Title of Invention

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

Abstract According to a novel process, 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarbox-amide is prepared by a) reacting 3,4-dichloroisothiazole-5-carbonyl chloride with anthranilamide in the presence of an acid acceptor and in the presence of an aprotic diluent and b) the resulting N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarbox-amide is then reacted with a dehydrating agent, if appropriate in the presence of an additional diluent. N-[2-(Aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide is novel.
Full Text The present invention relates to a novel process for preparing the known 3,4-dichloro-N-(2-cyanophenyl)-5-isothazolecarboxarnide which can be used as an active compound with microbicidal properties.
It is already known that 3,4-dlchloro-N-(2-cyanophenyl)-5-isothiazolecarboxarnide is obtained when 3,4-dichloroisothiazole-5-carbonyl chloride is reacted with 2-cyano-aniline . 3307/DEL/98 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-A2 115 624 and DE-A2 115 625). Thus, it is necessary to initially' react anthranilamide in the presence of dimethylfbrmamide with phosgene and then to treat the resulting N-2-cyanophenyl-N'N dimethyIfonnamidinium 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-isothiazolecarbox-amide of the formula
(Formula Removed)
is obtained when
a) 3,4-dichloroisomiazole-5-carbonyi chloride of the formula
(Formula Removed)
is reacted with anthranilamide of the formula
(Formula Removed)
in the presence of an acid acceptor and in the presence of an aprotic diluent and
b) the resulting N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarbox-amide of the formula
(Formula Removed)
is then reacted with a dehydrating agent, if appropriate in the presence of an additional aprotic diluent.
It has to be considered to be extremely surprising that 3,4-dichloro-N-(2-cyano-phenyl)-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.Formaco Ed. Sci. 39 (1984), 120; J. Heterocycl. Chem. 16 (1979) 711; J. prakt.Chem. 111 (1925) 48 and Egypt. J. Chem. 3_i (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 extremely 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 fjrststep is triethylamine and the dehydrating agent used in the second^step is a mixture of thionyl chloride and dimethyl formamide, the course of the reaction can be illustrated by the formula scheme below.
(Scheme Removed)
The 3,4-dichloroisothiazole-5-carbonyl chloride of the formula (II) required as starting material for carrying out the process according to the invention is known (cf.US-A5 240 951).
The anthranilamide required as reaction component is likewise known (cf.DE-A2 115 625).
Preferred acid acceptors for carrying out the first step of the process according to the invention are tertiary amines. Examples which may be mentioned are trimethylamine, triethylamine, tributylamine, N,N-dimethylbenzylamine, pyridine, N-methyl-piperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).
Suitable diluents for carrying out the first step of the process according to the invention are all customary aprotic organic solvents. Preference is given to using optionally halogenated aromatic hydrocarbons, such as toluene or chlorobenzene, furthermore chlorinated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane, and furthermore amides, such as dimethylformamide and dimethylacetamide. Particular preference is given to dimethylformamide.
N-[2-(Aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide of the formula (IV), which is obtained when the first step of the process according to the invention is carried out, has hitherto not been described.
Suitable dehydrating agents for carrying out the second step of the process according to the invention are all reagents suitable for eliminating water from amides. Preference is given to using mixtures of dimethylformamide and thionyl chloride, phosphorus oxychloride, phosgene or chloromethylenedimethylammmonium chloride.
Suitable diluents for carrying out the second step of the process according to the invention are all customary aprotic organic solvents. Preference is given to using optionally halogenated aromatic hydrocarbons, such as toluene or chlorobenzene, furthermore chlorinated hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane or trichloroethane, and furthermore amides, such as dimethylformamide and dimethylacetamide. Particular preference is given to dimethylformamide.
When carrying out the process according to the invention, the temperatures can be varied within a relatively wide range. In general, the first step is carried out at temperatures between 0°C and 160°C, preferably between 0°C and 120°C. The second step is generally carried out 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 step are generally carried out under atmospheric pressure. However, it is also possible to operate under elevated pressure.
When carrying out the first step of the process according to the invention, in general from 1 to 1.5 mol of anthranilamide of the formula (HI) and an equivalent amount of acid acceptor are employed per mole of 3,4-dichloroisothiazole-5-carbonyl chloride. Work-up is carried out by customary methods. In general, the reaction mixture is concentrated and the residue that remains is stirred with water, filtered off with suction, purified by treatment with a suitable solvent, filtered off with suction again and dried.
