Note: Descriptions are shown in the official language in which they were submitted.
CA 02337544 2001-02-19
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METHODS FOR MAKING OPTICALLY ACTIVE 3-AMINOPYRROLIDINE-2,5-
DIONE DERIVATIVE AND OPTICALLY ACTIVE 3-AMINOPYRROLIDINE
DERIVATIVE
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for making
optically active 3-aminopyrrolidine derivatives which are
useful as raw materials f'or drugs and agrochemicals and to a
method for ma:king optically active 3-aminopyrrolidine-2,5-
dione derivatives which are important intermediates thereof.
2. Description of the Related Art
Examples of the known methods for making optically
active 3-aminopyrrolidine derivatives include a method in
which racemic 1-benzyl-3-aminopyrrolidine is optically
resolved by an optical active carboxylic acid. However,
since the racemic 1-benzyl-3-aminopyrrolidine, which has
been produced by a complex route, is further optically
resolved, the method is expensive. Therefore, a method for
making optically active 3-aminopyrrolidine derivatives
inexpensively has been desired.
Examples of the known methods for making optically
active 3-aminopyrrolidine-2,5-dione derivatives includes a
method in which N-benzyl.oxycarbonyl-L-asparagine methyl
ester is reacted with 0.95 equivalent of sodium hydroxide to
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produce (S)-3-benzyloxycarbonylaminopyrrolidine-2,5-dione,
and then by way of the reaction described below, (S)-3-
benzyloxycarbonylaminopyrrolidine is produced as disclosed
in Tetrahedron; Asymmetry Vol. 3, 1239-1242 (1992). A
method for producing a compound having a substituent in the
first position is also disclosed in the same document, in
which N-benzylation is carried out by the subsequent
interphase reaction in the presence of a quaternary ammonium
salt as shown below.
\NHCOOCH2Ph ,\~NHCOOCH2Ph NHCOOCH2Ph
/__ 0.95eqNaOH ~ PhCH2Br
H2NOC COOCH3
O/ i O N 0
H CH2Ph
~NH2 N=CHR NHCH2Ph
.' .'
Hz ~.' R C110 LiA1H4
Pd(OH)2 N
O N p N 0 I
CH2Ph CH2Ph CHZPh
Although the above method, which has high reaction
selectivity, is superior in making optically active 3-
aminopyrrolidine derivatives, it is difficult to employ the
method for industrial use because (1) expensive L-asparagine
is used as a starting material; (2) the number of process
steps is increased, which is troublesome; and (3) a
moisture-sensitive, expensive reducing agent (LiAlH4) is
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used.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide
methods for making optically active 3-aminopyrrolidine-2,5-
dione derivatives and optically active 3-aminopyrrolidine
derivatives f:rom inexpensive raw materials, with a decreased
number of process steps, in high yields, and with high
optical purity.
The present inventors have carried out thorough
research to overcome the difficulties described above and
have achieved the present invention.
In one aspect of the present invention, a method for
making an optically active 3-aminopyrrolidine-2,5-dione
derivative represented by the following formula (3) includes
cyclizing an optically active asparagine ester derivative
represented by the following formula (1), an optically
active isoasparagine ester derivative represented by the
following formula (2) which is an isomer thereof, a mixture
of these substances, or an acid salt of these substances:
NR2R3 NR2R3
* (1) * (2)
R1HNOC COOR4 R400C CONHR'
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NR2R3
*
O N p
R
(3)
wherein R1 is a lower alkyl group having 1 to 4 carbon atoms,
an aryl group, or an aralkyl group; each of R2 and R3 is a
hydrogen atom, an alkyl group, an aryl group, an aralkyl
group, an acyl group, an alkoxylcarbonyl group, an
alkylsulfonyl group, an arylsulfonyl group, or an
aralkylsulfonyl group, F:2 and R3 being the same or different;
R4 is an alkyl group having 1 to 3 carbon atoms; and the
carbon atom with the asterisk * is an asymmetric center.
In another aspect of the present invention, a method
for making an optically active 3-aminopyrrolidine derivative
represented by the following formula (9) includes reducing
an optically active 3-aniinopyrrolidine-2,5-dione derivative
represented by the formula (3):
NR2R3
C *
N
R1
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(9)
wherein R1, R~'=, R3, and the asterisk * are the same as those
in the formula (1).
In another aspect of the present invention, a method
for making an optically active 3-aminopyrrolidine derivative,
in which the first position is unsubstituted, includes
hydrogenolyzing an optically active 3-aminopyrrolidine
derivative represented by the formula (9), wherein R1 is a
substituted or unsubstituted benzyl group.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present invention, either the optically active
asparagine ester derivative represented by the formula (1)
or the optically active isoasparagine ester derivative
represented by the formula (2) is referred to as an
optically active asparaqine ester derivative. Additionally,
either an optically acti_ve asparagine derivative represented
by the formula (6) below or an optically active asparagine
derivative represented by the formula (7) below which is an
isomer thereof is referred to as an optically active
asparagine derivative.
