts that: the desired dehydroxyfluorination reaction does not proceed
favorably under the disclosed reaction conditions; and the deprotection of the resultant
fluorinated compound does not proceed selectively, it cannot always be said that the
dehydroxyfluorination reaction of Patent Document I is practical for the production of the
target optically active fluoroamine of the present invention.
Furthermore, the dehydroxyfluorination agents such as Deoxo-F luor™ and DA ST are
expensive and have a danger of explosion whereby the use of these dehydroxyfluorination
agents is limited to small-scale production purposes. There is thus a strong demand for a
reaction agent that is not only capable of performing a desired dehydroxyfluorination reaction
favorably but also suitable for large-scale production uses.
As described above, it has been demanded to develop a high-selectivity, high-yield
production process suitable for mass production of an optically active fluoroamine of the
after-mentioned formula [6]. In order to satisfy such a demand, it is important to find out an
amino protecting group capable of preventing neighboring-group participation of the nitrogen
atom effectively and enabling easy protection and deprotection of the amino group, ft is also
necessary to clarify reaction conditions under which the dehydroxyfluorination of the
protected amino form proceeds favorably.

As a result of extensive researches made in view of the above problems, the present
inventors have found that: the selection of an amino protecting group for an optically active
hydroxyamine is important; and an imine-protected optically active hydroxyamine
(hereinafter occasionally simply referred to as "imine form") of the present invention can be
easily prepared by dehydrative condensation of an optically active hydroxyamine and an
aldehyde and undergoes a desired dehydroxyfluorination reaction favorably with almost no
side reaction such as rearrangement due to neighboring group participation of its nitrogen
atom. The present inventors have also found that, although there is a difficulty in obtaining
the imine form selectively by dehydrative condensation of the optically active hydroxyamine
and the aldehyde, an oxazolidine-protected optically active hydroxyamine (hereinafter
occasionally simply referred to as "oxazolidine form") generated as a by-product of the
dehydrative condensation also serves as a suitable substrate in the dehydroxyfluorination
reaction of the present invention (cf. Scheme 4).
[Chem. 4]
Scheme 4

The present inventors have further found that: the protected optically active fluoroamine
obtained by the dehydroxyfluorination reaction can be easily deprotected by hydrolysis under
acidic conditions; and, in contrast to the above-mentioned phthaloyl deprotection reaction
under the basic conditions, the deprotection reaction under the acidic conditions makes it
possible to limit nucleophilicity by protonation of the deprotected amino group and thus
proceeds selectively with almost no side reaction.
For the above reasons, both of the imine form and the oxazolidine form are suitable
protected amino forms in the present invention. In these protected amino forms, R2 is
particularly preferably an aromatic hydrocarbon group in view of the large-scale availability
of the raw aldehyde material, the ease and selectivity of protection and deprotection of the
amino group, the effect of preventing the reactivity of dehydroxyfluorination of the
hydroxyamine and the neighboring-group participation of the nitrogen atom, the large-scale

handling stability of various intermediates and the like.
On the other hand, the present inventors have found that: even if the suitable protected
amino form, i.e., the imine form, oxazolidine form or mixture thereof is reacted with sulfuryl
fluoride in the presence of triethylamine, which is heavily used as a typical organic base in
Patent Document 1, the desired dehydroxyfluorination reaction does not proceed favorably;
and the triethylamine nucleophilically attacks a fluorosulfuric acid ester intermediate in
preference to the fluorine anion (F~) so that there occurs a large amount of quaternary
ammonium salt as a by-product (cf. Comparative Example 1; Scheme 5).
[Chem. 5]
Scheme 5

Me: methyl
Ph: phenyl
Et: ethyl
Under these circumstances, the present inventors have focused attention on the steric
effect of an organic base and have found that the use of a tertiary amine having a carbon
number of 7 to 18, preferably a tertiary amine having a carbon number of 8 to 12 and
containing two or more alkyl groups of 3 or more carbon atoms (such as
diisopropylethylamine, tri-n-butylamine etc.), as the organic base makes it possible to
effectively prevent the generation of a quaternary ammonium salt as a by-product. The
desired steric effect of the tertiary amine can be obtained sufficiently when the tertiary amine
has a carbon number of up to 18. The carbon number of the tertiary amine is thus preferably
up to 18, more preferably up to 12, in view of the large-scale availability of the amine, the

productivity of the dehydroxyfluorination reaction system and the like.
Consequently, the present inventors have verified that it is important to use the suitable
protected amino form in combination with the above specific tertiary amine for production of
the target optically active fluoroamine of the present invention.
The present inventors have finally found a novel protected optically active fluoroamine
as a useful key intermediate in the present invention.
As described above, the present inventors have found the particularly useful techniques
for industrial production of the optically active fluoroamine. The present invention is based
on these findings.
According to the present invention, there is provided a process (first process) for
producing a protected optically active fluoroamine of the formula [3], comprising: reacting an
imine-protected optically active hydroxyamine of the formula [1], an oxazolidine-protected
optically active hydoxyamine of the formula [2] or a mixture thereof with sulfuryl fluoride
(SO2F2) in the presence of a tertiary amine (in which all of three ammonia hydrogen atoms
have been replaced by alkyl groups) having a carbon number of 7 to 18
[Chem. 6]

[Chem. 7]


[Chcm. 8]

where R1 and R2 each independently represent an alkyl group or an aromatic ring group: *
represents an asymmetric carbon; the stereochemistry of the asymmetric carbon is maintained
through the reaction; and the wavy line indicates in the formula (1) and in the formula (3) that
the nitrogen-carbon double bond is in an E-configuration, a Z-configuration or a mixture
thereof and indicates in the formula (2) that the substituent group R1 is in a syn-configuration,
an anti-configuration or a mixture thereof.
The first process may be a process (second process) for producing the protected
optically active fluoroamine, in wh ich:R2 of the imine-protected optically active
hydroxyamine of the formula [ 1 ] or the oxazolidine-protected optically active hydoxyamine of
the formula [2] is an aromatic hydrocarbon group; and the tertiary amine has a carbon number
of 8 to 12 and contains two or more alkyl groups of 3 or more carbon atoms.
The first or second process may be a process (third process) for producing the protected
optically active fluoroamine, in which the imine-protected optically active hydroxyamine of
the formula [1] or the oxazolidine-protected optically active hydroxyamine of the formula [2]
is obtained by dehydrative condensation of an optically active hydroxyamine of the formula
[4] and an aldehyde of the formula [5]
[Chem. 9]


