Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-10-30
2002-08-27
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C568S333000
Reexamination Certificate
active
06441219
ABSTRACT:
BACKGROUND OF THE INVENTION
Derivatives of 2-hydroxybenzoic acid esters are useful starting materials for natural product synthesis, for example F. M. Hauser, et al., Synthesis 1980, 72 or for the manufacture of fungicidal benzophenones such as those described in U.S. Pat. No. 5,773,663. Methods to prepare said 2-hydroxybenzoic acid esters are known, i.e. G. Schill, et al., Synthesis, 1980, 814 or Y. Hamada, et al, Tetrahedron, Vol. 47 (1991), 8635. However, these known methods require several steps and utilize corrosive or toxic reagents and are not amenable to large scale preparation or commercial manufacturing conditions.
The two-step syntheses cited in Synthesis and Tetrahedron hereinabove require the isolation of intermediates resulting in an undue solvent waste load on the environment. Further these syntheses require gaseous HCl and a separate oxidation procedure employing oxidizing reagents such as Br
2
or CuCl
2
.
Therefore, it is an object of this invention to provide an effective and efficient single-step process to prepare 5- and/or 6-substituted-2-hydroxybenzoic acid esters which is amenable to large scale preparations and commercial manufacturing procedures.
It is another object of this invention to provide an effective means of obtaining a substituted-2-hydroxy-benzoic acid ester in good yield under relatively mild reaction conditions from readily available starting materials and reagents.
It is a further object of this invention to provide an environmentally sound commercial source of substituted-2-hydroxybenzoic acid esters for the preparation of important phytopathogenic fungicidal agents and the continued exploration of natural product synthesis. These and other objects and features of the invention will become more apparent from the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a single-step process for the preparation of a compound of formula I
wherein
R is C
1
-C
6
alkyl; and
R
1
and R
2
are each independently H or C
1
-C
4
alkyl which process comprises reacting a compound of formula II
wherein R is C
1
-C
6
alkyl and X is halogen or OCOCH
3
with a compound of formula III
wherein R
1
and R
2
are each independently H or C
1
-C
4
alkyl, and formula III compound is understood to be cis, Trans, or a mixture thereof, in the presence of a C
1
-C
4
carboxylic acid salt and a solvent.
Also provided is the use of the formula I compound in the manufacture of a fungicidal benzophenone compound. In one embodiment, a process for the manufacture of a fungicidal benzophenone compound of formula K
wherein R
1
is independently H or C
1
-C
4
alkyl; and R
3
, R
4
, R
5
and R
3
, R
4
, R
5
and R
6
are each independently C
1
-C
6
alkyl which process comprises the following steps:
a) reacting a compound of formula II
wherein R is C
1
-C
6
alkyl and X is halogen or OCOCH
3
with a compound of formula IIIA
wherein R
1
is as described hereinabove in the presence of a C
1
-C
4
carboxylic acid salt and a solvent to form a compound of formula IA.
wherein R, R
1
and R
2
are described hereinabove;
b) alkylating the formula I compound with a di(C
1
-C
6
alkyl)sulfate in the presence of a base to form a compound of formula VA
wherein R
3
is C
1
-C
6
alkyl;
c) brominating the formula VA compound with a brominating agent such as bromine or N-bromosuccinimide, optionally in the presence of a base, to form a compound of formula L
wherein R, R
1
and R
3
are described hereinabove;
d) hydrolyzing the formula L compound in an aqueous acid or aqueous base to form a compound of formula M
wherein R
1
and R
3
are described hereinabove;
e) reacting the formula M compound with thionyl chloride to form the compound of formula N
wherein R
1
and R
3
are described hereinabove; and
f) reacting the formula N compound with at least one molar equivalent of a compound of formula VIII
wherein R
4
, R
5
and R
6
are each independently C
1
-C
6
alkyl, in the presence of a solvent, to give the desired fungicidal formula K benzophenone compound.
DETAILED DESCRIPTION OF THE INVENTION
Substituted-2-hydroxybenzoic acid esters of formula I are useful as key starting materials in natural product synthesis and in the manufacture of important benzophenone fungicidal agents. Said fungicidal agents help growers provide top quality food products and feed grains to U.S. consumers as well as the world. Virtually all seeds for U.S. corn and wheat crops and nearly one-third of soybeans are treated with fungicidal agents. Therefore, the efficient preparation of such fungicidally active compounds in an environmentally sound manner is highly desirable.
It has now been found that 5- and/or 6-substituted-2-hydroxybenzoic acid esters of formula I may be prepared in a single-step process from readily available starting materials and under relatively mild reaction conditions, allowing effective large scale commercial production. Advantageously, the process of the invention avoids the use of corrosive gaseous HCl and eliminates the need for oxidizing reagents such as Br
2
and CuCl
2
.
Preferred compounds prepared by the process of the invention are those compounds of formula I wherein R
1
is C
1
-C
4
alkyl and R
2
is hydrogen. More preferred compounds are those compounds of formula I wherein R
1
is methyl and R
2
is hydrogen.
Preferred compounds of formula II employed in the process of the invention are those compounds wherein X is halogen. More preferred compounds are those compounds of formula II wherein X is Cl.
Compounds of formula III may be represented in the cis or trans configuration or as a mixture thereof. In the specification and claims, compounds designated as formula III include the cis isomer, the trans isomer or a mixture thereof.
The term halogen as used in the specification and claims designates Cl, Br, F or I.
In accordance with the process of the invention, a &bgr;-ketoester of formula II is reacted with an &agr;,&bgr;-unsaturated aldehyde of formula III in the presence of a C
1
-C
4
carboxylic acid salt, preferably about 1.0-2.0 molar equivalents, more preferably about 1.0-1.5 molar equivalents and a solvent, preferably a C
1
-C
6
alkanol, a C
1
-C
4
carboxylic acid or a mixture thereof, more preferably methanol, ethanol, acetic acid or a mixture thereof to form the desired product of formula I. The reaction is shown in flow diagram I wherein M is an alkali metal or an alkaline-earth metal.
The formula I hydroxybenzoic acid ester product may be isolated using conventional isolation techniques such as precipitation, decantation, filtration, extraction, chromatographic separation or the like, preferably filtration or extraction.
In the process of the invention, reaction rate is directly related to reaction temperature, that is, the reaction rate increases with increased temperature. However, excessively high reaction temperatures may lead to decomposition and the formation of undesired by-products, thereby reducing product yield and purity. Suitable reaction temperatures in the process of the invention may range from room temperature to the reflux temperature of the solvent preferably about 25° C. to 125° C., more preferably about 75° to 120°.
Acid salts suitable for use in the process of the invention are aliphatic acid salts, preferably C
1
-C
4
-carboxylic acid alkali metal or alkaline-earth salts, more preferably acetic acid alkali metal salts such as sodium acetate or potassium acetate.
Suitable solvents for use in the inventive process include polar solvents, preferably protic solvents such as C
1
-C
6
alkanols, C
1
-C
4
carboxylic acids or a mixture thereof, more preferably methanol, ethanol, acetic acid or a mixture thereof.
In actual practice, the formula II &bgr;-ketoester and the formula III &agr;,&bgr;-unsaturated aldehyde are admixed with about 1.0 to 2.0, preferably about 1.0 to 1.5, more preferably about 1.2, molar equivalents of a C
1-C
4
carboxylic acid salt, preferably an alkali metal or an alkaline-earth metal salt, more preferably an alkali metal acetate in a
BASF Corporation
Costello Charles F.
Killos Paul J.
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