These compounds also include optically active
substances in which either the L-form (S-form) or the D-form
(R-form) is in excess arid also include an acid salt thereof.
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The optically active 1-substituted-3-aminopyrrolidine-
2,5-dione derivative represented by the formula (3), the
optically active 1-subst:ituted-3-aminopyrrolidine derivative
represented by the formula (9), and the optically active 3-
aminopyrrolidine derivative in which the first position is
unsubstituted also include optically active substances in
which either the L-form (S-form) or the D-form (R-form) is
in excess and. also include an acid salt thereof. The
optical purity of the optically active substances is
preferably 80% e.e. or niore, and more preferably 90% e.e. or
more.
In the present invention, the optically active
asparagine ester derivative represented by the formula (1)
or (2), or an acid salt thereof is cyclized to produce the
optically active 3-aminopyrrolidine-2,5-dione derivative
represented by the formula (3). In such a method, it is not
necessary to protect or deprotect an amino group in the
third position, and alsc> it is possible to produce an
optically active 3-aminopyrrolidine-2,5-dione derivative
from the optically active asparagine ester derivative
represented by the formula (1) or (2) with a decreased
number of process steps, in high yields, and with high
optical purity.
In the formula (1), RI is preferably a lower alkyl group
having 1 to 4 carbon atoms, a substituted or unsubstituted
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phenyl group, or a substituted or unsubstituted benzyl group,
and is more p:referably a. substituted or unsubstituted benzyl
group. Each of R2 and R3 is a hydrogen atom, an alkyl group,
an aryl group, an aralky'l group, an acyl group, an
alkoxylcarbonyl group, an alkylsulfonyl group, an
arylsulfonyl group, or an aralkylsulfonyl group, and R2 and
R3 may be the same or different as described above. When R2
is any one of an acyl group, an alkoxylcarbonyl group, an
alkylsulfonyl group, an arylsulfonyl group, and an
aralkylsulfonyl group, F:3 is preferably a hydrogen atom.
Preferably, as the aryl group, a substituted or
unsubstituted phenyl group is selected, and as the aralkyl
group, a substituted or unsubstituted benzyl group is
selected.
Each of 'the compounds represented by the formula (1)
and (2) may be used alor.ie or the compounds may be used as a
mixture thereof in any niixing ratio. Preferably, the
compounds have an optical purity of 90% e.e. or more.
The cyclization may be carried out in an organic
solvent or in water. Preferably, the cyclization is carried
out in an aqueous solution in which an organic solvent and
water are mixed. The pH of the reaction liquid is
preferably 3 to 8, more preferably 5 to 7.5, and most
preferably 6 to 7. The pH may be adjusted after an acid
salt of the optically active asparagine ester derivative is
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dissolved into an aqueous solution. Alternatively, after
the optically active asparagine ester derivative is
dissolved in the aqueous solution in which the pH is
preliminarily adjusted, the pH may be finely adjusted again.
As the organic solvent, although any compound which is inert
in the reaction and which is dissolved in water
homogeneously may be used, preferably, a lower alcohol, such
as methanol or ethanol, or a water-soluble ether, such as
tetrahydrofuran or glyme, is used, and more preferably,
methanol is used.
Preferably, the pH of the reaction liquid is adjusted
by adding an alkali metal salt to the reaction liquid
because the yield and the optical purity of the optically
active 3-aminopyrrolidine-2,5-dione derivative produced are
further increased. As the alkali metal salt, an alkali
metal organic acid salt, such as sodium formate, potassium
formate, sodium acetate, or potassium acetate; an alkali
metal carbonate, such as sodium carbonate or potassium
carbonate; an alkali metal hydrogencarbonate, such as sodium
hydrogencarbonate or potassium hydrogencarbonate; or a
mixture thereof may be used. Preferably, sodium acetate,
sodium carbonate, or sodium hydrogencarbonate is used, and
more preferably, sodium hydrogencarbonate is used.
The reaction temperature is preferably in the range of
0 to 80 C, and more preferably 20 to 60 C. The reaction
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time, which depends on the type of starting material and on
the reaction conditions, is 0.1 to 30 hours. Although the
racemization rate in the cyclizing reaction slightly differs
depending on the pH of the reaction mixture, the reaction
time, the type of alkali metal salt to be added, etc., by
using the production method described above, it is possible
to produce the optically active 1-substituted-3-
aminopyrrolidine-2,5-dione derivative represented by the
formula (3) having an optical purity of 80% e.e. or more.
If the optica:Lly active asparagine ester derivative used
represented by the formula (1) or (2) has an optical purity
of 95% e.e. or more, it is possible to obtain the optically
active 1-substituted-3-aminopyrrolidine-2,5-dione derivative
represented by the formula (3) having an optical purity of
90% e.e. or more.
