JPH1085503A - Crystallization - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily and accurately select a solvent with good filtering properties by using a solvent whose measured molar increase of boiling point is lower than that calculated based on the solvent used for the solution of a compound, when crystallizing the chemical compound by cooling the chemical compound solution. SOLUTION: Drugs generate byproducts or decomposed matter in their reaction process. Therefore, to remove the byproducts or the decomposed matter, a crystallization step is provided as a final manufacturing step. This crystallization step cools a chemical compound solution to crystallize the chemical compound. In this case, a solvent is used which shows lower actual measurements of an increase in the molar boiling point of a chemical compound solution, compared with the increase of the molar boiling point sought by calculation based on the solvent used for the chemical compound solution. In addition, to further lower the actual measurements of the increase in the molar boiling point sought by calculation based on the solvent used for the chemical compound solution, the solution composition is changed halfway through the crystallization process. The increase in the molar boiling point of the chemical compound solution is measured by experiments, and the solvent is selected which shows that the actual measurements of the increase in its boiling point are equivalent to 95% or less of the calculated increase in the boiling point.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a crystallization method for cooling a chemical solution and crystallizing the chemical.

[0002]

2. Description of the Related Art Pharmaceuticals, synthetic reagents, food raw materials, etc. are synthesized through several reaction steps, and by-products and decomposition products are generated in the reaction process. A crystallization step is provided.

[0003] As a crystallization method for the purpose of improving the filterability, a method of adding a seed crystal or precipitating a small amount of crystals in the early stage of crystallization and using the crystals as a seed crystal is known. In some cases, the effect of improving the filterability was not recognized. Furthermore, there is a method of controlling the size and shape of the crystal by adding a poor solvent or cooling operation. However, this method was not effective depending on the compound, and on the contrary, the filterability was deteriorated.

As described above, various attempts have been made to improve the filterability, but there are few methods applicable to any compound. Therefore, a method for improving the filterability by general solution cooling crystallization which is highly likely to be applicable to many compounds was studied. In solution cooling crystallization, when crystallization conditions are determined by lab experiments when determining crystallization conditions, there are many problems that the filterability etc. will change significantly due to the effects other than the solvent, which is the selection of the solvent. Was making it difficult. As described above, it was difficult to select a crystallization solvent because it was not known which factors were most affected by the precipitation of crystals and were not affected by other factors.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for extremely easily and accurately selecting a solvent having good filterability.

[0006]

The above object of the present invention is achieved by the following constitution.

(1) In a crystallization method in which a solution of a compound is cooled and the compound is crystallized, the measured value of the increase in the molar boiling point of the compound solution is determined by calculating the molar boiling point obtained from the calculation of the solvent used in the compound solution. A crystallization method characterized by using a solvent having a lower value than the above value.

(2) In a crystallization method in which a solution of a compound is cooled and the compound is crystallized, the crystallization is carried out so as to be lower than the molar boiling point increase value obtained from the calculation of the solvent used in the compound solution. A crystallization method, wherein the solution composition is changed.

(3) The crystal as described in (1) or (2) above, wherein the measured value of the increase in the molar boiling point of the compound solution is 95% or less of the value of the increase in the molar boiling point obtained from the calculation of the solvent used in the compound solution. Analysis method.

Hereinafter, the present invention will be described in detail. The present invention is a method for appropriately selecting a solvent from which crystals having good filterability can be obtained without being affected by various external conditions in experiments. The present inventors first studied the cause of the change in the particle size of the precipitated crystals by changing the solvent with reference to the following literature. The literature describes a method of measuring the dissolved state of a solute molecule by increasing the boiling point.

Studies on the self-association of acetamide and benzamide in dioxane solution and the interaction between m-aminobenzoic acid and nitrophenols by the melting point lowering method and the boiling point raising method; Tokuzo Somura; Journal of the Chemical Society of Japan, 1302-13
04, (1978) Self-association of phthalimide in dioxane solution by melting point lowering method and boiling point raising method; Tokuzo Sotomura et al .; 1298-1
299, (1980) In the above literature, the rise in boiling point is used for measuring the state of molecular association in a solution. However, in the present invention, the relationship between the state of molecular association and the particle size of precipitated crystals was examined. It has been found that there is a relationship between the degree of boiling point increase by the method and the crystal grain size.

In the present invention, the molar boiling point increase value refers to the solvent 100 to the boiling point of only the solvent in which the solute is not dissolved.
The degree of increase in the boiling point of a solution in which 1 mol of the target compound is dissolved in 0 g is shown. The calculation formula is shown below.

ΔKb = Kb · n ΔKb: Boiling point rise Kb: Constant specific to the solvent (molecular boiling point rise) n: Number of moles of solute Further, Kb is obtained by the following equation.

