Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-15
2002-03-19
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S844000, C203S063000, C203S064000, C203S066000
Reexamination Certificate
active
06359155
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a 3-hydroxytetrahydrofuran, particularly an optically active 3-(S)-hydroxytetrahydrofuran of high quality, in a simple, easy and industrially advantageous manner and in high yield.
BACKGROUND ART
3-Hydroxytetrahydrofuran is a compound of great value as a synthetic intermediate of medicinals and agrochemicals. The known technology for the production thereof comprises reducing a 4-halo-3-hydroxybutyric acid ester, which is readily available, and cyclizing the resulting 4-halo-1,3-butanediol. Specifically, production processes of 3-hydroxytetrahydrofuran are known which comprise reducing a 4-halo-3-hydroxybutyric acid ester with sodium borohydride in an organic solvent miscible with water, such as tetrahydrofuran (hereinafter referred to as THF), and cyclizing the resulting 4-halo-1,3-butanediol in aqueous hydrochloric acid to give 3-hydroxytetrahydrofuran [e.g. Japanese Kokai Publication Hei-09-77759; Liebigs Ann./Recl., page 1877 (1997)].
The steps involved in a typical production process among these as described are as follows:
Step 1: Reducing ethyl 4-chloro-3-hydroxybutyrate with sodium borohydride in THF;
Step 2: Adding aqueous hydrochloric acid to the concentration residue of the reaction mixture, extracting the mixture with ethyl acetate, dehydrating the extract with a solid desiccant, separating the desiccant by filtration and removing the extractant solvent by concentration, to give 4-chloro-1,3-butanediol as an oil;
Step 3: Dissolving this oil in aqueous hydrochloric acid and heating the solution to cause cyclization;
Step 4: Neutralizing the reaction mixture, removing water by concentration, adding methanol to the residue and removing the precipitated inorganic salt by filtration; and
Step 5: Concentrating and distilling the filtrate to recover 3-hydroxytetrahydrofuran.
However, such a process requires complicated procedural steps such as a plurality of concentration and solid-liquid separation procedures. If a concentration procedure is omitted and water is directly added to the reaction mixture, a mixed solvent composed of the solvent and water will be formed, since the solvent is miscible with water. Investigations made by the present inventors revealed that if the cyclization reaction is then carried out in such a solvent, unfavorable results are inevitable, for example the rate of reaction decreases and the impurity content increases. Therefore, in carrying out the reduction reaction using a organic solvent miscible with water, it is essential to interpose a step of removing this organic solvent prior to addition of water to the reaction mixture. The prior art processes are thus low in productivity and cannot be said to be fully suited for commercial production.
Furthermore, in the prior art processes, generally the yield in the reduction step is 86% and the yield in the cyclization step is 68 to 79%, hence the yield of the desired product is 58 to 68%. These figures are not necessarily satisfactory. The prior art processes have further problems with respect to the quality of the desired product; it is known that, in the reduction reaction, 3,4-epoxy-1-butanol is formed as a byproduct (the byproduct yield being about 16 to 21%; Japanese Kokai Publication Hei-02-174733) and, in the cyclization reaction, 2,5-dihydrofuran is formed as a byproduct [the byproduct yield being about 15%; Liebigs Ann./Recl., page 1877 (1997)].
As mentioned above, in the state of art, no simple, easy and efficient processes are known, to say nothing of processes that may be carried out on a commercial scale with advantage, for producing high-quality 3-hydroxytetrahydrofuran in high yield by reduction of a 4-halo-3-hydroxybutyric acid ester and cyclization of the resulting 4-halo-1,3-butanediol.
In view of the above state of the art, it is an object of the present invention to provide a simple, easy and industrially advantageous process for producing high-quality 3-hydroxytetrahydrofuran (3) by reducing a 4-halo-3-hydroxybutyric acid ester (1) and cyclizing the resulting 4-halo-1,3-butanediol (2).
