Title of Invention

"PROCESS FOR PREPARING 3,4-DICHLORO-N-[2-CYANOPHENYL]-5-ISOTHIAZOLECARBOXAMIDE"

Abstract Process for preparing 3,4-dichloro-N-(2-cyanophenyl)-5- isothiazolecarboxamidc of the formula (Formula Removed) characterized in that, in a one-potprocess a)    initially isotoic anhydride of the formula II is reacted with ammonium gas in the presence of dimethylformamide; b) the resulting anthranilamide of the formula is then, without: prior isolation, reacted with 3,4-dichloro- isothiazolcarbonyl.chloride,of theTformula IV in the presence of an acid acceptor and in the presence of dimethylformamide and; c) the resulting N-[2-(aminocarbonyl)phehyl]-3,4,-dichloro- isothiazolecarboxamide of the formula V is then, without priori isolation, reacted in the presence of dimethylformamide with; thionyl; chloride, phosphorus oxychloride, phosgene or chloromethylenedimethylammonium chloride.
Full Text The present invention relates to a novel process for preparing the known 3, 4-di-chloro-N-(2-cyanophenyl)-S-isothiazolecarboxamide which can be used as an active compound with microbicidal properties.
It is already known that 3, 4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide is obtained when 3, 4-dichloroisothiazole-5-carbonyl chloride is reacted with 2-cyano-aniline (cf. WO 99-24 413 corresponding to Indian Patent Application No. 3307/DEL/1998). The yield for this method of preparation is high. However, it is a disadvantage that 2-cyanoaniline, required as starting material, can only be obtained by a complicated synthesis (cf. DE-A 2 115624 and DE-A 2 115625). Thus, it is necessary to initially react anthranilamide in the presence of dimethylformamide with phosgene and then to treat the resulting N-2-cyanophenyl-N', N'-di-methylformamidinium hydrochloride in a second step with sodium acetate in an aqueous medium.
It has now been found that 3, 4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide of the formula
(Formula Removed)