In order to isolate the optically active 1-substituted-
3-aminopyrrol:idine-2,5--d.ione derivative from the reaction
mixture, any known method may be used. For example, the
reaction mixture is adjusted to be weakly basic, and then
extraction is performed using an organic solvent. As the
organic solvent, although any compound which is stable
during the extraction may be used, for example, toluene or
chloroform is preferably used. When the amino group in the
third position is basic in the compound represented by the
formula (3), it is possible to isolate as an acid salt
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thereof. When the substituent in the first position in the
optically active 1-substituted-3-aminopyrrolidine-2,5-dione
derivative represented by the formula (3) is an aryl group
or an aralkyl group, e.g., optically active 3-amino-l-
benzylpyrrolidine-2,5-dione, since extraction is easily
performed using the organic solvent, isolation and
purification are facilitated. The concentrate obtained by
subjecting the extract to vacuum concentration may be used
as it is in the subsequent step.
By reducing the optically active 1-substituted-3-
aminopyrrolidine-2,5-dione derivative represented by the
formula (3) thus produced, it is possible to produce the
optically active 1-substituted-3-aminopyrrolidine derivative
represented by the formula (9).
As the optically active 1-substituted-3-
aminopyrrolidine-2,5-dione derivative used represented by
the formula (3), the one: which is isolated and purified, the
concentrate of the extract, or an acid salt thereof may be
used. The compound preferably has an optical purity of 81%
e.e. or more.
As the reaction solvent used an ether, such as
tetrahydrofuran, glyme, diglyme, or butanol, may be used.
Preferably, tetrahydrofuran, glyme, or diglyme is used, and
more preferably, glyme is used.
As the reducing agent, aluminum lithium hydride or a
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boron hydride may be used. Preferably, the boron hydride
which is chemically stable and easy to handle is used.
Preferred examples of the boron hydrides include diborane,
borane diethyl ether, borane dimethyl sulfide, and sodium
borohydride. When sodium borohydride is used, an activating
reagent, such as sulfuric acid or trifluoroboron, may be
added thereto. The reaction temperature is preferably in
the range of -20 to 80 C, and more preferably in the range
of -10 to 30 C. The reaction time, which depends on the
conditions, is usually 3 to 20 hours.
After the reaction is complete, the produced optically
active 1-substituted-3-aminopyrrolidine derivative may be
isolated by a known method. For example, after methanol is
added to the reaction mixture, concentration is performed to
decompose and remove excess borane. The concentrate is
dissolved in water and is adjusted to be basic, and
extraction is performed using chloroform, and thus the
optically active 1-substituted-3-aminopyrrolidine derivative
is extracted in a chloroform layer. By concentrating the
resultant chloroform layer, the optically active 3-
aminopyrrolidine derivative is obtained. By using the
production method described above, the optically active 1-
substituted-3-aminopyrrolidine derivative represented by the
formula (9) having an optical purity of 80% e.e. or more can
be obtained. If the optically active 1-substituted-3-
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aminopyrrolidine-2,5-dione derivative represented by the
formula (3) used has an optical purity of 92% e.e. or more,
it is possible to obtain. the optically active 1-substituted-
3-aminopyrrolidine derivative represented by the formula (9)
having an optical purity of 90% e.e.
In the optically active 1-substituted-3-
aminopyrrolidine derivative represented by the formula (9)
thus obtained, when the substituent in the first position is
a substituted or unsubstituted benzyl group, by performing
hydrogenolysis in the presence of a noble metal catalyst, an
optically active 3-aminopyrrolidine derivative in which the
first position is unsubstituted is produced.
As the noble metal catalyst, palladium supported by
activated carbon is pref'erably used. The hydrogen pressure
is preferably 0.1 to 5 MPa and more preferably 0.5 to 1 MPa.
The hydrogenolysis is preferably performed in a solvent.
As the solvent, an alcohol such as methanol or ethanol, an
ether such as tetrahydrofuran, or an aromatic hydrocarbon
such as toluene is preferably used. More preferably,
methanol or ethanol is used.
The reaction temperature is preferably in the range of
20 to 100 C, and more preferably in the range of 40 to 70 C.
The reaction time, which depends on the conditions, is
usually 3 to 20 hours.
After the reaction is complete, the produced optically
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active 3-aminopyrrolidine derivative may be isolated by a
known method. For example, after the reaction mixture is
filtered to remove the noble metal catalyst, concentration
and distillation are performed, and thus the optically
active 3-aminopyrrolidin.e derivative is obtained. By using
the production method described above, the optically active
3-aminopyrrolidine derivative having an optical purity of
80% e.e. or more can be obtained.
