Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-07-25
2003-07-01
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06586616
ABSTRACT:
This application is a 371 of PCT/KR00/00052 filed Jan. 29, 2000.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing (R)-4-cyano-3-hydroxybutyric acid esters and more particularly, to a novel process for preparing optically pure (R)-4-cyano-3-hydroxybutyric acid esters expressed by the following formula (1) in high yield by performing cyanation and sequential esterfication of (S)-3,4-epoxybutyric acid salt as a starting material,
where in R represents a linear or branched alkyl group having 1~4 carbon atoms or a benzyl group.
2. Description of the Prior Art
Optically active (R)-4-cyano-3-hydroxybutyric acid ester expressed by the following formula (1) is useful as a key intermediate for hypolipidemic agents. Various methods for preparing hypolipidemic agents from optically active (R)-4-cyano-3-hydroxybutyric acid ester have been reported as introduced hereinafter.
U.S. Pat. No. 4,681,893 describes a process for the preparation of hypolipidemic agent, atorvastatin, from (R)-4-cyano-3-hydroxybutyric acid ester.
The use of (R)-4-cyano-3-hydroxybutyric acid ester as starting material is described in preparation of CI-981 which is an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A(HMG-CoA) reductase in
Tetrahedron Letters
, 33), 2279~2282 (1992).
As described above, there is a need for a simple and inexpensive method for the preparation of (R)-4-cyano-3-hydroxybutyric acid ester due to its usefullness for hypolipidemic agents. A large number of syntheses have been developed. For example, U.S. Pat. No. 4,611,067 describes a method for preparation of (R)-4-cyano-3-hydroxybutyric acid ester by the synthetic pathway from ascorbic acid. Ascorbic acid is degraded to afford 4-bromo-3-hydroxybutyric acid ester through D-threonate potassium salt which is then reacted with an appropriate reagent to protect the hydroxy function to silyl group prior to reaction with sodium cyanide in dimethyl sulfoxide for 16 hours to afford (R)-4-cyano-3-hydroxybutyric acid ester.
However, this conventional method requires multi-step synthesis and long reaction time for cyanation as well as difficulty in removing dimethyl sulfoxide which is used as a solvent. It generates large amount of side-products such as acrylate by dehydration due to the high acidic hydrogen on &agr;-position for the carboxy group and the corresponding acid by hydrolysis of ester groups. In addition, it is not applicable to produce various esters.
SUMMARY OF THE INVENTION
The inventors made extensive efforts to provide more economical and effective preparing methods of (R)-4-cyano-3-hydroxybutyric acid ester which is an essential intermediate for drugs. As a result, it was realized that the use of (S)-3,4-epoxybutyric acid salt as a starting material, followed by cyanation and sequential esterification could provide a novel and inexpensive preparing method of (R)-4-cyano-3-hydroxybutyric acid ester with excellent optical purity and yield.
The introduction of cyano functional group to (S)-3,4-epoxybutyric acid salt in the present invention has not only been tried to afford (R)-4-cyano-3-hydroxybutyric acid ester and but also provided a novelty, applicability and easiness in the method of preparing the same.
Therefore, the purpose of this invention is to provide the synthetic method of optically pure (R)-4-cyano-3-hydroxybutyric acid ester, as the target product, in maximum yield as well as high purity simultaneously inhibiting the side-reaction, hydrolysis or formation of acrylate which are usual problems in the coventional methods.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing optically pure (R)-4-cyano-3-hydroxybutyric acid esters expressed by the following formula (1) in high yield by performing cyanation and sequential esterification of (S)-3,4-epoxybutyric acid salt as a starting material,
wherein R represents a linear or branched alkyl group having 1~4 carbon atoms or a benzyl group.
The present invention is explained in more detail as set forth hereunder.
The process enables preparing optically pure (R)-4-cyano-3-hydroxybutyric acid esters economically due to use of aqueous condition in cyanation and introducing various ester groups by esterification without any side reaction.
The procedure described in this invention for the preparation of (R)-4-cyano-3-hydroxybutyric acid ester is briefly shown in the following reaction scheme 1,
wherein M represents an alkali metal atom, an alkaline earth metal atom or an ammoniun ion; R represents a linear or branched alkyl group having 1 to 4 carbon atoms or a benzyl group.
(S)-3,4-epoxybutyric acid salt used as a starting material in the present invention can be prepared from (S)-4-halo-3hydroxybutyric acid or ester thereof. For example, (S)-3,4-epoxybutyric acid salt is prepared by reacting (S)-4-halo-3hydroxybutyric acid with 1~50% of sodium hydroxide at −50~50° C. for 0.5~10 hours. Over 95% conversion of (S)-4-halo-3-hydroxybutyric acid to (S)-3,4-epoxybutyric acid salt can be detected by NMR.
The formation of a carboxylate anion in the present invention is very important. Generally, a method of (R)-4-cyano-3-hydroxybutyric acid ester is prepared by nucleophilic reaction of cyanide toward (S)-4-halo-3-hydroxybutyric acid ester. A hydrogen on &agr;-position of ester group is so acidic that it is very reactive with a base to produce acrylate by dehydration. However, the formation of a carboxylate anion decreases the acidity of hydrogen on &agr;-position of carboxylate and thus, there is no side reaction such as dehydration which is shown in conventional method.
Cyanation in the present invention is conducted with 1.0~5.0 equivalents of a cyanation reagent at the temperature of 0~100° C. for 0.5~5 hours. The cyanation reagent is selected from the group consisting of potassium cyanide, sodium cyanide and alkyl ammonium cyanide having 1~4 carbon atoms. Solvent used in cyanation can be water or a mixture of water and organic solvent. The organic solvent is selected from the group consisting of acetonitrile, dichloro methane, chloroform, linear or branched alcohol having 1~4 carbon atoms, tetrahydrofuran, benzene and toluene.
Esterification in the present invention is conducted by reacting cyanation reaction mixture with an acid such as sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid, followed by concentration of solvent prior to reaction with ROH at 0~100° C. wherein R represents linear or branched alkyl group having 1~4 carbon atoms or benzyl group.
(R)-4-cyano-3-hydroxybutyric acid ester with over 90% of yield and 99.8% of optical purity is obtained by performing the process described in the present invention.
REFERENCES:
patent: 5155251 (1992-10-01), Butler et al.
patent: 573184 (1993-05-01), None
Tetrahedron: asymmetry vol. 4 (1993) pp. 1082-1104. Beard et al. ‘Stereoselective Hydrolysis of Nitriles and Amides Under Mild Conditions Using a Whole Cell Catalyst’ *see p. 1089 scheme 3.
J. Org. Chem., vol. 61 (1996) pp. 3923-3925. F.J. Lakner et al. ‘Chloroperoxidase as Enantioselective Eposidation Catalyst: An Efficient Synthesis of ®-(-)-Mevalonolactone’ *see p. 3924 scheme 1 experimental.
Charles R. Degenhardt, Synthesis of Carnitine Homologues. Resactions of Tertiary Amines with Epoxy Esters, J. Org. Chem. 1980, 45, pp. 2763-2766.
Daniclc Bianchi et al., Enzymatic Hydrolysis of Alkyl 3,4-Epoxybutyrates. A New Route to ®-(-)-Carnitine Chloride, J. Org. Chem 1988, 53, pp. 104-107.
Hwang Dae Il
Kim Kyung Il
Lee Won Jang
Roh Kyoung Rok
Yu Ho Sung
Lowe Hauptman & Gilman & Berner LLP
McKane Joseph K.
Samsung Fine Chemicals Co. Ltd.
Shameem Golam M. M.
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