[Chem. 10]

where R1 and R2 each independently represent an alkyl group or an aromatic ring group; and *
represents an asymmetric carbon of which the stereochemistry is maintained through the
dehydrative condensation.
There is also provided according to the present invention a process (fourth process) for
producing an optically active fiuoroamine of the formula [6], comprising: performing, under
acidic conditions, hydrolysis of the protected optically active fiuoroamine of the formula [3]
produced by either one of the first to third processes
[Chem. 11]

where R1 represents an alkyl group or an aromatic ring group; and * represents an asymmetric
carbon of which the stereochemistry is maintained through the hydrolysis.
There is further provided according to the present invention a protected optically active
fiuoroamine of the formula [3]
[Chem. 12]

where R1 and R each independently represent an alkyl group or an aromatic ring group; *
represents an asymmetric carbon; and the wavy line indicates that the nitrogen-carbon double
bond is in an E-configuration, a Z-configuration or a mixture thereof.
In the formula [3], R2 may be an aromatic hydrocarbon group.

Detailed Description
The advantages of the present invention over the prior art technologies will be explained
below.
The present invention is advantageous over Patent Document 1, in that it is possible in
the present invention to improve the yield of the dehydroxyfluorination reaction significantly
and to enable selective, high-yield deprotection of the resultant fluorinated compound.
The present invention is advantageous over Non-Patent Documents 1 and 2, in that it is
possible in the present invention to limit the occurrence of a side reaction due to
neighboring-group participation of the nitrogen atom and to adopt the dehydroxyfluorination
agent suitable for large-scale production purposes. Sulfuryl fluoride used in the present
invention has widely been applied as a fumigant and can easily be processed to an inorganic
salt waste such as fluorite (CaF2) or calcium sulfate.
All of the raw materials and reaction agents used in the present invention are available
in large quantities and at relatively low cost. Further, the target compound can be produced
with high chemical purity and high yield and with almost no by-product generation as all of
the reaction steps are conducted under moderate reaction conditions. In addition, the
stereochemistry of the asymmetric carbon can be maintained throughout the reaction steps so
that the use of the raw material of higher optical purity leads to higher optical purity of the
target compound.
The production process of the present invention is therefore industrially readily
practicable and can solve all of the above-mentioned prior art problems.
The production process of the optically active fluoroamine according to the present
invention will be described in detail below. In the present invention, the production process
includes: a first step (dehydrative condensation reaction) for forming a protected optically
active hydroxyamine of the formula [1] or [2] (imine form, oxazolidine form or mixture
thereof) by dehydrative condensation of an optically active hydroxyamine of the formula [4]
and an aldehyde of the formula [5]; a second step (dehydroxyfluorination reaction) for
reacting the protected optically active hydroxyamine of the formula [I] or [2] (imine form,
oxazolidine form or mixture thereof) with sulfuryl fluoride in the presence of a tertiary amine
having a carbon number of 7 to 18, thereby converting the protected optically active
hydroxyamine to a protected optically active fluoroamine of the formula [3]; and a third step
(hydrolysis reaction) for forming an optically active fluoroamine of the formula [6] by

hydrolysis of the protected optically active fluoroamine of the formula [3] under acidic
conditions (cf. Scheme 6).
[Chem. 13]
Scheme 6

The first step (dehydrative condensation reaction) will be first explained in detail below.
In the optically active hydroxyamine of the formula [4], R1 represents an alkyl group or
an aromatic ring group. As the alkyl group, there can be used those having 1 to 18 carbon
atoms and having a linear structure, a branched structure or a cyclic structure (in the case of 3
or more carbons). (The cyclic structure may be a monocyclic structure, a condensed
polycyclic structure, a crosslinked structure, a spiro ring structure, a ring assembly structure or
the like.) Any of the carbon atoms of the alkyl group may be replaced by any number of and
any combination of hetero atoms such as nitrogen, oxygen and sulfur. (The nitrogen atom
may have an alkyl group, an aromatic ring group, a protecting group or the like as a
substituent; and the sulfur atom may have an oxygen atom as a substituent (-SO- or -SO2-).)
Two hydrogen atoms bonded to any (one) of the carbon atoms of the alkyl group may be
replaced by any number of and any combination of nitrogen, oxygen and sulfur atoms. (In
this case, the nitrogen, oxygen and/or sulfur atom forms an imino moiety, a carbonyl moiety or
a thiocarbonyl moiety together with the carbon atom; and the nitrogen atom may have an alkyl
group, an aromatic ring group, a protecting group or the like as a substituent.) Further, any
adjacent two of the carbon atoms of the alkyl group may be replaced by any number of and
any combination of unsaturated groups (double bond or triple bond). As the aromatic ring
group, there can be used those having 1 to 18 carbon atoms, such as aromatic hydrocarbon
groups, e.g., phenyl, naphthyl, anthryl etc. and aromatic heterocyclic groups containing