In accordance with the methods described above, it is
possible to produce optically active 3-aminopyrrolidine
derivatives and optically active 3-aminopyrrolidine-2,5-
dione derivatives which are the intermediates thereof from
the optically active asparagine ester derivative represented
by the formula (1) or (2) with a decreased number of process
steps, in high yields, and with high optical purity. In the
reduction reaction, a boron hydride which is chemically
stable and easy to handle can be used as the reducing agent,
which is also advantageous.
In the present invention, the optically active
asparagine ester derivative represented by the formula (1)
or (2) can be produced using inexpensive optically active
aspartic acid as a starting material, which is also
advantageous. In the present invention, although the
optically active aspartate ester derivative represented by
the formula (1) or (2) nlay be produced using a raw material
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other than the optically active aspartic acid, the
inexpensive optically active aspartic acid is preferably
used as the starting material in view of cost efficiency.
A method for producing the optically active asparagine
ester derivative represented by the formula (1) or (2) from
the optically active aspartic acid is not particularly
limited. One embodiment will be described below.
NH2 NRSRs NRsRs NR5R6
-- R1NH2
HOOC COOH (5) * , \
O A 0 R'HNOC COOH HOOC CONHR'
(4) (6) (7)
R40H NRZ R3 NR2R3 N R2R3 ~ NR2R3
(g) --- -~
RIHNOC COOR4 R OOC CONHR~
(~) (2) R1 O R1
(3) (9)
Using the optically active aspartic acid as the
starting material, an optically active aspartic anhydride
represented by the following formula (4) is produced:
NR5R6
0 0 0
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(4)
wherein each of R5 and R6 is a hydrogen atom, an alkyl group,
an aryl group, an aralkyl group, an acyl group, an
alkoxylcarbonyl group, an alkylsulfonyl group, an
arylsulfonyl group, or an aralkylsulfonyl group, R5 and R6
being the same or different. The optically active aspartic
acid preferably has an optical purity of 99% e.e. or more.
The optically active aspartic anhydride can be produced
by reacting the optically active aspartic acid with an
organic acid anhydride. As the organic acid anhydride, a
monoacid anhydride, such as formic anhydride, acetic
anhydride, or propionic anhydride, or a heteroacid anhydride,
such as formic acetic anihydride may be used. Preferably,
acetic anhydride or forn-ic acetic anhydride is used, and
more preferably, formic acetic anhydride is used.
Preferred examples of the optically active aspartic
anhydrides represented by the formula (4) include dialkyl
derivatives, such as N-dimethylaspartic anhydride and N-
methylbenzylaspartic anhydride; N-acyl derivatives, such as
N-formylaspartic anhydride, N-acetylaspartic anhydride, and
N-propionylaspartic anhydride; and sulfonyl derivatives,
such as N-benzenesulfonylaspartic anhydride. Among these
are preferably N-acyl aspartic anhydrides, such as N-
formylaspartic anhydride, N-acetylaspartic anhydride, and N-
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propionylaspartic anhydride because the N-acylaspartic
anhydride can be produced in only one step from the
optically active aspartic acid and the organic acid
anhydride by the reaction described above. Furthermore,
since the N-acyl group can be easily deprotected as
described below, the N-acylaspartic anhydride is more
preferably used when the 3-aminopyrrolidine-2,5-dione
derivative in which the amino group in the third position is
unsubstituted is produced. More preferably, N-
formylaspartic anhydride or N-acetylaspartic anhydri_de is
used, and most preferably, N-formylaspartic anhydride is
used.
A known method may be used for the reaction. For
example, formic acetic anhydride, which has been
preliminarily formed by mixing acetic anhydride and formic
acid, and L-aspartic acid are reacted with each other while
stirring at 50 to 70 C f'or 2 to 5 hours, followed by cooling
to room temperature, and toluene is added thereto to
crystallize N-formyl-L-aspartic anhydride, and then
filtration is performed. In such a step, the reaction
smoothly proceeds even without adding an acid catalyst, and
under the normal conditions, racemization does not
substantially occur.
Next, the optically active aspartic anhydride
represented by the formula (4) is reacted with an amine
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represented by the following formula (5):
Ri-NH2 (5)
wherein R1 is the same as that in the formula (1), to
produce an optically active asparagine derivative
represented by the following formula (6) or (7), or an acid
salt thereof:
NR5R6 NR5R6
1 H i (6'). 1 (7)
R HNOC ("OOH HOOC CONHR
wherein R1 and the asterisk * are the same as those in the
formula (1), and R5 and iR6 are the same as those in the
formula (4). As the optically active N-aspartic anhydride
represented by the formula (4), although either the L-form
or the D-form may be used depending on the application, the
optical purity is preferably 98% e.e. or more.
