Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-04
2001-02-27
Owens, Amelia (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06194590
ABSTRACT:
This application is a 371 of PCT/EP98/06213 Sep. 30, 1998.
The invention relates to an improved process for the preparation of optionally substituted benzofuran-3-ones which can be employed as precursors for the preparation of 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines, which in turn are known as starting substances for the preparation of compounds having fungicidal properties (WO 95-04728 and DE-A-19602095).
It has already been disclosed that optionally substituted benzofuran-3-ones can be prepared in accordance with the following reaction scheme (J. Org. Chem. 1962, 586-591):
A salicylic acid ethyl ester is first reacted with ethyl bromoacetate and the salicylic acid ether thus obtained is cyclized with sodium ethanolate in benzene to give a benzofuranonecarboxylic acid ethyl ester. This is hydrozysed in dilute sodium hydroxide solution and then decarboxylated with dilute sulphuric acid and the product is precipitated. The yields of this process are extremely unsatisfactory and the reaction times—the hydrolysis in particular lasts a week or more—are unacceptable for an industrial preparation.
An alternative synthesis for the preparation of optionally substituted benzofuranones is described in Synthetic Communications 1990, 809-816.
In this process, o-hydroxyacetophenone is first brominated with bromine in acetic acid and the brominated compound is cyclized with sodium acetate in dimethylformamide, hydrogen bromide being eliminated. In this process also, the yields are unsatisfactory. Furthermore, the bromine required as a reagent could be employed in an industrial synthesis only with a high expenditure on safety.
It has now been found that optionally substituted benzofuranones of the formula (I)
in which
R
1
represents hydrogen, alkyl or halogen,
are obtained in a high yield and high purity by a process in which salicylic acid ethers of the general formula (II)
in which
R
1
has the abovementioned meaning and
R
2
and R
3
are identical or different and independently of one another represent alkyl,
are reacted in a first step with a strong base, preferably an alkali metal alcoholate, under an inert gas atmosphere, optionally in the presence of a diluent, and the benzofuranonecarboxylic acid ester obtained in this manner, of the formula (III)
in which
R
1
has the abovementioned meaning and
R
2
represents alkyl,
is reacted in a second step first with potassium hydroxide, optionally in the presence of a diluent, and then with an acid to give the desired benzofuranones of the formula (I).
Benzofuranones of the formula (I) which can preferably be prepared are those in which
R
1
represents hydrogen, alkyl having 1 to 4 carbon atoms, fluorine or chlorine.
Benzofuranones of the formula (I) which can particularly preferably be prepared are those in which
R
1
represents hydrogen, methyl, ethyl, fluorine or chlorine.
Intermediate products of the formula (III) which can preferably be prepared are those benzofuranonecarboxylic acid esters of the formula (III) in which
R
1
represents hydrogen, alkyl having 1 to 4 carbon atoms, fluorine or chlorine and
R
4
represents alkyl having 1 to 4 carbon atoms.
Intermediate products of the formula (III) which can be particularly preferably prepared are those benzofuranonecarboxylic acid esters of the formula (III) in which
R
1
represents hydrogen, methyl, ethyl, fluorine or chlorine and
R
4
represents methyl or ethyl.
It is to be described as decidedly surprising that the first step of the process according to the invention tends towards less formation of by-products by working under the conditions according to the invention and thus gives substantially higher yields than the process known from the prior art. It is furthermore to be regarded as particularly surprising that the second step of the process according to the invention proceeds considerably faster and with considerably higher yields and purities by the use of the reaction conditions according to the invention than processes already described.
The process according to the invention is distinguished by a number of advantages. It thus allows the synthesis of benzofuranones of the formula (I) in a very high yield and purity. It is also favourable that the reaction components required are easy to prepare and are also available in relatively large amounts. Finally, another advantage is that carrying out the reaction and isolating the reaction products present no difficulties at all.
The general formula (II) provides a definition of the salicylic acid ethers required as starting substances for carrying out the first stage of the process according to the invention. In this formula (II), R
1
preferably or in particular has that meaning which has already been mentioned as preferred or as particularly preferred for R
1
in connection with the description of the compounds of the formula (I) which can be prepared according to the invention. R
2
and R
3
independently of one another represent alkyl, preferably having 1 to 4 carbon atoms, in particular ethyl or methyl.
The salicylic acid ethers of the formula (II) are known and/or can be prepared by known methods (compare, for example, B. J. Chem. Soc. 99 (1911), 911; and the preparation examples).
Possible diluents for carrying out the first stage of the process according to the invention are all the inert organic solvents. These include, preferably, aliphatic, alicyclic or aromatic hydrocarbons, such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; alcohols, such as methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether and diethylene glycol monoethyl ether, and any desired mixtures of the diluents mentioned.
The first stage of the process according to the invention is carried out in the presence of a base. Preferred possible bases are alkaline earth metal or alkali metal hydrides or alcoholates, such as, for example, sodium hydride, sodium methylate, sodium ethylate or potassium tert-butylate.
The first stage of the process according to the invention is preferably carried out under an inert gas atmosphere. Possible inert gases are, for example, nitrogen or argon, and also solvent vapours.
The reaction temperatures can be varied within a relatively wide range when carrying out the first stage of the process according to the invention. In general, the reaction is carried out at temperatures from 0° C. to 150° C., preferably at temperatures from 0° C. to 80° C.
For carrying out the first stage of the process according to the invention for the preparation of the compounds of the formula (I), in general 0.5 to 10 mol, preferably 1 to 4 mol, of base are employed per mole of the salicylic acid ether of the formula (II).
When carrying out the first stage of the process according to the invention, the procedure is in general as follows: the salicylic acid ether of the formula (II) is dissolved or suspended in a diluent and the solution or suspension is then heated. The base, which is optionally predissolved in a diluent, is slowly added. After the end of the reaction, the mixture is worked up by customary methods. For example, the reaction mixture is introduced into water, the organic phase which may be present is separated off and discarded, the aqueous phase is acidified and the crystallized product is filtered off with suction and, if appropriate, dried.
While carrying out the entire reacton and during the working up, access of air or oxygen to the product is avoided. This is achieved either by working under an inert gas atmosphere, for example under nitrogen or argon, or carefully shielding the reaction mixtures from the outside air, for example by the
Gallenkamp Bernd
Gayer Herbert
Gerdes Peter
Mulder Lubbertus
Rohe Lothar
Bayer Aktiengesellschaft
Gil Joseph C.
Owens Amelia
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