JP3298158B2 - Carbamate compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a novel crystal structure of isopropyl N- (3,4-diethoxyphenyl) carbamate (hereinafter referred to as IPC) and a method for producing the same, particularly a crystal structure excellent in pharmaceutical properties. And a method for selectively producing IPC. IPC is known as a bactericidal compound having an excellent effect on benzimidazole-resistant gray mold and the like.

[0002]

2. Description of the Related Art IPC is usually obtained by reacting 3,4-diethoxyaniline with isopropyl chloroformate in an organic solvent such as benzene or toluene, and then removing impurities, a solvent, etc. 58-74652, JP-A-58-12
No. 6856, JP-A-59-204165). IP obtained in this way
When C is used as a fungicide, it is usually mixed with a carrier and formulated into, for example, powders, wettable powders, flowables, emulsions and the like.

[0003]

However, the IPC obtained as described above is not sufficient in terms of pulverizability, cohesion, consolidation, etc. in the preparation process and its preparations. As a result of intensive studies for the purpose of obtaining an IPC free from such a problem, the inventor has found that the IPC has several types of crystal structures,
Was found to be able to obtain an IPC having a crystal structure that meets the above-mentioned object by cooling at a rate of 2 ° C./min or less for crystallization.

[0004]

That is, the present invention is excellent in the preparation of a preparation having specific diffraction peaks at 2θ of 10.6 ° and 12.2 ° in X-ray diffraction (CuKα: λ = 1.5412 °). IPC and IPC molten to 1 minute
2 ℃ cooled at a rate, there is provided a method for producing superior the IPC to by that formulation to precipitate crystals.

Hereinafter, the present invention will be described. The present inventors have crystallized IPC under various conditions, and have obtained X-ray, DSC, I
As a result of intensive analysis by analyzing using an apparatus such as R, MS, NMR, GC, LC, etc., it was found that there are four types of existence forms in IPC. That is, X-ray diffraction (CuKα: λ =
1.5412 °), 2θ is 10.6 ° and 1
One having a characteristic peak at 2.2 ° (hereinafter referred to as A-type crystal), one having a characteristic peak at 15.3 ° (hereinafter referred to as B-type crystal), and one having a characteristic peak at 16.9 ° (Hereinafter referred to as C-type crystal) and amorphous 4
Kind.

FIG. 1 shows X-ray diffraction patterns of A-type crystal, B-type crystal, C-type crystal and amorphous type of IPC. In the figure, the horizontal axis represents twice the diffraction angle (2θ), and the vertical axis represents the reflection intensity. As shown by arrows in the figure, each crystal structure has a unique reflection peak, and the A-type crystal has 2θ of 10.6 ° and 12.2.
°, B type crystal has 2θ of 15.3 °, and C type crystal has 2θ of 1
It has a unique diffraction peak at 6.9 °. Table 1 shows types A and B
The values of the diffraction peaks of the crystals of type C and type C are shown.

[0007]

[Table 1]

[0008] Among these crystal types, A-type and B-type do not show any change in the crystal structure even when heat-treated, but the C-type partially changes to the A-type by heat-treatment. In addition, the amorphous type appears only when IPC obtained by a conventional method is ultra-quenched with liquid nitrogen or the like,
It easily changes to C-type at room temperature.

FIG. 2 shows X-ray diffraction patterns of A-type crystal, B-type crystal, C-type crystal and amorphous type of IPC before and after heat treatment. Types A, B and C were heated at 70 ° C. for 24 hours, and amorphous types were heated at 20 ° C. for 15 minutes. In this figure, there is no change in the X-ray diffraction pattern before and after the heat treatment in the A type and the B type,
In the case of the C type, a diffraction pattern of the A type is partially observed after the heat treatment.
Further, it can be seen that the amorphous type has been changed to the C type.

The bactericidal activity of IPC against benzimidazole-resistant Botrytis cinerea is not affected by the crystal structure.
The crystal structure is greatly affected, and as will be described later, the A-type crystal is extremely excellent in terms of pulverizability, cohesiveness, consolidation and the like, but the B-type and C-type crystals are not sufficient in these respects. Even if about 3 to 5% of type B is mixed in the IPC of the type A crystal, there is no problem in practical formulation.