When carrying out the second step of the process according to the invention, in general from 1 to 2 mol of dehydrating agent and, if appropriate, an excess of dimethyl formamide are employed per mole of N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide of the formula (IV). Work-up is carried out by customary methods. In general, water is added to the reaction mixture and the resulting solid is filtered off with suction, washed and dried.
In a particular variant, the process according to the invention can be carried out as a one-pot reaction. Here, 3,4-dichloroisothiazole-5-carbonyl chloride of the formula
(II) is initially reacted with anthranilamide of the formula (III) in the presence of acid
acceptor and the dehydrating agent is then added without prior isolation of the N-[2-
(aminnocarbonyl)-phenyl]-3,4-dichloroisothiazolecarboxarriide of the formula (IV).
Work-up is again carried out by customary methods. In general, the procedure
mentioned above is used.
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 3307/DEL/ 98.
The process according to the invention is illustrated by the examples below.
Examples
Example 1
(Formula Removed)
At 60°C, a solution of 4.33 g (22 mmol) of 3,4-dichloroisothiazolecarbonyl chloride is added dropwise with stirring to a mixture of 15 ml of dimethylformamide, 3 g (22 mmol) an anthranilamide and 2.23 g (22 mmol) of triethylamine. The reaction mixture is then stirred for an additional hour at 60°C and then concentrated under reduced pressure. The residue that remains is stirred with 35 ml of water and then filtered off with suction. The resulting solid, which is still moist, is boiled with isopropanol, cooled to room temperature, filtered off with suction and dried.
This gives 5.44 g of a white solid which, according to HPLC, consists to 100% of N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide. Accordingly, the calculated yield is 86.0% of theory.
1H-NMR (400 MHz, d-DMSO): δ = 7.27-7.31 (m; 1H), 7.58-7.63 (m; 1H), 7.88-7.94 (m; 2H), 8.44-8.50 (m; 2H), 12.80 (s: 1H) ppm. Melting point: 244-248°C.
Example 2
(Formula Removed)
At 60°C and with stirring, 0.416 g (3.5 mmol) of thionyl chloride are added dropwise to a suspension of 0.79 g (2.5 mmol) of N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide in 5 ml of dimethylformamide. The reaction mixture is stirred at 60°C for another 4 hours and then cooled to room temperature, mixed with 5 ml of water and stirred for 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 10 ml of water and dried.
This gives 0.63 g of a white solid which, according to 'H-NMR spectrum, consists to 91% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the calculated yield is 76.9% of theory.
1H-NMR (400 MHz, d-DMSO): δ = 7.47-7.51 (m; 1H), 7.71-7.77 (m; 1H) 7.79-7.81 (m; 1H), 7.92-7.94 (m; 1H), 11.05 (s; 1H) ppm.
Example 3
(Formula Removed)
At 0°C, 1.67 g (14 mmol) of thionyl chloride are added dropwise with stirring to a suspension of 3.16 g (10 mmol) of N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-
isothiazolecarboxamide in 20 ml of dimethylformamide. The reaction mixture is stirred at 0°C for another 2 hours, and 25 ml of water are then added with ice-cooling and the mixture is stirred for 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 20 ml of water and dried.
This gives 2.95 g of a white solid which, according to HPLC, consists to 99% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the calculated yield is 98% of theory.
Example 4
(Formula Removed)
At room temperature, 0.9 g (7 mmol) of chloromethylenedimethylammonium chloride is added with stirring to a suspension of 1.58 g (5 mmol) of N-[2-(amino-carbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide in 10 ml of dimethylformamide. The reaction mixture is then stirred at 60°C for one hour, 25 ml of water are then added and the mixture is stirred for 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 20 ml of water and dried.
This gives 1.64 g of a white solid which, according to HPLC, consists to 88% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the calculated yield is 96% of theory.
Example 5
(Formula Removed)
At room temperature, a solution of 8.66 g (40 mmol) of 3,4-dichloroisothiazole-5-carbonyl chloride in 20 g of dimethylformamide is added dropwise with stirring to a solution of 6 g (44 mmol) of anthranilamide and 4.45 g (44 mmol) of triethylamine in 24 g of dimethylformamide. After the addition has ended, the reaction mixture is stirred at 20°C for one hour. At room temperature, 6.67 g (56 mmol) of thionyl chloride are added dropwise with stirring to the resulting suspension. The reaction mixture is stirred at room temperature for another 2 hours, and 80 ml of water are then added and the mixture is stirred for a further 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 40 ml of water and dried. The resulting product is boiled in 30 ml of isopropanol for 30 minutes. After cooling to room temperature, the resulting solid is filtered off with suction, washed twice with in each case 10 ml of isopropanol and dried. This gives 11.48 g of a solid which, according to HPLC, consists to 96.75% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the yield calculated for 2 steps is 93.1% of theory. This corresponds to a yield of 96.5% of theory per step.

