JPH0476721B2 - - Google Patents

Description

[Detailed description of the invention]

(a) Field of Industrial Application The present invention relates to a method for crystallizing polymorphic compounds, and more specifically to a method for crystallizing an organic compound having a desired crystal form from an organic compound solution having a plurality of crystal forms. It is related to. (b) Problems to be solved by the invention Crystals of organic compounds often have multiple crystal forms, and when producing these compounds,
Depending on the conditions, compounds having crystalline forms that are difficult to manipulate industrially may be produced. Furthermore, when these compounds are used as medicines, the rate of absorption into the human body varies depending on the crystal form, which may greatly affect the drug efficacy. Therefore, a method for arbitrarily crystallizing an organic compound having a desired crystal form has been desired. (c) Means for Solving the Problems The inventors of the present invention have made diligent efforts to solve the above problems, and as a result, have completed the present invention. That is, the present invention relates to a method for crystallizing an organic compound having a desired crystal form, which is characterized by controlling the temperature of an organic compound solution having a plurality of crystal forms. In a crystallization method in which a solution is added to a solvent maintained at a crystallization temperature and crystallized to obtain an organic compound having a desired crystal form, the organic compound has the general formula [1] (In the formula, X represents a halogen atom and R represents a lower alkyl group.) This invention relates to a method for crystallizing an optically active quinoxaline compound represented by the following formula. Optically active forms include D- and L-quinoxaline compounds. Examples of the halogen atom that is X include fluorine, chlorine,
Examples include bromine and iodine. The lower alkyl group represented by R includes a methyl group,
Ethyl group, n-propyl group, i-propyl group, n
-butyl group, i-butyl group, t-butyl group, etc. Among the optically active quinoxaline compounds of general formula [1], compounds in which X is a chlorine atom and R is an ethyl group are desirable, and compounds in which X is a chlorine atom and R is an ethyl group in the D form are more desirable. The above-mentioned solvents and the solvent for preparing the organic compound solvent solution having multiple crystal forms include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, aromatic hydrocarbon solvents such as benzene and toluene, and aromatic solvents such as benzene and toluene. Mixed solvents of group hydrocarbon solvents and aliphatic hydrocarbon solvents such as n-hexane and n-heptane, aliphatic ether solvents such as diisopropyl ether and dibutyl ether, halogen-containing solvents such as dichloroethane and chloroform, dichloroethane and chloroform. Mixed solvents of halogen-containing solvents such as halogen-containing solvents and aliphatic hydrocarbon solvents such as n-hexane and n-heptane are used. Hereinafter, the present invention will be described as an optically active quinoxaline compound of the general formula [1], in which X of the D form is a chlorine atom, R ¹
is an ethyl group [abbreviated as D-compound (1)]. ]
will be explained in detail using an example. D-Compound (1) has two crystal forms according to X-ray diffraction measurements, and microscopic observation shows that one is a fine needle-like crystal form and the other is a plate-like crystal form. Ta. Moreover, the difference between these crystal forms was also confirmed as a difference in melting point by differential scanning calorimetry. The characteristics of the two crystal forms are shown below. Melting point Crystal form Low melting point type (α type) 75~76℃ Plate high melting point type (β type) 82~84℃ Fine needle shape D- As a factor to crystallize the crystals having the desired crystal shape of compound (1) The crystallization temperature is particularly important. When the crystallization temperature is low, low melting point crystals are obtained, and when the temperature is high, high melting point crystals are obtained. The temperature boundary is around 20℃. First, a method for crystallizing low melting point crystals (plate-like) of D-Compound (1) will be described. For the crystallization method, 1 part by weight of D-compound (1) is added to a solvent.
A solution dissolved in 0.6 to 2 parts by weight is dropped into 2 to 3.5 parts by weight of a solvent kept at the crystallization temperature to cause crystallization. The crystallization temperature is usually 5-20℃ depending on the size of the crystals.
Preferably the temperature is 15-20°C. Further, the dropping time of the D-compound (1) solution is usually 30 minutes to 10 hours, preferably 30 minutes to 2 hours, depending on the size of the crystals.
Good time. The drying temperature of the crystallized crystals is usually lower than 70°C, preferably lower than 50°C. Drying time is usually 4 to 24 hours, preferably 6 to 24 hours.
10 hours is good. If the crystallized crystals are dried at a temperature exceeding 70°C for 5 hours or more, the low melting point crystals may change to high melting point crystals. In addition, for the purpose of obtaining large crystals, D-compound (1)