Kb = (R · Tb ² ) / 1000 · h R: Gas constant (J / g) Tb: Boiling point of pure solvent (K) h: Heat of evaporation per gram of solvent (J / g) Representative solvent For, the value of heat of evaporation of pure solvent is listed.

[0015]

[Table 1]

The increase in the molar boiling point of the target compound solution is measured by experiments. As the experimental device, a container having a stirring blade and a condenser is used, and a mercury or alcohol thermometer that can read up to 0.1 ° C. or a thermocouple temperature sensor is used for temperature measurement. 0.5 mol of solute and 1000 g of solvent are charged into the above-mentioned container, and the container is heated to about 10 ° C. higher than the boiling point of the pure solvent in a water bath or oil bath, and the solute is dissolved while stirring. The temperature at which the temperature rise of the solution in the chamber becomes constant is measured. However, from the viewpoint of measurement accuracy, it is easier to measure the degree of increase in boiling point when dissolved by about 1.0 mol. By selecting a solvent such that the actually measured boiling point rise value is 95% or less, preferably 80% or less, more preferably 50% or less of the calculated boiling point rise value, a crystal having good filterability and a large particle size is obtained by selecting a solvent. Is obtained.

Also, by adding a solvent such that the molar boiling point rise value decreases during the crystallization, crystals having good filterability can also be obtained. The present invention is particularly effective for crystallization of yellow couplers, magenta couplers, cyan couplers and the like used in silver halide color photographic light-sensitive materials.

[0018]

【Example】

Example 1 The degree of increase in molar boiling point of each of the yellow couplers (1) having the following structural formula with respect to each solvent was measured by the method described above.
ET was measured by the following method, and the results are shown in Table 2.

In a 50 ml glass sample bottle,
10 g of the yellow coupler (1) was charged, and the solvent 2 was added thereto.
After addition of 0 ml, the mixture was stoppered and placed in a 50 ° C. water bath and heated to completely dissolve. After complete dissolution, the sample bottle was taken out of the water bath and allowed to cool naturally at room temperature. The mixture was allowed to stand at room temperature for one day and night, and after sufficient crystals were precipitated, the crystals were filtered. The obtained crystals were transferred to a Petri dish, air-dried at room temperature for half a day, dried in a drier at about 40 ° C., and BET (m ² /
g) was measured.

[0020]

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[0021]

[Table 2]

From Table 2, acetonitrile, ethyl acetate and ethanol are expected to be solvents having good filterability, and methanol is expected to be a solvent having poor filterability.

Example 2 The increase in molar boiling point of the yellow coupler (2) having the following structural formula with respect to methanol, ethyl acetate and methanol: ethyl acetate = 2: 1 was measured by the above-mentioned method. The results are shown in Table 3. . BET of methanol and ethyl acetate
Was measured by the method of Example 1, and the BET of methanol: ethyl acetate = 2: 1 was measured by the following method. The results are shown in Table 3.

In a glass sample bottle having a capacity of 50 ml,
10 g of the yellow coupler (2) was added thereto, and 20 ml of methanol was added thereto. The mixture was capped, placed in a water bath at 50 ° C., and heated to completely dissolve. After complete dissolution, the sample bottle was taken out of the water bath and allowed to cool naturally at room temperature. One hour after the precipitation of crystals was observed, 10 ml of ethyl acetate was added, stoppered, and the sample bottle was shaken gently to mix the solution therein well. Thereafter, the mixture was allowed to stand at room temperature for one day and night, and after sufficient crystals were precipitated, the mixture was filtered.
Dried in ℃ dryer was measured BET (m ² / g).

[0025]

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[0026]

[Table 3]

According to Table 3, the BET value of the obtained crystal is reduced by adding a new solvent during the crystallization so that the measured value of the increase in the molar boiling point is lower than the calculated value. In an actual experiment, it was recognized that the filterability was greatly improved.

[0028]

According to the present invention, a solvent having good filterability can be easily selected.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI B01D 9/02 625 B01D 9/02 625A (72) Inventor Masami Akiyama 1st Sakuramachi, Hino City, Tokyo Konica Corporation

Claims (3)

[Claims] In a crystallization method for cooling a solution of a compound and crystallizing the compound, the measured value of the increase in the molar boiling point of the compound solution is determined by the calculation of the molar boiling point of the solvent used in the compound solution. A crystallization method characterized by using a lower solvent. 2. A crystallization method comprising cooling a solution of a compound and crystallizing the compound, during the crystallization such that the molar boiling point rise value is further lower than the molar boiling point obtained from the calculation of the solvent used in the compound solution. A crystallization method characterized by changing a solution composition. 3. The method according to claim 1, wherein the measured value of the increase in molar boiling point of the compound solution is 95% or less of the value of the increase in molar boiling point obtained from the calculation of the solvent used in the compound solution.
Or the crystallization method according to 2.