heteroatoms such as nitrogen, oxygen and sulfur, e.g., pyrrolyl, furyl, thienyl, indolyl,
benzofuryl, benzothicnyl etc. (The nitrogen atom may have an alkyl group, an aromatic ring
group, a protecting group or the like as a substituent; and the aromatic heterocyclic group may
have a monocyclic structure, a condensed polycyclic structure, a ring assembly structure or the
like.)
The alkyl group or aromatic ring group may have any number of and any combination
of substituents on any of the carbon atoms thereof. Examples of the substituents are: halogen
atoms such as fluorine, chlorine, bromine and iodine; azide group; nitro group; 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; lower
alkylamino groups such as dimethylamino, diethylamino and dipropylamino; lower alkylthio
groups such as methylthio, ethylthio and propylthio; cyano group; lower alkoxycarbonyl
groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; aminocarbonyl group
(CONH2); lower aminocarbonyl groups such as dimethylaminocarbonyl,
diethylaminocarbonyl and dipropylaminocarbonyl; unsaturated groups such as alkenyl and
alkynyl; aromatic ring groups such as phenyl, naphthyl, pyrrolyl, furyl and thienyl; aromatic
ring oxy groups such as phenoxy, naphthoxy, pyrrolyloxy, furyloxy and thienyloxy; aliphatic
heterocyclic groups such as piperidyl, piperidino and morpholinyl; protected hydroxyl groups;
protected amino groups (including amino acids and peptide residues); protected thiol groups;
protected aldehyde groups; protected carboxyl groups; and the like.
In the present specification, the following terms have the following meanings. The
term "lower" means that the group to which the term is attached has 1 to 6 carbon atoms and
has a linear structure, a branched structure or a cyclic structure (in the case of 3 carbons or
more). It means that, when the "unsaturated group" is a double bond (alkenyl group), the
double bond can be in an E-configuration, a Z-configuration or a mixture thereof. It means
that the "protected hydroxyl, amino (including amino acid or peptide residue), thiol, aldehyde
and carboxyl groups" may be those having protecting groups described in "Protective Groups
in Organic Synthesis", Third Edition, 1999, John Wiley & Sons, Inc. and the like. (In this
case, two or more functional groups may be protected with one protecting group.)
Further, the "unsaturated group", "aromatic ring group", "aromatic ring oxy group" and
"aliphatic heterocyclic group" may be substituted with halogen atoms, azide group, nitro
group, lower alkyl groups, lower haloalkyl groups, lower alkoxy groups, lower haloalkoxy

groups, lower alkylamino groups, lower alkylthio groups, cyano group, lower alkoxycarbonyi
groups, aminocarbonyl group, lower aminocarbonyl groups, protected hydroxyl groups,
protected amino groups (including amino acids and peptide residues), protected thiol groups,
protected aldehyde groups, protected carboxyl groups or the like.
Although the alkyl group or aromatic ring group is suitably used as R1 in the optically
active hydroxyamine of the formula [4], R1 is preferably the alkyl group of 1 to 9 carbon
atoms. The optically active hydroxyamine in which R1 is the alkyl group of 1 to 9 carbon
atoms is preferred in that: a raw material of the optically active hydroxyamine, i.e., an
optically active a-amino acid is easily available on a large scale; and the optically active
hydroxyamine can be easily prepared by reduction of the optically active a-amino acid. The
optically active hydroxyamine in which R1 is the alkyl group of 1 to 6 is commercially
available in various forms and is thus particularly preferred as the starting material of the
present invention.
In the optically active hydroxyamine of the formula [4], * represents an asymmetric
carbon. The stereochemistry (absolute configuration and optical purity) of the asymmetric
carbon is maintained through the dehydrative condensation reaction.
The absolute configuration of the asymmetric carbon can be either a R-configuration or
a S-configuration and be set appropriately depending on the absolute configuration of the
target optically active fluoroamine of the formula [6].
The optical purity of the asymmetric carbon can be indicated by enantiomer excess (ee).
It suffices that the enantiomer excess is 80%ee or higher in view of the use of the target
optically active fluoroamine of the formula [6] as a pharmaceutical/agrichemical intermediate.
The enantiomer excess is generally preferably 90%ee or higher, more preferably 95%ee or
higher.
In the aldehyde of the formula [5], R2 represents an alkyl group or an aromatic ring
group.
Examples of the alkyl group or aromatic ring group R2 are the same as R1 in the
optically active hydroxyamine of the formula [4]. Among others, aromatic hydrocarbon
groups are preferred. Particularly preferred are phenyl, substituted phenyl, naphthyl and
substituted naphthyl. The aldehyde in which R2 is phenyl, substituted phenyl, naphthyl or
substituted naphthyl has the advantage of being industrially available at low cost in addition to
the advantage of the use of the aromatic hydrocarbon group as R2 described above in "Means

for Solving the Problems".
It suffices to use the aldehyde of the formula [5] in an amount of 0.7 mol or more per 1
mol of the optically active hydroxyamine of the formula [4]. The amount of the aldehyde of
the formula [5] used is generally preferably in the range of 0.8 to 5 mol, more preferably 0.9 to
3 mol, per 1 mole of the optically active hydroxyamine of the formula [4].
In the first step, the reaction is performed preferably in the presence of an acid catalyst
or under dehydrative conditions. Depending on the combination of the raw substrate
materials, the reaction may proceeds favorably even without the adoption of these reaction
conditions.
Examples of the acid catalyst are: inorganic acids such as hydrogen chloride
(hydrochloric acid), sulfuric acid, phosphoric acid, zinc chloride, titanium tetrachloride and
tetraisopropoxy titanium; and organic acids such as benzenesulfonic acid,
para-toluenesulfonic acid, pyridinium para-toluenesulfonate (PPTS) and 10-camphorsulfonic
acid. Among others, sulfuric acid, para-toluenesulfonic acid and pyridinium
para-toluenesulfonate (PPTS) are preferred. Particularly preferred are para-toluenesulfonic
acid and pyridinium para-toluenesulfonate (PPTS). It suffices to use a catalytic amount of
the acid catalyst per 1 mol of the optically active hydroxyamine of the formula [4]. The
amount of the acid catalyst used is generally preferably in the range of 0.001 to 0.7 mol, more
preferably 0.005 to 0.5 mol, per 1 mol of the optically active hydroxyamine of the formula [4].
Further, the reaction under the dehydrative conditions can be performed by using, as a
reaction solvent, an aromatic hydrocarbon solvent that is inmiscible with water, lower in
specific gravity than water and azeotropic with water, and refluxing the reaction system while
removing by-product water with a Dean-Stark trap.
Examples of the reaction solvent are: aliphatic hydrocarbon solvents such as n-hexane,
cyclohexane and n-heptane; aromatic hydrocarbon solvents such as benzene, toluene,
ethylbenzene, xylene and mesitylene; halogenated hydrocarbon solvents such as methylene
chloride, chloroform and 1,2-dichloroethane; ether solvents such as diethyl ether,
tetrahydrofuran, diisopropyl ether and tert-butyl methyl ether; ester solvents such as ethyl
acetate and n-butyl acetate; amide solvents such as N,N-dimethylformamide,
N,N-dimethylacetoamide, N-methyl-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; nitrile
solvents such as acetonitrile and propionitrile; dimethyl sulfoxide; and the like.
Among others, n-hexane, n-heptane, toluene, xylene, mesitylene, methylene chloride,

tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ethyl acetate,
N,N-dimethylformamide, N,N-dimethylacetoamidc, acetonitrile, propionitrilc and dimethyl
sulfoxide are preferred. Particularly preferred are toluene, xylene, methylene chloride,
tetrahydrofuran, diisopropyl ether, ethyl acetate, N,N-dimethylformamide and acetonitrile.
These reaction solvents can be used alone or in combination thereof. Alternatively, the
reaction may be performed in the absence of the reaction solvent in the first step.
It suffices to use the reaction solvent in an amount of 0.01 L (liter) or more per 1 mol of
the optically active hydroxyamine of the formula [4]. The amount of the reaction solvent
used is generally preferably in the range of 0.05 to 5 L, more preferably 0.1 to 3 L, per 1 mol
of the optically active hydroxyamine of the formula [4].
Further, it suffices that the temperature condition ranges from -20 to +200°C. The
temperature condition is generally preferably in the range of-10 to +175°C, more preferably
0 to+150°C.
The reaction time is generally 72 hours or less. As the reaction time depends on the
combination of the raw substrate materials and the adopted reaction conditions, it is preferable
to determine the time at which the raw substrate materials have almost disappeared as the end
of the reaction while monitoring the progress of the reaction by any analytical means such as
gas chromatography, thin-layer chromatography, liquid chromatography or nuclear magnetic
resonance.
The target protected optically active hydroxyamine of the formula [1] or [2] can be
obtained as the imine form, ozazolidine form or mixture thereof by ordinary post treatment of
the reaction-terminated liquid. Herein, the nitrogen-carbon double bond of the imine form is
in an E-configuration, a Z-configuration or a mixture thereof; and the oxazolidine form is in a
syn-configuration, an anti-configuration or a mixture thereof with respect to the substituent
group R1. Although the ratio of these isomers depends on the combination of the raw
substrate materials and the adopted reaction conditions, the dehydroxyfluorination reaction of
the second step proceeds favorably without the influence of such an isomer ratio. Further,
the target compound can be purified to a high chemical purity, as needed, by purification
operation such as activated carbon treatment, distillation, recrystallization or column
chromatography.
In the first step, the reaction proceeds favorably with high selectivity. It is thus
possible to obtain the target compound of sufficient quality as the raw substrate material for

the dehydroxyfluorination reaction of the second step only by evaporating the reaction solvent
for removal of the by-product water. Such simple post treatment is suitable in view of
industrial production uses. Next, the second step (dehydroxyfluorination reaction) will be
explained in detail below.
It suffices to use the sulfuryl fluoride (SO2F2) in an amount of 0.7 mol or more per 1 mol
of the protected optically active hydroxyamine of the formula [1] or [2] (imine form,
oxazolidine form or mixture thereof). The amount of the sulfuryl fluoride used is generally
preferably in the range of 0.8 to 10 mol, more preferably 0.9 to 5 mole, per 1 mol of the
protected optically active hydroxyamine derivative of the formula [1] or [2].
In the second step, trifluoromethanesulfonyl fluoride (CF3SO2F) or
perfluorobutanesulfonyl fluoride (C4F9SO2F) may alternatively be used as the
dehydroxyfluorination agent. There is however no particular advantage to using these
reaction agents in view of their large-scale availability, waste disposal and the like.
As already explained above, it is important in the second step to perform the reaction in
the presence of the tertiary amine of carbon number 7 to 18. In the present specification, the
term "carbon number" refers to a total number of carbons of three alkyl groups; and the term
"tertiary amine" refers to an amine in which all of three hydrogen atoms of ammonia have
been replaced by alkyl groups. The tertiary amine of carbon number 7 to 18 has alkyl groups,
each of which is either linear, branched or cyclic (in the case of 3 carbons or more). It is
particularly preferable that the tertiary amine has a carbon number of 8 to 12 and contains two
or more alkyl groups of 3 or more carbon atoms.
Preferred examples of the tertiary amine are: diisopropylethylamine (having a carbon
number of 8 and containing two alkyl groups of 3 or more carbon atoms); tri-n-propylamine
(having a carbon number of 9 and containing three alkyl groups of 3 or more carbon atoms);
diisopropylisobutylamine (having a carbon number of 10 and containing three alkyl groups of
3 or more carbon atoms); di-n-butylisopropylamine (having a carbon number of 11 and
containing three alkyl groups of 3 or more carbon atoms); tri-n-butylamine (having a carbon
number of 12 and containing three alkyl groups of 3 or more carbon atoms); and the like.
Among others, diisopropylethylamine and tri-n-butylamine are preferred. Particularly
preferred is diisopropylethylamine. The tertiary amine is suitable for industrial production
uses as it has high lipophilicity and thus can be easily recovered and recycled without
reactivity deterioration.

It suffices to use the tertiary amine of carbon number 7 to 18 in an amount of 0.7 mol or
more per I mol of the protected optically active hydroxyamine of the formula [1] or [2] (imine
form, oxazolidine form or mixture thereof). The amount of the tertiary amine used is
generally preferably in the range of 0.8 to 10 mol, more preferably 0.9 to 5 mol, per 1 mole of
the protected optically active hydroxyamine of the formula [1] or [2].
In the second step, the reaction may be performed in the presence of "a salt or complex
of a tertiary amine having a carbon number of 7 to 18 and hydrogen fluoride". However, the
reaction proceeds favorably even in the absence of such a salt or complex. There is thus no
need to perform the reaction in the presence of the salt or complex.
The same reaction solvent as that in the first step (dehydrative condensation reaction)
can be used in the second step. Preferred examples and particularly preferred examples of
the reaction solvent in the second step are also the same as those in the first step. The
reaction solvents can be used alone or in combination thereof. Alternatively, the reaction
may be performed in the absence of the reaction solvent in the second step.
It suffices to use the reaction solvent in an amount of 0.1 L (liter) or more per 1 mol of
the protected optically active hydroxyamine of the formula [1 ] or [2] (imine form, oxazolidine
form or mixture thereof). The amount of the reaction solvent used is generally preferably in
the range of 0.2 to 10 L, more preferably 0.3 to 5 L, per 1 mol of the protected optically active
hydroxyamine of the formula [I] or [2].
It suffices that the temperature condition ranges from -100 to +100°C. The
temperature condition is generally preferably in the range of-50 to +50°C, more preferably
-40 to +40°C. In the case where the temperature condition is set to be higher than or equal to
a boiling point (-49.7°C) of the sulfuryl fluoride, the reaction can be conducted using a
pressure-proof reaction vessel.
It suffices that the pressure condition ranges from atmospheric pressure to 2 MPa. The
pressure condition is generally preferably in the range of atmospheric pressure to 1.5 MPa,
more preferably atmospheric pressure to 1 MPa. It is thus preferable to conduct the reaction
using a pressure-proof reaction vessel made of a stainless steel (SUS) material, a glass
(glass-lined) material or the like. Further, it is efficient for large-scale charging of the
sulfuryl fluoride into the pressure-proof reaction vessel to develop a negative pressure
atmosphere in the reaction vessel, and then, introduce the sulfuryl fluoride in gas or liquid
form under vacuum while increasing the pressure.

