TECHNICAL FIELD
[0001] This invention relates to a production process for
a-trifluoromethyl-ß-substituted-ß-amino acids which are important as
intermediates of drugs and medicines.
BACKGROUND OF INVENTION
[0002] a-trifluoromethyl-ß-substituted-ß-amino acids are important as
intermediates of drugs and medicines. As conventional production processes,
there are (1) a process of allowing
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters to react with
hydrogen azide (HN3) (see Non-patent Citation 1), (2) a process for
allowing derivative of 2-bromo-3,3,3-trifluoropropanoic acid to react with
imines (see Non-Patent Citation 2), and the like.
[0003] While many synthesis examples for ß-position non-substituted body
by reaction of derivative of a-trifluoromethyl acrylic acid and nitrogen
nucleophile have been reported, production process for ß-position
substituted body has been extremely limited.
PRIOR ART CITATIONS
NON-PATENT CITATIONS
[0004] Non-patent Citation 1: Tetrahedron (Great Britain), 2006, Volume
62, p.11760-11765
Non-patent Citation 2: Chemical Communications (Great Britain), 2006,
p. 3628-3630
SUMMARY OF INVENTION
[0005] An object of the present invention is to provide practical production
methods for a-trifluoromethyl-ß-substituted-ß-amino acids. For this
purpose, it is required to solve the problems in conventional techniques.
[0006] For Non-patent Citation 1, it is required to avoid use of hydrogen
azide which is explosive and toxic. For Non-patent Citation 2, it is required
to improve atomic economy. Further, in these Non-patent Citations,
ß-position substituent is limited to aromatic ring group or substituted
aromatic ring group.
[0007] Additionally, in production of amino acids like the present
invention, it is eagerly required to produce free amino acid [N2N-CO2H] in
which protective groups for amino group and carboxyl group are freely
selectable according to use. In order to design a synthesis process
(including a de-protection step for functional group) of
a-trifluoromethyl-ß-substituted-ß-amino acids which are free amino acids
and objects of the present invention, it is required to sufficiently take
account of side-reactions (epimerization, de-hydrogen fluoride, de-ammonia,
and the like) due to a high acid degree of a-position proton. Actually it has
been reported that hydrolysis of a product obtained by Reformatsky reaction
to carboxyl group cannot easily proceed (see Non-patent Citation 2).
[0008] Lastly a control of stereochemistry to a-position trifluoromethyl
group becomes an important problem for ß-position substituted body.
[0009] The present inventors have made eager studies in view of the
above-mentioned problems. As a result, it has been found that
a-trifluoromethyl-ß-substituted-ß-amino acids can be produced by allowing
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters to react with
hydroxylamine to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated
esters into dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acids (a first step), and by
hydrogenolyzing the dehydrogenated closed-ring body (a second step).
According to this production process, free amino acid which has substituent
at ß-position and whose functional group is not protected can be produced.
Additionally, ß-position substituent is not limited to aromatic ring group or
substituted aromatic ring group. Further, it has become apparent that a
relative configuration of a-trifluoromethyl-ß-substituted-ß-amino acids as
object products can be controlled even if a stereochemistry of double bond
of a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters as raw material
substrates is a mixture of E-body and Z-body (the relative configuration can
be highly controlled particularly in case that ß-position substituent is alkyl
group or substituted alkyl group).
[0010] Dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acids obtained at the first step are
novel compounds, and it can be easily converted into
a-trifluoromethyl-ß-substituted-ß-amino acids by hydrogenolysis, and
therefore it is a very useful precursor of the amino acids. Additionally,
a-trifluoromethyl-ß-substituted-ß-amino acids corresponding to free amino
acids obtained by the present invention are also novel compounds and very
important not only as intermediates of drugs and medicines but also as
analog of natural P-amino acids having biological activity.
[0011] In other words, the present invention includes [Invention 1] to
[Invention 6] and provides practical production processes for
a-trifluoromethyl-ß-substituted-ß-amino acids.
[0012] [Invention 1] A process of producing
a-trifluoromethyl-ß-substituted-ß-amino acids represented by a general
formula [4]
[chem.4]

by allowing a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by a general formula [1]
[chem.1]

to react with hydroxylamine represented by a general formula [2]
[chem.2]

to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters into
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [3]
[chem.3]

, and by hydrogenolyzing the dehydrogenated closed-ring body,
Wherein, in the formulae, R1 is alkyl group, substituted alkyl group,
aromatic ring group, substituted aromatic ring group, alkoxycarbonyl group
or substituted alkoxycarbonyl group, and R is alkyl group or substituted
alkyl group; a wavy line in the general formula [1] indicates that
stereochemistry of double bond is E-body, Z-body or a mixture of E-body
and Z-body; and a wavy line in the general formula [3] and in the general
formula [4] indicates that stereochemistry of R1 to trifluoromethyl group is
syn-body, anti-body, or a mixture of syn-body and anti-body.
[0013] [Invention 2] A process of producing
a-trifluoromethyl-ß-substituted-ß-amino acids represented by a general
formula [7]
[chem.8]

by allowing a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by a general formula [5]
[chem.5]

to react with hydroxylamine represented by a general formula [2]
[chem.6]

to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters into
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [6]
[chem.7]