In the method of obtaining IPC having such a crystal structure, A-type and B-type are obtained depending on the cooling rate of the molten IPC.
Type, C type, A type + B type and B type + C type crystal structure I
As PC is obtained and the cooling rate is increased, the crystal structure obtained from type A to type A + B, type B, type B + C, and type C changes. A, B and C crystal structures IPC
Is about 2 ° C./min or less, about 2.5-10
It can be obtained by cooling and crystallizing at a temperature of at least about 12 ° C./min.

[0012] The IPC of type A crystal excellent in formulation can be obtained by cooling the molten IPC at a cooling rate of about 2 ° C / min or less and crystallization. When such a method is industrially performed, for example, a method in which molten IPC is flaked using a drum dryer (drum-type solidifier) can be employed. In this case, it is important to use relatively high-temperature drum cooling water and to maintain the cooling rate of the molten IPC at about 2 ° C./min or less. The temperature of the cooling water slightly varies depending on the size of the drum dryer, the rotation speed of the drum, the melting temperature, and the like.
When the temperature is 5 to 125 ° C. and the drum rotation speed is 1 rpm, the object can be sufficiently achieved by setting the temperature of the drum cooling water to 65 ° C. or higher. In addition, using a belt-type solidifier,
By keeping the cooling rate at about 2 ° C./min or less, IPC of A-type crystal can be obtained as in the case of the drum-type solidifier.

Further, a method of cooling and crystallizing the molten IPC by dripping the molten IPC into water using a dropping granulator can also be adopted.
Also in this case, the water temperature is raised and the cooling rate of the molten IPC is set to about 2 ° C.
/ Min. For example, when the temperature of the molten IPC is 100 to 130 ° C., although it depends on the size of the droplet, it is usually possible to obtain the IPC of the A-type crystal by dropping it into hot water whose water temperature is maintained at 40 ° C. or higher. it can.

In these methods, the temperature of the molten IPC is preferably from 100 to 130 ° C. from the viewpoint of deterioration of the IPC, and if necessary, a surfactant such as sodium dioctyl sulfosuccinate may be added to the molten IPC. You can also.

[0015]

According to the present invention, it is possible to efficiently produce IPC having a crystal structure excellent in formulation properties.

[0016]

The present invention will be described in more detail with reference to the following Preparation Examples and Formulation Tests, but the present invention is not limited thereto.

Production Example 1 5 g of each IPC was placed in a glass tube, and each was placed at 130 ° C. for 3 g.
After heating and melting for 0 minutes, the mixture was cooled and crystallized under the conditions of 1 to 1.3 ° C / minute, 2.5 to 3 ° C / minute, and 12 to 15 ° C / minute. As a result, IPCs of almost A-type, B-type, and C-type crystal structures were generated, respectively.

Production Example 2 10 kg of IPC was heated to 115 to 120 ° C. with steam.
After melting, a drum dryer (drum size: 200 mm
(φ × 300 mml), flakes were formed at a drum rotation speed of 1 rpm, and the relationship between the cooling water temperature of the drum dryer and the generation rate of A-type crystals in the obtained IPC crystals was examined. FIG. 4 shows the outline of the apparatus used, and FIG. 5 shows the results.
The generation rate of the A-type crystal was 2θ = 1 in the X-ray diffraction diagram.
2.2 °, 15.3 °, 16.9 ° area intensity of I
a, Ib, and Ic were calculated according to the following equations. A-type crystal ratio (%) = [1.998 (Ia−0.876 Ic) × 100
] [1.998 (Ia-0.876 Ic) + 2.357 Ib + 13.274 Ic] In the above equation, the coefficient 0.876 is the ratio of the C-type peak appearing at 2θ = 12.3 °. As shown in FIG.
It can be seen that IPC having an A-type crystal structure can be obtained by making the above (the estimated cooling rate is about 2 ° C./min or less).

Production Example 3 7.8 kg of IPC heated and melted at 110 ° C. with steam
Was dropped into 30.3 kg of hot water of 45 to 50 ° C. to which 0.04 kg of a 4% aqueous solution of sodium dioctyl sulfosuccinate was added as a surfactant per 1 kg of IPC.
And crystallized. Thereafter, the mixture was filtered and dried to obtain 7.4 kg of A-type crystals of IPC.

Production Example 4 2 g of IPC heated and melted at 130.degree.
g, to precipitate crystals. The obtained crystals were of the C type.

