JPWO2014051056A1 - Crystal of glycine derivative and pharmaceutical use thereof - Google Patents

Abstract

The present invention provides (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pento- having excellent chemical and physical stability. It aims at providing the crystal | crystallization of 4-enoic acid and its pharmacologically acceptable salt, and its pharmaceutical use. The present invention relates to (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid or a pharmacologically acceptable salt thereof. Provided is a salt crystal.

Description

  The present invention relates to crystals of a glycine derivative and pharmaceutical use thereof.

  The quality of pharmaceuticals must be maintained over long-term processes such as distribution and storage, and the compounds that are active ingredients or their pharmacologically acceptable salts have high chemical and physical stability. Is required. For this reason, it is common that a compound that is an active ingredient of a pharmaceutical or a pharmacologically acceptable salt thereof is a crystal that can be expected to have higher stability than an amorphous substance.

  In the process of screening for crystals of compounds that are active ingredients of pharmaceuticals, it is difficult not only to find the optimum conditions and salt species for obtaining crystals, but also when crystals are obtained, The existence of shapes is often a problem. This is because the crystalline form of each compound as an active ingredient is different in chemical and physical stability because the molecular packing mode is different in spite of having the same structure in the molecular unit.

  In addition, if the crystal form to be used as an active ingredient of pharmaceuticals is wrongly selected, it may be difficult to maintain the compound at a certain quality due to a decrease in purity, hydration change, crystal form transition, etc. depending on the external environment during storage. Therefore, depending on the crystal form, an unexpected situation such as a decrease in drug efficacy and side effects may be caused. For this reason, when acquisition of the crystal | crystallization of the compound used as an active ingredient of a pharmaceutical is successful, the strict evaluation examination is needed also about the crystal polymorphism.

On the other hand, (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid represented by the following chemical formula (I) Are known to exert therapeutic effects on inflammatory bowel disease, allergic dermatitis, multiple sclerosis and leukemia (Patent Documents 1 to 4).

International Publication No. 2006/068213 International Publication No. 2007/145282 International Publication No. 2007/148648 International Publication No. 2007/148676

  However, it is impossible to predict the presence or absence of crystal polymorphism, the salt species that form crystals, or the stable crystal form from the structure of the compound, and it is possible to obtain compounds that cannot form crystals and crystals that can be stably stored. In some cases, there are some compounds that do not exist, so it is necessary to study various conditions for forming crystals for each compound or pharmacologically acceptable salt thereof. In addition, (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid is high as an active ingredient of pharmaceuticals. In spite of its effectiveness, the existence of crystal polymorphism, including pharmacologically acceptable salts, is not known at all. Acquisition of a simple crystal form has been an important issue in developing a pharmaceutical product.

  Accordingly, the present invention provides (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent having excellent chemical and physical stability. An object is to provide crystals of -4-enoic acid and pharmacologically acceptable salts thereof, and pharmaceutical uses thereof.

  As a result of intensive studies to solve the above problems, the present inventors have obtained (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino). Succeeded in obtaining crystals of phenyl] pent-4-enoic acid and pharmacologically acceptable salts and hydrates thereof, and (S, E) -2- (2,6-dichlorobenzamide)- 5- [4- (Isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid includes polymorphs of A, B, C, D, F, G and H crystals. The present invention was completed by discovering that E-type crystals exist in the potassium salt. A-form, C-form, D-form, E-form, G-form and H-form crystals have excellent physical stability under high temperature conditions, and B-form and E-form crystals have improved optical purity in the crystallization process. It was recognized and extremely excellent in terms of purification efficiency. Above all, the A-form crystal was low in hygroscopicity and exhibited extremely chemically stable characteristics even in contact with various preparation bases.

That is, this invention provides the crystal | crystallization described in the following (1)-(14), and its pharmaceutical use.
(1) (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid or a pharmacologically acceptable salt thereof Salt crystals.
(2) The powder X-ray diffraction described in (1) above having peaks at diffraction angles 2θ (°) of 6.2, 13.3, 17.0, 19.6, 22.2 and 23.0 °. Crystal.
(3) The crystal according to (2) above, which has a heat absorption peak at 237 to 247 ° C. in simultaneous differential thermothermal weight measurement.
(4) In powder X-ray diffraction, diffraction angles 2θ (°) 5.7, 6.1, 7.9, 12.2, 12.3, 12.9, 13.4, 16.2, and 17.0 The crystal according to (1), which has a peak at °.
(5) In powder X-ray diffraction, peaks are observed at diffraction angles 2θ (°) of 5.5, 5.9, 7.6, 12.0, 12.5, 13.2, 16.6, and 23.1 °. The crystal according to the above (1).
(6) In the X-ray diffraction differential scanning calorimetric simultaneous measurement, the diffraction angles 2θ (°) have peaks at 12.0, 13.8, 18.1, 19.3, 19.9 and 22.8 ° The crystal as described in 1).
(7) The crystal according to the above (1), which has peaks at diffraction angles 2θ (°) 11.6, 12.0 and 17.1 ° in powder X-ray diffraction.
(8) In powder X-ray diffraction, the diffraction angles 2θ (°) have peaks at 5.7, 6.2, 10.9, 11.5, 13.3, 17.0, and 19.6 °, The crystal as described in 1).
(9) The crystal according to (1), wherein the salt is a potassium salt.
(10) In powder X-ray diffraction, peaks are observed at diffraction angles 2θ (°) of 4.1, 7.6, 8.2, 8.8, 10.0, 14.2, 15.2, and 19.2 °. The crystal according to (9), which has
(11) The crystal according to (9) or (10) above, which is a hydrate crystal.
(12) A medicament comprising the crystal according to any one of (1) to (11) as an active ingredient.
(13) A therapeutic or prophylactic agent for inflammatory bowel disease, allergic dermatitis, multiple sclerosis or leukemia, comprising the crystal according to any one of (1) to (11) as an active ingredient.

  The crystal of the present invention is excellent in chemical and physical stability as compared with an amorphous body, and can be suitably used as an active ingredient of a pharmaceutical product. Moreover, the crystal | crystallization of this invention can be utilized as an active ingredient of the therapeutic agent or preventive agent of inflammatory bowel disease, allergic dermatitis, multiple sclerosis, or leukemia.

(S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid by powder X-ray diffraction measurement It is the obtained powder X-ray diffraction pattern. Simultaneous differential thermothermal gravimetric measurement of Form A crystals of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is a figure which shows the differential thermal analysis curve and thermogravimetric curve which were obtained by this. X-ray powder X-form crystals of potassium salt of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is a powder X-ray diffraction diagram obtained by diffraction measurement. Differential heat of E-form crystals of potassium salt of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is a figure which shows the differential thermal analysis curve and thermogravimetric curve which were obtained by the simultaneous weight measurement. By powder X-ray diffraction measurement of D-form crystals of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is the obtained powder X-ray diffraction pattern. By powder X-ray diffraction measurement of B-form crystals of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is the obtained powder X-ray diffraction pattern. X-ray diffraction differential scanning calorimetry of C-form crystals of (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is a figure which shows the X-ray diffraction obtained by simultaneous measurement. By powder X-ray diffraction measurement of F-form crystals of (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is the obtained powder X-ray diffraction pattern. By powder X-ray diffraction measurement of G-form crystals of (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is the obtained powder X-ray diffraction pattern. By powder X-ray diffraction measurement of H-form crystals of (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid It is the obtained powder X-ray diffraction pattern.