As the amine represented by the formula (5), a lower.
alkylamine having 1 to 4 carbon atoms, such as methylamine
or propylamine, an arylamine, such as aniline or anisidine,
or an aralkylamine, such as benzylamine, may be used. When
the produced optically active asparagine derivative
represented by the formula (6) or (7) is continuously used
as the raw material for the cyclization and the reduction
reaction, the amine may be selected according to the
relevant compound. In view of the,extraction efficiency by
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the organic solvent from the reaction system, the
deprotection in the subsequent step, etc., benzylamine is
preferably used. The amount of the amine used is preferably
0.8 to 5 equivalent, and more preferably 0.99 to 1.5
equivalent relative to the optically active aspartic
anhydride represented by the formula (4). If the amount of
the amine used is in the above range, both the reaction
yield and the cost efficiency are increased. If a large
amount of amine is used, the cost efficiency is decreased,
and the optically active asparagine derivative represented
by the formula (6) or (7) is also easily racemized, which is
disadvantageous.
In the reaction, dilution is preferably carried out
using an organic solvent. As the solvent, any compound
which does not react with. the substrate may be used.
Examples of the solvent include alcohols, such as ethanol;
ethers, such as tetrahydrofuran; aromatic hydrocarbons, such
as toluene; alkyl halides, such as chloroform; ketones, such
as acetone; carboxylic acids, such as acetic acid; and
esters, such as butyl acetate. The preferred solvent is
tetrahydrofuran or acetic acid. These solvents may be used
alone or as a mixture thereof. Although the amount of the
solvent used is not particularly limited as long as the
content allows the stirring operation, in view of cost
efficiency, the content is usually set so that the substrate
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content is approximately 5 to 30% by weight. The reaction
temperature is preferably 0 to 60 C, and more preferably 10
to 40 C. Since the racemization may also occur if the
reaction temperature is increased, the reaction is
preferably carried out in the range described above. The
reaction time, which depends on the conditions, is usual:Ly 1
to 20 hours.
The resultant optically active asparagine derivative
represented by the formula (6) or (7) is concentrated or
cooled, and then is isolated by filtering the precipitate.
The concentrate may be used as it is for the esterification
in the subsequent step. By using the method described above,
the optically active asparagine derivative represented by
the formula (6) or (7) having an optical purity of 90% e.e.
or more can be obtained.
Next, the optically active asparagine derivative
represented by the formula (6) or (7) is reacted with an
alcohol represented by the following formula (8):
R4OH (8)
wherein R4 is an alkyl group having 1 to 3 carbon atoms, to
produce the optically active aspartate ester derivative
represented by the formula (1) or (2). The optically active
asparagine derivative represented by the formula (6) may be
used alone, the optically active isoasparagine derivative
represented by the formula (7) may be used alone, or a
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mixture of both may be used. The optically active
asparagine derivative preferably has an optical purity of
95% e.e. or more.
As the alcohol represented by the formula (8), methanol,
ethanol, propanol and .isopropanol may be used. Preferably,
methanol or ethanol is used, and more preferably, methanol
is used. In view of the reaction yield and the reaction
time, the amount of the alcohol to be used is preferably 3
to 5 molar times the amount of the optically active
asparagine derivative represented by the formula (6) or (7).
When the alcohol is also used as a reaction solvent, it is
preferably 14 to 30 molar times, and more preferably 15 to
20 molar times. The alcohol may be mixed with an organic
solvent. As the organic solvent, an ether such as
tetrahydrofuran, an aromatic hydrocarbon such as toluene, a
ketone such as acetone, or a halide such as chloroform may
be used.
When the esterification is performed, an acid is
preferably added thereto. As the concomitant acid, a
mineral acid, such as hydrochloric acid or sulfuric acid; a
sulfonic acid, such as toluenesulfonic acid; a Lewis acid,
such as ferric chloride or zinc chloride, a cation exchange
resin, or the like may be used. In such a case, preferably,
the reaction is carried out while removing water produced by
the esterification from the system. Although the required
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amount of the acid to be used is the sum of the amount for
neutralizing the amino group in the optically active
asparagine ester derivative represented by the formula (1)
or (2) to be produced and the amount for catalyzing the
esterification, in view of the reaction rate, the cost
efficiency, and the load in the purification process, the
amount of the acid is preferably 1.02 to 1.10 molar times
the amount of the optically active asparagine ester
derivative.
Instead of the acid, thionyl chloride may be used. In
such a case, since water is not produced in the
esterification, the reaction process is simplified and the
reaction yield is also improved, thus being particularly
advantageous. The amount of thionyl chloride to be used is
preferably 0.9 to 2.5 molar times, more preferably 1.1 to
2.0 molar times, the amount of the optically active
asparagine ester derivative. Since hydrochloric acid by-
produced in the reaction and excess thionyl chloride can be
removed from the system by simple process, such as
concentration, it is possible to use a large amount of
thionyl chloride in order to increase the reaction rate.
