JP3417085B2 - Method for producing fungicide inclusion compound - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a fungicide inclusion compound, and more particularly to a method for efficiently producing microcrystals thereof.

[0002]

2. Description of the Related Art As a method for industrially producing a clathrate compound using a fungicide as a guest compound, a method of precipitating crystals of the clathrate compound from a solution, filtering and drying it is generally employed. ing. At this time, as a method of precipitating the clathrate compound from the solution, while stirring the solution in which the host compound is dissolved in an organic solvent such as methanol, a solution in which a guest compound is separately added thereto is added little by little. There are many methods of precipitating an inclusion compound.

[0003]

However, this method has hitherto had the following problems. 1) Depending on the reaction conditions such as temperature, the clathrate compound may not be precipitated. 2) Even when the clathrate compound is deposited, the timing at which the deposition starts may change due to differences in the lots of raw material chemicals, etc., making it difficult to accurately predict the timing at which the deposition starts. 3) Even if the clathrate compound is deposited, the crystal grain size may become too large. For this reason, the yield of the desired fine crystals may be reduced, and it may be necessary to crush the coarse crystals.

For the above reasons, it has been difficult with the prior art to produce the target inclusion compound having a minute particle size in a high yield and with good reproducibility.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a method for producing a fungicide inclusion compound by pouring a solution of a fungicide dissolved in a solution of a host compound capable of clathrating a fungicide under stirring. In, there is provided a method for producing a minute bactericide inclusion compound with high reproducibility and high yield. In the method of the present invention, seed crystals of the sterilizing agent inclusion compound prepared in advance in the host compound solution are added to the mixed solution solution during the step of pouring the sterilizing agent solution into the host solution with stirring. The present invention is a bactericidal agent in which a host compound is dissolved in an organic solvent such as methanol, and while stirring the solution, a solution in which a bactericidal guest compound is separately poured little by little to precipitate a bactericidal inclusion compound. Provided is a method for producing a fine bactericide clathrate compound crystal in a high yield, with good reproducibility, and in a stable manner, in the method for producing an inclusion compound. In the method of the present invention, a seed crystal of the clathrate compound prepared in advance is added in the middle of the step of pouring the solution in which the bactericidal guest compound is dissolved little by little.

That is, the inclusion according to claim 1 of the present invention
The method for producing a compound is a method for producing a bactericide inclusion compound by pouring and depositing a solution in which a sterilizer is dissolved in a solution in which a sterilizer is included in a solution in which a bactericide can be clathrated under stirring. 5-chloro-2-methyl as the bactericide
-4-isothiazolin-3-one was used to
A solution of 2-methyl-4-isothiazolin-3-one was added to the solution of the host compound that was being added to the solution of 5-chloro
By adding a seed crystal of the inclusion compound of 2--2-methyl-4-isothiazolin-3-one , 5-
Inclusion of loro-2-methyl-4-isothiazolin-3-one
It is a method for producing precipitation of a compound.

A method for producing an inclusion compound according to claim 2
The method according to claim 1, wherein the host compound is bis
Phenolic compounds, phenolic compounds, deoxyco
Acid, dicarboxylic acid, or aromatic carboxylic acid
Is the law.

The method for producing an inclusion compound according to claim 3 is
In this method, the grain size of the seed crystal is 1 to 300 μm.

Furthermore, the production of an inclusion compound according to claim 4
The method according to any one of claims 1 to 3,
0.1-10 with respect to the inclusion compound that precipitates the seed crystal
This is a method of adding 00 mg / Kg.

The bactericidal compound used in the method of the present invention is capable of forming an inclusion compound with a suitable host compound, and is widely known as an effective water-soluble bactericidal compound.

[0011]

[Chemical 1]

5-chloro-2-methyl-4 represented by
-Isothiazolin-3-one (hereinafter abbreviated as Cl-MIT) is used. This water-soluble germicide is 1 to 50% by weight,
It is preferably used as an aqueous solution of 10 to 20% by weight.

The host compound used in the method of the present invention is not particularly limited as long as it forms an inclusion compound with Cl-MIT which is a bactericidal agent , and the following compounds can be mentioned. 1) Bisphenol compounds

[0014]

[Chemical 2]

In the formula, R is an alkylene group or alkylidene group having 1 to 4 carbon atoms, X is a hydrogen atom or a halogen atom,
Show. Specific examples include 4,4'-ethylidene bisphenol, 2,4'-isopropylidene bisphenol, 4,
4'-isopropylidene bisphenol, 2,2'-methylene bis (4-chlorophenol) and the like can be mentioned. 2) phenol compounds

[0016]

[Chemical 3]

In the formula, R1 and R2 each represent an alkyl group having 1 to 4 carbon atoms. Specific examples include 2,4-di-t-butylphenol, 2,4-di-propylphenol and 2-
Propyl-4-t-butylphenol may be mentioned. 3) Deoxycholic acid 4) Dicarboxylic acid