The reaction time is generally 72 hours or less. As the reaction time depends on the
combination of the raw substrate material and the tertiary amine of carbon number 7 to 18 and
the adopted reaction conditions, it is preferable to determine the time at which the raw
substrate material has almost disappeared as the end of the reaction while monitoring the
progress of the reaction by any analytical means such as gas chromatography, thin-layer
chromatography, liquid chromatography or nuclear magnetic resonance.
The target protected optically active fluoroamine of the formula [3] can be obtained by
ordinary post treatment of the reaction-terminated liquid. Further, the target compound can
be purified to a high chemical purity, as needed, by purification operation such as activated
carbon treatment, distillation, recrystallization or column chromatography.
One effective technique of the post treatment is to concentrate the reaction-terminated
liquid, dilute the concentration residue with an organic solvent such as toluene or ethyl acetate,
wash the residue with an aqueous solution of an inorganic base such as potassium carbonate,
further wash the residue with water, and then, concentrate the recovered organic phase. It is
possible by such post treatment to obtain the target compound of sufficient quality as the raw
substrate material for the hydrolysis reaction of the third step.
Finally, the third step (hydrolysis reaction) will be explained in detail below.
In the third step, the hydrolysis reaction is performed under the acidic condition. More
specifically, the hydrolysis reaction can be performed by reacting the protected optically
active fluoroamine of the formula [3] with an aqueous solution of an acid catalyst.
Examples of the acid catalyst are: inorganic acids such as hydrogen chloride, hydrogen
bromide, hydrogen iodide, sulfuric acid and nitric acid; and organic acids such as formic acid,
acetic acid, benzenesulfonic acid and paratoluenesulfonic acid. Among others, inorganic
acid are preferred. Particularly preferred are hydrogen chloride and sulfuric acid. It suffices
to use the acid catalyst in an amount of 0.1 mol or more per I mole of the protected optically
active fluoroamine of the formula [3]. The amount of the acid catalyst used is generally
preferably in the range of 0.3 to 30 mol, more preferably 0.5 to 20 mol, per 1 mole of the
protected optically active fluoroamine of the formula [3].
Further, it suffice to use water in an amount of 1 mol or more per 1 mol of the protected
optically active fluoroamine of the formula [3]. The amount of the water used is generally
preferably in the range of 3 to 300 mol, more preferably 5 to 150 mol, per 1 mole of the
protected optically active fluoroamine of the formula [3].

Examples of the reaction solvent are: aliphatic hydrocarbon solvents such as n-hexane,
cyclohexane and n-heptane; aromatic hydrocarbon solvents such as benzene, toluene,
ethylbenzene, xylene and mesitylene; ether solvents such as diethyl ether, tetrahydrofuran,
diisopropyl ether and tert-butyl methyl ether; and alcohol solvents such as methanol, ethanol,
n-propanol and isopropanol; and the like. Among others, n-hexane, n-heptane, toluene,
xylene, diisopropyl ether, methanol, ethanol and isopropanol are preferred. Particularly
preferred are n-heptane, toluene, xylene and methanol. These reaction solvents can be used
alone or in combination thereof. Alternatively, the reaction may be performed in the absence
of the reaction solvent or in two-phase reaction system in the third step.
It suffices that the temperature condition ranges from -20 to +150°C. The temperature
condition is generally preferably in the range of-10 to +125°C, more preferably 0 to + 100°C.
The reaction time is generally 72 hours or less. As the reaction time depends on the
combination of the raw substrate material and the acid catalyst and the adopted reaction
conditions, it is preferable to determine the time at which the raw substrate material has almost
disappeared as the end of the reaction while monitoring the progress of the reaction by any
analytical means such as gas chromatography, thin-layer chromatography, liquid
chromatography or nuclear magnetic resonance.
The target optically active fluoroamine of the formula [6] can be obtained by ordinary
post treatment of the reaction-terminated liquid. Further, the target compound can be
purified to a high chemical purity, as needed, by purification operation such as activated
carbon treatment, distillation, recrystallization or column chromatography.
In particular, the aldehyde of the formula [5] generated as a by-product can be
effectively removed by washing the acidic aqueous solution of the target compound with an
organic solvent such as toluene. It is feasible to obtain the same effects as above by a simple
operation of performing the reaction in two-phase reaction system using an organic,
water-inmiscible solvent such as toluene. The target compound can be obtained with high
chemical purity in the form of a salt of the acid catalyst by concentrating the recovered acidic
aqueous solution of the target compound, subjecting the concentrated residue to azeotropic
dehydration with an organic solvent such as ethyl acetate, and further subjecting the
dehydrated residue to hot washing with an organic solvent such as ethyl acetate. In some
cases, it may be efficient to recover the target compound in the form of having its amino group
protected with a protecting group. As such an amino protecting group, there can be used