  The crystal of the present invention contains (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid (hereinafter referred to as “this”). And a pharmacologically acceptable salt thereof, and these hydrate crystals are also included. Representative examples of the crystals of (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid include the following: A-type crystals, B-type crystals, C-type crystals, D-type crystals, F-type crystals, G-type crystals, and H-type crystals, which are described in detail in the following. Can be mentioned.

  (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid or a pharmaceutically acceptable salt thereof Each crystal form is characterized by a powder X-ray diffraction diagram (hereinafter referred to as “XRD diffraction diagram”) obtained by powder X-ray diffraction measurement or powder X-ray diffraction differential scanning calorimetry simultaneous measurement (hereinafter referred to as “XRD-DSC”). Or an endothermic or exothermic peak indicated by a differential thermal analysis curve (hereinafter, “DTA curve”) obtained by simultaneous differential thermothermal gravimetric measurement (hereinafter, “TG-DTA”). Note that the XRD diffractogram and the DTA curve may vary somewhat depending on the measurement conditions. For example, the diffraction angle 2θ in the XRD diffractogram generally allows an error of about ± 0.2 °.

  Examples of the pharmacologically acceptable salt of the present compound include a base or a salt with an acid. Examples of the salt with a base include an alkali metal salt such as a sodium salt or a potassium salt, a calcium salt or a magnesium salt, and the like. Alkali earth metal salts, ammonia, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine, and other amine salts, or arginine, lysine, and other basic amino acid salts. Examples of salts with acids include, for example, hydrochloric acid Inorganic acid salts such as salt, sulfate, nitrate, hydrobromide or phosphate, acetate, lactate, citrate, maleate, benzoate, oxalate, glutarate, malic acid Organic carboxylate such as salt, tartrate, fumarate, mandelate, succinate or pamoate or methanesulfone And organic sulfonates such as p-toluenesulfonic acid or camphorsulfonic acid, sodium salt, potassium salt, hydrochloride, sulfate, hydrobromide, phosphate, maleate, methanesulfonate Alternatively, p-toluenesulfonate is preferable, and potassium salt is more preferable.

  As shown in FIG. 1, the A-form crystal of the present compound has diffraction angles 2θ (°) 6.2, 13.3, 17.0, 19.6, 22.2 in the XRD diffraction pattern by powder X-ray diffraction measurement. And a characteristic peak at 23.0 °. Further, Form A crystal of this compound gives the DTA curve shown in FIG. 2 and has an endothermic peak in the range of 239 ° C., that is, 237 to 247 ° C.

  As shown in FIG. 3, the E-type crystals of the potassium salt of the present compound have diffraction angles 2θ (°) 4.1, 7.6, 8.2, 8.8, It has characteristic peaks at 10.0, 14.2, 15.2, and 19.2 °. Further, the E-type crystal of the potassium salt of this compound gives the thermogravimetric curve shown in FIG. The weight loss due to evaporation of water is shown, and the DTA curve shown in FIG. 4 has a gentle endothermic peak in the range of 150 to 200 ° C.

  As shown in FIG. 5, the D-form crystal of the present compound has diffraction angles 2θ (°) 5.7, 6.1, 7.9, 12.2, 12.3 in an XRD diffraction diagram by powder X-ray diffraction measurement. , 12.9, 13.4, 16.2 and 17.0 °.

  As shown in FIG. 6, the B-form crystal of the present compound has diffraction angles 2θ (°) 5.5, 5.9, 7.6, 12.0, 12.5 in an XRD diffraction pattern by powder X-ray diffraction measurement. , 13.2, 16.6 and 23.1 ° with characteristic peaks.

  As shown in FIG. 7, the C-form crystal of the present compound has a diffraction angle 2θ (°) of 12.0, 13.8, 18.1, 19.3, 19.9 and XRD-DSC. It has a characteristic peak at 22.8 °.

  As shown in FIG. 8, the F-form crystal of the present compound has diffraction angles 2θ (°) 5.9, 7.9, 11.7, 12.4, 12.7 in the XRD diffraction pattern by powder X-ray diffraction measurement. , 16.7, 18.2, 21.1 and 23.8 °.

  As shown in FIG. 9, the G-form crystal of the present compound has characteristic peaks at diffraction angles 2θ (°) 11.6, 12.0 and 17.1 ° in an XRD diffraction diagram by powder X-ray diffraction measurement. .

  As shown in FIG. 10, the H-form crystal of the present compound has diffraction angles 2θ (°) 5.7, 6.2, 10.9, 11.5, 13.3 in the XRD diffraction pattern by powder X-ray diffraction measurement. , 17.0 and 19.6 ° with characteristic peaks.

  The powder X-ray diffraction measurement of A-type, B-type, D-type, F-type and G-type crystals can be performed under the following conditions using a powder X-ray diffractometer. The measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and leveling the sample surface.

≪Powder X-ray diffraction conditions≫
X-ray source: CuKα ray * Uses a curved crystal monochromator (graphite) Output: 40 kV / 50 mA
Divergent slit: 1/2 °
Divergence length restriction slit: 5mm
Scattering slit: 1/2 °
Receiving slit: 0.15 mm
Detector: Scintillation counter Scan method: 2θ / θ scan, continuous scan Measurement range (2θ): 3-35 °
Scan speed (2θ): 4 ° / min
Counting step (2θ): 0.02 °

  The powder X-ray diffraction measurement of the E-type crystal can be performed under the following conditions using a powder X-ray diffractometer. The measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and leveling the sample surface.

≪Powder X-ray diffraction conditions≫
X-ray source: CuKα ray * Uses a curved crystal monochromator (graphite) Output: 40 kV / 50 mA
Divergent slit: 1/2 °
Divergence length restriction slit: 5mm
Scattering slit: 1/2 °
Receiving slit: 0.15 mm
Detector: Scintillation counter Scan method: 2θ / θ scan, continuous scan Measurement range (2θ): 3-35 °
Scan speed (2θ): 5 ° / min
Counting step (2θ): 0.10 °

  The above crystals may be potassium salt E-form hydrate crystals and retain the same chemical and physical stability as potassium salt E-form crystals. Here, the crystal water forming the E-form hydrate crystals of the potassium salt is interstitial water taken into the gaps in the crystal structure or clathrate confined in the crystal structure, and is resistant to changes in humidity or temperature. The water content changes continuously.

  The powder X-ray diffractometry of the H-form crystal can be measured under the following conditions using a powder X-ray diffractometer. The measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and leveling the sample surface.

≪Powder X-ray diffraction conditions≫
X-ray source: CuKα ray * Uses a curved crystal monochromator (graphite) Output: 40 kV / 50 mA
Divergent slit: 1/2 °
Divergence length restriction slit: 5mm
Scattering slit: 1/2 °
Receiving slit: 0.15 mm
Detector: Scintillation counter Scan method: 2θ / θ scan, continuous scan Measurement range (2θ): 3-35 °
Scan speed (2θ): 2 ° / min
Counting step (2θ): 0.02 °

  Powder X-ray diffraction measurement of C-form crystals can be performed under the following conditions using an XRD-DSC apparatus. The measurement sample is prepared by filling a sample plate (material: aluminum; depth: 0.2 mm) with the sample and leveling the sample surface.

