Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-08-21
2003-03-11
Berch, Mark L (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C546S123000, C548S546000, C548S557000
Reexamination Certificate
active
06531594
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing 1H-3-aminopyrrolidine and derivatives thereof, more particularly optically active 1H-3-aminopyrrolidine and derivatives thereof. More specifically, the present invention relates to an improved process for producing 1H-3-aminopyrrolidine and derivatives thereof, more particularly optically active 1H-3-aminopyrrolidine and derivatives thereof, from an aspartic acid starting material, more particularly an optically active aspartic acid starting material. The present invention also relates to methods for preparing certain antibacterial and psychotropic compounds by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
DISCUSSION OF THE BACKGROUND
Optically active 1H-3-aminopyrrolidine of the 3R or 3S configuration obtained by the invention is useful as an intermediate for various organic compounds including medicines and agricultural chemicals. In particular, the optically active compound is useful as an intermediate for antibacterial (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3S)-3-(L-prolyl-amino)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid; psychotropic (S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-(cyclopropylcarbonyl-amino)-2-methoxybenzamide; and the like.
Conventional processes for producing optically active 1H-3-aminopyrrolidine include (1) a method in which a racemate is optically resolved, (2) a method in which a prochiral starting material is used, and (3) a method in which the target compound is synthesized from an optically active starting material.
With respect to (1) above, known examples thereof include a process comprising subjecting racemic N-benzyl-3-aminopyrrolidine as a starting material to preferential crystallization using an optically active carboxylic acid such as, e.g., D- and L-tartaric acids, L-(+)-mandelic acid, or L-(−)-pyroglutamic acid as a resolving agent to obtain an optically active N-benzyl-3-aminopyrrolidine and then eliminating the protective group to obtain optically active 1H-3-aminopyrrolidine (see JP-A-2-218664 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”)) and a process in which preferential crystallization is conducted using D- and L-tartaric acid derivatives as a resolving agent to obtain optically active N-benzyl-3-aminopyrrolidine (see JP-A-9-176115). However, these processes are inefficient, for example, because: (1) the synthesis of the starting material, i.e., racemic N-benzyl-3-aminopyrrolidine, requires many steps; (2) the theoretical yield in the resolution step is 50% at the most; and (3) because many steps are necessary for the recovery and recycling of the resolving agent and the antipode.
With respect to (2) above, a process is, for example, known which comprises subjecting N-benzyl-3-pyrroline to asymmetric hydroboration to stereoselectively incorporate a hydroxyl group into the 3-position, converting the hydroxylated compound into an azide through mesylation and nucleophilic substitution, and then reducing the azide (see
J. Med. Chem
., vol. 31, p. 1586 (1988)). However, this process is industrially disadvantageous because the N-benzyl-3-pyrroline used as a starting material and the other reagents are expensive.
With respect to (3) above, a process is, for example, known which comprises reacting optically active 1,2,4-tris(methanesulfonyl)butane obtained from an optically active 1,2,4-trisubstituted butane with benzylamine to produce 1-benzyl-3-methanesulfonoxypyrrolidine, which has one configuration in a central part of the molecule, and then subjecting it to a substitution reaction with benzylamine to produce optically active 1-benzyl-3-benzylpyrrolidine through inversion of configuration (see C. K. Ingold, Structure and Mechanism in Organic Chemistry, 2nd ed., Comel University Press, 1969, p.519). However, this process is disadvantageous in that a technique for mass-producing the optically active 1,2,4-trisubstituted butane for use as a starting material has not been established.
On the other hand, examples of the production of optically active 1H-3-aminopyrrolidine and derivatives thereof from optically active aspartic acid include the following two processes. One known process comprises protecting the amino group of optically active aspartic acid, reducing the carboxyl groups to hydroxyl groups, protecting the hydroxyl groups to conduct cyclization, and finally eliminating the protective groups to obtain the target compound (see JP-W-7-506110, which corresponds to U.S. Pat. No. 5,177,217 (the term “JP-W” as used herein means an “unexamined published PCT application”) and JP-A-8-053412). The other known process comprises adding paraformaldehyde to N-benzyloxycarbonyl-L-aspartic acid, cyclizing the acid with the aid of p-toluenesulfonic acid as a catalyst, subsequently causing the cyclized compound to add benzylamine, isolating the resultant acid amide, esterifying it with thionyl chloride and an alcohol, and then cyclizing the ester to stereoselectively produce (3S)-1-benzyl-3-benzyloxy-carbonylaminopyrrolidine-2,5-dione (see
Arch. Pharm. Res
., vol. 19(4), pp. 312-316 (1996)).
However, these processes are unsatisfactory for industrial production, for example, because they involve many reaction steps and it is difficult to purify or isolate the compound produced in each step.
Also known is a process for stereoselectively producing (3S)-1-benzyl-3-benzyloxycarbonylamino-pyrrolidine-2,5-dione (succinimide compound) which comprises converting N-benzyloxycarbonyl-L-aspartic acid into its anhydride, causing the anhydride to add benzylamine, isolating the resultant acid amide, and cyclizing it with acetic anhydride (see JP-A-1-110626, which corresponds to EP 0 302 372). However, an investigation made by the present inventors revealed that racemization occurs in the step of succinimide synthesis in this process (see, Comparative Example 1 below). Furthermore, this process cannot be regarded as industrially advantageous because lithium aluminum hydride, which is used in the subsequent step of reducing the succinimide compound (Comparative Example 2), is expensive.
SUMMARY OF THE INVENTION
Accordingly it is one object of the invention to provide a novel process for producing 1H-3-aminopyrrolidine and derivatives thereof.
It is another object of the present invention to provide a novel process for producing optically active 1H-3-aminopyrrolidine and derivatives thereof.
It is another object of the present invention to provide a novel process for producing 1H-3-aminopyrrolidine and derivatives thereof from an aspartic acid starting material.
It is another object of the present invention to provide a novel process for producing optically active 1H-3-aminopyrrolidine and derivatives thereof from an optically active aspartic acid starting material.
It is another object of the present invention to provide an industrially advantageous process for safely producing high-quality optically active 1H-3-aminopyrrolidine and derivatives thereof at low cost from optically active aspartic acid.
It is another object of the present invention to provide a novel process for preparing 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compounds (succinimide compounds), which are useful as intermediates in such a process.
It is another object of the present invention to provide novel processes for preparing certain antimicrobial drugs by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
It is another object of the present invention to provide novel processes for preparing certain psychotic by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
These and other objects which will become apparent during the following detailed description, have been achieved by the inventors' discovery that an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound (succinimide compound) can be produced, while avoiding a decrease in opt
Ichikawa Shuji
Kanno Kazuaki
Nakato Takeshi
Takehara Jun
Watanabe Michi
Berch Mark L
Mitsubishi Chemical Corporation
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