, and by hydrogenolyzing the dehydrogenated closed-ring body,
Wherein, in the formulae, R3 is alkyl group or substituted alkyl group, and
R4 is alkyl group; a wavy line in the general formula [5] indicates that
stereochemistry of double bond is E-body, Z-body or a mixture of E-body
and Z-body; representation of relative configuration in the general formula
[6] indicates that stereochemistry of R3 to trifluoromethyl group is
anti-body; and representation of relative configuration in the general
formula [7] indicates that stereochemistry of R to trifluoromethyl group is
syn-body.
[0014] [Invention 3] A dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid, represented by a general
formula [3]
[chem.9]

where R1 is alkyl group, substituted alkyl group, aromatic ring group,
substituted aromatic ring group, alkoxycarbonyl group or substituted
alkoxycarbonyl group; and a wavy line indicates that stereochemistry of R1
to trifluoromethyl group is syn-body, anti-body, or a mixture of syn-body
and anti-body.
[0015] [Invention 4] A dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [6]
[chem.10]

where R3 is alkyl group or substituted alkyl group; and representation of
relative configuration indicates that stereochemistry of R to
trifluoromethyl group is anti-body.
[0016] [Invention 5] a-trifluoromethyl-ß-substituted-ß-amino acids
represented by a general formula [4]
[chem.11]

where R1 is alkyl group, substituted alkyl group, aromatic ring group,
substituted aromatic ring group, alkoxycarbonyl group or substituted
alkoxycarbonyl group; and a wavy line indicates that stereochemistry of R1
to trifluoromethyl group is syn-body, anti-body, or a mixture of syn-body
and anti-body.
[0017] [Invention 6] a-trifluoromethyl-ß-substituted-ß-amino acids
represented by a general formula [7]
[chem.12]

