Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-04-10
2003-08-12
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S587000
Reexamination Certificate
active
06605741
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a synthetic method of an &agr;-ketol unsaturated fatty acid and, in particular, to improve the yield in a synthesis of an &agr;-ketol unsaturated fatty acid having a double bond at a &bgr;-position to the ketone group thereof.
BACKGROUND OF THE INVENTION
Heretofore, various actions of ketol fatty acids have been known in the art, and in recent years it has been reported that some of ketol fatty acids have a flower bud formation inducing effect (Japanese Unexamined Patent Publication Nos. 9-295908 and 11-29410).
Several attempts have been made for preparing ketol fatty acids efficiently. As in the case of &agr;-ketol unsaturated fatty acid (1) represented below, however, due to a double bond existing at a &bgr;-position to the ketone group there is a problem that it is hard to be efficiently prepared by organic synthetic methods.
As for examples of synthetic methods of &agr;-ketols, the following Reaction Formulae I to III may be provided.
The Reaction Formula I shows a method to provide &agr;-ketol (12) by condensing acid chloride (10) and aldehyde (11) in the presence of samarium iodide (Tetrahedron Letters, Vol. 33, No. 19, 2621-2624 (1992), and Tetrahedron Letters, Vol. 35. No. 11, 1723-1726 (1994)). However, Reaction Formula I provided only a complicated mixture as a resulting product. Furthermore, the purification of such a product only gave compound (13) in which the double bond of &agr;-ketol (12) was transferred at low yield, so that Reaction Formula I could not allow the isolation of desired &agr;-ketol (12).
The Reaction Formula II shows a method that dithiane (14) is converted into its lithio-derivative by a lithiation process using alkyl lithium such as n-butyllithium and then the lithio-derivative is condensed with aldehyde (11) to provide compound (15), followed by converting a dithio part of compound (15) into a carbonyl group to obtain an &agr;-ketol (12) (J. Org. Chem., Vol. 33, No. 1, 298-300 (1968), and J. C. S. Chem. Comm., 100-101 (1979)). In this case, however, the resultant was also a complicated mixture, so that the target compound could not be isolated therefrom.
The Reaction Formula III shows a method using methylthiomethyl p-tolylsulfone derivative (16) which anions may present more stable than those of the dithiane. Namely, the methylthiomethyl p-tolylsulfone derivative (16) is reacted with aldehyde (11) just as in the case of Reaction Formula II to provide compound (17), followed by converting a thiomethylsulfone part of compound (17) into a carbonyl group to obtain &agr;-ketol (12) (Tetrahedron Letters, Vol. 27, No. 31, 3665-3668 (1986), and Tetrahedron Letters, Vol. 24, No. 51, 5761-5762 (1983)). In this method, compound (17) could be isolated but the yield was extremely low as 20% or less. Also, subsequent conversion reaction to a ketone gave a complicated mixture, so that the isolation was extremely difficult.
Thus, in the case of &agr;-ketol unsaturated fatty acid in which a double bond is present at a &bgr;-position to the ketone, the yield of its skeleton-forming reaction is extremely low as the double bond may be easily transferred. This is the reason why it is hard to obtain the desired &agr;-ketol unsaturated fatty acid efficiently.
SUMMARY OF THE INVENTION
The present invention has been accomplished in view of the above problems of the prior art. It is, therefore, a object of this invention to provide a method for efficiently synthesizing &agr;-ketol unsaturated fatty acid having a double bond at a &bgr;-position to the ketone.
As a result of the diligent studies conducted by the inventors for attaining the above object, it has be found that by a reaction between a monosubstituted acetylene and an epoxide a carbon skeleton of &agr;-ketol unsaturated fatty acid can be formed efficiently. Thus, the present invention has been accomplished.
Namely, a method of synthesizing an &agr;-ketol unsaturated fatty acid in accordance with the present invention comprises the steps of:
preparing compound (4) by reacting monosubstituted acetylene (2) with epoxide (3); and
preparing &agr;-ketol unsaturated fatty acid (1) from said compound (4), as shown in the following Reaction Formula 1:
wherein
R
1
represents an alkyl group of 1-18 carbon atoms or an aliphatic hydrocarbon group of 2-18 carbon atoms having 1-5 double or triple bonds at given positions;
R
2
represents a protecting group for a hydroxyl group;
R
3
represents a protecting group for a carboxyl group;
R is identical to R
1
or, when R
1
has one or more triple bonds, R represents an aliphatic hydrocarbon group in which each triple bond of R
1
is converted to a double bond; and
A represents an alkylene group of 1-18 carbon atoms.