is obtained by a one-pot process when
a) initially isatoic anhydride of the formula
is reacted with ammonium gas in the present of dimethylformamide, b) the resulting anthranilamide of the formula
(Formula Removed)
is then, without prior isolation, reacted with 3,4-dichloroisothiazolecarbonyl chloride of the formula
(Formula Removed)
in the presence of an acid acceptor and in the presence of dimethylformamide and,
c) the resulting N-[2-(aminocarbonyl)phenyl]-3,4-dichloro-isothiazolcarbox-amide of the formula
(Formula Removed)
is then, without prior isolation, reacted in the presence of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene or chlormetbylene-dimethylarhmonium chloride.
It has to be considered to be extremely surprising that 3,4-dichloro-N-(2-cyano-pherry)-5-isothiazolecarboxamide of the formula (I) can be prepared by the process according to the invention in a smooth reaction without interfering side'reactions. Thus, based on the known prior art, it had to be expected that N-acylated anthanilic acid derivatives are, under acidic, basic or neutral conditions and with elimination of water, easily cyclized to benzoxazinones or quinazolinols or quinazolinones (cf. Farmaco Ed. Sci. 39 (1984), 120; J. Heterocycl. Chem. 16 (1979) 711; J. prakt. Chem. HI (1925) 48 and Egypt. J. Chem. H (1988) 241). Contrary to expectations, however, the reaction according to the invention is not adversely affected by such undesirable condensations.
The process according to the invention has a number of advantages. Thus, it allows the synthesis of the 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide of the formula (I) in high yield and with excellent purity. Also favourable is the fact that the practice of the reaction and the isolation of the reaction product do not cause any difficulties. Moreover, the process according to the invention can be scaled up to an industrial scale without any problems.
If, in the practice of the process according to the invention, the acid acceptor used in the second step is triethylamine and the dehydrating agent used in the third step is a mixture of thionyl chloride and dimethylformamide, the course of the reactions can be illustrated by the formula scheme below.
(Formula Removed)
The isatoic anhydride of formula (II) required as starting material for carrying out the process according to the invention is already known (cf. DE-A 26 28 055).
The 3,4-dichloroisothiazolecarbonyl chloride of formula (IV) used as reaction component in the second step is likewise already known (cf. US-A 5 240 951). This also applies to the anthranilamide intermediate of formula (III).
However, the N-[2-(amiocarbonyl)phenyl]-3,4,-dichloroisothiazolecarboxamide of formula (V), which serves as starting material in the third step of the process according to the invention, is novel.
When carrying out the first step of the process according to the invention, ammonium serves as a reaction component. It is introduced into the reaction mixture in dry form.
Preferred acid acceptors for carrying out the second step of the process according to the invention are tertiary amines. Examples which may be mentioned are trimeth-ylamine, triethylamine, tributylamine, N,N-dimethylaninline, N,N-dimethylbenzyl-amine, pyridine, N-methylpiperidine, N-methylmorpholine, N,N-diinethylaminopy-ridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloun-decene (DBU).
When carrying out the tliird step of the process according to the invention, a mixture of dimethylformarnide and thionyl chloride, phosphorus oxychloride, phosgene or chloromethylenedimethylammonium chloride acts as dehydrating agent.
When carrying out the third step of the process according to the invention, an excess of dimethylformarnide is employed such that as it acts not only as a reaction component but also as diluent.
When carrying out the process according to the invention, the reaction temperatures can be varied within a relatively wide range. In general, the process is carried out
in the first step at temperatures between 0°C and 100°C, preferably between 0°C and 70°C,
in the second step at temperatures between 0°C and 120°C, preferably between 0°C and 80°C,
in the third step at temperatures between -20°C and +80°C, preferably between 0°C and 60°C.
When carrying out the process according to the invention, both the reaction of the first step and the reaction of the second and third step are generally carried out in each case under atmospheric pressure. However, it is also possible to operate in each case under elevated pressure.
When carrying out the process according to the invention, in general in the first step a large excess of gaseous ammonium is employed per mole of isatoic anhydride of formula (H), in the second step from 0.8 to 1.0 mot of 3,4-dichloroisothiazolecar-bonyl chloride of the formula (IV) and an equivalent amount or else an excess of acid acceptor are then added and in the third step, the mixture is finally reacted with 1 to 2 mols of dehydrating agent.
Specifically, in general, in the first step dry ammonium gas is initially introduced to a solution of isatoic anhydride of the formula (II) and dimethylformamide, and the excess ammonium is then removed using a stream of inert gas. In the second step, a solution of 3,4-dichloroisothiazolecarbonyl chloride of the formula (IV) in dimethylformamide is then added dropwise to the reaction mixture, and the acid chloride in question is then added in the third step. Working up is carried out by customary methods, hi general, water is added to the reaction mixture and the resulting solid is filtered off with suction, washed and dried. If further purification is required, this can be carried out by customary methods, for example, chromatography or recrystalliza-tion.
The 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide of the formula (I) obtainable by the process according to the invention and its use for controlling unwanted microorganisms are known (cf. WO 99-24 413).
The process according to the invention is illustrated by the examples below.
(Formula Removed)
At 60°C, 7 g of dry ammonium gas are introduced with vigorous stirring over a period of 1 hour into a solution of 3.59 g (22 mmol) of isatoic anhydride in 15 g of di-methylformamide. Excess ammonium is then removed by passing argon through the reaction mixture heated at 60°C, for a period of 30 minutes. At 60°C, initially 2.23 g (22 mmol) of triethylamine and then, dropwise, a solution of 4.33 g (20 mmol) of 3,4-dichloroisothiazolecarbonyl chloride in 10 ml dimethylformamide are added with stirring to the reaction mixture. After the addition has ended, the mixture is stirred at 60°C for another hour. At 60°C, 3.33 g (28 mmol) of thionyl chloride are then added dropwise with stirring. Stirring at 60°C is continued for another hour, the reaction mixture is then cooled, 40 ml of water are added and the mixture is stirred for 15 min. The resulting solid is filtered off with suction, washed twice with in each case 20 ml of water and dried. This gives 4.44 g of a solid which, according to 'H-NMR spectrum, comprises 92% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarbox-amide. Accordingly, the yield is calculated as 68.4% of theory, based on the isatoic anhydride employed. This corresponds to a yield of 88% of theory per step.