where R3 is alkyl group or substituted alkyl group; and representation of
relative configuration indicates that stereochemistry of R to
trifluoromethyl group is syn-body.
DETAILED DESCRIPTION
[0018] Advantageous points of the present invention over prior art will be
discussed hereinafter.
[0019] According to the production process of the present invention, it is
not required to use explosive and toxic reaction agents, and atomic economy
is extremely high. Additionally, according to the present production process,
novel a-trifluoromethyl-ß-substituted-ß-amino acids which are free amino
acids whose functional groups are not protected can be produced; ß-position
substituent cannot be also limited to aromatic ring group or substituted
aromatic ring group; and relative stereochemistry of a-position and
ß-position can be also controlled.
[0020] Thus, the production process of the present invention is a
production process which not only solves all problems of prior art but also
is easily industrially carried out because of being simple in operation and
high in productivity while hardly by-producing impurities which are
difficult to be separated.
[0021] Detailed discussion will be made on production process of
a-trifluoromethyl-ß-substituted-ß-amino acids, according to the present
invention.
[0022] The present invention is a process of producing
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the general
formula [4] by allowing a-trifluoromethyl-ß-substituted-a,ß-unsaturated
esters represented by a general formula [1] to react with hydroxylamine
represented by the general formula [2] to convert
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters into dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid
represented by the general formula [3] (the first step), and by
hydrogenolyzing the dehydrogenated closed-ring body (the second step).
[0023] (1) First Step
R1 of a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by the general formula [1] is alkyl group, substituted alkyl
group, aromatic ring group, substituted aromatic ring group, alkoxycarbonyl
group or substituted alkoxycarbonyl group. Of these, alkyl group and
substituted alkyl group are preferable, and particularly alkyl group is more
preferable.
[0024] Alkyl group has a carbon number of from 1 to 18 and can take
linear or branched chain structure or cyclic structure (in case that the carbon
number is not less than 3). Aromatic ring group has a carbon number of
from 1 to 18 and can be aromatic hydrocarbon group such as phenyl group,
naphthyl group, anthryl group or the like, or aromatic heterocycle group
containing heteroatom such as nitrogen atom, oxygen atom, sulfur atom or
the like, for example, pyrrolyl group, furyl group, thienyl group, indolyl
group, benzofuryl group, benzothienyl group or the like. Alkyl group (R) of
alkoxycarbonyl group (-CO2R) is the same as the above-mentioned alkyl
group.
[0025] The alkyl group, aromatic ring group and alkoxycarbonyl group
may have an arbitrary number of substituents on arbitrary atoms and in an
arbitrary combination (corresponding to substituted alkyl group, substituted
aromatic ring group and substituted alkoxycarbonyl group, respectively).
Examples of such substituents are halogen atom such as fluorine, chlorine,
bromine and/or iodine; azide group; nitro group; lower alkyl group such as
methyl group, ethyl group, propyl group and/or the like; lower haloalkyl
group such as fluoromethyl group, chloromethyl group, bromomethyl group
and/or the like; lower alkoxy group such as methoxy group, ethoxy group,
propoxy group and/or the like; lower haloalkoxy group such as
fluoromethoxy group, chloromethoxy group, bromomethoxy group and/or
the like; lower alkylamino group such as dimethylamino group,
diethylamino group, dipropylamino group and/or the like; lower alkylthio
group such as methylthio group, ethylthio group, propylthio group and/or
the like; cyano group; lower alkoxycarbonyl group such as
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group
and/or the like; aminocarbonyl group (CONH2); lower aminocarbonyl group
such as dimethylaminocarbonyl group, diethylaminocarbonyl group,
dipropylaminocarbonyl group and/or the like; unsaturated group such as
alkenyl group, alkynyl group and/or the like; aromatic ring group such as
phenyl group, naphthyl group, pyrrolyl group, furyl group, thienyl group
and/or the like; aromatic ring oxy group such as phenoxy group, naphthoxy
group, pyrrolyloxy group, furyloxy group, thienyloxy group and/or the like;
aliphatic heterocycle group such as piperidyl group, piperidino group,
morpholinyl group and/or the like; hydroxyl group; protected hydroxyl
group; amino group (including amino acid or peptide residue group);
protected amino group; thiol group; protected thiol group; aldehyde group;
protected aldehyde group; carboxyl group; protected carboxyl group; and/or
the like.
[0026] In the present specification, the following terms are used to mean
matters mentioned below: "lower" means linear or branched chain structure
having carbon number of from 1 to 6, or cyclic structure (in case that carbon
number is not less than 3) having carbon number of from 1 to 6. In case that
"unsaturated group" is double bond (alkenyl group), either geometrical
isomerism of E-body or Z-body can be taken. As "protective groups for
hydroxyl group, amino group, thiol group, aldehyde group and carboxyl
group", protective groups or the like described in Protective Groups in
Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. may be
used (two or more functional groups may be protected by one protective
group). Additionally, to "unsaturated group", "aromatic ring group",
"aromatic ring oxy group" and "aliphatic heterocycle group", substitution of
halogen atom, azide group, nitro group, lower alkyl group, lower haloalkyl
group, lower alkoxy group, lower haloalkoxy group, lower alkylamino
group, lower alkylthio group, cyano group, lower alkoxycarbonyl group,
aminocarbonyl group, lower alkylaminocarbonyl group, hydroxyl group,
protected hydroxyl group, amino group, protected amino group, thiol group,
protected thiol group, aldehyde group, protected aldehyde group, carboxyl
group, protected carboxyl group, and/or the like can be made. These
substituents include one serving as nucleophilic agent in the first step and
one which is reduced in the second step, in which desired reaction in each
step can be selectively accomplished by employing preferable reaction
condition.
[0027] R of a-tnfluorornethyl-ß-substituted-a,ß-unsaturated esters
represented by the general formula [1] is alkyl group or substituted alkyl
group. Of these, alkyl group is preferable, and particularly methyl group
and ethyl group are more preferable.
[0028] Alkyl group and substituted alkyl group are the same as alkyl group
and substituted alkyl group of the above-mentioned R1.
[0029] A wavy line in a-trifluoromethyl-ß-substituted-a,ß-unsaturated
esters represented by the general formula [1] indicates that stereochemistry
of double bond is E-body, Z-body or a mixture of E-body and Z-body.
[0030] a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters represented
by the general formula [1] can be produced with reference to Journal of
Fluorine Chemistry (Holland), 2002, Volume 113, p. 177-183 and
Tetrahedron Letters (Great Britain), 2001, Volume 42, p. 5929-5931, and the
like.
[0031] A used amount of hydroxylamine represented by the formula [2] is
preferably not less than 0.7 mole, usually preferably 0.8 to 10 moles, and
particularly more preferably 0.9 to 5 moles, relative to 1 mole of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters represented by the
general formula [1].
[0032] As hydroxylamine represented by the formula [2], its aqueous
solution, its polymer-carried body, its salt (hydrochloric acid salt, sulfuric
acid salt, phosphoric acid salt, nitric acid salt and the like) formed with acid,
and the like can be used in addition to hydroxylamine itself. In case of using
the salt produced with acid, a method in which hydroxylamine is made free
in the presence of base in a reaction system to be provided to reaction is
convenient.
[0033] Examples of such base are organic base such as triethylamine,
diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine,
2,4-lutidine, 2,6-lutidine, 3,5-lutidine, 2,4,6-collidine and the like, and
inorganic base such as sodium hydrogencarbonate, potassium
hydrogencarbonate, sodium carbonate, potassium carbonate, sodium
hydroxide, potassium hydroxide and the like. Of these, triethylamine,
diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, sodium
carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide
are preferable, and particularly triethylamine, diisopropylethylamine,
pyridine, 2,6-lutidine, sodium carbonate and potassium carbonate are more
preferable.
[0034] A used amount of such base is not less than 0.7 mole, usually
preferably 0.8 to 10 moles, particularly more preferably 0.9 to 5 moles,
relative to 1 mole of hydroxylamine contained in salt produced with acid.
[0035] Examples of the reaction solvent are aliphatic hydrocarbon family
such as n-hexane, cyclohexane, n-heptane and the like; aromatic
hydrocarbon family such as benzene, toluene, xylene and the like;
halogenated hydrocarbon family such as methylene chloride, chloroform,
1,2-dichloroethane and the like; ether family such as diethyl ether,
tetrahydrofuran, diisopropyl ether, tert-butylmethyl ether and the like; ester
family such as ethyl acetate, n-butyl acetate and the like; nitrile family such
as acetonitrile, propionitrile and the like; amide family such as
N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone and the like; dimethylsulfoxide; alcohol
family such as methanol, ethanol, n-propanol, isopropanol, n-butanol and
the like; water; and the like. Of these, n-hexane, n-heptane, toluene, xylene,
methylene chloride, tetrahydrofuran, diisopropyl ether, tert-butylmethyl
ether, ethyl acetate, acetonitrile, propionitrile, N,N-dimethylformamide,
dimethylsulfoxide, methanol, ethanol, n-propanol and isopropanol are
preferable, and particularly n-heptane, toluene, methylene chloride,
tetrahydrofuran, ethyl acetate, acetonitrile, N,N-dimethylformamide,
methanol, ethanol and isopropanol are more preferable. These reaction
solvents may be used singly or in combination. Additionally, for the present
invention, reaction can be made by using no solvent.
[0036] A used amount of the reaction solvent is not less than 0.01 L (liter),
usually preferably 0.03 to 10 L, particularly more preferably 0.05 to 7 L,
relative to 1 mole of a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by the general formula [1].
[0037] A temperature condition is sufficient to be within a range of from
-30 to +120 °C, and usually preferably from -20 to +110 °C and particularly
more preferably from -10 to +100 °C.
[0038] A reaction time is sufficient to be within a range of not longer than
72 hours, and different according to raw material substrate and reaction
condition. Therefore, it is preferable to track the progressing status of a
reaction by using analytical means such as gas chromatography, liquid
chromatography, nuclear magnetic resonance or the like and to determine a
time at which the raw material substrate is almost diminished, as a terminal
point.
[0039] An after-treatment is made as follows: A reaction-terminated liquid
(the reaction solvent is concentrated if necessary) is diluted with an organic
solvent (for example, n-hexane, n-heptane, toluene, xylene, methylene
chloride, diisopropyl ether, tert-butylmethyl ether, ethyl acetate or the like),
and washed with water or an aqueous solution of an inorganic base of alkali
metal (for example, sodium hydrogencarbonate, potassium
hydrogencarbonate, sodium carbonate, potassium carbonate or the like)
(dried over a drying agent such as anhydrous sodium sulfate, anhydrous
magnesium sulfate or the like if necessary), followed by concentrating a
recovered organic layer, so that dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [3] can be obtained as a crude product. A wavy line in the general
formula [3] indicates that the stereochemistry of R1 to trifluoromethyl group
is syn-body, anti-body, or a mixture of syn-body and anti-body. Particularly
in case that ß-position substituent is alkyl group or substituted alkyl group,
a relative configuration can be controlled to anti-body at a high level [not
less than 90%de (diastereomer excess)]. The crude product can be purified
to a high chemical purity by activated carbon treatment, distillation,
recrystallization, column chromatography and/or the like, if necessary.
According to column chromatography, minor diastereomer can be also
isolated.
[0040] In the present invention, the second step can be continuously
carried out without carrying out the after-treatment at the first step.
Specifically, hydrogenolyzing can be carried out by adding a transition
metal catalyst into a reaction-terminated liquid at the first step (adding the
reaction solvent at the second step if necessary), and putting the liquid in an
atmosphere of hydrogen gas (H2). An object of the present invention is to
provide a practical production process for
a-trifluoromethyl-ß-substituted-ß-amino acids. From such a viewpoint, it
can be said that the above-mentioned one-pot reaction is a preferable mode.
[0041] The stereochemistry of dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the general
formula [6] is the same as that of compound represented by a general
formula [8] because of representing a relative configuration.
[chem.13]