≪Powder X-ray diffraction conditions≫
X-ray source: CuKα ray * Uses a curved crystal monochromator (graphite) Output: 40 kV / 50 mA
Measurement temperature: Room temperature Diverging slit: 1 °
Divergence length restriction slit: 5mm
Scattering slit: 1 °
Light receiving slit: 0.3 mm
Detector: Scintillation counter Scan method: 2θ / θ scan, continuous scan Measurement range (2θ): 3-35 °
Scan speed (2θ): 40 ° / min
Counting step (2θ): 0.04 °

  The endothermic peak refers to the temperature at the peak top indicated by the DTA curve. Here, TG-DTA for obtaining a DTA curve can be measured under the following conditions using a TG-DTA apparatus.

≪TG-DTA condition≫
Temperature increase rate: 5 ° C./min Atmosphere: Nitrogen (flow rate: 800 mL / min)
Sample cell: Aluminum open cell Sample amount: 10 to 11 mg (when measuring A-type crystals)
4-5mg (when measuring E-type crystals)

  Form A crystal of the present compound comprises an arbitrary amount of the present compound at a concentration of 0.1 to 100 mg / mL, preferably 1 to 15 mg / mL, at a temperature below the boiling point, alcohol-based, aromatic-based, ether-based, It can be obtained by dissolving in a ketone-based, ester-based or halogen-based solvent and standing or stirring under open conditions at 0-30 ° C for 1-30 days.

  In addition, the A-form crystal of this compound is an alcohol of the present compound prepared in Reference Example 1 at a concentration of 0.1 to 1000 mg / mL, preferably 15 to 250 mg / mL at 0 to 30 ° C. It can be obtained by dissolving in a system, aromatic system, ether system, ketone system, ester system or halogen solvent, and standing or stirring at 0-30 ° C. for 1-30 days.

  The E-form crystal of the potassium salt of the present compound is an alcohol-based amorphous form of the potassium salt of the present compound prepared in Reference Example 2 at a concentration of 0.1 to 20 mg / mL, preferably 0.5 to 5 mg / mL. Alternatively, it can be obtained by dissolving in a ketone solvent and allowing to stand at 0 to 30 ° C. for 1 to 30 days or stirring.

  In addition, the E form crystal of the potassium salt of the present compound is obtained by dissolving the present compound in any form in an alcoholic or ketone solvent at a concentration of 0.1 to 20 mg / mL, preferably 0.5 to 5 mg / mL, Add 1 to 5 equivalents of potassium hydroxide and concentrate to a concentration of 10 to 300 mg / mL, preferably 70 to 200 mg / mL. After confirming the precipitate, leave at 0 to 30 ° C. for 1 to 120 hours. Can be obtained.

  D-form crystals of this compound are prepared by dissolving any form of this compound in a mixed solvent of an ester solvent and an alcohol solvent in an arbitrary ratio to a concentration of 10 to 300 mg / mL, preferably 70 to 200 mg / mL. After confirming the precipitate, it can be obtained by standing at 0 to 30 ° C. for 1 to 120 hours.

  Form B crystals of this compound were prepared in (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4 prepared in Reference Example 4. -1-10 mol / L hydrochloric acid was added to ethyl enoate, suspended, and stirred at 25-80 ° C for 1-10 hours. Then, 1-10 mol / L sodium hydroxide aqueous solution was added, and ether and ester solvents. The solution after extraction is concentrated to a concentration of 10 to 300 mg / mL, preferably 70 to 200 mg / mL. After confirming the precipitate, the solution can be left standing at 0 to 30 ° C. for 1 to 120 hours. .

  Form C crystals of the present compound can be obtained by heating the form B crystals of the present compound to 70 to 150 ° C, preferably 90 to 130 ° C.

  Form F crystals of this compound are obtained by dissolving the present compound in any form in an ether solvent at a concentration of 0.1 to 200 mg / mL, preferably 1 to 50 mg / mL at 0 to 30 ° C. It can obtain by concentrating at 10-40 degreeC until it does not remain | survive visually.

  G-form crystals of the present compound are prepared by dissolving the present compound in any form in an alcohol solvent at a concentration of 0.1 to 100 mg / mL, preferably 1 to 15 mg / mL at 0 to 30 ° C. It can be obtained by concentrating at ° C.

  The H-form crystals of this compound are obtained by dissolving any form of this compound in an ester solvent at a concentration of 0.05 to 50 mg / mL, preferably 0.1 to 15 mg / mL at 0 to 30 ° C. It can be obtained by concentrating at ˜40 ° C.

  Examples of the alcohol solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, and 3-methyl-1-butanol. However, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or 2-butanol is preferable.

  Examples of the aromatic solvent include benzene, chlorobenzene, toluene, xylene, and cumene, and toluene is preferable.

  Examples of the ether solvent include diethyl ether, tetrahydrofuran, t-butyl methyl ether, and 1,4-dioxane, and ethyl ether, tetrahydrofuran, and t-butyl methyl ether are preferable.

  Examples of the ketone solvent include acetone, methyl ethyl ketone, methyl isobutyl ketone, and methyl butyl ketone, and acetone, methyl ethyl ketone, and methyl isobutyl ketone are preferable.

  Examples of the ester solvent include ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, and n-butyl acetate, but ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate. Or isobutyl acetate is preferable.

  Examples of the halogen-based solvent include chloroform, dichloromethane, and 1,2-dichloroethene, but chloroform is preferable.

  Crystals of the present compound or a pharmacologically acceptable salt thereof are, for example, inflammatory bowel disease, allergic to mammals (for example, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human). It can be used as a pharmaceutical effective for the treatment or prevention of dermatitis, multiple sclerosis or leukemia.

  The dose when clinically administering the compound or a pharmaceutically acceptable salt crystal thereof or a hydrate thereof as a pharmaceutical is appropriately selected according to symptoms, age, body weight, sex or administration method, etc. For example, in the case of injections, 0.01 mg to 5 g per day as the amount of active ingredient is suitable for adults, and in the case of oral preparations, 0.1 mg to 10 g is preferable, and it is administered once or several times. can do.

  The dosage form for clinical administration of the present compound or a pharmacologically acceptable salt thereof as a pharmaceutical is not particularly limited as long as it is a pharmacologically acceptable dosage form. Oral preparations such as capsules, granules, powders or syrups, or parenteral preparations such as inhalants, injections, eye drops, nasal drops, suppositories, ointments, creams, lotions or patches Is mentioned. These dosage forms can be prepared according to methods generally used in the pharmaceutical field. In this case, additives such as excipients, stabilizers, preservatives, buffering agents, solubilizers, emulsifiers, diluents or isotonic agents generally used in the pharmaceutical field are appropriately mixed as necessary. May be. Examples of the pharmacologically acceptable additive used for the preparation of the above-mentioned dosage form include a binder (gelatin, gum arabic, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sorbitol, polyvinylpyrrolidone, polyvinyl alcohol or Tragacanth, etc.), excipients (sucrose, lactose, D-mannitol, erythritol, crystalline cellulose, ethyl cellulose, corn starch, calcium phosphate, sorbitol or glycine, etc.), disintegrants (partially pregelatinized starch, croscarmellose sodium, crospovidone or low Substitution degree hydroxypropylcellulose) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, sucrose fatty acid ester, etc.).

