Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-06-09
2003-09-16
Keys, Rosalynd (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S660000, C568S679000, C568S680000
Reexamination Certificate
active
06620977
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing a butanetriol derivative, which is important as an intermediate in making antidiabetics having protein kinase C inhibiting activity and relates to a novel intermediate of the butanetriol derivative.
BACKGROUND ART
Butanetriol derivatives are used as intermediates in making antidiabetics having protein kinase C inhibiting activity. It is known that butanetriol derivatives are prepared by reacting glycidyl trityl ether and vinylmagnesium bromide, by allyl-etherification and by ozonolysis of resulting olefin, followed by treatment of resulting aldehyde with sodium borohydride (U.S. Pat. No. 5,541,347).
Glycidyl trityl ether, however is expensive and the reactions with vinylmagnesium bromide and by ozonolysis have to be carried out at lower temperature, −20° C. and −35 to −50° C., respectively. The procedures, therefore are troublesome. Furthermore, ozone is harmful to human body and there is a possibility of explosion. Thus, the known methods are not satisfactory for application to industrially scaled production. The superior method has been desired.
DISCLOSURE OF INVENTION
As a result of extensive investigation on an improved method for preparing butanetriol derivatives, the present inventors have found that butanetriol derivatives can be favorably prepared in industrial scale by using the starting material which is easily available.
The present invention relates to a novel process for preparing a butanetriol derivative, which is important as an intermediate in making antidiabetics having protein kinase C inhibiting activity and relates to a novel intermediate thereof.
The process for preparing a butanetriol derivative (1) of the present invention is shown as the following reaction scheme.
In the above formulae, R
1
and R
2
are, different from each other, protecting groups for alcohol and said protecting groups are such that only R
2
is removed when deprotection reaction is carried out. R
3
and R
4
are, the same or different, hydrogen, C
1
-C
4
alkyl or phenyl, or may form a C
3
-C
6
cycloalkyl group together with the adjacent carbon atom. X is halogen atom or sulfonyloxy group.
Each step is explained below in detail.
Process for Preparing Compound (6)
Compound (6) is prepared from compound (7).
Introduction of the protecting group (R
2
) except tetrahydropyranyl group is carried out by etherifying hydroxy group for compound (7) in the presence of a base to give compound (6).
Examples of the protecting group are silyl ether-protecting groups, such as triethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, benzyl-protecting groups, such as benzyl, p-methoxybenzyl or trityl, and acetal-protecting groups such as methoxymethyl etc.
Introduction of tetrahydropyranyl group is carried out by reacting compound (7) and dihydropyrane in the presence of acid catalyst, such as p-toluenesulfonic acid or pyridinium p-toluenesulfonate.
Preferable protecting groups are tert-butyldimethyl-silyl, tert-butyldiphenylsilyl, benzyl and p-methoxybenzyl, especially tert-butyldimethylsilyl and benzyl.
Introduction of the protecting group except tetrahydropyranyl group is carried out by reacting hydroxy group of compound (7) with an alkylating agent in the presence of a base.
Examples of the base used in this reaction are alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal hydrogen carbonates, such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal or alkaline earth metal carbonates, such as sodium carbonate or potassium carbonate, alkali metal or alkaline earth metal hydrides, such as sodium hydride or potassium hydride, organic alkali metal salts, such as dimethyl sodium, n-butyllithium, sec-butyllithium or tert-butyllithium, and alkali metal amides, such as lithium diisopropylamide, potassium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium hexamethyl-disilazide.
Amount of the base is equimole or more than equimole to the substrate, preferably 1.0 to 1.2 moles. Regarding of silyl ether-protecting groups or benzyl-protecting groups, examples of the reacting agent used for protection are silyl halides, such as tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, alkyl halides, such as benzyl chloride or benzyl bromide and sulfonic acid esters such as trifluoromethane-sulfonic acid tert-butyldimethylsilyl ester. Regarding acetal-protecting groups, examples of the reacting agent used for protection are alkoxymethyl halides such as methoxymethyl chloride.
Amount of the reacting agent is equimole or more than equimole to the substrate, preferably 1.0 to 1.2 moles.
Examples of a solvent used are aprotic solvents, such as N,N-dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide, hydrocarbons, such as benzene or toluene, ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or triglyme, or a mixture thereof, when as the base are used alkali metal or alkaline earth metal hydrides, such as sodium hydride or potassium hydride, organic alkali metal salts, such as dimethyl sodium, dimethyl potassium, n-butyllithium, sec-butyllithium or tert-butyllithium, or alkali metal amides, such as lithium diisopropylamide, potassium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium hexamethyldisilazide.
Examples of a solvent used are aprotic solvents, such as N,N-dimethylformamide, dimethyl sulfoxide or hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene, ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or triglyme, halogen compounds, such as dichloromethane, chloroform or 1,2-dichloroethane, water or a mixture with an organic solvent thereof and water, preferably ethers, aprotic solvents or a mixture of an aprotic solvent and water, especially preferably N,N-dimethylformamide, dimethyl sulfoxide or a mixture of dimethyl sulfoxide and water, when as the base are used alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal hydrogen carbonates, such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal or alkaline earth metal carbonates, such as sodium carbonate or potassium carbonate.
The reaction temperature is from −78° C. to reflux temperature of the solvent.
The reaction proceeds without catalyst, but the reaction is promoted in the presence of iodo compounds, such as cesium iodide, potassium iodide or sodium iodide, bromo compounds, such as cesium bromide, potassium bromide or sodium bromide, quaternaryammonium phase transfer catalysts, such as tetrabutylammonium chloride or trimethylbenzyl-ammonium bromide, Crown ethers such as 18-Crown-6, 4-N,N-dimethylaminopyridine, 2,6-lutidine or 4-methoxypyridine, especially effective when a leaving group for the reacting agent used for protection is chlorine atom.
As the reaction promoter, alkali metal bromides or iodides are preferable, especially sodium bromide, potassium bromide, sodium iodide and potassium iodide.
Amount of the reaction promoter is 0.5 to 1.1 moles to compound (7). To use too small amount causes decrease of reaction rate and is not practical.
When R
2
is silyl ether-protecting groups, such as triethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, phenyl-substituted methyl-protecting groups, such as benzyl or trityl, or acetal-protecting groups such as methoxymethyl, the protection reaction can be also carried out with halogeno silane compounds, such as trityl chloride or tert-butyldimethylsilyl chloride, alkyl halides, such as benzyl chloride, or benzyl bromide, sulfonic acid esters, such as tert-butyldimethylsilyl trifluoromethanesulfonate, or alkoxymethyl halides such as methoxymethyl chloride in the presence of a tertiary amine, such as triethylamine or pyridine.
Amount of said reagent is equimole or more than equimole to the substrate, preferably 1.0 to 1.2 moles.
Examples of a solvent used
Furukawa Yoshiro
Hirata Makoto
Mikami Masafumi
Daiso Co. Ltd.
Keys Rosalynd
LandOfFree
Process for producing butanetriol derivative does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for producing butanetriol derivative, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing butanetriol derivative will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3097637