[0042] (2) Second Step
The second step is accomplished by allowing dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid
represented by the general formula [3] to react with hydrogen gas (H2) in
the presence of a transition metal catalyst.
[0043] Examples of the transition metal catalyst are platinum catalyst such
as platinum black, platinum/activated carbon, platinum/graphite,
platinum/alumina, platinum/zirconia, platinum oxide and the like; nickel
catalyst such as reduced nickel, Raney nickel, Raney nickel sponge, Raney
nickel provided with platinum, and the like; iridium catalyst such as iridium
black, iridium/calcium carbonate, iridium oxide and the like; palladium
catalyst such as palladium black, palladium sponge, palladium/activated
carbon, palladium/alumina, palladium/calcium carbonate,
palladium/strontium carbonate, palladium/barium sulfate, palladium
hydroxide, palladium acetate, palladium chloride and the like; and the like.
Of these, palladium catalyst is preferable, and particularly
palladium/activated carbon, palladium/alumina, palladium/calcium
carbonate, palladium/barium sulfate and palladium hydroxide are more
preferable. These transition metal catalysts may be used singly or in
combination. A carried amount of transition metal in case of using a catalyst
in which transition metal is carried on a carrier is sufficient to be from 0.1
to 50 wt%, and usually preferably from 0.5 to 40 wt%, particularly more
preferably from 1 to 30 wt%. Additionally, transition metal catalyst may be
used in the form of hydrated product. Further, transition metal catalyst
preserved in water or inactive liquid may be used in order to improve safety
for treatment and in order to prevent a metal surface from oxidation.
[0044] A used amount of transition metal catalyst is sufficient to be a
catalytic amount, and usually preferably from 0.00001 to 0.5 mole,
particularly more preferably from 0.0001 to 0.3 mole, relative to 1 mole of
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the general
formula [3].
[0045] A used amount of hydrogen gas is sufficient to be not less than 1
mole, and usually preferably an excessive amount, particularly more
preferably an excessive amount under a pressured condition, relative 1 mole
of dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the general
formula [3].
[0046] Such pressured condition for hydrogen gas is sufficient to be within
a range of not higher than 5 MPa, usually preferably from 0.01 to 4 MPa,
particularly more preferably from 0.03 to 3 MPa.
[0047] Examples of the reaction solvent are aromatic hydrocarbon family
such as benzene, toluene, xylene and the like; ether family such as diethyl
ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether and the
like; ester family such as ethyl acetate, n-butyl acetate and the like; alcohol
family such as methanol, ethanol, n-propanol, isopropanol, n-butanol and
the like; water; and the like. Of these, toluene, xylene, tetrahydrofuran,
diisopropyl ether, tert-butyl methyl ether, ethyl acetate, methanol, ethanol,
n-propanol and isopropanol are preferable, and particularly toluene,
tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol are more
preferable. These reaction solvents may be used singly or in combination.
Additionally, for the present invention, reaction can be made by using no
solvent.
[0048] A used amount of the reaction solvent is sufficient to be not less
than 0.01 L, and usually preferably from 0.03 to 20 L, particularly more
preferably from 0.05 to 10 L, relative to 1 mole of dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid
represented by the general formula [3].
[0049] A temperature condition is sufficient to be within a range of from
-30 to +150 °C, and usually preferably from -20 to +125 °C and particularly
more preferably from -10 to +100 °C.
[0050] A reaction time is sufficient to be within a range of not longer than
48 hours, and different according to raw material substrate and reaction
condition. Therefore, it is preferable to track the progressing status of a
reaction by using analytical means such as gas chromatography, liquid
chromatography, nuclear magnetic resonance or the like and to determine a
time at which the raw material substrate is almost diminished, as a terminal
point.
[0051] An after-treatment is made as follows: The transition metal catalyst
remaining in a reaction-terminated liquid is filtered, and then a filtrate is
concentrated, thereby making it possible to obtain
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the general
formula [4] as a crude product. A wavy line in the general formula [4]
indicates that the stereochemistry of R1 to trifluoromethyl group is syn-body,
anti-body, or a mixture of syn-body and anti-body. Particularly in case that
ß-position substituent is alkyl group or substituted alkyl group, a relative
configuration can be controlled to syn-body at a high level [not less than
90%de (diastereomer excess)]. The crude product can be purified to a high
chemical purity by activated carbon treatment, distillation, recrystallization,
column chromatography and/or the like, if necessary. According to column
chromatography, minor diastereomer can be also isolated. Additionally,
isolation can be made upon conversion to "salt formed with acid" or "salt
formed with base", and purification to a further high chemical purity can be
made by recrystallization or the like of the salt if necessary.
[0052] Examples of such acid are inorganic acid such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid and the like, and organic acid
such as maleic acid, fumaric acid, phthalic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, malic acid, tartaric acid,
mandelic acid and the like (arbitrary optically active body can be used in
case that optical isomers exist, if necessary).
[0053] Examples of such base are inorganic base such as lithium hydroxide,
sodium hydroxide, potassium hydroxide, calcium hydroxide and the like,
and organic base such as triethylamine, diisopropylethylamine,
dicyclohexylamine, cis- or trans-1,2-diaminocyclohexane (arbitrary
optically active body can be used in case that optical isomers exist, if
necessary) and the like.
[0054] The stereochemistry of a-trifluoromethyl-ß-substituted-ß-amino
acids represented by the general formula [7] is the same as that of
compound represented by a general formula [9] because of representing a
relative configuration.
[chem.14]