The reaction temperature is preferably 0 to 80 C, and
more preferably 10 to 40 C. Within such a range, the
reaction yield is increased and the racemization is
inhibited. T:he reaction. time, which depends on the
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conditions, is usually 1 to 20 hours.
The resultant optically active asparagine ester
derivative represented by the formula (1) or (2), or an acid
salt thereof is isolated by a conventional method. When a
large amount of alcohol is used, vacuum concentration is
performed to remove the alcohol and the acid with a low
boiling point or excess thionyl chloride, and then an
organic solvent, such as tetrahydrofuran, is added again,
followed by stirring. The precipitated crystal is filtered
or vacuum concentration is performed, followed by drying.
Thus, the acid salt of the optically active aspartate ester
derivative represented by the formula (1) or (2) is isolated.
Additionally, the concer.itrate obtained by vacuum
concentration may be used as it is as a raw material for the
cyclization.
By the method described above, it is possible to
produce the optically active asparagine ester derivative
represented by the formula (1) or (2) having an optical
purity of 90% e.e. or more, or an acid salt thereof. If the
optically active asparaqine derivative represented by the
formula (6) or (7) which has been used has an optical purity
of 98% e.e. or more, it is possible to obtain the optically
active asparagine ester derivative represented by the
formula (1) or (2) having an optical purity of 95% e.e. or
more. Additionally, although the produced acid salt of the
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optically active asparacline ester derivative represented by
the formula (1) or (2) may be neutralized to form a free
optically active asparacline ester derivative, preferably it
is preserved as the acid salt since the free optically
active asparagine ester derivative is chemically unstable.
In the esterification, when R5 is an acyl group and R6
is a hydrogen atom in the optically active asparagine
derivative represented by the formula (6) or (7), i.e., in
the case of N-acylasparagine ester derivative, the
deprotection of the N-acyl group can be carried out
simultaneously with the esterification, which is, therefore,
particularly advantageous when a 3-aminopyrrolidine-2,5-
dione derivative in which the amino group in the third
position is unsubstitute:d is produced.
By using the optically active asparagine ester
derivative represented by the formula (1) or (2) thus
obtained as the raw material for the reaction in the present
invention, it is possible to produce optically active 3-
aminopyrrolidine derivatives and optically active 3-
aminopyrrolidine-2,5-dione derivatives which are the
intermediates thereof from the inexpensive optically active
aspartic acid. as the raw material, with a decreased number
of process steps, in hiqh yields, and with high optical
purity.
The present invention will be described more in detail
CA 02337544 2001-02-19
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based on the examples below. However, the present invention
is not limited thereto. Additionally, the chemical purity
of the optically active asparagine ester derivative
represented by the formula (1) or (2) was determined by HPLC.
After hydrolysis and cor.Lversion to a tartaric acid
derivative according to the formula below, the optical
purity was determined by HPLC.
H3C F\ COO --~ O
O
H3C COO" H3C 4~\ COO COOH
NHRz H;~O NHRz O
H. ~ -- H3C ~- ~ COO: CONRz
R'HNOC COOR3 R'HNOC COOH ~.7
(1) (6) HOOC CONHR'
H3C 2/ \\ CO O
O
O
H3C COO'' H3C / \~COO COOH
NRz HzO NHRz 0
f H3C F~ COO' CON~
R300C CONHR' HOOC CONHR'
(2) (7) R'HNOC COOH
The optical purity was calculated according to the
following formula:
Optical Purity (%ee) == ~+ y x 100
X: L-derivative (or D-derivative)
Y: D-derivative (or L-derivative)
CA 02337544 2001-02-19
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The optical purity of the 1-substituted-3-
aminopyrrolidine-2,5-dione derivative represented by the
formula (3) was determined by HPLC analysis after the
chemical derivation according to the following formula:
H3C // \\_COO O
O
* H3C COO~~ H3C ~ \ COO COOH
NHR O
~ H3C F\ COO',I CONR2
O N O ,~
R~ O N O
(3) R1
Additionally, the optical purity of the 1-substituted-
3-aminopyrrolidine derivative was determined in a manner
similar to the above. I'he reagents used in the examples
were commercially available extra-pure reagents.
EXAMPLE 1
Into a 50 ml three-necked flask with a stirrer, a
Dimroth condenser, and a thermometer, 2.7 g (0.01 mol;
optical purity of 98% e.,e.) of L-asparagine benzylamide
methyl ester hydrochloride, 8 g of methanol, and 1.0 g of
sodium hydrogencarbonate were introduced, followed by
stirring at 55 C for 2 hours. The reaction mixture had a pH
of 6.9. By the analysis of the reaction mixture by HPLC, it
was confirmed that 1-benzyl-3-aminopyrrolidine-2,5-dione was
CA 02337544 2001-02-19
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obtained in the yield of' 65% with an optical purity of 81%
e.e. 28% of the raw material L-asparagine benzylamidomethyl
ester remained.
