Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-19
2003-08-19
Solola, Tacfiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06608214
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel production process capable of substantially producing optically active 3-hydroxy-&ggr;-butyrolactone useful as a synthetic intermediate for pharmaceutical preparations and agrochemicals and as a functional material.
2. Description of the Related Art
The conventional process for producing optically active 3-hydroxy-&ggr;-butyrolactone includes e.g. (1) a process for producing the same in 7 steps from D-isoascorbic acid and L-ascorbic acid as the starting materials (Synthesis, pp. 570-573, 1987), (2) a process for producing the same by reducing L-malic acid diester with a dimethyl sulfide/borane reagent and then subjecting the resultant diol ester to cyclization reaction with trifluoroacetic acid (Chemistry Letters, pp. 1389-1392, 1984), and (3) a process for producing the same by forming ethyl 4-tert-butoxy-3-hydroxybutyrate in 2 steps from ethyl 4-chloro-3-oxobutyrate and then cyclizing it in trifluoroacetic acid (Synthesis, pp. 37-40, 1986).
However, the process (1) is conducted through plural steps as many as 7 to make the procedure complicated, and this process is not desirable in respect of yield too. The process (2) has a problem that the dimethyl sulfide/borane reagent used in the production is expensive and difficult to handle. In the process (3), the product is produced in relatively short steps, but corrosive and toxic trifluoroacetic acid serving not only as a reagent but also as a solvent is used in a large amount, and low-temperature reaction is required, so this process cannot be said to be an industrial process.
Further, 3-hydroxy-&ggr;-butyrolactone is water-soluble, and in any processes (1) to (3), washing with water is necessary at the stage of post-treatment after the reaction is finished, thus making the procedure troublesome and often lowering the yield, and therefore these cannot be said to be efficient processes.
Accordingly, it cannot be said from an economical viewpoint and in respect of efficiency that the prior art processes are industrially suitable production processes, and there is demand for development of an industrially suitable process for producing optically active 3-hydroxy-&ggr;-butyrolactone.
SUMMARY OF THE INVENTION
The object of this invention is to provide a novel process for producing optically active 3-hydroxy-&ggr;-butyrolactone in a short step, which is superior economically and in efficiency and industrially suitable by using a starting material which is inexpensive and easily available and reagents easy to handle.
Under these circumstances, the present inventors made an extensive study for solving the object described above. As a result, they found that an optically active 4-substituted oxy-3-hydroxybutyrate obtained by asymmetrically hydrogenating an easily available 4-substituted oxy-3-oxobutyrate is hydrogenated in the presence of a heterogeneous hydrogenation catalyst and an acidic substance followed by deprotection and simultaneous ring closure thereof, whereby optically active 3-hydroxy-&ggr;-butyrolactone of high optical purity can be obtained in high yield, and this invention was thereby completed.
That is, this invention relates to a process for producing optically active 3-hydroxy-&ggr;-butyrolactone represented by formula I:
wherein the symbol * means an asymmetric carbon atom, which comprises hydrogenating an optically active 4-substituted oxy-3-hydroxybutyrate represented by formula II:
wherein R
1
represents a C
1-4
lower alkyl group, R
2
represents a protective group for a hydroxyl group deprotected by hydrogenation with a heterogeneous hydrogenation catalyst, and the symbol * has the same meaning as defined above, in the presence of a heterogeneous hydrogenation catalyst and an acidic substance followed by deprotection and simultaneous ring closure thereof.
Further, this invention relates to the process for producing optically active 3-hydroxy-&ggr;-butyrolactone, wherein the optically active 4-substituted oxy-3-hydroxybutyrate represented by the general formula II above is obtained by asymmetrically hydrogenating a 4-substituted oxy-3-oxobutyrate represented by the general formula III:
wherein R
1
and R
2
have the same meanings as defined above, in the presence of a ruthenium complex comprising an optically active phosphine compound as a ligand.
Further, this invention relates to the process for producing optically active 3-hydroxy-&ggr;-butyrolactone, wherein R 2is an optionally substituted benzyl group, more preferably a benzyl group.
Further, this invention relates to the process for producing optically active 3-hydroxy-&ggr;-butyrolactone, wherein the metal catalyst is a heterogeneous catalyst of palladium, iridium, rhodium, ruthenium, nickel, osmium or platinum.
Further, this invention relates to the process for producing optically active 3-hydroxy-&ggr;-butyrolactone, wherein the acidic substance is p-toluenesulfonic acid, methanesulfonic acid, camphor sulfonic acid, sulfuric acid, trifluoroacetic acid, ferric chloride, zinc chloride or stannic chloride.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, this reaction is described in more detail.
The process for producing optically active 3-hydroxy-&ggr;-butyrolactone according to this invention is conducted according to the following reaction scheme:
wherein R
1
represents a C
1-4
lower alkyl group, R
2
represents a protective group for a hydroxyl group deprotected by hydrogenation with a heterogeneous hydrogenation catalyst, and the symbol * means an asymmetric carbon atom.
That is, the optically active 4-substituted oxy-3-hydroxybutyrate (II) is hydrogenated in the presence of a heterogeneous hydrogenation catalyst and an acidic substance followed by deprotection and simultaneous ring closure thereof, whereby optically active 3-hydroxy-&ggr;-butyrolactone (I) is formed. The optically active 4-substituted oxy-3-hydroxybutyrate (II) used as the starting material in this process can be produced by asymmetrically hydrogenating preferably a 4-substituted oxy-3-oxobutyrate (III) in the presence of a ruthenium complex comprising an optically active phosphine compound as a ligand.
The reaction scheme described above shows a series of these reactions.
In this invention, R
1
in the optically active 4-substituted oxy-3-hydroxybutyrate (II) may be a group capable of cleavage with its adjacent oxygen atom by participating in the reaction under the reaction conditions used, and the type of this group is not important, but the group is preferably a lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tert-butyl group, more preferably a C
1-4
lower alkyl group.
In this invention, R
2
in the optically active 4-substituted oxy-3-hydroxybutyrate (II) may be a hydroxyl-protecting group capable of cleavage upon deprotection under the reaction conditions for producing optically active 3-hydroxy-&ggr;-butyrolactone (I), and the protective group for a hydroxyl group deprotected by hydrogenation with the heterogeneous hydrogenation catalyst is preferably a benzyl group which may have one or more substituent groups thereon. The substituent groups on the benzyl group are not particularly limited insofar as the benzyl group can act as a protective group capable of deprotection, and preferable examples thereof include a lower alkyl group such as methyl group and ethyl group, a lower alkoxy group such as methoxy group, an aryl group such as phenyl group, p-methoxyphenyl group and naphthyl group, a halogen atom such as fluorine atom and chlorine atom, and a nitro group. The benzyl group may be substituted with these substituent groups on either its phenyl ring or its methylene group.
Examples of R
2
include a benzyl group, p-methyl phenyl methyl group, p-ethyl phenyl methyl group, p-methoxy phenyl methyl group, 3,5-dimethyl phenyl methyl group, 3,5-dimethoxy phenyl methyl group, p-fluorophenyl methyl group, p-chlorophenyl methyl group, 2,6-dichlorophenyl methyl group, &agr;-phenyl ethyl group, o-nitrophe
Matsumoto Takaji
Miura Takashi
Sotoguchi Tsukasa
Takenaka Motonobu
Corless Peter F.
Edwards & Angell LLP
O'Day Christine C.
Solola Tacfiq
Takasago International Corporation
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