those described in the above-mentioned reference book.
The thus-obtained salt or protected form of the target compound can be purified to a
higher chemical purity by recrystallization etc. Further, the salt or protected form of the
target compound can be easily converted to a free base or deprotected form by ordinary
deionization (neutralization) or deprotection.
As described above, there is provided according to the present invention the production
process of the optically active fluoroamine, including the steps of forming the protected
optically active hydroxyamine (imine form, oxazolidine form or mixture thereof) by
dehydrative condensation of the optically active hydroxyamine and the aldehyde, reacting the
protected optically active hydroxyamine with sulfuryl fluoride (SO2F2) in the presence of the
tertiary amine of carbon number 7 to 18 to thereby convert the protected optically active
hydroxyamine to the protected optically active fluoroamine, and then, performing hydrolysis
of the protected optically active fluoroamine under the acidic conditions.
The present production process can be industrially easily carried out by the use of the
aromatic hydrocarbon group-containing aldehyde and the tertiary amine having a carbon
number of 8 to 12 and containing two or more alkyl groups of 3 or more carbon atoms.
Further, there is provided the novel protected optically active fluoroamine as a useful
key intermediate for the present production process.
The protected optically active fluoroamine, derived from the aromatic hydrocarbon
group-containing aldehyde, serves as a particularly useful key intermediate for easy industrial
application of the present production process.
The present invention will be described in more detail below by way of the following
examples. It should be noted that these examples are illustrative and are not intended to limit
the present invention thereto.
In the following examples, the abbreviations for chemical groups are as follows: Me =
methyl; Ph = phenyl; Boc = tert-butoxycarbonyl; i-Pr = isopropyl; and El = ethyl.
[Example 1]
To 200 mL of toluene, 30.00 g (399.41 mmol, 1.00 eq, S-configuration, optical
purity: 97%ee or higher) of an optically active hydoxyamine of the following formula:
[Chem. 14]

43.60 g (410.86 mmol, 1.03 eq) of an aldehyde of the following formula:
[Chem. 15]

and 0.76 g (4.00 mmol, 0.01 eq) of para-toluenesulfonic acid monohydrate were added. The
resulting liquid was stirred for 2 hours at room temperature. The conversion rate of the
reaction was determined to be 100% by gas chromatography of the reaction-terminated liquid.
The reaction-terminated liquid was vacuum concentrated and vacuum dried, thereby yielding
66.77 g of a 83:17 mixture of an imine-protected optically active hydroxyamine (imine form)
of the following formula:
[Chem. 16]

and an oxazolidine-protccted optically active hydroxyamine (oxazolidine form, oxazolidine
isomer ratio: about 3:2) of the following formula:
[Chem. 17]

The yield of the reaction product was quantitative (theoretical yield: 65.19 g). The gas
chromatographic purity of the reaction product was 98.9%. The 1H-NMR measurement
results of the reaction product (only the 1H-NMR peaks specific to the imine form and to the
oxazolidine form) are indicated below.
1H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / imine: 8.31

(s, 1H), oxazolidine (syn-anti isomer mixture): 5.46, 5.57 (s each, 1H in total; the attributions
of these isomer peaks was unidentified).
A pressure-proof reaction vessel of stainless steel (SUS) was charged with 30.00 g
(assumed as 179.46 mmol, 1.00 eq) of the mixture of the imine- and oxazolidine-protected
optically active hydroxyamines of the above formulas, 120 mL of acetonitrile and 28.51 g
(220.60 mmol, 1.23 eq) of diisopropylethylamine, followed by immersing the reaction vessel
in a cooling bath of-78°C and blowing 44.92 g (440.13 mmol, 2.45 eq) of sulfuryl fluoride
(SO2F2) from a cylinder into the reaction vessel. The resulting liquid was stirred for one
night at room temperature. The conversion rate of the reaction was determined to be 100%
by gas chromatography of the reaction-terminated liquid. The reaction-terminated liquid was
vacuum concentrated. The concentration residue was diluted with 100 mL of toluene,
washed twice with 50 mL of a saturated aqueous potassium carbonate solution and further
washed twice with 50 mL of water. The recovered organic phase was vacuum concentrated
and vacuum dried, thereby yielding 29.49 g of a protected optically active fluoroamine of the
following formula:
[Chem. 18]

The yield of the reaction product was 99%. The gas chromatographic purity of the recovered
organic phase was 92.1%. The 1H-NMR and 19F-NMR measurement results of the reaction
product are indicated below.
1 H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / 1.26 (d,
6.8Hz, 3H), 3.70 (m, 1H), 4.46 (dd, 45.9Hz, 6.8Hz, 2H), 7.40 (Ar-H, 3H), 7.75 (Ar-H, 2H),
8.34 (s, 1H).
19F-NMR [reference material: C6F6, deuterium solvent: CDCl3] δ ppm / 207.22 (dt,
15.0Hz, 45.9Hz, 1F).
To 100 mL of methanol, 20.40 g (123.48 mmol, 1.00 eq) of the protected optically active
fluoroamine of the above formula and 61.18 g (587.30 mmol, 4.76 eq) of 35% hydrochloric
acid were added. The resulting liquid was stirred for one night at room temperature. The
conversion rate of the reaction was determined to be 100% by 19F-NMR of the

reaction-terminated liquid. The reaction-terminated liquid was vacuum concentrated. The
concentration residue was diluted with 50 mL of water and washed three times with 50 mL of
toluene. With this, there was obtained about 75 mL of an aqueous solution containing an
optically active fluoroamine hydrochloride salt of the following formula:
[Chem. 19]

To the whole (assumed as 123.48 mmol, 1.00 eq) of the aqueous solution of the optically
active fluoroamine hydrogen chloride salt of the above formula, 100 mL of toluene, 73.44 g
(725.76 mmol, 5.88 eq) of triethylamine and 24.00 g (109.97 mmol, 0.89 eq) of Boc2O. The
resulting liquid was stirred for one night at room temperature. The conversion rate of the
reaction was determined to be 100% by 19F-NMR of the reaction-terminated liquid. The
reaction-terminated liquid was separated into two phases. The recovered organic phase was
washed twice with 30 mL of water, vacuum concentrated and vacuum dried, thereby yielding
19.71 g of a Boc-protected optically active fluoroamine (as a crude product) of the following
formula:
[Chem. 20]

The total yield of the crude product from the protected optically active fluoroamine via the
above two reaction steps was 90%. The gas chromatographic purity of the crude product was
94.4%.
The crude product was subjected to solvent displacement treatment by adding 30 mL of
n-heptane to the whole (19.71 g) of the crude product and vacuum concentrating the resulting
liquid. Then, 12.44 g of a purified product of the Boc-protected optically active fluoroamine
was obtained by recrystallization of the crude product from 40 mL of n-heptane. The
recovery of the purified product was 63%. The total yield of the purified product from the
optically active hydroxyamine via the above four reactions steps (including the
recrystallization) was 56%. The gas chromatographic purity of the purified product was
99.4%. The optical purity of the purified product was determined to be 98.6%ee by

