AU719276B2 - Thifluzamide with stabilized efficacy - Google Patents

Description

.r

S

S

Sc

S

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Rohm and Haas Company ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street,, Melbourne, 3000.

INVENTION TITLE: Thifluzamide with stablilized efficacy The following statement is a full description of this invention, including the best method of performing it known to me/us:- DN 96-016 JPN This invention relates to N-(2,6-dibromo-4-trifluoromethoxyphenyl)-2carboxyamide (common name: thifluzamide) with an altered crystalline form, its preparation method, and agricultural chemical composition containing thifluzamide as its effective ingredient.

Brief explanation of drawings Fig. 1 Powder X-ray diffraction pattern of the a-crystalline thifluzamide obtained in the Reference Example.

Fig. 2 Powder X-ray diffraction pattern of the p-crystalline thifluzamide obtained in the Example 1.

Thifluzamide is a compound that has a high pesticidal activity against rice leaf spot withering disease. Because the time to use a chemical against rice leaf spot withering disease in the cultivation of rice plant is when the rice field is covered with a lesser amount of water, rate of release/diffusion of the effective ingredient affects the exterminating effect significantly. However, since water solubility of thifluzamide is extremely low, about 1.6 mg/1 it is desirable to develop a method that can increase the rate of its release in water and stabilize its efficacy.

We have discovered that thifluzamide synthesized by ordinary preparation method changes its crystalline form when heat-melted and then cooled and that releasability of thifluzamide to water can be improved. As a result, the pesticidal efficacy can be stabilized by preparing an agricultural chemical composition using the thifluzamide with an altered crystalline form.

Based on this discovery, the present invention was perfected.

Therefore, this invention is a process for preparing thifluzamide with an altered crystalline form, comprising heat-melting thifluzamide at a temperature above the melting point, preferably 180 0 C 250 0 C, more preferably 180 0 C 2000 C and then cooling to a temperature below the melting point.

Another embodiment of this invention is thifluzamide showing endothermic peak at 175 180°C by differential scanning calorimeter and having no other peak at less than that temperature.

A third embodiment of this invention is thifluzamide showing a peak at 2 0=17.68, 20.04, 23.04, 28.88 and 29.52 by powder X-ray diffraction analysis.

A further embodiment of this invention is an agricultural chemical composition comprising thifluzamide with an altered crystalline form as an effective ingredient.

The melting point of thifluzamide is known to be 177.9 178.6°C (Pesticide Manual, 1994). However, the thifluzamide synthesized in the -2- DN 96-016 JPN Reference Example to be stated later shows an endothermic peak in the vicinity of 178 0 C by differential scanning calorimeter (DSC), and it shows an additional endothermic peak of 2.0 2.5 cal/g in the vicinity of 161 0 C. And, in powder X-ray diffraction analysis, it shows a diffraction pattern such like Fig. 1. In the following, thifluzamide of such crystalline form is called "a-crystal".

The thifluzamide of this invention with an altered crystalline form has a crystalline structure different from the a-crystal by powder X-ray diffraction analysis and DSC, as illustrated by the thifluzamide obtained in the Example 1 which will be stated later. Specifically, it shows an endothermic peak only in the vicinity of 178°C by DSC and does not show an endothermic peak at less than that temperature. In powder X-ray diffraction analysis, it shows a diffraction pattern like Fig. 2 and shows a peak at 20=17.68, 20.04, 23.04, 28.88 and 29.52.

In the following, thifluzamide having such crystalline form is called "-crystal".

The P-crystalline thifluzamide of this invention is prepared by the following method. After heat-melting a-crystalline thifluzamide at a temperature higher than the normal melting point, preferably 180 250°C, more preferably 180 200°C, it is then cooled to lower than the melting point and recrystallized.

Although the cooling rate is not critical, in this case, the cooling rate, in terms of the time required to crystallize from 190 0 C, is preferably 0.01 second minutes, more preferably 0.01 20 seconds.

The B-crystalline thifluzamide of this invention can be prepared easily by transferring a-crystalline thifluzamide, which is molten at a temperature higher than its melting point, from a heating device such as a dryer to an environment that has a temperature lower than its melting point such as room temperature.