a-trifluoromethyl-ß-substituted-ß-amino acids represented by the general
formula [7] are obtained from dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the general
formula [6], while a-trifluoromethyl-ß-substituted-ß-amino acids
represented by the general formula [9] are obtained from dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid
represented by the general formula [8].
[0055] According to the present invention,
a-trifluoromethyl-ß-substituted-ß-amino acids can be produced by allowing
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters to react with
hydroxylamine to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated
esters into dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid and by hydrogenolyzing the
dehydrogenated closed-ring body (Mode 1)
[0056] Concerning the raw material substrate, it is more preferable that
substituent at ß-position is alkyl group or substituted alkyl group, and ester
group is alkyl ester. The raw material substrate is readily available,
featuring that desired reaction effectively proceeds and that the relative
configuration of obtained a-trifluoromethyl-ß-substituted-ß-amino acids
can be also controlled at a high level (Mode 2).
[0057] Dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid, obtained in Mode 1 is novel
compound and can be easily converted to
a-trifluoromethyl-ß-substituted-ß-amino acids under hydrogenolysis so as
to be very useful precursor of the amino acids (Mode 3).
[0058] In Mode 3, a case that substituent at ß-position is alkyl group or
substituted alkyl group is more preferable mode (Mode 4).
[0059] a-trifluoromethyl-ß-substituted-ß-amino acids as free amino acids,
obtained in Mode 1 are also novel compounds and very important not only
as intermediates of drugs and medicines but also as analog of natural
P-amino acid having biological activity (Mode 5).
[0060] In Mode 5, a case that substituent at ß-position is alkyl group or
substituted alkyl group is more preferable mode (Mode 6).
[0061] [Examples]
Modes carrying out the invention will be specifically discussed with
reference to Examples, in which the present invention is not limited to these
Examples.
[0062] [Example 1]
To 500 mg (2.379 mmol, 1.00 eq) of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters (E-body : Z-body =
44 : 56) represented by the following formula:
[chem.15]

, 5 mL of methanol, 563 mg (5.564 mmol, 2.34 eq) of triethylamine and 333
mg (4.792 mmol, 2.01 eq) of hydrochloric acid salt of hydroxylamine
represented by the following formula:
[chem.16]

were added, and then stirring was made at room temperature for 2 hours. A
conversion rate was 99 % according to gas chromatography of a
reaction-terminated liquid. The reaction-terminated liquid was diluted with
30 mL of ethyl acetate, and washing was made two times with 30 mL of
water. A recovered organic layer was dried over anhydrous magnesium
sulfate, concentrated under reduced pressure, and dried under vacuum,
thereby obtaining 300 mg of dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the following
formula:
[chem.17]

A yield was 64 %. A gas chromatography purity (an analytical value at the
time of measuring the conversion rate of the reaction-terminated liquid) was
90.8 %. A product was single diastereomer according to 1H-NMR and
19F-NMR (a relative configuration was determined to be anti-body
according to a single crystal X-ray structural analysis which will be
discussed after)
[0063] Results of 1H-NMR and 19F-NMR of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters and dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid are
shown below.
[0064] a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters (gas
chromatography purity: 97.5 %):
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
1.09 (m, 6H), 1.33 (m, 3H), 3.08 (Z-body, m, 1H in total), 3.29 (E-body, m,
1H in total), 4.29 (m, 2H), 6.56 (E-body, d, 10.2 Hz, 1H in total), 6.97
(Z-body, d, 11.0 Hz, 1H in total); and 19F-NMR (reference material: C6F6,
deuterated solvent: CDCl3), d ppm: 97.80 (E-body, s, 3F in total), 103.05
(Z-body, s, 3F in total).
[0065] Dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid:
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
1.03 (d, 7.2 Hz, 3H), 1.05 (d, 7.2 Hz, 3H), 1.99 (m, 1H), 3.31 (dq, 4.2 Hz,
9.2 Hz, 1H), 3.74 (m, 1H), 7.10 (br, 1 H); and 19F-NMR (reference material:
C6F6, deuterated solvent: CDCl3), d ppm: 94.35 (s, 3F).
[0066] A HR-MS of dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid is shown below.
Obsd. m/z: 198.073 (Calc. Mass: 198.074, Error (ppm): -1.4, Assignment:
C7H11NO02F3+, Calc. Structure: [M+H]+).
[0067] To 100 mg (0.507 mmol, 1.00 eq) of dehydrogenated closed-ring
body of a-trifluoromethyl-ß-substituted-ß-amino acid represented by the
above formula, 3 mL of methanol and 2.4 mg (50% hydrated product,
0.00056 mmol, 0.001 eq) of 5% palladium/activated carbon were added, and
the pressure of hydrogen gas (H2) was set at 0.6 MPa, followed by making
stirring over night at room temperature. A conversion rate was 92 %
according to gas chromatography of the reaction-terminated liquid. The
reaction-terminated liquid was Celite-filtered, and the filtrate was
concentrated under vacuum and dried under reduced pressure, thereby
obtaining 109 mg of a-trifluoromethyl-ß-substituted-ß-amino acids
represented by the following formula:
[chem.18]