EXAMPLE 2
The reaction was carried out in a manner similar to
that in Example 1 apart from the fact that the solvent for
the reaction was changed.from methanol to water. By the
analysis of the reaction mixture by HPLC, it was confirmed
that 1-benzyl-3-aminopyrrolidine-2,5-dione was obtained in
the yield of 81% with an optical purity of 85% e.e.
EXAMPLE 3
The reaction was carried out in a manner similar to
that in Example 1 apart from the fact that the solvent for
the reaction was changed from methanol to 50% methanol
aqueous solution. By the analysis of the reaction liquid by
HPLC, it was confirmed that 1-benzyl-3-aminopyrrolidine-2,5-
dione was obtained in the yield of 88% with an optical
purity of 92% e.e.
EXAMPLE 4
Into a 5() ml three-necked flask with a stirrer, a
Dimroth condenser, and a thermometer, 5.4 g (0.02 mol;
optical purity of 98% e.e.) of L-asparagine benzylamide
methyl ester hydrochloride, 8 g of methanol, 8 g of water,
and 1.6 g of sodium acetate were introduced, followed by
stirring at 55 C for 0.5 hour. The reaction mixture had a
CA 02337544 2001-02-19
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pH of 7Ø By the ana:Lysis of the reaction liquid by HPLC,
it was confirmed that 1-benzyl-3-aminopyrrolidine-2,5-dione
was obtained in the yield of 79% with an optical purity of
83% e.e.
EXAMPLE 5
The reaction was carried out in a manner similar to
that in Example 4 apart from the fact that sodium carbonate
was used instead of sodium acetate. 1-benzyl-3-
aminopyrrolidine-2,5-d.ione was obtained in the yield of 80%
with an optical purity of 85% e.e. The reaction liquid :had
a pH of 7Ø
EXAMPLE 6
Into a 500 ml four-necked flask with a stirrer, a
dropping funnel, a Dimrath condenser, and a thermometer,
112.5 g (1.10 mol) of acetic anhydride were introduced, and
30 g (0.65 mol) of formic acid were added dropwise thereto
while stirring at room temperature. After stirring was
performed at room temperature for 2 hours, 66.5 g (0.5 mol)
of L-aspartic acid with an optical purity of 99.5% e.e. were
added thereto, the tempE:rature was increased to 60 to 700C,
and stirring was perfornied for 10 hours. The temperature
was decreased to room temperature while stirring, and 80 g
of toluene were further added thereto, followed by stirring.
The precipitated crystal was subjected to filtration under
reduced pressure and was rinsed with 10 g of toluene. The
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crystal was subjected to vacuum drying, and thus 60.1 g of
N-formyl-L-aspartic anhydride was obtained. The chemical
purity was 99%, and the optical purity was 99% e.e. or more.
Into a 200 ml four-necked flask with a stirrer, a
dropping funnel, a Dimroth condenser, and a thermometer, 7.2
g (0.05 mol) of the N-.formyl-L-aspartic anhydride and 60 g
of toluene were introduced, followed by stirring at 20 to
30 C. While maintaining the liquid temperature, 5.4 g (0.05
mol) of benzy.lamine were added dropwise, and then stirring
was performed for 4 hours. The precipitated crystal was
subjected to filtration under reduced pressure and was
rinsed with 10 g of toluene. The crystal was subjected to
vacuum drying, and thus 14.2 g of a mixture of N-formyl-L-
asparagine benzylamide (hereinafter referred to as "FAB")
and N-formyl-L-isoasparagine benzylamide (hereinafter
referred to as "IFAB") were obtained.
Into a 100 ml four-necked flask with a stirrer, a
dropping funnel, a Dimroth condenser, and a thermometer,
14.2 g (0.048 mol) of the mixture of FAB and IFAB and 17.3 g
(5.4 mol) of methanol were introduced, followed by stirring
at 30 to 35 C. While maintaining the liquid temperature at
30 to 35 C, 7.4 g (0.062 mol) of thionyl chloride were added
dropwise, and then the temperature was increased to 40 to
45 C, followed by stirring for 3 hours. Vacuum
concentration was performed at 40 C, and thus 20.9 g of a
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mixture of L-asparagine benzylamide methyl ester
hydrochloride (hereinafter referred to as "ABN
hydrochloride") and L-isoasparagine benzylamide methyl ester
hydrochloride (hereinafter referred to as "IABN
hydrochloride") were obtained.