It can also be prepared easily by adding dropwise or spraying the molten acrystalline thifluzamide into a liquid such as water which is inert to thifluzamide and does not substantially dissolve the thifluzamide, or by spraying the thifluzamide into a gas such as air which is inert to the thifluzamide.

Even though there is no particular restriction about the form of the agent of the agricultural chemical composition of this invention wherein B-crystalline thifluzamide is used as the effective ingredient, powder, hydrates, pellets, tablets, granular hydrates, and suspension and so on can be mentioned as examples. Each of them can be prepared by ordinary methods known to those skilled in agricultural chemical formulation art. Furthermore, there is no particular restriction about the additives other than the 0-crystalline thifluzamide to be added to the agricultural chemical composition of this invention. Also, other effective ingredients than p-crystalline thifluzamide may DN 96-016 JPN be added as the effective ingredients in the agricultural chemical composition of this invention.

We have discovered that the pesticidal efficacy and releasability of thifluzamide leaching into water from the agricultural chemical composition wherein the B-crystalline thifluzamide obtained in accord with this invention serves as the effective ingredient are improved, compared to when a-crystalline thifluzamide is used.

In addition to p-crystalline thifluzamide, the agricultural chemical composition of this invention includes also the situation where both a- and 3crystals of thifluzamides are used as a mixture, but the mixing ration of 0crystalline form is preferably 20 100%, more preferably 50 100%, from the viewpoint of improvement of solubility in water.

This invention is explained by the Reference Examples, Examples, and Examples of Tests illustrated below. However, this invention is not limited only to those examples. Incidentally, "parts" in the following Examples and Comparative Example means "parts by weight". And, DSC and powder X-ray diffraction analysis shown in the Reference Examples and Examples were run under the test conditions illustrated below.

.o -4- DN 96-016 JPN DSC determination (in air) Equipment DSC-3100, by Mac Science Co.

Weight of sample 3 mg Sample pan Aluminum Sampling rate 1.0 second Rate of temperature elevation Powder X-ray diffraction analysis Equipment JDX-8200T, by Nippon Denshi K.K.

Target Cu 20 50 500 Step angle 0.040 Counting time 0.5 second Tube voltage 30.0 kV Tube current 100.0 mA Reference Example Synthesis of a-crystalline thifluzamide 2-Methyl-4-trifluoromethyl-5-chlorocarbonyl thiazole 6.47g and 2,6dibromo-4-trifluoromethoxy aniline 8.91g were added in acetonitrile 16.8 ml, and they were heated to reflex for 6.5 hours. Solvent was removed from the reaction mixture by distillation under a reduced pressure, and then ethyl acetate 420g and water 300 ml were added and they were agitated. After standing calmly, the ethyl acetate layer was collected, and washed with 300 ml each of water, saturated sodium bicarbonate solution, and water in succession. Then, after drying over anhydrous sodium sulfate, solvent was removed by distillation under a reduced pressure, to obtain thifluzamide 13.9g.

The starting materials, 2-methyl-4-trifluoromethyl-5-chlorocarbonyl thiazole and 2,6-dibromo-4-trifluoromethoxy aniline, were synthesized by the procedures described in Example 1 of Japanese Kokai Patent No. 184680/1990.

The thus-obtained crystal showed an endothermic peak of 2.1 cal/g in the vicinity of 161 0 C and another endothermic peak of 9.0 cal/g in the vicinity of 178 oC by DSC. And by powder X-ray diffraction analysis, as illustrated in Fig. 1, the relative peak intensity at 20=17.70 was I/Io=12, and at 20=23.00 was I/Io 11. The crystal obtained in this Reference Example was called a "a-crystal".

Example 1 Synthesis of 1-crystalline thifluzamide The a-crystalline thifluzamide 200 mg obtained in the Reference Example was placed in a glass Petri dish having a diameter of 3 cm. After the dish was placed in a dryer at 190 0 C to melt the thifluzamide completely, it was taken out of the dryer, and then allowed to sit at room temperature to DN 96-016 JPN recrystallize. In this case, the time required by the thifluzamide taken out from the 190°C dryer to crystallize completely was 20 seconds.