A yield was quantitative. The product was single diastereomer according to
1H-NMR and 19F-NMR.
[0068] An excessive amount of concentrated hydrochloric acid was added,
and concentration under vacuum and drying under reduced pressure were
made, thereby obtaining HC1 salt of
a-trifluoromethyl-ß-substituted-ß-amino acids as crystal. According to the
single crystal X-ray structural analysis, the relative configuration of
a-position and ß-position was syn-body.
[0069] To 40 mL of methanol, 4.52 g (19.2 mmol) of the hydrochloric acid
salt similarly produced and 3.65 g (19.2 mmol, 1.00 eq) of
p-toluenesulfonic acid monohydrate were added. Dissolving under heating
was made at 40 to 50 °C, and methanol was concentrated under reduced
pressure. Then, 27 mL of isopropanol and 6 mL of n-heptane were added to
the residue, and dissolving under heating was made at 90 °C, followed by
gradually lowering the temperature to room temperature. Precipitated
crystal was filtered and washed with a small amount of n-heptane, followed
by being dried under vacuum, thereby obtaining 6.12 g of p-toluenesulfonic
acid salt of a-trifluoromethyl-ß-substituted-ß-amino acids. The recovery
was 86 %. The diastereomer ratio was syn-body : anti-body = >98 : 2
according to 1H-NMR and 19F-NMR analyses.
[0070] Results of 1H-NMR and 19F-NMR of
a-trifluoromethyl-ß-substituted-ß-amino acids, the HC1 salt and the
p-toluenesulfonic acid salt are shown below.
[0071] a-trifluoromethyl-ß-substituted-ß-amino acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), d
ppm: 0.90 (d, 6.8 Hz, 3H), 0.94 (d, 6.8 Hz, 3H), 2.00 (m, 1H), 3.29 (m, 1H),
3.46 (m, 1H); and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), d ppm:
12.33 (d, 9.4 Hz, 3F).
[0072] HC1 salt of a-trifluoromethyl-ß-substituted-ß-amino acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), 8
ppm: 0.90 (d, 6.8 Hz, 3H), 0.93 (d, 6.8 Hz, 3H), 2.00 (m, 1H), 3.53 (m, 2H);
and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), d ppm:
12.51 (d, 12.0 Hz, 3F).
[0073] p-Toluenesulfonic acid salt of
a-trifluoromethyl-ß-substituted-ß-amino acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), d
ppm: 0.92 (d, 7.0 Hz, 3H), 0.95 (d, 7.0 Hz, 3H), 2.02 (m, 1H), 2.27 (s, 3H),
3.43 - 3.54 (m, 2H), 7.24 (d, 8.3 Hz, 2H), 7.56 (d, 8.3 Hz, 2H) / NH2, CO2H
and SO3H could not be identified; and 19F-NMR (reference material:
CF3SO3K, deuterated solvent: D2O), d ppm: 12.43 (d, 9.0 Hz, 3F).
[0074] A HR-MS of a-trifluoromethyl-ß-substituted-ß-amino acids is
shown below.
Obsd. m/z: 200.089 (Calc. Mass: 200.089, Error (ppm): -0.6, Assignment:
C7H13NO2F3+, Calc. Structure: [M+H]+).
[0075] [Example 2]
To 45 mL of methanol, 7.70 g (42.3 mmol, 1.00 eq) of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters (E-body : Z-body =
61 : 39) represented by the following formula:
[chem.19]

was added, and cooling was made by an ice bath. Then, 2.79 g (42.2 mmol,
1.00 eq) of 50% aqueous solution of hydroxylamine represented by the
following formula:
[chem.20]

was added, and stirring was made at 20 °C over night. Further, stirring was
made at 30 to 35 °C for 3 hours and 30 minutes. According to ]H- and
19F-NMR analyses of the reaction mixture liquid, it was confirmed that
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the following
formula:
[chem.21]

was quantitatively produced as single diastereomer (>95 : 5)(the relative
configuration of major diastereomer was determined to be anti-body from
the similarity to Example 1).
[0076] Results of 1H- and 19F-NMR of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters and dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid are
shown below.
[0077] a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters:
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
1.33 (m, 3H), 2.09 (Z-body, m, 3H in total), 2.17 (E-body, m, 3H in total),
4.29 (m, 2H), 6.95 (E-body, m, 1H in total), 7.33 (Z-body, m, 1H in total);
and
19F-NMR (reference material: C6H6, deuterated solvent: CDCl3), d ppm:
97.62 (E-body, s, 3F in total), 102.98 (Z-body, s, 3F in total).
[0078] Dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid:
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
1.47 (d, 6.4 Hz, 3H), 3.19 (m, 1H), 4.14 (m, 1H) / NH could not be
identified; and
l9F-NMR (reference material: C6H6, deuterated solvent: CDCl3), d ppm:
94.42 (d, 6.0 Hz, 3F).
[0079] To the reaction-terminated liquid (prepared to be 42.3 mmol) of
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the above
formula, 40 mL of methanol and 900 mg (50% hydrated product, 0.211
mmol, 0.005 eq) of 5% palladium/activated carbon were added, and the
pressure of hydrogen gas (H2) was set at 0.5 MPa, followed by stirring at
room temperature for 2 hours and 30 minutes. According to H- and
19F-NMR analyses of the reaction mixture liquid, it was confirmed that
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the following
formula:
[chem.22]