The higher the purity of D-compound (1), the shorter the dropping time of the D-compound (1) solution can be. The crystals of D-compound (1) crystallized by this crystallization method are of a low melting point type and have a plate-like crystal shape, and the average particle size is 10 to 35 μm. Further, the solvent slurry containing the low-melting point type crystals can be easily moved, and the crystallized crystals can be easily filtered and dried. In addition, the solvent slurry containing low melting point crystals is
When the low melting point type crystals are present in an amount of 70% by weight or more, operability such as filterability is good, and when the content is 90% by weight or more, operability such as filterability and drying characteristics are good. Therefore, when a mixture of low melting point crystals and high melting point crystals in which the content of low melting point crystals is 70% by weight or more is desired, the crystallization conditions are as follows. The crystallization temperature is usually preferably 20 to 25°C. The time for dropping the D-compound (1) solution is usually 30 minutes to 5 hours, preferably 1 to 2 hours. The drying temperature of the crystallized crystals is usually lower than 70°C, preferably lower than 50°C. Drying time is usually 4 to 24 hours, preferably 6 to 24 hours.
10 hours is good. In addition, as another crystallization method for obtaining low melting point crystals (plate-like) of D-compound (1), D-
Solvent 3 kept at 5 to 10°C to 1 part by weight of compound (1)
By adding ~10 parts by weight over a short period of time (1 to 5 minutes) and setting the crystallization temperature to 15 to 20°C, low melting point crystals can be selectively obtained. However, this method requires that the solvent be added dropwise in a short period of time, and crystals may adhere to the walls of the reaction vessel during the crystallization operation. Next, a method for crystallizing high melting point type crystals (acicular) of D-Compound (1) will be described. In the crystallization method, a solution of 1 part by weight of D-Compound (1) dissolved in 2 to 5 parts by weight of a solvent is slowly cooled while stirring to maintain the crystallization temperature. By this method, crystals containing 95% or more of high melting point crystals can be easily obtained. The crystallization temperature is usually 35°C or higher, preferably 38°C or higher. Further, the time for maintaining the D-compound (1) solution at the crystallization temperature is usually 30 minutes to 10 hours, preferably 1 to 10 hours.
2 hours is good. The drying temperature of the crystallized crystals is usually lower than 70°C, preferably lower than 50°C. Drying time is usually 4 to 24 hours, preferably 6 to 24 hours.
10 hours is good. The crystals of D-Compound (1) crystallized by this crystallization method have a high melting point, have a needle-like crystal shape, and have an average particle size of about 10 μm. However, microscopic observation revealed that this crystal was an agglomeration of microcrystals of 1 μm or less. Therefore, it may be difficult to move a solvent slurry containing these high melting point crystals, filter the crystals that have crystallized, and dry them. (d) Effect The present invention is effective for the crystallization of optically active quinoxaline compounds, and is particularly effective for crystallization of low melting point crystals of D-compound (1),
High melting point type crystals and mixtures thereof can optionally be crystallized. (E) Examples Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Example 1 A solution prepared by dissolving 100 g of the above D-Compound (1) (purity 98%) in 110 g of ethanol at 60 to 70°C was added dropwise over 30 minutes to 350 g of ethanol maintained at a crystallization temperature of 15°C. After dropping, cool and stir at 0 to 5°C for 1 hour.
The crystallized solid was filtered and dried to obtain 91 g of D-compound (1).
I got it. The obtained crystal is a low melting point crystal (plate-like)
100%, and the average particle size measured using a Coulter Counter was 33μ. Example 2 Regarding a solution in which 100 g of D-compound (1) (purity 98%) of Example 1 was dissolved in 110 g of ethanol at 60 to 70° C., the dropwise addition time and crystallization temperature were varied to obtain the results shown on the next page.

【table】

[Table] Example 3 Add ethanol to 100g of D-Compound (1) (98% purity)
When 250 g of the solution was added and dissolved by heating to 60°C, and the solution was gradually cooled, crystals began to precipitate at 38 to 40°C. Further, the mixture was cooled to 0 to 5°C and maintained at this temperature for 1 hour, then filtered and dried to obtain 90 g of D-Compound (1).
The obtained crystals were 95% high melting point type crystals (acicular) and had an average particle size of 10 μm.

Claims (1)

[Scope of Claims] 1. A crystallization method for obtaining an organic compound having a desired crystal form by adding a solution of an organic compound having a plurality of crystal forms to a solvent maintained at a crystallization temperature and crystallizing the organic compound. General formula [1] (In the formula, X represents a halogen atom and R represents a lower alkyl group.) A method for crystallizing an optically active quinoxaline compound represented by the following formula.