  The medicament containing a crystal of the present compound or a pharmacologically acceptable salt thereof as an active ingredient preferably contains 0.001 to 90% by weight of the crystal of the present compound per dosage unit. It is more preferable to contain by weight.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Example 1 Production of Form A Crystal of the Compound (Method 1)
The present compound (19.0 g) produced by the method described in Patent Document 1 was weighed into a flask, suspended by adding ethyl acetate (75 mL), and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with ethyl acetate (15 mL), and dried under reduced pressure. The obtained solid (14.8 g) was weighed into a flask, tetrahydrofuran (110 mL) was added and dissolved under heating to reflux. To this solution, n-hexane (110 mL) was added and allowed to cool to room temperature. Furthermore, it cooled to 0 degreeC and stirred for 30 minutes at 0 degreeC. The precipitate was collected by filtration, washed with a mixed solution (30 mL) of n-hexane / tetrahydrofuran = 2/1 (v / v), and then dried under reduced pressure to obtain 13.4 g (yield) of Form A crystals of the compound as a white powder. 71%). About the obtained crystal, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Corporation; 2200 / RINT ultrama ⁺ PC) and TG using a TG-DTA apparatus (Rigaku Corporation; TG810D) -DTA was performed. The results of these measurements are shown in FIGS.
Diffraction angle 2θ: 6.2, 13.3, 17.0, 19.6, 22.2, 23.0 °
Endothermic peak: 239 ° C

(Reference Example 1): Preparation of Amorphous Compound of the Compound The A-form crystal (1.2 g) of the compound prepared in Example 1 was dissolved in tetrahydrofuran (50 mL) and until about 2 mL of tetrahydrofuran remained in an evaporator. After concentration under reduced pressure, it was immediately dried under reduced pressure with a vacuum pump, followed by drying under reduced pressure for 19 hours while heating to 80 ° C. to obtain an amorphous form of the present compound.

(Reference Example 2): Preparation of Amorphous Form of Potassium Salt of the Compound The Form A crystal (417 mg) of the compound prepared in Example 1 was added to a 200 mL flask, and tetrahydrofuran (200 mL) was added and dissolved. To this solution, a solution of potassium hydroxide (47 mg) dissolved by adding methanol (20 mL) was added. After concentrating with an evaporator, it was dried under reduced pressure for 15 hours to obtain 465 mg (yield 100%) of an amorphous form of the potassium salt of this compound.

２０００ｍＬのフラスコにＬ−アリルグリシンエチルエステルトシル酸塩（１００ｇ）を量り取り、系内をアルゴン雰囲気に置換した後、トルエン（５００ｍＬ）とトリエチルアミン（８８．５ｍＬ）とを加えて懸濁した。この懸濁液を０℃に冷却した後、塩化２，６−ジクロロベンゾイル（５０．０ｍＬ）を２０分間かけて滴下し、０℃で４５分間撹拌した。反応液に炭酸水素ナトリウム（５６ｇ）を水（８５０ｍＬ）に溶解して加え、撹拌後、分液した。水層をトルエン（４００ｍＬ）で抽出した後、有機層を合わせて水（４００ｍＬ）で洗浄した。有機層を２８５ｍＬまで減圧濃縮し、得られたトルエン溶液を０℃に冷却した。この溶液にヘプタン（１０００ｍＬ）を滴下し、０℃で２時間撹拌した。析出物を濾取し、氷冷したヘプタン（２００ｍＬ）で洗浄後、減圧乾燥して、８８．３ｇ（収率８８％）の（Ｓ）−２−（２，６−ジクロロベンゾイルアミノ）ペンタ−４−エン酸エチルを得た。
¹H NMR (400 MHz, CDCl₃)δ 1.31 (3H, t, J =7.1Hz), 2.66 (1H, m), 2.80 (1H, m), 4.20-4.30 (2H, m), 4.93 (1H, ddd, J =5.4, 5.4, 7.8Hz), 5.15 (1H, d, J =9.8Hz), 5.19 (1H, d, J =15.6Hz), 5.78 (1H, m), 6.41 (1H, br.d, J =5.4Hz), 7.25-7.34 (3H, m).Reference Example 3 Production of ethyl (S) -2- (2,6-dichlorobenzoylamino) pent-4-enoate

L-allylglycine ethyl ester tosylate (100 g) was weighed into a 2000 mL flask and the system was replaced with an argon atmosphere, and then toluene (500 mL) and triethylamine (88.5 mL) were added and suspended. After this suspension was cooled to 0 ° C., 2,6-dichlorobenzoyl chloride (50.0 mL) was added dropwise over 20 minutes, followed by stirring at 0 ° C. for 45 minutes. Sodium hydrogen carbonate (56 g) was dissolved in water (850 mL) and added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with toluene (400 mL), and then the organic layers were combined and washed with water (400 mL). The organic layer was concentrated under reduced pressure to 285 mL, and the resulting toluene solution was cooled to 0 ° C. To this solution was added dropwise heptane (1000 mL), and the mixture was stirred at 0 ° C. for 2 hours. The precipitate was collected by filtration, washed with ice-cooled heptane (200 mL), and then dried under reduced pressure to obtain 88.3 g (yield 88%) of (S) -2- (2,6-dichlorobenzoylamino) penta- Ethyl 4-enoate was obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (3H, t, J = 7.1Hz), 2.66 (1H, m), 2.80 (1H, m), 4.20-4.30 (2H, m), 4.93 (1H, ddd, J = 5.4, 5.4, 7.8Hz), 5.15 (1H, d, J = 9.8Hz), 5.19 (1H, d, J = 15.6Hz), 5.78 (1H, m), 6.41 (1H, br.d , J = 5.4Hz), 7.25-7.34 (3H, m).

１００ｍＬのフラスコに、参考例３で製造した（Ｓ）−２−（２，６−ジクロロベンゾイルアミノ）ペンタ−４−エン酸エチル（５．００ｇ）、特許文献１記載のＮ−（４−ヨードフェニル）−Ｎ−イソプロピルピリミジン−２−アミン（５．６３ｇ）、炭酸カリウム（４．３７ｇ）、臭化テトラｎ−ブチルアンモニウム（５．１０ｇ）及び酢酸パラジウム（７１．０ｍｇ）を順次加え、系内をアルゴン雰囲気に置換した後、Ｎ，Ｎ−ジメチルホルムアミド（４５．０ｍＬ）及びエタノール（５．０ｍＬ）を加え、撹拌しながら系内を再度アルゴン雰囲気に置換した。５０〜５５℃で１７時間撹拌した後、反応液を室温まで冷却し、酢酸エチル（２００ｍＬ）を加えた後、水（１５０ｍＬ）で洗浄した。有機層を５％チオ硫酸ナトリウム水溶液（１５０ｍＬ）で２回、飽和塩化ナトリウム水溶液（１５０ｍＬ）で２回洗浄した。洗浄後の有機層に硫酸ナトリウム（２０．０ｇ）を加えて乾燥し、さらに活性炭（２．５０ｇ）を加えて室温で撹拌した。活性炭を濾別した後、濾液を減圧濃縮し、粗生成物を８．４９ｇ得た。粗生成物（１．０１ｇ）をナスフラスコに量り取り、２−プロパノール（４．０ｍＬ）を加えて溶解し、続いて、ｎ−ヘキサン（８．０ｍＬ）を加えて室温、開放状態で２４時間撹拌した。析出物を確認した後、析出物を濾取して減圧乾燥を行い、０．６４４ｇの（Ｓ，Ｅ）−２−（２，６−ジクロロベンズアミド）−５−［４−（イソプロピル−ピリミジン−２−イルアミノ）フェニル］ペント−４−エン酸エチルを得た。
¹H NMR (400 MHz, CDCl₃)δ 1.15 (6H, d, J =6.8Hz), 1.33 (3H, t, J =7.1Hz), 2.79-2.90 (1H, m), 2.90-3.03 (1H, m) 4.18-4.36 (2H, m), 4.95-5.06 (1H, m), 5.06-5.23 (1H, m), 6.07-6.21 (1H, m), 6.41-6.59 (3H, m), 7.07 (2H, d, J =8.1Hz), 7.19-7.42 (4H, m), 8.28 (2H, d, J =4.9Hz).Reference Example 4 Preparation of ethyl (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoate

In a 100 mL flask, ethyl (S) -2- (2,6-dichlorobenzoylamino) pent-4-enoate (5.00 g) prepared in Reference Example 3 and N- (4-iodo described in Patent Document 1 were prepared. Phenyl) -N-isopropylpyrimidin-2-amine (5.63 g), potassium carbonate (4.37 g), tetra-n-butylammonium bromide (5.10 g) and palladium acetate (71.0 mg) were added in that order. After replacing the inside with an argon atmosphere, N, N-dimethylformamide (45.0 mL) and ethanol (5.0 mL) were added, and the inside of the system was again replaced with an argon atmosphere while stirring. After stirring at 50-55 ° C. for 17 hours, the reaction mixture was cooled to room temperature, ethyl acetate (200 mL) was added, and the mixture was washed with water (150 mL). The organic layer was washed twice with 5% aqueous sodium thiosulfate solution (150 mL) and twice with saturated aqueous sodium chloride solution (150 mL). Sodium sulfate (20.0 g) was added to the organic layer after washing and dried, and activated carbon (2.50 g) was further added and stirred at room temperature. After the activated carbon was filtered off, the filtrate was concentrated under reduced pressure to obtain 8.49 g of a crude product. The crude product (1.01 g) was weighed into an eggplant flask and dissolved by adding 2-propanol (4.0 mL), followed by addition of n-hexane (8.0 mL) at room temperature for 24 hours. Stir. After confirming the precipitate, the precipitate was collected by filtration and dried under reduced pressure, and 0.644 g of (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidine- 2-ethylamino) phenyl] pent-4-enoic acid ethyl ester was obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.15 (6H, d, J = 6.8Hz), 1.33 (3H, t, J = 7.1Hz), 2.79-2.90 (1H, m), 2.90-3.03 (1H, m) 4.18-4.36 (2H, m), 4.95-5.06 (1H, m), 5.06-5.23 (1H, m), 6.07-6.21 (1H, m), 6.41-6.59 (3H, m), 7.07 (2H , d, J = 8.1Hz), 7.19-7.42 (4H, m), 8.28 (2H, d, J = 4.9Hz).

Example 2 Production of Form A Crystal of the Compound (Method 2)
The amorphous form (25 mg) of the compound prepared in Reference Example 1 was weighed into a borosilicate glass vial, added with an excess of acetone (12.5 mL) compared to the saturated solubility, and stirred at room temperature. A dilute solution was prepared. This was left still in an open state at room temperature. After confirming the precipitate, the solvent was removed with a Pasteur pipette and dried under reduced pressure for 30 minutes to obtain Form A crystals of the present compound as a powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and it confirmed that a result corresponded in FIG.1 and FIG.2.

Example 3 Production of Form A Crystal of the Compound (Method 3)
The amorphous form (25 mg) of the present compound prepared in Reference Example 1 was weighed into a borosilicate glass vial and dissolved by adding acetone (100 μL) with stirring at room temperature. This was left still at room temperature in an airtight state. After confirming the precipitate, the solvent was removed with a Pasteur pipette and dried under reduced pressure for 30 minutes to obtain Form A crystals of the present compound as a powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and it confirmed that a result corresponded in FIG.1 and FIG.2.

Example 4 Production of Form E Crystal of Potassium Salt of the Compound (Method 1)
The amorphous potassium salt (20 mg) of this compound prepared in Reference Example 2 was weighed into a borosilicate glass vial, added with acetone (10 mL), and stirred at room temperature for dissolution. This was left still in an open state at room temperature. After confirming the precipitate, the solvent was removed with a Pasteur pipette and dried under reduced pressure for 30 minutes to obtain E-form crystals of the potassium salt of this compound as a powder. The obtained crystals were subjected to powder X-ray diffraction measurement, TG-DTA, measurement of potassium content by inductively coupled plasma mass spectrometry, and ¹ H-NMR measurement. The result of the powder X-ray diffraction measurement is shown in FIG. 3, and the result of TG-DTA is shown in FIG.
Diffraction angle 2θ: 4.1, 7.6, 8.2, 8.8, 10.0, 14.2,
15.2, 19.2 °
Potassium content: 6.9%
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.08 (6H, d, J = 6.8 Hz), 2.58-2.72 (1H, m), 2.72-2.85 (1H, m), 3.94-4.10 (1H, m ), 4.96-5.16 (1H, m), 6.18-6.35 (1H, m), 6.42 (1H, d, J = 15.9Hz), 6.61 (1H, t, J = 4.8Hz), 7.03 (2H, d, J = 8.3Hz), 7.27-7.54 (5H, m), 7.80 (1H, br.s), 8.28 (2H, d, J = 4.6Hz).

Example 5 Production of Form E Crystal of Potassium Salt of the Compound (Method 2)
The A-form crystal (1.40 g) of this compound prepared in Example 1 was weighed into a 1000 mL flask, and ethanol (400 mL) was added and dissolved. To this solution was added a solution of potassium hydroxide (158 mg) dissolved in ethanol. Concentration was performed using an evaporator, and when the precipitate was confirmed, the concentration was completed, and the mixture was allowed to stand at room temperature for 15 hours. The precipitate was collected by filtration and dried under reduced pressure to obtain 872 mg (yield 56%) of the potassium salt E form crystal of this compound as a white powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and it confirmed that a result corresponded in FIG.3 and FIG.4.

Example 6: Production of Form D Crystal of the Compound A Form Crystal (150 mg) of the Compound prepared in Example 1 was weighed into a flask and dissolved by adding ethyl acetate (50 mL) and ethanol (50 mL). . Concentration was performed with an evaporator, and when the precipitate was confirmed, the concentration was completed, and the mixture was allowed to stand at room temperature for 24 hours. The precipitate was collected by filtration and dried under reduced pressure to obtain D-form crystals of this compound as a white powder. The obtained crystal was subjected to powder X-ray diffraction measurement. The measurement results are shown in FIG.
Diffraction angle 2θ: 5.7, 6.1, 7.9, 12.2, 12.3, 12.9,
13.4, 16.2, 17.0 °

Example 7 Production of Form B Crystal of the Compound (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidine) produced in Reference Example 4 in a 500 mL flask Ethyl-2-ylamino) phenyl] pent-4-enoate (528 mg) was weighed and 4 mol / L hydrochloric acid (10 mL) was added and suspended. The suspension was stirred at 45-55 ° C. for 5 hours. At 1 hour from the start of stirring, tetrahydrofuran (1 mL) was added to make the system uniform. The reaction solution was cooled to 0 ° C., and 4 mol / L aqueous sodium hydroxide solution (8.5 mL) was added. Tetrahydrofuran (15 mL) was added, followed by extraction with ethyl acetate (20 mL). The organic layer was washed twice with a saturated aqueous sodium chloride solution (10 mL), ethanol (5 mL) was added, and the mixture was concentrated under reduced pressure. When the precipitate was confirmed, the concentration was completed, and the precipitate was collected by filtration, washed with ethanol (5 mL), and dried under reduced pressure to obtain 120 mg of Form B crystal (first crystal) of this compound. The filtrate was allowed to stand still open. After confirming the precipitate, the precipitate was collected by filtration and dried under reduced pressure to obtain 66 mg of the B-form crystal (second crystal) of this compound. Powder X-ray diffraction measurement was performed on the crystals mixed with the first crystal (total 186 mg, yield 38%). The measurement results are shown in FIG.
Diffraction angle 2θ: 5.5, 5.9, 7.6, 12.0, 12.5, 13.2,
16.6, 23.1 °

