Process for producing 4-substituted benzopyran derivatives

Details Process for producing 4-substituted benzopyran derivatives Process for producing 4-substituted benzopyran derivatives

2002-09-26

2003-08-19

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C568S314000, C568S315000, C568S337000

Reexamination Certificate

active

06608217

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for producing a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl) -2H-1-benzopyran-4-carboxylic acid represented by the general formula [1], which is a 4-substituted benzopyran derivative useful as an intermediate for medicines and agricultural chemicals,
wherein R
1
is a perfluoroalkyl group that is represented by C
n
F
2n+1
where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the perfluoroalkyl group.
It is disclosed in WO/00/18754 and Bioorganic and Medicinal Chemistry 8 (2000), 1393-1405 that the above carboxylic acid can be synthesized by five (5) steps from a starting material of 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-one (represented by the general formula [2]; hereinafter referred to “benzopyranone [2]” for simplification) via 4-bromo- 2,2- bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran (represented by the general formula [11]),
where R
1
is defined as above. Hereinafter, various compounds may be referred to for simplification in a manner similar to that the benzopyranone represented by the general formula [2] is referred to as the benzopyranone [2]. As shown by the following scheme, the five steps are explained in more detail. At first, the benzopyranone [2] is reduced in the first step by sodium borohydride or the like. The resulting benzopyranol [12] is dehydrated in the second step by a dehydrating agent (e.g., &rgr;-toluenesulfonic acid). The resulting benzopyran derivative [13] is brominated in the third step by bromine. The resulting dibromobenzopyran [14] is reacted in the fourth step with a base. The resulting 4-bromobenzopyran [11] is reacted in the fifth step with carbon monoxide in the presence of a palladium complex compound and a base to obtain the benzopyran carboxylic acid [1],
where R
1
is defined as above.
It is further disclosed in WO/00/18754 that the 4-bromobenzopyran [1] is obtained by four steps from a 3,4-dihalogeno-1-perfluoroalkylbenzene [15], that it is obtained by four steps from an acetylene derivative [16], and that it is obtained by subjecting an acetylene derivative [17] to a thermal cyclization,
where R
1
is defined as above, and X and Y are independently halogen atoms.
Of the above-mentioned conventional processes, one using the benzopyranone [2] as a starting material has advantages over others in terms of reagents availability and selectivity of the reaction. However, even that process requires taking the above-mentioned five steps to obtain the benzopyran carboxylic acid [1], thus making it cumbersome. Therefore, there is a demand for a process for producing the benzopyran carboxylic acid with fewer steps.
The present invention further relates to a process for producing hydroxyacetophenones, which are useful as intermediates for medicines and agricultural chemicals, and particularly to 2-hydroxy-5-(perfluoroalkyl)acetophenones.
There are known the following two (2) processes for producing a 2-hydroxy-5-(perfluoroalkyl)acetophenone represented by the general formula [5],
where R
1
is defined as above.
DE 2653601 A1 discloses that 2-hydroxy-5-(trifluoromethyl)acetophenone was obtained by mixing together 4-(trifluoromethyl)phenol and hydrofluoric acid anhydride, then by adding acetyl chloride to the mixture, and then by heating the mixture at 100° C. under a pressurized condition.
J. Chem. Soc., Chem. Commun. (1995) 19, 2009-10 discloses that 4-(trifluoromethyl)phenol and pinacolone were dissolved in benzene, followed by irradiation with light, thereby obtaining 2-hydroxy- 5-(trifluoromethyl)acetophenone with a yield of about 13%.
In general, benzene rings having a perfluoroalkyl group (e.g., trifluoromethyl group and pentafluoroethyl group) are low in reactivity in Friedel-Crafts type electrophilic substitution reactions. Thus, it is necessary to have a severe condition, for example, by heating at 100° C. or higher or by light irradiation in the presence of a strong acid or strong base in order to directly introduce an acyl group onto 4-perfluoroalkylphenol by Friedel-Crafts reactions. Such severe condition, however, may gradually decompose the perfluoroalkyl group, thereby lowering selectivity of the target reaction. This may lower the yield of 2-hydroxy-5-(perfluoroalkyl)acetophenone or may makes it difficult to conduct purification by adverse effects of by-products.
Thus, there is a demand for processes for producing 2-hydroxy-5-(perfluoroalkyl)acetophenones in an industrial manner with a mild reaction condition.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a process for efficiently producing a 2,2-bis(fluoromethyl) -6-(perfluoroalkyl)- 2H- 1 -benzopyran-4-carboxylic acid.
It is another object of the present invention to provide a process for producing 2-hydroxy-5-(perfluoroalkyl) acetophenones in an industrial manner under a mild reaction condition.
According to a first aspect of the present invention, there is provided a novel first process for producing a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran-4-carboxylic acid represented by the general formula [1]. The process comprises the steps of:
(a) reacting a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-one, represented by the general formula [2], with a perfluoroalkanesulfonic acid anhydride, represented by the general formula [3], in the presence of a base, thereby obtaining a perfluoroalkanesulfonic 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-yl ester represented by the general formula [4]; and
(b) reacting the benzopyranyl ester with carbon monoxide in the presence of a palladium complex compound and a base, thereby obtaining the carboxylic acid,
where R
1
is a perfluoroalkyl group that is represented by C
n
F
2n+1
where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the perfluoroalkyl group;
each of R
2
and R
3
is independently a lower perfluoroalkyl group that is represented by C
n
F
2n+1
where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the lower perfluoroalkyl group; and
R
4
is identical with the R
2
or R
3
.
Hereinafter, the 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran-4-one, represented by the general formula [2], may be referred to as the benzopyranone [2] for simplification. Various other compounds may also be referred to in a manner similar to this.
It is disclosed in Bioorganic & Medicinal Chemistry 8 (2000) 1393-1405 that the benzopyranone [2], which is the starting material of the step (a), can be produced by the step (e) reacting a 2-hydroxy-5-(perfluoroalkyl) acetophenone, represented by the general formula [5], with 1,3-difluoroacetone in the presence of a base,
where R
1
is defined as above. Thus, in case that this reaction is conducted prior to the step (a), the acetophenone [5] can be the starting material for producing the carboxylic acid [1].
According to a second aspect of the present invention, there is provided a novel second process for producing such acetophenone [5]. The second process comprises the steps of:
(c) reacting a 4-(perfluoroalkyl)alkoxybenzene, represented by the general formula [6], with acetic anhydride or an acyl halide in the presence of a Lewis acid, thereby obtaining a 2- alkoxy-5- (perfluoroalkyl)acetophenone represented by the general formula [7]; and
(d) dealkylating the 2-alkoxy-5-(perfluoroalkyl) acetophenone by a dealkylating agent, thereby obtaining the 2 -hydroxy-5 - (perfluoroalkyl) acetophe none,
where R
1
is defined as above; and R
5
is a straight-chain or non-straight-chain alkyl group having a carbon atom number of 1-20. Thus, it is possible by the present invention to produce the

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