Example 6
(Formula Removed)
At 0°C, a solution of 8.66 g (40 mmol) of 3,4-dichloroisothiazole-5-carbonyl chloride in 20 g of dimethylformamide is added dropwise with stirring to a solution of 6 g (44 mmol) of anthranilamide and 4.45 g (44 mmol) of triethylamine in 24 g of dimethylformamide. After the addition has ended, the reaction mixture is stirred at 0°C for 2 hours. At 0°C, 6.67 g (56 mmol) of thionyl chloride are added dropwise with stirring to the resulting suspension. The reaction mixture is stirred at 0°C for another 2 hours, and 80 ml of water are then added and the mixture is stirred for a further 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 40 ml of water and dried. The resulting product is boiled in 30 ml of isopropanol for 30 minutes. After cooling to room temperature, the resulting solid is filtered off with suction, washed twice with in each case 10 ml of isopropanol and dried. This gives 10.9 g of a solid which, according to HPLC, consists to 96.5% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the yield calculated for 2 steps is 90.0% of theory.
Example 7
(Formula Removed)
At room temperature, a solution of 4.33 g (20 mmol) of 3,4-dichloroisothiazole-5-carbonyl chloride in 10 g of dimethylformamide is added dropwise with stirring to a solution of 3 g (22 mmol) of anthranilamide and 2.23 g (22 mmol) of triethylamine in 12 g of dimethylformamide. After the addition has ended, the reaction mixture is stirred at 20°C for one hour. At 0°C, 4.3 g (28 mmol) of phosphorus oxychloride are added dropwise with stirring to the resulting suspension. The reaction mixture is stirred at 0°C for another 2 hours, and 40 ml of water are then added and the mixture is stirred for a further 15 minutes. The resulting solid is filtered off with suction, washed twice with in each case 20 ml of water and dried. The resulting product is boiled in 15 ml of isopropanol for 10 minutes. After codling to room temperature, the resulting solid is filtered off with suction, washed twice with in each case 5 ml of isopropanol and dried. This gives 5.43 g of a solid which, according to HPLC, consists to 98.6% of 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide. Accordingly, the yield calculated for 2 steps is 89.7% of theory.
Example 8
(Formula Removed)
At room temperature, a solution of 8.66 g (40 mmol) of 3,4-dichloroisothiazole-5-carbonyl chloride in 20 g of dimethylformamide is added dropwise with stirring to a solution of 6 g (44 mmol) of anthranilamide and 4.46 g (44 mmol) of triethylamine in 24 g of dimethylformamide. After the addition has ended, the reaction mixture is stirred at 20°C for one hour. At 20-25°C, 5.6 g (56 mmol) of phosgene are introduced with stirring into the resulting suspension. The reaction mixture is stirred at room temperature for another 2 hours, 80 ml of water are then added with ice-cooling and the mixture is stirred for a further 15 minutes. The resulting solid is filtered off with
suction, washed twice with in each case 40 ml of water and dried. The resulting product is boiled in 30 ml of isopropanol for 10 minutes. After cooling to room temperature, the resulting solid is filtered off with suction, washed twice with in each case 10 ml of isopropanol and dried. This gives 10.73 g of a solid which, according to 1H0-NMR spectrum, consists to 57% of 3,4-dichloro-N-(2-cyanophenyl)-5- isothiazolecarboxamide. Accordingly, the yield calculated for 2 steps is 51% of theory.
Comparative Example A
(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 tetrahydromran 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-isothiazolecarboxamide in the form of a solid of melting point 191-193°C.