Example 8 Production of Form C Crystal of the Compound Form B Compound (3.1 mg) of the Compound produced in Example 7 was weighed onto a sample plate (material: aluminum; depth: 0.2 mm), It heated at 130 degreeC with the XRD-DSC apparatus, and obtained C-form crystal | crystallization of this compound. Powder X-ray diffraction measurement was performed while heating to about 130 ° C. The measurement results are shown in FIG.
Diffraction angle 2θ: 12.0, 13.8, 18.1, 19.3, 19.9
22.8 °

≪DSD conditions for XRD-DSC≫
Temperature increase rate: 5 ° C./min Atmosphere: Nitrogen (flow rate: 50 mL / min)

Example 9 Production of Form F Crystal of the Compound Form A crystal (1.41 g) of the compound prepared in Example 1 was dissolved in tetrahydrofuran (100 mL), and tetrahydrofuran was visually observed at room temperature using an evaporator. The mixture was concentrated under reduced pressure for about 30 minutes until it did not remain, and F-form crystals of this compound were obtained as a powder. The obtained crystal was subjected to powder X-ray diffraction measurement. The measurement results are shown in FIG.
Diffraction angle 2θ: 5.9, 7.9, 11.7, 12.4, 12.7, 16.7, 18.2, 21.1, 23.8 °

(Example 10): Production of G-form crystal of this compound The A-form crystal (104 mg) of this compound prepared in Example 1 was dissolved in methanol (15 mL), and methanol remained visually at room temperature using an evaporator. The mixture was concentrated under reduced pressure for about 20 minutes until it disappeared to give G-form crystals of the compound as a powder. The obtained crystal was subjected to powder X-ray diffraction measurement. The measurement results are shown in FIG.
Diffraction angle 2θ: 11.6, 12.0, 17.1 °

Example 11 Production of Form H Crystal of the Compound Form A crystal (10.4 mg) of the compound prepared in Example 1 was dissolved in ethyl acetate (50 mL), and the ethyl acetate was dissolved at room temperature using an evaporator. Concentration under reduced pressure for about 20 minutes until it did not remain visually gave H-form crystals of the compound as a powder. The obtained crystal was subjected to powder X-ray diffraction measurement. The measurement results are shown in FIG.
Diffraction angle 2θ: 5.7, 6.2, 10.9, 11.5, 13.3, 17.0, 19.6 °

(Test Example 1): Hygroscopic evaluation Maximum equilibrium time: 180 minutes Measurement range: Relative humidity 5% to relative humidity 95% to relative humidity 5%
Measurement interval: 5% relative humidity

  In addition, in order to evaluate the presence or absence of changes in the crystal form, powder X-ray diffraction measurement was performed on the A-form and E-form crystals and the amorphous body after the hygroscopic evaluation test. The results are shown in Table 1.

  As shown in Table 1, the A-form crystal of the present compound showed almost no change in the amount of weight increase accompanying humidification, and the crystal form was not changed. Comparison with the amount of moisture absorbed by the amorphous form of this compound revealed that the A-form crystal has low moisture absorption. Moreover, although the E form crystal | crystallization of the potassium salt of this compound showed the big weight increase with humidification, the crystal form did not change. From these results, it became clear that the A-type crystal and the E-type crystal are crystals having excellent physical stability against humidification.

(Test Example 2): Solubility evaluation A temperature-humidity test tank (Nordoa) in which A-form crystals and amorphous bodies (30.0 mg each) of this compound were weighed into borosilicate glass vials and adjusted to 37 ° C. [alpha]; Améflex Co., Ltd.) Japanese Pharmacopoeia 16th revised disintegration test liquid 2nd liquid (10 mL) was added and stirred in a suspended state. The suspension (1.5 mL) after stirring for 2 hours is weighed with a measuring pipette, added to a 1.5 mL Eppendorf tube, and centrifuged at 10,000 rpm for 10 minutes using a centrifuge (MD-16N; Pasolina). separated. The supernatant liquid after centrifugation (1 mL) is weighed with a whole pipette, put into a 20-50 mL volumetric flask, and the total volume is adjusted to 20-50 mL with the Japanese Pharmacopoeia 16th revised disintegration test liquid 2nd liquid. The sample solution for analysis of high performance liquid chromatography (hereinafter “HPLC”) was combined. By quantifying the concentration of the sample solution for analysis by HPLC under the following conditions, the solubility in the second solution of Japanese Pharmacopoeia 16th revised disintegration test solution at 37 ° C. was evaluated. In addition, the phosphate (sodium) buffer solution (pH 2.2) used for the mobile phase of HPLC measured sodium dihydrogen phosphate dihydrate (6.24 g), and dissolved by adding distilled water (2 L). After that, phosphoric acid was added while stirring until the pH reached 2.2. Moreover, about the solubility with respect to Japanese Pharmacopoeia 16th revision disintegration test liquid 2nd liquid at 37 degreeC of the E form crystal | crystallization of the potassium salt of this compound, weigh E form crystal | crystallization (10.3 mg) in a 10 mL centrifuge tube, 37 degreeC. In a temperature and humidity test tank (Nordoa α) adjusted to, add 100 μL of the Japanese Pharmacopoeia 16th revision disintegration test solution 2 with a micropipette while stirring and make sure that the solid matter dissolves visually. The concentration above the confirmation was taken as the solubility. The results are shown in Table 2.

<< HPLC conditions >>
Detector: UV-visible spectrophotometer (measurement wavelength: 260 nm)
Column: Chromollis Performance RP-18e (Merck)
Inner diameter 3mm, length 10cm
Mobile phase A: Phosphate (sodium) buffer (pH 2.2)
Mobile phase B: acetonitrile Composition of mobile phase B: 0 to 4 minutes: 5 → 70%,
4-5 minutes: 70%,
5 to 5.1 minutes: 70 → 5%,
5.1-6.5 minutes: 5%
Flow rate: 3.0mL / min
Column temperature: 40 ° C
Sample injection volume: 10 μL

  As shown in Table 2, the form A crystals and amorphous form of this compound had a solubility of 1 mg / mL or less, whereas the form E crystals of the potassium salt of this compound showed a solubility of 50 mg / mL or more. It was. From this result, it was revealed that the E-type crystal is extremely excellent in solubility.

(Test Example 3): Physical stability evaluation against heat TG-DTA of the B-form, D-form, G-form and H-form crystals of this compound is performed, and the presence or absence of exothermic or endothermic changes is confirmed from the DTA curve. The physical stability against heat was evaluated. The results are shown in Table 3.

«TG-DTA conditions for B, G and H crystals»
Temperature increase rate: 5 ° C./min Atmosphere: Nitrogen (flow rate: 50 mL / min)
Sample cell: Aluminum open cell Sample amount: 8 to 10 mg (when measuring B-type crystals)
Sample amount: 4 to 6 mg (when measuring G-type crystals)
Sample amount: 1-3 mg (when measuring H-shaped crystals)
≪TG-DTA conditions for D-type crystals≫
Temperature increase rate: 5 ° C./min Atmosphere: Nitrogen (flow rate: 800 mL / min)
Sample cell: Aluminum open cell Sample amount: 8-10mg

  As shown in Table 3, the B form crystal of this compound undergoes a tautomeric transition at 29-46 ° C., then crystal transition to C form at 73-93 ° C., and further from C form to A at 150-170 ° C. Crystal transition to form. The D form crystal of this compound crystallized to form A at 150-170 ° C. G-form crystals of this compound crystallized to form A at 150-170 ° C. The H form crystal of this compound crystallized to form A at 195-215 ° C. From these results, it became clear that the C-type, D-type and G-type crystals are physically stable even under high temperature heating of less than 150 ° C. It became clear that the H-form crystals are physically stable even under high temperature heating below 195 ° C.