was quantitatively produced as single diastereomer (>95 : 5)(the relative
configuration of major diastereomer was determined to be syn-body from
the similarity to Example 1). To the reaction-terminated liquid (prepared to
be 42.3 mmol) of a-trifluoromethyl-ß-substituted-ß-amino acids
represented by the above formula, 4 mL (48.7 mmol, 1.15 eq) of 37%
hydrochloric acid and 6 mL of water were added, and Celite-filtration was
made. The residue was washed with a small amount of methanol, and
concentration under reduced pressure and drying under vacuum were made.
Further, azeotropic dehydration with 10 mL of toluene was made thereby
obtaining 8.00 g of hydrochloric acid salt of
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the
above-mentioned formula.
[0080] To 15 mL of methanol, 1.30 g (prepared to be 6.87 mmol) of the
hydrochloric acid salt and 1.36 g (7.15 mmol, 1.04 eq) of p-toluenesulfonic
acid monohydrate were added, and dissolving under heating was made at 40
to 50 °C, followed by making concentration of almost whole methanol
(about 13 mL) under reduced. The precipitated crystal was filtered, and
washed with a small amount of n-heptane, followed by being subjected to
drying under vacuum, thereby obtaining 960 mg of p-toluenesulfonic acid
salt (refined product) of a-trifluoromethyl-ß-substituted-ß-amino acids
represented by the above-mentioned formula. The total yield from
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters was 41 %. The
diastereomer ratio was syn-body : anti-body = >98 : 2 according to 'H- and
19F-NMR analyses.
[0081] Results of 1H-NMR and 19F-NMR of hydrochloric acid salt and
p-toluenesulfonic acid salt of a-trifluorornethyl-ß-substituted-ß-amino
acids are shown below.
[0082] Hydrochloric acid salt of a-trifluoromethyl-ß-substituted-ß-amino
acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), 8
ppm: 1.35 (d, 6.8 Hz, 3H), 3.50 (m, 1H), 3.89 (m, 1H) / NH2, CO2H and HCl
could not identified; and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), 8 ppm:
13.59 (d, 9.0 Hz, 3F).
[0083] p-Toluenesulfonic acid salt of
a-trifluoromethyl-ß-substituted-ß-amino acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), 5
ppm: 1.36 (d, 6.8 Hz, 3H), 2.28 (s, 3H), 3.46 (m, 1H), 3.89 (m, 1H), 7.25 (d,
8.4 Hz, 2H), 7.57 (d, 8.4 Hz, 2H) / NH2, CO2H and SO3H could not be
identified; and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), 8 ppm:
13.50 (d, 9.0 Hz, 3F).
[0084] [Example 3]
To 70 mL of methanol, 16.0 g (76.1 mmol, 1.00 eq) of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters (E-body : Z-body -
55 : 45) represented by the following formula:
[chem.23]

was added, and cooling was made by an ice bath. Then, 5.03 g (76.1 mmol,
1.00 eq) of 50% aqueous solution of hydroxylamine represented by the
following formula:
[chem.24]

was added, and stirring was made at room temperature for 1 day. Further,
stirring was made at 35 °C for 6 hours. According to 1H- and 19F-NMR
analyses of the reaction mixture liquid, it was confirmed that
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the following
formula:
[chem.25]

was quantitatively produced as single diastereomer (>95 : 5)(the relative
configuration of major diastereomer was determined to be anti-body from
the similarity to Example 1).
[0085] Results of 'H- and 19F-NMR of
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters and dehydrogenated
closed-ring body of a-trifluoromethyl-ß-substituted-ß-amino acid are
shown below.
[0086] a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters:
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
0.97 (m, 3H), 1.33 (m, 3H), 1.54 (m, 2H), 2.46 (Z-body, m, 2H in total),
2.57 (E-body, m, 2H in total), 4.29 (m, 2H), 6.82 (E-body, m, 1H in total),
7.20 (Z-body, m, 1H in total); and
19F-NMR (reference material: C6H6, deuterated solvent: CDCl3), d ppm:
97.77 (E-body, s, 3F in total), 103.08 (Z-body, s, 3F in total).
[0087] Dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid:
1H-NMR (reference material: (CH3)4Si, deuterated solvent: CDCl3), d ppm:
0.99 (t, 7.2 Hz, 3H), 1.25 - 1.90 (m, 4H), 3.21 (m, 1H), 4.01 (m, 1H) / NH
could not be identified; and
19F-NMR (reference material: C6H6, deuterated solvent: CDCl3), d ppm:
94.54 (d, 9.0 Hz, 3F).
[0088] To the reaction-terminated liquid (prepared to be 76.1 mmol) of
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by the above
formula, 80 mL of methanol and 3.24 g (50% hydrated product, 0.761 mmol,
0.01 eq) of 5% palladium/activated carbon were added, and the pressure of
hydrogen gas (H2) was set at 0.5 MPa, followed by stirring at room
temperature for 2 hours and 30 minutes. According to 1H- and 19F-NMR
analyses of the reaction mixture liquid, it was confirmed that
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the following
formula:
[chem.26]