19F-NMR of a Mosher's acid amide of the product (derived after the Boc deprotection). The
1H-NMR. and 19F-NMR measurement results of the purified product are indicated below.
1H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / 1.22 (d,
6.8Hz, 3H), 1.45 (s, 9H), 3.90 (br-d, 1H), 4.33 (ddd, 46.8Hz, 9.2Hz, 3.8Hz, 1H), 4.39 (ddd,
48.0Hz, 9.2Hz, 3.8Hz, 1H), 4.63 (br, 1H).
19F-NMR [reference material: C6F6, deuterium solvent: CDCl3] δ ppm / 196.03 (m,
1F).
[Example 2]
To 130 mL of toluene, 17.50 g (169.64 mmol, 1.00 eq, S-configuration, optical
purity: 97%ee or higher) of an optically active hydroxyamine of the following formula:
[Chem. 21]

18.60 g (175.27 mmol, 1.03 eq) of an aldehyde of the following formula:
[Chem. 22]

and 0.32 g (1.68 mmol, 0.01 eq) of para-toluenesulfonic acid monohydrate were added. The
resulting liquid was stirred for one night at room temperature. The conversion rate of the
reaction was determined to be 100% by 1H-NMR of the reaction-terminated liquid. The
reaction-terminated liquid was vacuum concentrated and vacuum dried, thereby yielding 36.14
g of a 57:43 mixture of an imine-protected optically active hydroxyamine (imine form) of the
following formula:
[Chem. 23]


and an oxazolidine-protected optically active hydroxyamine (oxazolidine form, oxazolidine
isomer ratio: about 2:1) of the following formula:
[Chem. 24]

The yield of the reaction product was quantitative (theoretical yield: 32.45 g). The gas
chromatographic purity of the reaction product was 96.7%. The 'H-NMR measurement
results of the reaction product (only the 1H-NMR peaks specific to the imine form and the
oxazolidine form) are indicated below.
1H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / imine: 8.29
(s, 1H), oxazolidine (syn-anti isomer mixture): 5.45, 5.48 (s each, 1H in total; the attributions
of these isomer peaks was unidentified).
A pressure-proof reaction vessel of stainless steel (SUS) was charged with the whole
(assumed as 169.64 mmol, 1.00 eq) of the mixture of the imine- and oxazolidine-protected
optically active hydroxyamines of the above formulas, 170 mL of acetonitrile and 87.00 g
(673.17 mmol, 3.97 eq) of diisopropylethylamine, followed by immersing the reaction vessel
in a cooling bath of-78°C and blowing 34.58 g (338.82 mmol, 2.00 eq) of sulfuryl fluoride
(SO2F2) from a cylinder into the reaction vessel. The resulting liquid was stirred for one
night at room temperature. The conversion rate of the reaction was determined to be 98% by
gas chromatography of the reaction-terminated liquid. The reaction-terminated liquid was
vacuum concentrated. The concentration residue was diluted with 100 mL of toluene,
washed twice with 50 mL of a saturated aqueous potassium carbonate solution and further
washed twice with 50 mL of water. The recovered organic phase was vacuum concentrated
and vacuum dried, thereby yielding 35.00 g of a protected optically active fluoroamine of the
following formula:
[Chem. 25]


The yield of the reaction product was quantitative (theoretical yield: 32.78 g). The gas
chromatographic purity of the reaction product was 93.8%. The 'H-NMR and ,9F-NMR
measurement results of the reaction product are indicated below.
1H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / 0.94 (d,
6.8Hz, 3H), 0.97 (d, 6.8Hz, 3H), 1.98 (m, 1H), 3.20 (m, 1H), 4.54 (dt, 47.2Hz, 8.6Hz, 1H),
4.65 (ddd, 47.2Hz, 8.6Hz, 3.8Hz, IH), 7.42 (Ar-H, 3H), 7.77 (Ar-H, 2H), 8.26 (s, 1H).
19F-NMR [reference material: C6F6, deuterium solvent: CDCl3] δ ppm / 202.81 (dt,
15.4Hz, 47.2Hz, 1F).
The whole (assumed as 169.64 mmol, 1.00 eq) of the protected optically active
fluoroamine of the above formula and 175.82 g (1687.79 mmol, 9.95 eq) of 35% hydrochloric
acid were added to 70 mL of toluene. The resulting liquid was stirred for one night at SOX.
The conversion rate of the reaction was determined to be 100% by 19F-NMR of the
reaction-terminated liquid. The reaction-terminated liquid was separated into two phases.
The recovered aqueous phase was vacuum concentrated and subjected three times to
azeotropic dehydration (vacuum concentration) with 50 mL of ethyl acetate. The
thus-obtained residue was washed by stirring with 75 mL, of ethyl acetate for 1 hour under
reflux, and then, subjected to hot filtration and vacuum drying, thereby yielding 17.99 g of an
optically active fluoroamine hydrogen chloride salt of the following formula:
[Chcm. 26]

The total yield of the product from the optically active hydroxyamine via the above three
reaction steps was 75%. The gas chromatographic purity of a free base of the product was
97.3%. The optical purity of the product was determined to be 99.9%ee by gas
chromatography of a Mosher's acid amide of the product (derived after the deionization).

