Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-23
2001-07-31
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06268515
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel process for preparing a 3-hydroxy-&ggr;-butyrolactone derivative which is useful as an intermediate in making medicines and agrochemicals.
BACKGROUND ART
A 3-hydroxy-&ggr;-butyrolactone derivative is used as an intermediate in making medicines and agrochemicals. The known methods for preparing it are as follows: (i) The method by reacting 3-hydroxy-&ggr;-butyrolactone with lithium diisopropylamide to form a dianion, followed by adding an alkylating agent (J. Org. Chem., 46, 4319 (1981)). (ii) The method of preparing a 3-hydroxy-&ggr;-butyrolactone derivative by using 2-butenoic acid as a starting material (J. Chem. Res. (S), 274 (1996)).
DISCLOSURE OF INVENTION
The above known methods, however have following problems: The method (i) by reacting 3-hydroxy-&ggr;-butyrolactone with lithium diisopropylamide to form a dianion, followed by adding an alkylating agent takes many hours in reaction and is low in yield. Furthermore, since hexamethylphosphoramide, which is carcinogenic, must be used as an additive, the method is not suitable for mass production.
The method (ii) of preparing a 3-hydroxy-&ggr;-butyrolactone derivative by using 2-butenoic acid as a starting material needs to use a peracid not suitable for mass production and that requires many steps.
As a result of extensive investigation on an improved method for preparing a 3-hydroxy-&ggr;-butyrolactone derivative, the present inventors have found that the 3-hydroxy-&ggr;-butyrolactone derivative can be prepared by treating a metal salt of hexamethyldisilazane and 3-hydroxy-&ggr;-butyrolactone as a starting material prior to reacting an electrophilic reagent such as an alkylating agent, and that a 3-hydroxy-&ggr;-butyrolactone derivative can be prepared in good yield and in short times by undergoing the reaction with the electrophilic reagent in the presence of a reaction promoter.
The present invention relates to a novel process for preparing the 3-hydroxy-&ggr;-butyrolactone derivative which is useful as an intermediate in making medicines and agrochemicals, namely to the process for preparing a 3-hydroxy-&ggr;-butyrolactone derivative represented by the following formula (1):
wherein R is C
1
-C
6
alkyl, 3 to 6-membered cycloalkyl, aralkyl, 2-alkenyl, acyl, &agr;-hydroxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl, which is characterized in treating 3-hydroxy-&ggr;-butyrolactone with a metal salt of hexamethyldisilazane and then, reacting it with an electrophilic reagent, optionally in the presence of a reaction promoter.
The reaction of the present invention is shown in following reaction scheme:
wherein R is the same as defined above.
The reaction is in detail explained as follows.
At first by reacting 3-hydroxy-&ggr;-butyrolactone with a metal salt of hexamethyldisilazane under inert gas, such as argon or nitrogen under cooling to form a dianion. Then, the anionic compound is reacted with an electrophilic reagent, if necessary in the presence of a reaction promoter to prepare an objective compound (1).
Examples of a metal salt of hexamethyldisilazane are lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide, preferably lithium hexamethyldisilazide or sodium hexamethyldisilazide.
Amount of the metal salt to the substrate is 2-4 moles, preferably 2-2.5 moles.
Examples of the electrophilic reagent are alkyl halide-reagents, such as C
1
-C
6
alkyl halide, 3 to 6-membered cycloalkyl halide, aralkyl halide or 2-alkenyl halide, aldehyde-reagents, ketone-reagents, ester-reagents, &agr;-haloester-reagents, carbonate-reagents, or sulfonic acid ester-reagents, preferably alkyl halide-reagents.
Examples of the alkyl halide-reagent are alkyl chloride-reagents, such as methyl chloride, isopropyl chloride, cyclopropylmethyl chloride, cyclopentylmethyl chloride, cyclohexyl chloride, benzyl chloride, allyl chloride or methallyl chloride, alkyl bromide-reagents, such as methyl bromide, isopropyl bromide, cyclopropylmethyl bromide, cyclopentylmethyl bromide, cyclohexyl bromide, benzyl bromide, allyl bromide or methallyl bromide, or alkyl iodide-reagents, such as methyl iodide, isopropyl iodide, cyclopropylmethyl iodide, cyclopentylmethyl iodide, cyclohexyl iodide, benzyl iodide, allyl iodide or methallyl iodide. Especially preferable alkyl halide-reagents are methyl iodide, benzyl chloride, benzyl bromide, allyl chloride or allyl bromide.