[0018]

[Chemical 4]

In the formula, R3 represents a single bond or an alkylene group having 1 to 4 carbon atoms, an alkenylene group or an alkynylene group. Specific examples include oxalic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, maleic acid and acetylenedicarboxylic acid. 5) Aromatic carboxylic acid

[0020]

[Chemical 5]

In the formula, R4, R5 and R6 are each independently
Hydrogen, halogen, carboxyl group, hydroxyl group, nitro group,
An amino group, a carboxylic acid anhydride, or an alkyl group having 1 to 4 carbon atoms, an alkenyl group, an alkynyl group, an alkoxy group, an alkanone group, or an alkanal group is shown. Specific examples include benzoic acid, 4-chlorobenzoic acid, 2,4-dichlorobenzoic acid, 2,4-dibromobenzoic acid and 2,4,6.
-Tribromobenzoic acid, 4-iodobenzoic acid, 2,4-
Diiodobenzoic acid, 2,4,6-triiodobenzoic acid,
3,5-diiodosalicylic acid, 4-chloro-3-nitrobenzoic acid, 2-chloro-4-nitrobenzoic acid, 4-chloro-2-nitrobenzoic acid, 4-chloro-2-nitrobenzoic acid, phthalic acid , Isophthalic acid, terephthalic acid, trimellitic acid, pyromellitic acid, 4-nitro-benzoic acid,
2,4-dinitrobenzoic acid, 4-nitrophthalic acid, 3,5
-Dinitrosalicylic acid, 2-aminobenzoic acid, trimellitic anhydride, gentisic acid (2,5-dihydroxybenzoic acid), protocatechuic acid (3,4-dihydroxybenzoic acid), salicylic acid, 2,4,6-trihydroxybenzoic acid Acid, 4-methylbenzoic acid, 4-methoxybenzoic acid, 4-
Carboxybenzamide, 4-vinylbenzoic acid, 4-ethynylbenzoic acid, 4-acetylbenzoic acid, 4-carboxybenzaldehyde and the like can be mentioned. These host compounds use a water-soluble solvent such as methanol, ethanol or acetone, and are usually used as a 10 to 70% by weight solution. The optimum solvent and its concentration are determined by preliminary experiments. The amount of bactericide solution added to the host compound solution is 0.
2-5 (weight ratio) is suitable.

The seed crystal used in the present invention is a crystal of a preliminarily prepared fungicide inclusion compound which is the same as the fungicide inclusion compound to be manufactured now, and has a particle size of 1 to 300 μm, preferably 10 to 150 μm. Use the adjusted one. As an adjusting method, it may be pulverized in a mortar or the like and then sieved. This seed crystal was used in an amount of 0.1 to 1000 mg /
The solution for precipitating the clathrate compound is added while thoroughly stirring so that the concentration of Kg, preferably 1 to 100 mg / Kg. The timing of adding the seed crystal depends on the type and concentration of the host solution, the type and concentration of the bactericide solution, etc., so a preliminary test is performed in advance at room temperature using the seed crystal, but generally the sterilizer solution is used. The time when the inclusion compound becomes supersaturated in the mixed solution after pouring is a guide. Practically, the time when the bactericide solution is added about 1/3 may be used as a guide.
Even after the pouring of the bactericide solution is completed, stirring is continued for 1 hour to 1 day to sufficiently precipitate crystals. After that, solid-liquid separation is performed with a vacuum filter, a centrifugal filter, a pressure filter, or the like, and the product is washed with demineralized water.

[0023]

EXAMPLES (Reference Example) 75 g of methanol and a host compound, 4,4′-ethylidene bisphenol (Lot) were placed in a 1 L separable flask.
No. 1) 50g was added, and the meniscus stirring blade (length 5c
The host compound was completely dissolved by stirring in m). Keep the separable flask in a constant temperature bath at 20 ° C and stir the contents at a rotation speed of 500 rpm while sterilizing caisson WT.
(Registered trademark, manufactured by Rohm and Haas. An aqueous solution containing 10 to 12% by weight of Cl-MIT) 300 g was continuously added over 30 minutes. Precipitation of the clathrate compound started 9 minutes after the start of pouring Caisson WT. After completion of the pouring, stirring was continued for 1 hour to sufficiently deposit the inclusion compound. The obtained clathrate was 79.8 g, and the bactericide / host molar ratio was 1/1,
The particle size was 95% or more when the particle size was 300 μm or less.

Comparative Example 1 The same operation as in the above (Reference Example) was performed. However, 4, 4'-
The ethylidene bisphenol used was a lot (Lot No. 2) different from that of (Reference Example). The deposition start time of the clathrate was different from that of the reference example, and was 10 minutes after the start of caisson WT injection. As described above, it was found that when the lots of 4,4′-ethylidene bisphenol were different, the initiation time of precipitation of the clathrate compound was sometimes different.