The mass spectrum of the free base (by Cl method) was 106 (M+1). The 1H-NMR and
19F-NMR measurement results of the product are indicated below.
1H-NMR [reference material: (CH3)4Si, deuterium solvent: (CD3)2SO] δ ppm / 0.97 (d,
6.8Hz, 3H), 0.99 (d, 6.8Hz, 3H), 1.98 (m, 1H), 3.18 (br-d, 1H), 4.64 (ddd, 46.8Hz, 10.4Hz,
5.2Hz, 1H), 4.72 (ddd, 47.2Hz, 10.4Hz, 3.2Hz, 1H), 8.44 (br, 2H).
19F-NMR [reference material: C6F6, deuterium solvent: (CD3)2SO] δ ppm / 197.65
(m, 1F).
[Comparative Example 1]
With reference to Example 1, an imine-protected optically active hydroxyamine
(imine form) of the following formula:
[Chem. 27]

and an oxazolidine-protected optically active hydroxyamine (oxazolidine form) of the
following formula:
[Chem. 28]

were produced (R-configuration, optical purity: 97%ee or higher, imine-to-oxazolidine ratio:
88:12, oxazolidine isomer ratio: about 3:2).
A pressure-proof reaction vessel of stainless steel (SUS) was charged with 1.000 g
(6.127 mmol, 1.00 eq) of the mixture of the imine- and oxazolidine-protected optically active
hydroxyamines of the above formulas, 6 mL of acetonitrile and 2.468 g (24.390 mmol, 3.98
eq) of triethylamine, followed by immersing the reaction vessel in a cooling bath of-78°C
and blowing 1.807 g (17.705 mmol, 2.89 eq) of sulfuryl fluoride (SO2F2) from a cylinder into
the reaction vessel. The resulting liquid was stirred for one night at room temperature. The
conversion rate of the reaction was determined to be 96% by gas chromatography of the
reaction-terminated liquid. The reaction-terminated liquid was diluted with 20 mL of ethyl

acetate, washed with 10 mL of a saturated aqueous potassium carbonate solution and further
washed three times with 10 mL of water. The recovered organic phase was vacuum
concentrated and vacuum dried, thereby yielding 0.813 g of a 24:76 mixture of a protected
optically active fluoroamine of the following formula:
[Chem. 29]

and a quaternary ammonium salt of the following formula:
[Chem. 30]

The yield of the product was 44% (protected optically active fluoroamine: 11%, quaternary
ammonium salt: 33%). The 1H-NMR measurement results of the product (only the
1 H-NMR peaks specific to the protected optically active fluoroamine and to the quaternary
ammonium salt) are indicated below.
1 H-NMR [reference material: (CH3)4Si, deuterium solvent: CDCl3] δ ppm / protected
optically active fluoroamine: 8.34 (s, 1H), quaternary ammonium salt: 8.49 (s, 1H).
It is seen from the above results that: the target compound was produced, but the product
yield remained low, in Comparative Example 1 using triethylamine i.e. tertiary amine of
carbon number less than 7; whereas the target protected optically active fluoroamine was
produced with much higher yield in the production process of the present invention
(Examples).

WE CLAIM:-
I. A process for producing a protected optically active fluoroamine of the formula [3],
comprising: reacting an iminc-protcctcd optically active hydroxyamine of the formula [1], an
oxazolidine-protected optically active hydroxyamine of the formula [2] or a mixture thereof
with sulfuryl fluoride (SO2F2) in the presence of a tertiary amine (in which all of three
ammonia hydrogen atoms have been replaced by alkyl groups) having a carbon number of 7 to
18
[Chem.3l]

[Chcm. 32]

[Chem. 33]

where R1 and R2 each independently represent an alkyl group or an aromatic ring group: *
represents an asymmetric carbon; the stereochemistry of the asymmetric carbon is maintained
through the reacting; and the wavy line indicates in the formula (1) and in the formula (3) that
the nitrogen-carbon group is in an E-configuration, a Z-configuration or a mixture thereof and
indicates in the formula (2) that the substituent group R1 is in a syn-configuration, an
anti-configuration or a mixture thereof.

2. The process for producing the protected optically active fluoroamine according to claim
1, wherein R2 of the imine-protected optically active hydroxyamine of the formula [1] or the
oxazolidine-protected optically active hydoxyamine of the formula [2] is an aromatic
hydrocarbon group; and the tertiary amine has a carbon number of 8 to 12 and contains two or
more alkyl groups of 3 or more carbon atoms.
3. The process for producing the protected optically active fluoroamine according to claim
1 or 2, comprising forming the imine-protected optically active hydroxyamine of the formula
[1] or the oxazolidine-protected optically active hydroxyamine of the formula [2] by
dchydrative condensation of an optically active hydroxyamine of the formula [4] and an
aldehyde of the formula [S]
[Chem. 34]

[Chcm. 35]

where R1 and R2 each independently represent an alkyl group or an aromatic ring group; and *
represents an asymmetric carbon of which the stereochemistry is maintained through the
dehydrative condensation.
4. The process for producing the protected optically active fluoroamine according to claim
3, wherein R1 is an alkyl group having 1 to 9 carbon atoms in the formula [4].
5. The process for producing the protected optically active fluoroamine according to claim
3 or 4, wherein the dehydrative condensation is preformed in the presence of an acid catalyst.

6. The process for producing the protected optically active fluoroamine according to claim
5, wherein the acid catalyst is either para-toluenesulfonic acid or pyridinium
para-toluenesulfbnate.
7. The process for producing the protected optically active fluoroamine according to any
one of claims 1 to 6, wherein the tertiary amine is diisopropylethylamine.
8. A process for producing an optically active fluoroamine of the formula [6], comprising:
performing, under acidic conditions, hydrolysis of the protected optically active fluoroamine
of the formula [3] produced by the process according to any one of claim 1 1 to 7
[Chem. 36]

where R1 represents an alkyl group or an aromatic ring group; and * represents an asymmetric
carbon of which the stereochemistry is maintained through the hydrolysis.
9. The process for producing the optically active fluoroamine according to claim 8,
wherein the hydrolysis is performed by reacting the protected optically active fluoroamine of
the formula [3] with an aqueous solution of an acid catalyst; and the acid catalyst is either
hydrogen chloride or sulfuric acid.
10. A protected optically active fluoroamine of the formula [3]
[Chem. 37]

where R1 and R2 each independently represent an alkyl group or an aromatic ring group; *
represents an asymmetric carbon; and the wavy line indicates that the nitrogen-carbon double

Disclosed is a process for producing a protected optically active fluoroamine, which comprises the step of reacting
an imine-protected optically active hydroxyamine, an oxazolidine-protected optically active hydroxyamine, or a mixture of the
imine-protected optically active hydroxyamine and the oxazolidine-protected optically active hydroxyamine with sulfuryl fluoride
(SO2F2) in the presence of a tertiary amine having 7 to 18 carbon atoms (an amine produced by substituting all of three hydrogen
atoms in ammonia by alkyl groups). The desired optically active fluoroamine can be produced by hydrolyzing the protected optically
active fluoroamine under acidic conditions.