The method of the present invention preferably comprises the steps of:
reducing said compound (4) to produce compound (5);
oxidizing a hydroxyl group of said compound (5) to produce compound (6); and
deprotecting R
2
and R
3
of said compound (6) to produce said &agr;-ketol unsaturated fatty acid (1), as shown in Reaction Formula 2:
wherein R
1
, R
2
, R
3
, R, and A are the same as defined in said Reaction Formula 1.
Also, the method of the present invention preferably comprises the steps of:
reducing said compound (4) to produce compound (5);
deprotecting R
3
of said compound (5) to produce compound (7);
oxidizing a hydroxyl group of said compound (7) to produce compound (8); and
deprotecting R
2
of said compound (8) to produce said &agr;-ketol unsaturated fatty acid (1), as shown in Reaction Formula 3:
wherein R
1
, R
2
, R
3
, R, and A are the same as defined in said Reaction Formula 1.
In the present invention, R
1
preferably represents R
4
—C≡C—CH
2
—, where R
4
represents an alkyl group of 1-7 carbon atoms.
R
4
preferably represents ethyl group.
“A” preferably represents an alkylene group expressed by —(CH
2
)n—, where n is an integer of 1 to 10.
“n” is preferably 7.
R
2
preferably represents an ether-type protecting group.
The double bond of &agr;-ketol unsaturated fatty acid (1) preferably has a cis-configuration.
An intermediate for synthesis of &agr;-ketol unsaturated fatty acid (1) in accordance with the present invention is represented by the general formula (4):
wherein
R
1
represents an alkyl group of 1-18 carbon atoms or an aliphatic hydrocarbon group of 2-18 carbon atoms having 1-5 double or triple bonds at given positions;
R
2
represents a protecting group for a hydroxyl group;
R
3
represents a protecting group for a carboxyl group; and
A represents an alkylene group of 1-18 carbon atoms.
In a method of synthesizing an optically active &agr;-ketol unsaturated fatty acid in accordance with the present invention, it is preferably that in any methods mentioned above an asymmetric carbon atom of —C(OR
2
)— in said epoxide (3) has either of R-configuration or S-configuration and that an asymmetric carbon atom in the &agr;-ketol structure of &agr;-ketol unsaturated fatty acid (1) has either of R-configuration or S-configuration.
Also, the method preferably comprises the steps of:
preparing compound (4A) by reacting said monosubstituted acetylene (2) with (R)-epoxide (3A) obtained from compound (21A) which asymmetric carbon atom at an aryl position has R-configuration; and
preparing (R)-&agr;-ketol unsaturated fatty acid (1A) from said compound (4A), as shown in the following Reaction Formula 1A:
wherein R
1
, R
2
, R
3
, R, and A are the same as defined in said Reaction Formula 1.
Also, the method preferably comprises the steps of:
preparing compound (4B) by reacting said monosubstituted acetylene (2) with (S)-epoxide (3B) obtained from compound (21B) which asymmetric carbon atom at an aryl position has S-configuration; and
preparing (S)-&agr;-ketol unsaturated fatty acid (1B) from said compound (4B), as shown in the following Reaction Formula 1B:
wherein R
1
, R
2
, R
3
, R, and A are the same as defined in said Reaction Formula 1.
An optically active intermediate for synthesis of said &agr;-ketol unsaturated fatty acid (1A) or (1B) is represented by the general formula (4A
Kobayashi Koji
Yamamura Shosuke
Yokokawa Yoshihiro
Chao Fei-Fei
Killos Paul J.
Shiseido Co. Ltd.
Venable LLP
LandOfFree
Synthetic method of &agr;-ketol unsaturated fatty acids does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Synthetic method of &agr;-ketol unsaturated fatty acids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthetic method of &agr;-ketol unsaturated fatty acids will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3114781