Into a 200 ml four-necked flask with a stirrer, a
dropping funnel, a Dimroth condenser, and a thermometer,
20.9 g of the mixture of ABN hydrochloride and IABN
hydrochloride and 50 g of water were introduced, and 4.0 g
of sodium hydrogencarbonate were added thereto while
stirring at room temperature. The reaction liquid had a pH
of 7Ø The temperature was increased to 55 C and stirring
was performed for 0.5 hour, and then concentrated
hydrochloric acid was added thereto to adjust the pH to be 2
or less, followed by cooling to room temperature. At room
temperature, 10% sodium hydroxide aqueous solution was added
thereto to adjust the pH to be 10 to 11, and then extraction
was performed three times using 100 ml of chloroform. All
the chloroform layers were subjected to vacuum concentration,
and thus 9.5 g of (S)-3.-benzyl-3-aminopyrrolidine-2,5-dione
were obtained. The optical purity was 91% e.e. The through
yield from L-aspartic acid was 78%.
Into a 200 ml four-necked flask with a stirrer, a
dropping funnel, a Dimroth condenser, and a thermometer, 9.5
g (46.5mmol) of the (S)-1-benzyl-3-aminopyrrolidine-2,5-
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dione, 50 ml of tetrahydr.ofuran, and 8.8 g (0.23 mol) of
sodium borohydride were introduced, and a solution in which
11.5g (0.12 mol) of 98% sulfuric acid were diluted with 20
ml of tetrahydrofuran was added dropwise over approximately
30 minutes while stirring under an ice-bath, and then
stirring was performed f'or 2 hours. The reaction mixture
was heated to 65 C and was stirred for 2 hours. After the
reaction was complete, vacuum concentration was performed.
70 g of water was added for dissolution, and 25 g of
concentrated hydrochloric acid were added thereto, followed
by stirring at 65 C for 4 hours. The reaction mixture was
cooled to room temperature and was neutralized by adding 32
g of 46% sodium hydroxidle while stirring. Extraction was
performed three times using 100 ml of toluene, and all the
toluene layers were simultaneously subjected to vacuum
concentration. The concentrate was subjected to vacuum
distillation, and thus 7.3 g of (S)-1-benzyl-3-
aminopyrrolidine were obtained as the distillate collected
at 130 to 133 C/1.3 kPa. As a result of analysis, the
chemical purity was 99% and the optical purity was 91% e.e.
7.0 g of the (S)-1-benzyl-3-aminopyrrolidine, 25 ml of
methanol, and 0.7 g of 54 Pd/C were introduced into a 100 ml
autoclave, and hydrogen was adjusted to have a pressure of 1
MPa. The temperature was increased to 70 C and stirring was
performed for 8 hours. After the reaction was complete, the
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temperature was decreased to room temperature and the
pressure was released. The content was filtered and the
mother liquor was concentrated and distilled, and thus 3.2 g
of (S)-3-aminopyrrolidine were obtained as the distillate
collected at 80 to 83 C/40 kPa. As a result of analysis,
the chemical :purity was 99% and the optical purity was 90%
e.e.
EXAMPLE 7
Into a 2,000 ml four-necked flask with a stirrer, a
dropping funnel, a Dimroth condenser, and a thermometer,
336.7 g (1.23 mol; optical purity of 98% e.e.) of D-
asparagine benzylamide methyl ester hydrochloride, 407 g of
methanol, and 378 g of water were introduced, and 129.4 g
(1.54 mol) of powdered sodium hydrogencarbonate were added
thereto over 10 minutes while stirring at 30 C. The pH was
6.9. The mixed liquid was heated to 55 C and stirring was
performed for 50 minutes, and then 150 g (1.44 mol) of 35%
hydrochloric acid was added to adjust the pH to be 2 or less
while maintaining the liquid temperature at 30 C or less.
The reaction mixture was subjected to vacuum concentration
to remove methanol, and 763.5 g of the concentrate were
obtained. As a result of analysis, it was confirmed that
257.6 g of (R)-1-benzyl-3-aminopyrrolidine-2,5-dione
hydrochloride was obtained. The yield was 86.7%. The
optical purity was 93% e.e.
CA 02337544 2001-02-19
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EXAMPLE 8
Into a 50 ml three-necked flask with a stirrer, a
Dimroth condenser, and eL thermometer, 19.7 g (0.1 mol;
optical purity of 98% e.e.) of L-isoasparagine
methylamidomethyl ester hydrochloride, 50 g of methanol, 50
g of water, and 8.4 g of' sodium hydrogencarbonate were
introduced, followed by stirring at 30 C for 2 hours. The
reaction liquid had a pH of approximately 6. By the
analysis of the reaction liquid by HPLC, it was confirmed
that 1-methyl-3-aminopyrrolidine-2,5-dione was obtained in
the yield of 75% with an optical purity of 84% e.e. 18% of
the raw material L-isoasparagine methylamidomethyl ester
remained.
Using a method of the present invention an optically
active 3-aminopyrrolidine derivatives which are useful as
raw materials for drugs and a optically active 3-
aminopyrrolidine-2,5-dione derivatives which are important
intermediates thereof can be produced with a decreased
number of process steps, in high yields, and with high
optical purity.