Comparative Example 2 In the same manner as in the above (Reference Example), 4,4′-ethylidene bisphenol (Lot No. 1) was used, but the temperature of the constant temperature bath was lowered to 10 ° C. for operation. The inclusion compound crystals are
After completion of pouring Caisson WT, precipitation did not occur even if stirring was continued for 1 hour. Then, when the stirring was stopped and the solution in the flask was tried to be taken out, crystals rapidly precipitated. Particles of this crystal were mutually solidified to form a lump as a whole, which was fixed to the inner wall of the flask and was difficult to take out. However, even with this crystal, the sterilizing agent / host molar ratio was the same as (Comparative Example 1) 1 /.
It was an inclusion compound of 1. As described above, it was found that when this clathrate compound was produced at 10 ° C., it was difficult to predict the time to start the precipitation of crystals, and fine crystals could not be obtained.

(Example 1) In the same manner as in (Comparative Example 2 ) above, operation was performed using 4,4'-ethylidene bisphenol (Lot No. 2). However, seed crystals of 4,4'-ethylidene bisphenol / Cl-MIT (particle size 150
1 μm or less) was added. Simultaneously with the addition of this seed crystal, precipitation of the clathrate compound started. As described above, it was found that the seed start time can be controlled by using the seed crystal.

Example 2 The same operation as in (Comparative Example 2) was performed. However, 10 minutes after the start of the caisson WT injection, seed crystals of 4,4'-ethylidene bisphenol / Cl-MIT inclusion compound (particle size 15
1 μm) was added. Simultaneously with the addition of this seed crystal, precipitation of the clathrate compound started. The inclusion compound yield was 80.1 g, the fungicide / host molar ratio was 1/1, and the crystal grain size was 95% or more when the particle size was 300 μm or less. By comparing the above Comparative Examples and Examples, by adding a seed crystal, it is possible to control the precipitation time of the clathrate compound, and it is possible to precipitate even under conditions where precipitation at low temperature is difficult, and a minute crystal You can see that you can get it.

[0028]

According to the present invention, in low temperature conditions in winter,
Precipitation can be initiated even under conditions in which the inclusion compound crystals are unlikely to precipitate. Further, by carrying out the present invention, coarsening of precipitated crystals is suppressed, and fine crystals are obtained with good reproducibility and high yield. Therefore, the manufacturing process of the inclusion compound can be rationalized.

[0029]

Continuation of front page (56) Reference JP-A-5-163104 (JP, A) JP-A-2-164835 (JP, A) JP-A-3-178906 (JP, A) JP-A-2-178243 (JP , A) JP 5-85954 (JP, A) JP 5-32570 (JP, A) JP 7-33755 (JP, A) JP 4-283528 (JP, A) JP 63-175068 (JP, A) Mitsutaka Kitamura, Molecular Recognition and Polymorphic Precipitation of Inclusion Compounds in Mixed Isomers, Proceedings of the Autumn Meeting of the Chemical Society of Japan, Japan, 1992, Vol. 25th, No. Pt1, pp. 355 Mitsutaka Kitamura, Polymorphism Control in Crystallization Operation, Separation Technology, November 25, 1994, Volume 24, No. 6, pages 365-369 Hiroshi Nakagawa, Formulation of poorly soluble drugs, JJS HP; 1988 , VoL. 24, No. 11, pp. 1175-1182 (58) Fields surveyed (Int.Cl. ⁷ , DB name) A01N 43/80 A01N 25/22 C07D 275/02 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A method for producing a disinfectant inclusion compound by pouring a solution in which a disinfectant is dissolved into a solution in which a host compound capable of encapsulating a disinfectant is dissolved under stirring to prepare a disinfectant inclusion compound, 5-chloro-2-methyl-4 as an agent
-Isothiazolin-3-one using the 5-chloro-
A solution of 2-methyl-4-isothiazolin-3-one was added to the solution of the host compound that was being added to the pre-conditioned 5-chloro-
By adding a seed crystal of the 2-methyl-4-isothiazolin-3-one inclusion compound , 5-chloro-5
2-Methyl-4-isothiazolin-3-one inclusion compound
A method for producing an inclusion compound, comprising producing a product. 2. The host compound is bisphenol-based
Compound, phenolic compound, deoxycholic acid, dicar
Characterized by being a boric acid or an aromatic carboxylic acid
The method for producing an inclusion compound according to claim 1. 3. The grain size of the seed crystal is 1 to 300 μm.
The inclusion compound according to claim 1 or 2, characterized in that
Production method. 4. An inclusion compound for precipitating the seed crystal
Characterized by adding 0.1 to 1000 mg / Kg
A process for producing an inclusion compound according to any one of claims 1 to 3.
Build method.