Examples of the aldehyde-reagent are formaldehyde, acetaldehyde, benzaldehyde or cinnamaldehyde.
Examples of the ketone-reagent are acetone, diethyl ketone, vinylacetone or benzophenone.
Examples of the ester-reagent are methyl acetate, ethyl acetate, ethyl propionate or ethyl benzoate.
Examples of the &agr;-halo ester-reagent are ethyl bromoacetate or ethyl 2-bromopropionate.
Examples of the carbonate-reagent are dimethyl carbonate, diethyl carbonate, diphenyl carbonate, methyl chlorocarbonate, ethyl chlorocarbonate or phenyl chlorocarbonate.
Examples of the sulfonic acid ester-reagent are p-toluenesulfonic acid ester, such as p-toluenesulfonic acid methyl ester, p-toluenesulfonic acid ethyl ester or p-toluenesulfonic acid glycidyl ester, methanesulfonic acid ester, such as methanesufonic acid methyl ester or methanesulfonic acid ethyl ester, or 3-nitrobenzenesulfonic acid ester such as 3-nitrobenzenesulfonic acid glycidyl ester.
Amount of the elecrophilic reagent is 1-4 moles to the substrate, preferably 1-2 moles.
Examples of a solvent used in this reaction are aprotic solvents, such as N,N-dimethylformamide or dimethyl sulfoxide, ethers, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol monomethyl ether, halogeno compounds such as dichloromethane or 1,2-dichloroethane, or a mixture thereof. In view of going up yield, tetrahydrofuran and 1,2-dimethoxyethane are preferable solvents.
The reaction temperature is −100° C. to reflux temperature of the solvent, preferably −45° C. to room temperature.
When the electrophilic reagent is reacted, the reaction is promoted by adding a reaction promoter, and there is obtained the object compound (1) in a short time in good yield.
Examples of the reaction promoter are 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone or tetramethylethylenediamine, preferably 1,3-dimethyl-2-imidazolidinone or 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.
Amount of the promoter to the substrate is 1 to 20 moles, preferably 2 to 10 moles.
The starting materials used in the process of the present invention and the objective compounds (1) have asymmetric carbons and therefore, the optically active objective compound (1) is obtained by using an optically active compound as a starting material.
According to the process of the present invention, by using (S)-3-hydroxy-&ggr;-butyrolactone, a (2S,3S)-3-hydroxy-&ggr;-butylolactone derivative is predominantly prepared in a (2S,3S)-3-hydroxy-&ggr;-butyrolactone derivative and a (2R,3S)-3-hydroxy-&ggr;-butyrolactone derivative. On the other hand, by using (R)-3-hydroxy-&ggr;-butyrolactone, a (2R,3R)-3 -hydroxy-&ggr;-butylolactone derivative is predomiantly prepared in a (2R,3R)-3-hydroxy-&ggr;-butyrolactone derivative and a (2S,3R)-3-hydroxy-&ggr;-butyrolactone derivative.
When 3-hydroxy-&ggr;-butylolactone having highly optical purity is used, there is obtainable a 3-hydroxy-&ggr;-butyrolactone derivative having highly optical purity without marked racemization on the way of the reaction.
REFERENCES:
patent: 3928581 (1975-12-01), Dahlberg et al.
patent: 4056672 (1977-11-01), Dahlberg et al.
Buisson, D. et al, “New Chiral Building . . . Synthons”, Tetrahedron Letters, vol. 28, No. 42 (1987), pp. 5033-5036.
Furukawa Yoshiro
Hinoue Kazumasa
Katsumura Shigeo
Takehira Yoshikazu
Daiso Co. Ltd.
Jacobson & Holman PLLC
McKane Joseph K.
Wright Sonya N.
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