(Formula Removed)
At 5-10°C, 38.1 g (0.15 mol) of 3,4-dichloroisothiazole-5-carbonyl chloride are added dropwise.with stirring, over a period of 10 minutes, to a mixture of 20.8 g (0.1725 mol) of 2-cyanoaniline and 250 ml of pyridine. After the addition is ended, 70 ml of absolute tetrahydrofuran and 30 ml of pyridine are added to the reaction mixture, and the mixture is allowed to warm to room temperature and then stirred at room temperature for 75 minutes. The reaction mixture is then concentrated under reduced pressure. The residue that remains is stirred with 800 ml of water and 800 ml of ethyl acetate. The precipitate obtained in the two-phase mixture is filtered off, washed with ethyl acetate and dried, This gives 31.7 g of a crystalline product of melting point 191-193°C.
From the biphasic filtrate, the aqueous phase is separated off and extracted twice with in each case 150 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The residue that remains is stirred with 100 ml of petroleum ether and 25 ml of ethyl acetate. The resulting solid is filtered off with suction, washed with ethyl acetate and dried.
This gives a total of 40 g (89% of theory) of 3,4-dichloro-N-(2-cyanophenyl)-5-iso-thiazolecarboxamide in the form of a solid of melting point 191 to 193°C.







We Claims:
1. Process for preparing 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide of the formula
(Formula Removed)

characterized in that, in a one-pot process,
a) initially isotoic anhydride of the formula
is reacted with ammonium gas in the presence of dimethylformamide; b) the resulting anthranilamide of the formula

is then, without prior isolation, reacted with 3,4-dichloro-isothiazolcarbonyl chloride of the formula

(Formula Removed)
in the presence of an acid acceptor and in the presence of dimethylformamide and;
c) the resulting N-[2-(aminocarbonyl)phenyl]-3,4,-dichloro-
isothiazolecarboxamide of the formula

(Formula Removed)
is then, without prior isolation, reacted in the presence of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene or chloromethylenedimethylammonium chloride.
2. Process as claimed in claim 1, wherein a mixture of dimethylformamide and thionyl chloride as dehydrating agent is used for carrying out the third step.
3. Process as claimed in claim 1, wherein the first step is carried out at temperatures between 0°C and 70°C.
4. Process as claimed in claim 1, wherein the second step is carried out at a temperatures between 0°C and 120°C.
5. Process as claimed in claim 1, wherein the third step is carried out at temperatures between -20°C and +80°C.

Documents:

4074-delnp-2004-abstract.pdf

4074-delnp-2004-claims-(cancelled).pdf

4074-delnp-2004-claims.pdf

4074-delnp-2004-complete specification (granted).pdf

4074-DELNP-2004-Correspondence-Others (15-10-2009).pdf

4074-delnp-2004-correspondence-others.pdf

4074-DELNP-2004-Description (Complete).pdf

4074-delnp-2004-form-1.pdf

4074-delnp-2004-form-18.pdf

4074-delnp-2004-form-2.pdf

4074-DELNP-2004-Form-3-(15.10.2009).pdf

4074-delnp-2004-form-3.pdf

4074-delnp-2004-form-5.pdf

4074-delnp-2004-gpa.pdf

4074-delnp-2004-pct-210.pdf

4074-delnp-2004-pct-304.pdf

4074-delnp-2004-pct-409.pdf


Patent Number 242944
Indian Patent Application Number 4074/DELNP/2004
PG Journal Number 39/2010
Publication Date 24-Sep-2010
Grant Date 21-Sep-2010
Date of Filing 21-Dec-2004
Name of Patentee BAYER CROPSCIENCE AKTIENGESELLSCHAFT
Applicant Address ALFRED-NOBEL-STR. 50, D-40789 MONHEIM, GERMANY
Inventors:
# Inventor's Name Inventor's Address
1 THOMAS HIMMLER SCHOME AUSSICHT 1B, D-51519 ODENTHAL, GERMANY
PCT International Classification Number C07D 275/03
PCT International Application Number PCT/EP2003/006361
PCT International Filing date 2003-06-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 102 28 731.7 2002-06-27 Germany