Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-20
2002-02-19
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S546000
Reexamination Certificate
active
06348600
ABSTRACT:
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 for drugs and agrochemicals and to a method for making 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-benzyloxycarbonyl-L-asparagine methyl ester is reacted with 0.95 equivalent of sodium hydroxide to 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.
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 (LiAlH
4
) is 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 from 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:
wherein R
1
is a lower alkyl group having 1 to 4 carbon atoms, an aryl group, or an aralkyl group; each of R
2
and R
3
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, R
2
and R
3
being the same or different; R
4
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-aminopyrrolidine-2,5-dione derivative represented by the formula (3):
wherein R
1
, R
2
, R
3
, 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 R
1
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 asparagine ester derivative. Additionally, either an optically active 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 and also include an acid salt thereof.
The optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (3), the optically active 1-substituted-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 more, 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 also 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), R
1
is preferably a lower alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group, and is more preferably a substituted or unsubstituted benzyl group. Each of R
2
and R
3
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, and R
2
and R
3
may be the same or different as described above. When R
2
is any one of an acyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, and an aralkylsulfonyl group, R
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 alone or the compounds may be used as a mixture thereof in any mixing 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 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 yi
Ono Takae
Sato Haruyo
Schnader Harrison Segal & Lewis LLP
Shameem Golam M. M.
Toray Industries Inc.
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