(Test Example 4): Solid Stability Evaluation The form A of the present compound and the form E and the amorphous form of the potassium salt of the present compound were stored at 60 ° C. in an airtight state for 4 weeks and subjected to HPLC under the following conditions. The purity before and after storage was measured. Moreover, the measurement of the powder X-ray diffraction and TG-DTA were performed, and the presence or absence of the change of the crystal form by storage was evaluated. The results are shown in Table 4. In addition, a phosphate (potassium) buffer solution (pH 2.2) (hereinafter referred to as “phosphate buffer solution (pH 2.2)”) used for the mobile phase of HPLC measures potassium dihydrogen phosphate (5.44 g). Distilled water (2 L) was added and dissolved, and then phosphoric acid was added while stirring until the pH reached 2.2. The HPLC analysis sample was prepared by weighing each crystal (5.0 mg) and amorphous form (5.0 mg) of this compound into a 50 mL volumetric flask and adding acetonitrile (25 mL) to dissolve, The total volume was adjusted to 50 mL with an acid buffer (pH 2.2).

<< HPLC conditions >>
Detector: UV-visible spectrophotometer (measurement wavelength: 210 nm)
Column: Capsule Pack C18 MGII (Shiseido)
Inner diameter 4.6 mm, length 25 cm, particle diameter 5 μm
Mobile phase A: phosphate buffer (pH 2.2) / acetonitrile = 70: 30 (v / v)
Mobile phase B: acetonitrile / phosphate buffer (pH 2.2)
= 70: 30 (v / v)
Composition of mobile phase B: 0 to 80 minutes: 0 → 100%
80-85 minutes: 100%
85-86 minutes: 100 → 0%
86-95 minutes: 0%
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Sample injection volume: 25 μL

  As shown in Table 4, there was almost no change in the purity of Form A of the present compound and Form E of the potassium salt of the present compound. In addition, the A-form and E-form crystals did not change during storage. From these results, it became clear that the A-form and E-form crystals are extremely excellent in chemical stability and physical stability as compared with the amorphous body.

(Test Example 5): Stability evaluation in combination with excipients Form A crystals (20 mg) of this compound, lactose (200 mg; DMV International; Pharmatose (registered trademark) grade 200M), D-mannitol (200 mg; Towa Kasei; Mannit (registered trademark) grade P), corn starch (200 mg; Nissho Chemical; grade ST-C) or crystalline cellulose (200 mg; Asahi Kasei; Theolas (registered trademark) grade PH-101) and brown glass The sample was weighed into a vial, and distilled water (30 μL) was added and mixed with a glass rod to prepare a blended sample. The blended sample was stored at 40 ° C. in an open state for 4 weeks, and the purity before and after storage was measured by HPLC under the following conditions. The results are shown in Table 5. For HPLC analysis samples, methanol (10 mL) was added to each compounded sample in a glass vial, and the suspension was irradiated with ultrasonic waves for 10 minutes using an ultrasonic cleaner. Aliquot into a 10 mL centrifuge tube, centrifuge at 3,000 rpm for 10 minutes using a centrifuge, and weigh the resulting supernatant (1 mL) with a whole pipette into a 20 mL volumetric flask. The total volume was adjusted to 20 mL with a lysis solution [phosphate buffer (pH 2.2) / acetonitrile = 50: 50 (v / v)].

<< HPLC conditions >>
Detector: UV-visible spectrophotometer (measurement wavelength: 210 nm)
Column: Capsule Pack C18 MGII (Shiseido)
Inner diameter 4.6 mm, length 25 cm, particle diameter 5 μm
Mobile phase A: phosphate buffer (pH 2.2) / acetonitrile = 70: 30 (v / v)
Mobile phase B: acetonitrile / phosphate buffer (pH 2.2)
= 70: 30 (v / v)
Composition of mobile phase B: 0 to 80 minutes: 0 → 100%
80-85 minutes: 100%
85-86 minutes: 100 → 0%
86-95 minutes: 0%
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Sample injection volume: 25 μL

  As shown in Table 5, the purity of the A-form crystals of this compound is the same as before and after storage even when blended with any of the excipients lactose, D-mannitol, corn starch and crystalline cellulose that are frequently used in pharmaceutical formulations. There was little change. From these results, it was clarified that the A-form crystals were not excellent in chemical stability without undergoing a change in formulation even under contact with the basic formulation excipient.

(Test Example 6): Stability evaluation under blending with various pharmaceutical bases A-form crystals (20 mg), lactose (110 mg; DMV International; Pharmatose (registered trademark) 200M) and corn starch (60 mg; Japanese starch) of this compound Chemistry; Grade ST-C) was added to a brown glass vial and mixed, then low-substituted hydroxypropylcellulose (10 mg; Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium (10 mg; Asahi Kasei Chemicals), hydroxypropylcellulose. (10 mg; Nippon Soda) or hydroxypropylmethylcellulose (10 mg; Shin-Etsu Chemical Co., Ltd.) was added, and distilled water (30 μL) was further added and mixed with a glass rod to prepare a blended sample. The blended sample was stored at 40 ° C. in an open state for 4 weeks, and the purity before and after storage was measured by HPLC under the following conditions. The results are shown in Table 6. The HPLC analysis sample was prepared by adding methanol (10 mL) to each blended sample in a brown glass vial, irradiating with ultrasonic waves for 10 minutes in a suspended state, and then suspending. Aliquot the solution into a 10 mL centrifuge tube, centrifuge at 3,000 rpm for 10 minutes using a centrifuge, and weigh the resulting supernatant (1 mL) with a whole pipette into a 20 mL volumetric flask. The sample solution [phosphate buffer (pH 2.2) / acetonitrile = 50: 50 (v / v)] was prepared to a total volume of 20 mL.

<< HPLC conditions >>
Detector: UV-visible spectrophotometer (measurement wavelength: 210 nm)
Column: Capsule Pack C18 MGII (Shiseido)
Inner diameter 4.6 mm, length 25 cm, particle diameter 5 μm
Mobile phase A: phosphate buffer (pH 2.2) / acetonitrile = 70: 30 (v / v)
Mobile phase B: acetonitrile / phosphate buffer (pH 2.2)
= 70: 30 (v / v)
Composition of mobile phase B: 0 to 80 minutes: 0 → 100%
80-85 minutes: 100%
85-86 minutes: 100 → 0%
86-95 minutes: 0%
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Sample injection volume: 25 μL

  As shown in Table 6, the A-form crystals of this compound are prepared by any disintegrant such as low-substituted hydroxypropylcellulose and croscarmellose sodium, and binders such as hydroxypropylcellulose and hydroxypropylmethylcellulose. Even when blended with the base, its purity was almost unchanged before and after storage. From these results, it was clarified that the A-form crystals were not excellent in chemical stability without undergoing a change in composition even under contact with the basic preparation base.

