Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
1999-08-12
2001-05-01
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S068000, C560S055000, C560S056000
Reexamination Certificate
active
06225484
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to an improved process for the preparation of 7-aryl-3,5-dialkoxy-4-alkyl-hepta-2,6-dienoic acid alkyl ester which comprises reacting the corresponding 3-aryl-propenal with a 3-oxo-alkanoic acid alkyl ester to afford a 7-aryl-3,5-dihydroxy-4-alkyl-hepta-2,6-dienoic acid alkyl ester which is then subsequently alkylated.
7-aryl-3,5-dialkoxy-4-alkyl-hepta-2,6-dienoic acid alkyl esters are useful as intermediates for the preparation of a variety of beta-methoxyacrylates which are useful as fungicides. In particular, they are key intermediates in the preparation of myxothiazole and oudemansins which are described, for example, in Martin et al., Tetrahedron Letters, 32, 5151, 1993.
7-aryl-3,5-dialkoxy-4-alkyl-hepta-2,6-dienoic acid alkyl esters are generally disclosed in WO 99/12892 but there is no specific disclosure of their preparation.
Martin et al., Tetrahedron Letters, 34, 32, 5151, 1993 disclose a method for the preparation of myxothiazole which comprises reacting 3-phenyl-propenal with 3-oxo-pentanoic acid methyl ester followed by three methylation steps to yield 7-phenyl-3,5-dimethoxy-4-alkyl-hepta-2,6-dienoic acid methyl ester as an intermediate for myxothiazole. This process requires many steps to achieve an overall yield of the desired 7-aryl-3,5-dialkoxy-4-methyl-hepta-2,6-dienoic acid alkyl ester of less than 20%.
The novel process of the present invention has been found to be advantageous in producing 7-aryl-3,5-dialkoxy-4-alkyl-hepta-2,6-dienoic acid alkyl esters with high overall yields in only one or two steps.
It is an object of the present invention to provide an efficient and improved process for the preparation of 7-aryl-3,5-dialkoxy-4-alkyl-hepta-2,6-dienoic acid alkyl esters of formula I.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following description and the appended claims.
SUMMARY OF THE INVENTION
The compounds of formula I
wherein
R
1
represents an optionally substituted aryl group,
R
2
represents an optionally substituted alkyl group, and
R
3
and R
4
each individually represent an alkyl group;
are obtained in high overall yields by an improved process which comprises
heating of a mixture which consists essentially of
(i) a compound of formula II
wherein R
1
, R
2
and R
4
are as hereinbefore defined,
(ii) an alcohol of formula III,
R
3
—OH (III)
wherein R
3
is as hereinbefore defined,
(iii) a tri-alkoxymethane of formula IV,
CH(OR
3
)
3
(IV)
wherein R
3
is as hereinbefore defined, and
(iv) an acid, and, optionally, an inert diluent.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The instant invention relates to an improved process for the preparation of the compounds of formula I which comprises by heating a mixture consisting essentially of a compound of formula II, an alcohol of formula III, a tri-alkoxymethane of formula IV, an acid, and, optionally, an inert diluent. The compounds of formula II can be obtained by reacting a 3-aryl-propenal with a 3-oxo-alkanoic acid alkyl ester in the presence of a strong base and an inert diluent.
The advantage of the improved process is that the compound of formula I is obtained in high yields and high purity by a one or two step synthesis.
In general terms, unless otherwise stated herein, the term “alkyl” as used herein with respect to a radical or moiety refers to a straight or branched chain radical or moiety. As a rule, such radicals have up to 10, in particular, up to 6, carbon atoms. Preferably an alkyl moiety has from 1 to 6 carbon atoms, and more preferably, from 1 to 3 carbon atoms. A particularly preferred alkyl moiety is the methyl group or ethyl group being optionally substituted by one or more halogen atoms.
In general terms, unless otherwise stated herein, the term “aryl” as used herein with respect to a radical or moiety refers to an aryl group having 6, 10 or 14 carbon atoms, and preferably, 6 or 10 carbon atoms. A particularly preferred aryl moiety is the phenyl group being optionally substituted by one or more halogen atoms, nitro, cyano, alkyl, preferably, C
1-6
alkyl, haloalkyl, preferably, C
1-6
haloalkyl, alkoxy, preferably C
1-6
alkoxy, alkoxyiminoalkyl, preferably 1-(C
1-6
alkoximino) C
2-6
alkyl.