Formulation Test Example 1 Crystals of type A, type B, and type C IPCs produced according to Production Example 1 were tested for crushability, cohesiveness, and caking properties as respective wettable powders. For crushability, IP
5 parts of white carbon and 50 parts of Solpol 50
50 parts (dispersing agent, manufactured by Toho Chemical Co., Ltd.) was added to obtain a wettable powder, which was pulverized with a centrifugal pulverizer at 20,000 rpm for 25 minutes, and the average particle size was measured. As a result, type A was 5.6μ
Types m and B were 7.8 μm, type C was 12 μm, and type A had the best crushability.

Regarding the cohesiveness, the above ground product was placed in a plastic bag and allowed to stand at room temperature for 25 days.
The mixture was sieved with a 6-mesh sieve. As a result, there was no problem with the cohesion of the A-type crystal of 16% or more in the case of the A-type crystal.
It was 55% for the mold and 48% for the C type.

Regarding the caking property, about 20 g of a sample prepared in the above wettable powder was weighed into a stainless steel cylinder having an inner diameter of 5 cm, the upper surface thereof was flattened, and a load of 25 g / cm ² was applied. Stored for 2 weeks. Thereafter, the sample was taken out, a cube having a side of 1 cm was cut out, a load was applied thereto, and the weight at which the cube was broken was used as an index of solidification. As a result, type A is 10 g, type B is 100 g or more,
Form C weighed 100 g or more, while forms B and C were consolidated.

Table 2 summarizes the physical properties of IPC type A, B type and C type crystals and the evaluation results of the formulation.

[0025]

[Table 2]

[Brief description of the drawings]

FIG. 1 is a diagram showing X-ray diffraction patterns of A-type crystal, B-type crystal, C-type crystal and amorphous type of IPC.

FIG. 2 is a diagram showing X-ray diffraction diagrams of an A-type crystal, a B-type crystal, a C-type crystal, and an amorphous type of IPC before and after heat treatment.

FIG. 3 is a diagram showing a cooling rate of molten IPC in Production Example 1.

FIG. 4 is a diagram showing an outline of an apparatus used in Production Example 2.

FIG. 5 shows drum cooling water temperature and A-type IP in Production Example 2.
It is a figure which shows the production ratio of C crystal.

Continuation of front page (72) Inventor Yoshitaka Hirao 5-1 Sokai-cho, Niihama-shi, Ehime Sumitomo Chemical Industries, Ltd. (56) References JP-A-58-74652 (JP, A) JP-A-58-126856 (JP, A) JP-A-59-204165 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. X-ray diffraction (CuKα: λ = 1.5412)
Isopropyl N- (3,4-diethoxyphenyl) carbamate having characteristic diffraction peaks at 2θ of 10.6 ° and 12.2 ° in Å). 2. X-ray diffraction (CuKα: λ = 1.5412)
Isopropyl N- (3,4-diethoxyphenyl) carbamate having a specific diffraction peak at 2θ of 15.3 ° in Å). 3. X-ray diffraction (CuKα: λ = 1.5412)
Isopropyl N- (3,4-diethoxyphenyl) carbamate having a unique diffraction peak at 2θ of 16.9 ° in Å). 4. An isopropyl N- (3,4-) in a molten state.
2. The method for producing isopropyl N- (3,4-diethoxyphenyl) carbamate according to claim 1, wherein the diethoxyphenyl) carbamate is cooled at a rate of 2 ° C. or less per minute to precipitate crystals. 5. The isopropyl N- (3,4) according to claim 4, wherein the isopropyl N- (3,4) is carried out using a drum-type solidifier or a belt-type solidifier.
A process for the production of (diethoxyphenyl) carbamate. 6. An isopropyl N- (3,4) in a molten state.
The method for producing isopropyl N- (3,4-diethoxyphenyl) carbamate according to claim 1, wherein -diethoxyphenyl) carbamate is dropped into warm water at 40 ° C or higher to precipitate crystals. 7. The method for producing isopropyl N- (3,4-diethoxyphenyl) carbamate according to claim 6, wherein the method is carried out using a dropping granulator. 8. The isopropyl N- (3,4-diethoxyphenyl) carbamate according to claim 4, wherein isopropyl N- (3,4-diethoxyphenyl) carbamate in a molten state at 100 to 130 ° C. is used. Manufacturing method.