DISCLOSURE OF THE INVENTION
The present invention provides a process for producing a 3-hydroxytetrahydrofuran of the general formula (3):
by reducing a 4-halo-3-hydroxybutyric acid ester of the general formula (1):
wherein R represents an ester-forming protective group and X represents a halogen atom
and cyclizing the resulting 4-halo-1,3-butanediol of the general formula (2):
wherein X represents a halogen atom which comprises:
Step 1: Reducing a 4-halo-3-hydroxybutyric acid ester (1) with a boron hydride compound and/or an aluminum hydride compound as a reducing agent in an organic solvent immiscible with water;
Step 2: Treating the obtained reaction mixture with an acid and water to thereby effect conversion to the corresponding 4-halo-1,3-butanediol (2) and at the same time giving an aqueous solution containing said compound;
Step 3: Carrying out the cyclization reaction of the 4-halo-1,3-butanediol (2) in said aqueous solution;
Step 4: Extracting the resulting 3-hydroxytetrahydrofuran (3) from the obtained aqueous solution containing 3-hydroxytetrahydrofuran with an organic solvent immiscible with water; and
Step 5: Isolating the 3-hydroxytetrahydrofuran (3) by concentration and/or distillation of the solution obtained.
The present invention also provides a process for producing a 4-halo-1,3-butanediol
which comprises reducing a 4-halo-3-hydroxybutyric acid ester (1) with a boron hydride compound and/or an aluminum hydride compound as a reducing agent in an organic solvent immiscible with water
and treating the obtained reaction mixture with an acid and water to thereby effect conversion to the corresponding 4-halo-1, 3-butanediol (2) and at the same time giving an aqueous solution containing said compound.
The present invention further provides a process for producing a 3-hydroxytetrahydrofuran (3) by cyclizing a 4-halo-1,3-butanediol (2) in an aqueous solution
which comprises carrying out the cyclization reaction under weakly acidic to neutral conditions.
The present invention further provides a process for recovering a 3-hydroxytetrahydrofuran
which comprises extracting 3-hydroxytetrahdyrofuran from an aqueous solution containing 3-hydroxytetrahydrofuran with an organic solvent immiscible with water at a temperature not lower than 40° C.
The present invention further provides a process for recovering a 3-hydroxytetrahydrofuran
which comprises extracting 3-hydroxytetrahydrofuran from an aqueous solution containing 3-hydroxytetrahydrofuran with a monohydric alcohol containing 4 to 8 carbon atoms.
The present invention further provides a process for recovering a 3-hydroxytetrahydrofuran from a mixture comprising 3-hydroxytetrahydrofuran and a boron compound and/or an aluminum compound by distillation
which comprises treating the mixture comprising 3-hydroxytetrahydrofuran and a boron compound and/or an aluminum compound with a monohydric alcohol containing 1 to 3 carbon atoms or a polyhydric alcohol containing at least 6 carbon atoms in carrying out the distillation.
Lastly, the present invention provides a process for recovering a 3-hydroxytetrahydrofuran
which comprises carrying out distillation (inclusive of rectification) of 3-hydroxytetrahydrofuran in the presence of a base.
In the following, the present invention is described in detail.
The five-step process for producing a 3-hydroxytetrahydrofuran is described below in detail. The processes according to other aspects of the present invention can also be carried out by the same techniques mentioned hereinbelow.
In the first step of this production process, a 4-halo-3-hydroxybutyric acid ester represented by the above general formula (1) [hereinafter referred to also as “4-halo-3-hydroxybutyric acid ester (1)”] is reduced with a boron hydride compound and/or an aluminum hydride compound in an organic solvent immiscible with water to cause formation of the corresponding 4-halo-1,3-butanediol represented by the above gene
Fuse Yoshihide
Honda Tatsuya
Kinoshita Koichi
Moroshima Tadashi
Nagashima Nobuo
Dentz Bernard
Kaneka Corporation
Sughrue & Mion, PLLC
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