The thus-acquired crystal showed an endothermic peak of 9.5 cal/g in the vicinity of 178 0 C by DSC, but it did not show a peak in the vicinity of 161°C. By powder X-ray diffraction analysis, as illustrated in Fig. 2, it showed a peak at =17.68, 20.04, 23.04, 28.88 and 29.52, and the relative peak intensity at 20=17.6° was I/Io 100 and the relative peak intensity at 20=23.00 was I/Io =59, and thus its crystalline form was different from that of a-crystal. The crystal obtained in this Example was called "p-crystal".

Example 2 Pellet 1 (0-crystal) The p-crystalline thifluzamide obtained in Example 1 was fractured by a jet crusher (A-0 Jet Mill, manufactured by Seishin Kigyo This fractured material 2.0 parts, sodium lignin sulfonate 5.0 parts, alkylbenzene sulfonic acid 0.5 part, sodium polyacrylate 1.0 part, sodium tripolyphosphate 2.0 parts, bentonite 40 parts, calcium carbonate 49.5 parts, and water 16 parts were mixed and blended in an Almighty Mixer (manufactured by Dalton and it was pelletized by using an extruder type pelletizer equipped with a screen having 0.8 mm apertures (BR-200, manufactured by Fuji Powdal This pellet was dried at 50 0 C, to obtain a pellet 1 (p-crystal).

Example 3 Pellet 2 (mixture of a B crystals) The thifluzamide (a-crystal) 35 parts obtained in the Reference Example and the thifluzamide (p-crystal) 65 parts obtained in the Example 1 were mixed/blended in a jet crusher (A-O Jet Mill). This mixed/fractured thifluzamide showed an endothermic peak of 0.71 cal/g in the vicinity of 161°C and another endothermic peak of 9.1 cal/g in the vicinity of 178 0 C by DSC. And, the X-ray diffraction analysis confirmed that is was a mixture of a-crystal and p-crystal.

This mixed/fractured thifluzamide (a-crystal: p-crystal 35: 65) 2.0 parts was processed like Example 2, to obtain a pellet 2 (mixture of a 0 crystals).

Comparative Example a-crystal Procedure of Example 2 was applied on 2.0 parts of the jet-fractured thifluzamide (a-crystal) obtained in the Reference Example, to obtain a comparative pellet (a-crystal).

Example of Test 1 Dissolution test of pellets Forty five milligrams each of the pellets 1 and 2 and comparative pellet were added in a beaker containing hard water (hardness =100) 1000 ml and kept at water temperature of 300C. After standing calmly for 7 days, a portion of the solution was taken out from the center portion of the beaker, and content of -6- P:\OPER\AXD\14767-97.SPE 3/3/00 -7A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

e.

ee a

Claims (8)

1. A process for preparing thifluzamide with an altered crystalline form, comprising heat- melting thifluzamide at a temperature above the melting point and then cooling to a temperature below the melting point.

2. Thifluzamide showing endothermic peak at 175 180°C by differential scanning calorimeter and having no other peak at less than that temperature. 10

3. Thifluzamide showing a peak at 20 =17.68, 20.04, 23.04, 28.88 and 29.52 by powder X-ray diffraction analysis.

4. An agricultural chemical composition comprising thifluzamide prepared by the process of claim 1 as an effective ingredient.

5. The process of claim 1 wherein the thifluzamide is heat-melted at a temperature of S. from 180 0 C to 250 0 C.

6. The process of claim 1 wherein the thifluzamide is heat-melted at a temperature of from 180 0 C to 200°C.

7. A process for preparing thifluzamide according to claim 1 substantially as hereinbefore described with reference to the Examples.

8. Thifluzamide when prepared by a process of claim 1 or 7. DATED this 3rd day of March, 2000 ROHM AND HAAS COMPANY by its Patent Attorneys 1 30 DAVIES COLLISON CAVE