Suitable alcohols of formula IlIl for use in the present invention are aliphatic alcohols having 1 to 10 carbon atoms, and preferably 1 to 4 carbon atoms, most preferably primary alcohols, in particular methanol or ethanol.
Suitable tri-alkoxymethanes of formula IV are tri-alkoxymethanes having 4 to 13 carbon atoms, preferably 4 to 10 carbon atoms, in particular, trimethoxymethane or triethoxymethane.
Suitable acids for use in the present invention are weak acids, preferably optionally substituted alkylsulfonic acids, arylsulfonic acids, benzoic acids or alkanoic acids, and most preferably, substituted arylsulfonic acids, such as p-toluenesulfonic acid.
Suitable bases for use in the present invention are strong bases, preferably alkali metal hydrides, alkali metal alkanes and alkali metal dialkylamides or mixtures thereof, most preferred being sodium hydride and/or butyl lithium.
Suitable inert diluents are those selected from the group consisting of cyclic ethers, aliphatic ethers, aliphatic hydrocarbons, aromatic hydrocarbons, dimethylsulfone or N,N-dimethylformamide. Most preferred are cyclic ethers such as tetrahydrofuran.
A preferred embodiment of the present invention is a process wherein:
the reaction mixture is heated to temperatures from about 20 to 100° C.; preferably from about 50° C. to 80° C., in particular, from about 60° C. to 70° C.; and most preferably to about 65° C.;
the reaction is carried out at atmospheric pressure;
the reaction mixture consists of a compound of formula II, a primary alcohol, a trialkoxymethane and catalytic amounts of an organic acid, preferably p-toluenesulfonic acid; in a particularly preferred embodiment the mixture consists of 1 mole of a compound of formula II, 20 to 200 moles, in particular 40 to 150 moles, most preferably about 100 moles of a primary alcohol, 5 to 50 moles, in particular, 15 to 40 moles, most preferably about 25 moles of a trialkoxymethane and 0.01 to 0.1 moles, preferably 0.02 to 0.08 moles of an organic acid;
R
1
represents an aryl group being optionally substituted by one or more halogen atoms, optionally substituted alkyl groups or alkoxy groups, in particular wherein R
1
represents a phenyl group;
R
2
represents a C
1-4
alkyl group being optionally substituted by one or more halogen atoms, in particular, wherein R
2
represents a methyl or ethyl group;
R
3
represents a C
1-4
alkyl group, in particular, wherein R
3
represents a methyl or ethyl group;
R
4
represents a C
1-4
alkyl group, in particular, wherein R
4
represents a methyl group.
In a preferred embodiment of the invention, the preparation of a compound of formula I is carried out in a two-step synthesis comprising the steps of
a) reaction of a 3-aryl-propenal with a the dianion of an 3-oxo-alkanoic acid alkyl ester of formula V
which is generated in situ with the aid of 1.8 to 2.6 equivalents of a strong base, preferably sodium hydride and/or butyl lithium in an inert diluent, subsequently treating the resulting mixture with a dilute acid, and
b) treating the resulting 7-aryl-3,5-dihydroxy-4-alkyl-hepta-2,6-dienoic acid alkyl esters with an alcohol, a tri-alkoxymethane and an acid, optionally, in an inert diluent.
Another preferred embodiment of the present invention is a process wherein in step a)
the reaction is carried out at temperatures between −5 and 30° C.; preferably between −3° C. and 20° C., in particular at about 0° C.;
the reaction is carried out at atmospheric pressure;
the reaction comprises treating a compound of formula V with 1.8 to 2.6 equivalents of a strong base, preferably a mixture of sodium hydride and butyl lithium in an inert diluent, subsequently treating the resulting dianion with a vinylformyl compound of formula VI, and finally treating the add
Petry Thomas
Simon Werner
American Cyanamid Co.
Barts Samuel
Faulkner Diedra
Maurer Barbara V.
Renda Barbara L.
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