We claim
1. Process for preparing 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxaniide of the
formula
(Formula Removed)
characterized in that
a) 3,4-dichloroisothiazoIe-5-carbonyI chloride of the formula
(Formula Removed)
is reacted with anthranilamide of the formula
(Formula Removed)
in the presence of an acid acceptor selected from trimethylamine, triethylamine, tri-butylamine, N,N-dimethylbenzylamtne, pyridine, N-methylpiperidine, N-methylmor-pholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclo-nonene (DBN) or diazabicycloundecene (DBU), and in the presence of an aprotic diluent selected from toluene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dimethylformamide and dimethylacet-amide, and
b) the resulting N-[2-(aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide of the formula
(Formula Removed)
is then reacted with a dehydrating agent selected from mixtures of dimethylformamide and thionyl chloride, phosphorus oxychloride, phosgene or chloromethylene-
dimemylammmonium chloride, in the absence or in the presence of an additional aprotic diluent selected from toluene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dimethylformamide and dimethylacetamide.
2. Process as claimed in Claim 1, in that the diluent used for carrying out both the first and the
second step is dimethylformamide.
3. Process as claimed in Claim 1, in that a mixture of dimethylformamide and thionyl chloride,
phosphorus oxychloride, phosgene or chloromethylenedimethylammonium chloride as
dehydratingagent is used for carrying out the second step.
4. Process as claimed in Claim 1, in that the first step is carried out at temperatures between 0°C
and 160°C.
5. Process as claimed in Claim 1, in that the second step is carried out at temperatures between -
20°C and+80°C.
6. Process as claimed in Claim 1, in that the first and the second step of the reaction are carried
out as a one-pot reaction, where 3,4-dichloroisothiazoIe-5-carbonyl chloride of the formula (II) is initially reacted with anthranilamide of the formula (EOT) in the presence of acid acceptor and the dehydrating agent is then added without prior isolation of the N-[2-(aminocarbonyl)-phenyl]-3,4-dichloroisothiazolecarboxamide of the formula (TV).
7. N-[2-(Aminocarbonyl)-phenyl]-3,4-dichloro-5-isothiazolecarboxamide of the formula

Documents:

4107-delnp-2004-abstract.pdf

4107-delnp-2004-claims.pdf

4107-delnp-2004-correspondence-others.pdf

4107-delnp-2004-correspondence-po.pdf

4107-delnp-2004-description (complete).pdf

4107-delnp-2004-form-1.pdf

4107-delnp-2004-form-18.pdf

4107-delnp-2004-form-2.pdf

4107-delnp-2004-form-3.pdf

4107-delnp-2004-form-4.pdf

4107-delnp-2004-form-5.pdf

4107-delnp-2004-gpa.pdf

4107-delnp-2004-pct-210.pdf

4107-delnp-2004-pct-304.pdf

4107-delnp-2004-pct-409.pdf

4107-delnp-2004-petition-137.pdf

4107-delnp-2004-petition-138.pdf


Patent Number 242973
Indian Patent Application Number 4107/DELNP/2004
PG Journal Number 39/2010
Publication Date 24-Sep-2010
Grant Date 23-Sep-2010
Date of Filing 23-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 SCHONE AUSSICHT 1B, D-51519 ODENTHAL, GERMANY
PCT International Classification Number C07D 257/03
PCT International Application Number PCT/EP2003/006360
PCT International Filing date 2003-06-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 102 28 732.5 2002-06-27 Germany