was quantitatively produced as single diastereomer (>95 : 5)(the relative
configuration of major diastereomer was determined to be syn-body from
the similarity to Example 1). The reaction-terminated liquid (prepared to be
76.1 mmol) of a-trifluoromethyl-ß-substituted-ß-amino acids represented
by the above-mentioned formula was Celite-filtered, and the residue was
washed with a small amount of methanol. To the filtrate and washing liquid,
6.3 mL (76.7 mmol, 1.01 eq) of 37% hydrochloric acid and 20 mL of water
were added, and concentration under reduced pressrue and drying under
vacuum were made. Further, azeotropic dehydration with 40 mL of toluene
was made thereby obtaining 20.0 g of hydrochloric acid salt of
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the
above-mentioned formula.
[0089] To 20 mL of methanol, 2.00 g (prepared to be 7.61 mmol) of the
hydrochloric acid salt and 1.61 g (8.46 mmol, 1.11 eq) of p-toluenesulfonic
acid monohydrate were added, and dissolving under heating was made at 40
to 50 °C, followed by making concentration under reduced pressure and
drying under vacuum. To the residue, 14 mL of isopropanol and 8 mL of
n-heptane were added, and then dissolving was made under heating at 90 °C,
followed by gradually lowering the temperature to 0 °C. The precipitated
crystal was filtered, and washed with a small amount of n-heptane, followed
by being subjected to drying under vacuum, thereby obtaining 1.71 g of
p-toluenesulfonic acid salt (refined product) of
a-trifluoromethyl-ß-substituted-ß-amino acids represented by the
above-mentioned formula. The total yield from
a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters was 60 %. The
diastereomer ratio was syn-body : anti-body = >98 : 2 according to H- and
19F-NMR analyses.
[0090] Results of 1H-NMR and 19F-NMR of hydrochloric acid salt and
p-toluenesulfonate of a-trifluoromethyl-ß-substituted-ß-amino acids are
shown below.
[0091] Hydrochloric acid salt of a-trifluoromethyl-ß-substituted-ß-amino
acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), d
ppm: 0.82 (t, 7.4 Hz, 3H), 1.33 (m, 2H), 1.67 (m, 2H), 3.61 (m, 1H), 3.76
(m, 1H) / NH2, CO2H and HCl could not be identified; and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), d ppm:
13.47 (d, 9.0 Hz, 3F).
[0092] p-Toluenesulfonic acid salt of
a-trifluoromethyl-ß-substituted-ß-amino acids:
1H-NMR (reference material: internal lock, deuterated solvent: D2O), d
ppm: 0.81 (t, 7.2 Hz, 3H), 1.32 (m, 2H), 1.66 (m, 2H), 2.26 (s, 3H), 3.50 (m,
1H), 3.72 (m, 1H), 7,24 (d, 8.0 Hz, 2H), 7.55 (d, 8.0 Hz, 2H) / NH2, CO2H
and SO3H could not be identified; and
19F-NMR (reference material: CF3SO3K, deuterated solvent: D2O), d ppm:
13.34 (d, 9.0 Hz, 3F).
WE CLAIM
1. A process of producing a-trifluoromethyl-ß-substituted-ß-amino acids
represented by a general formula [4]

by allowing a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by a general formula [1]

to react with hydroxylamine represented by a general formula [2]

to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters into
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [3]

, and by hydrogenolyzing the dehydrogenated closed-ring body,
Wherein, in the formulae, R1 is alkyl group, substituted alkyl group,
aromatic ring group, substituted aromatic ring group, alkoxycarbonyl group
or substituted alkoxycarbonyl group, and R is alkyl group or substituted
alkyl group; a wavy line in the general formula [1] indicates that
stereochemistry of double bond is E-body, Z-body or a mixture of E-body
and Z-body; and a wavy line in the general formula [3] and in the general
formula [4] indicates that stereochemistry of R1 to trifluoromethyl group is
syn-body, anti-body, or a mixture of syn-body and anti-body.
2. A process of producing a-trifluoromethyl-ß-substituted-ß-amino acids
represented by a general formula [7]

by allowing a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters
represented by a general formula [5]

to react with hydroxylamine represented by a general formula [2]

to convert a-trifluoromethyl-ß-substituted-a,ß-unsaturated esters into
dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [6]

, and by hydrogenolyzing the dehydrogenated closed-ring body,
Wherein, in the formulae, R is alkyl group or substituted alkyl group, and
R4 is alkyl group; a wavy line in the general formula [5] indicates that
stereochemistry of double bond is E-body, Z-body or a mixture of E-body
and Z-body; representation of relative configuration in the general formula
[6] indicates that stereochemistry of R to trifluoromethyl group is
anti-body; and representation of relative configuration in the general
formula [7] indicates that stereochemistry of R3 to trifluoromethyl group is
syn-body.
3. A dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [3]

where R1 is alkyl group, substituted alkyl group, aromatic ring group,
substituted aromatic ring group, alkoxycarbonyl group or substituted
alkoxycarbonyl group; and a wavy line indicates that stereochemistry of R1
to trifluoromethyl group is syn-body, anti-body, or a mixture of syn-body
and anti-body.
4. A dehydrogenated closed-ring body of
a-trifluoromethyl-ß-substituted-ß-amino acid represented by a general
formula [6]

where R3 is alkyl group or substituted alkyl group; and representation of
relative configuration indicates that stereochemistry of R to
trifluoromethyl group is anti-body.
5. a-trifluoromethyl-ß-substituted-ß-amino acids represented by a
general formula [4]

where R1 is alkyl group, substituted alkyl group, aromatic ring group,
substituted aromatic ring group, alkoxycarbonyl group or substituted
alkoxycarbonyl group; and a wavy line indicates that stereochemistry of R1
to trifluoromethyl group is syn-body, anti-body, or a mixture of syn-body
and anti-body.
6. a-trifluoromethyl-ß-substituted-ß-amino acids represented by a
general formula [7]
[chem.38]

where R is alkyl group or substituted alkyl group; and representation of
relative configuration indicates that stereochemistry of R to
trifluoromethyl group is syn-body.

α-Trifluoromethyl-β-substituted-β-amino acids can be produced by
allowing α-trifluoromethyl-β-substituted-α,β-unsaturated esters to react
with hydroxylamine to convert
α-trifluoromethyl-β-substituted-α,β-unsaturated esters into dehydrogenated
closed-ring body of α-trifluoromethyl-β-substituted-β-amino acid, and by
hydrogenolyzing the dehydrogenated closed-ring body. According to this
production process, novel α-trifluoromethyl-β-substituted-β-amino acids
which are free amino acids whose functional groups are not protected can be
produced, in which β-position substituent is not limited to aromatic ring
group or substituted aromatic ring group while the relative stereochemistry
of α-position and β-position can be also controlled.