(Test Example 7): Evaluation of purification efficiency related to optical purity Form A crystals of the present compound described in Example 1, Form B crystals of the present compound described in Example 7, and potassium of the present compound described in Example 5 The optical purity before and after the preparation of the salt E-form crystals was measured by HPLC under the following conditions. Regarding the B-form crystal, first, (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pentoate described in Reference Example 4 was used. Optical purity was measured using a crude product of ethyl-4-enoate (chemical purity: 85%) as a starting material. Next, the crude product (1.00 g) was weighed into an eggplant flask, dissolved by adding 2-propanol (4.0 mL), and then added with n-hexane (8.0 mL) at room temperature at an open state. After stirring for a period of time and confirming the precipitate, the precipitate was collected by filtration and dried under reduced pressure to increase the chemical purity (S, E) -2- (2,6-dichlorobenzamide) -5- [ Ethyl 4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoate (0.644 g, chemical purity: 93%) was obtained, and the B-form crystals of this compound were obtained by the method described in Example 7. It was prepared and the optical purity of this crystal was measured. The results are shown in Table 7. In addition, the phosphate (potassium) buffer (pH 2.0) used for the mobile phase of HPLC measured potassium dihydrogen phosphate (5.44 g), dissolved in distilled water (2 L), and then stirred. However, it was prepared by adding phosphoric acid until the pH reached 2.0.

<< HPLC for measuring optical purity of ethyl (S, E) -2- (2,6-dichlorobenzamide) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoate Conditions >>
Detector: UV-visible spectrophotometer (measurement wavelength: 254 nm)
Column: CHIRALCEL OD-H (Daicel)
Inner diameter 4.6 mm, length 25 cm, particle diameter 5 μm
Mobile phase: 0.1% diethylamine-containing hexane / ethanol = 94: 6 (v / v)
Analysis time: 20 minutes Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Sample injection volume: 10 μL
Sample concentration: 0.5 mg / mL
Sample diluent: ethanol / hexane = 60: 40 (v / v)

<< HPLC conditions for measuring optical purity of this compound or potassium salt of this compound >>
Detector: UV-visible spectrophotometer (measurement wavelength: 260 nm)
Column: CHIRALCEL OJ-RH (Daicel)
Inner diameter 4.6 mm, length 15 cm, particle diameter 5 μm
Mobile phase: Phosphate (potassium) buffer (pH 2.0) /
Acetonitrile = 72.5: 27.5 (v / v)
Analysis time: 30 minutes Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Sample injection volume: 5 μL
Sample concentration: 0.4 mg / mL
Sample diluent: acetonitrile / water = 80: 20 (v / v)

  As shown in Table 7, a result that the optical purity of the A-form crystal of this compound was improved before and after the preparation was obtained. In addition, it became clear that the B-form crystal of the present compound and the E-form crystal of the potassium salt of the present compound have significantly improved optical purity before and after preparation, and are extremely excellent in purification efficiency related to optical purity. It was.

Example 12: Effect of solvent evaporation method on crystal form of crystal of the present compound In the production of the crystal of this compound, in order to confirm the effect of solvent evaporation method on the crystal form of the obtained crystal, Crystals were produced using three types of solvents, tetrahydrofuran, methanol, and ethyl acetate, respectively, and the following methods 1 to 3 as methods for distilling off the solvent.
Method 1: Evaporate the solvent at room temperature for 1-5 days in an open state
Method 2: Using an evaporator, concentrate under reduced pressure for about 20-30 minutes until no solvent remains visually
Method 3: Concentrate under reduced pressure using an evaporator until about 2 mL of solvent remains, then immediately dry under reduced pressure with a vacuum pump

Entry 1 Solvent: Tetrahydrofuran Solvent evaporation method: Method 1
Form A crystals (25 mg) of this compound prepared in Example 1 were weighed into a borosilicate glass vial, tetrahydrofuran (2 mL) was added, and the mixture was stirred at room temperature to prepare a diluted solution and allowed to stand. A precipitate was confirmed after 5 hours from standing, and it was confirmed that tetrahydrofuran was completely evaporated one day after standing. Drying under reduced pressure for 30 minutes gave crystals of the compound as a powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and since a result corresponds with FIG.1 and FIG.2, it confirmed that it was an A form crystal | crystallization.

Entry2 Solvent: Methanol Method of evaporation: Method 1
Form A crystals (25 mg) of this compound prepared in Example 1 were weighed into a borosilicate glass vial, methanol (8 mL) was added, and the mixture was stirred at room temperature to prepare a dilute solution and allowed to stand. The precipitate was confirmed 3 days after standing, and it was confirmed that methanol was completely evaporated after 5 days from standing. Drying under reduced pressure for 30 minutes gave crystals of the compound as a powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and since a result corresponds with FIG.1 and FIG.2, it confirmed that it was an A form crystal | crystallization.

Entry3 Solvent: ethyl acetate Method of evaporating solvent: Method 1
Weigh out the A-form crystal (25 mg) of this compound prepared in Example 1 into a borosilicate glass vial, add ethyl acetate (12.5 mL), and stir while heating to 75 ° C. Prepared and allowed to stand. After 5 hours from standing, the precipitate was confirmed, and after 1 day from standing, the solvent was removed with a Pasteur pipette and dried under reduced pressure for 30 minutes to obtain crystals of the compound as a powder. About the obtained crystal | crystallization, the measurement of powder X-ray diffraction and TG-DTA were performed, and since a result corresponds with FIG.1 and FIG.2, it confirmed that it was an A form crystal | crystallization.

Entry4 Solvent: Tetrahydrofuran Solvent evaporation method: Method 2
Example 9 corresponds to this.

Entry5 Solvent: Methanol Method of evaporation: Method 2
Example 10 corresponds to this.

Entry 6 Solvent: Ethyl acetate Method of evaporating solvent: Method 2
Example 11 corresponds to this.

Entry7 Solvent: Tetrahydrofuran Solvent evaporation method: Method 3
Reference Example 1 corresponds to this.

Entry 8 Solvent: Methanol Method of evaporation: Method 3
The A-form crystal (100 mg) of the compound prepared in Example 1 was weighed into a 50 mL volumetric flask, dissolved in methanol (15 mL), the solvent was distilled off, and the residue was dried under reduced pressure at 0 to 30 ° C. for 30 minutes. Was obtained as a powder. The obtained crystal was subjected to powder X-ray diffraction measurement and coincided with FIG. 9 to confirm that it was a G-type crystal.

Entry9 Solvent: Ethyl acetate Method of evaporating solvent: Method 3
The A-form crystal (29.3 mg) of this compound prepared in Example 1 was weighed into a 200 mL volumetric flask, dissolved in ethyl acetate (150 mL), the solvent was distilled off, and the residue was dried under reduced pressure at 0-30 ° C. for 30 minutes. The crystals of this compound were obtained as a powder. The obtained crystal was subjected to powder X-ray diffraction measurement, and was consistent with FIG.

  As shown in Table 8, even if this compound was the same solvent, it became clear that a different crystal form was obtained if the method of solvent distillation differed.

  The crystal of the present invention can be used as a therapeutic agent or a preventive agent for pharmaceuticals, particularly inflammatory bowel disease, allergic dermatitis, multiple sclerosis or leukemia.

Claims (13)

  (S, E) -2- (2,6-dichlorobenzamido) -5- [4- (isopropyl-pyrimidin-2-ylamino) phenyl] pent-4-enoic acid or a pharmaceutically acceptable salt thereof crystal.   The crystal according to claim 1, which has peaks at diffraction angles 2θ (°) 6.2, 13.3, 17.0, 19.6, 22.2 and 23.0 ° in powder X-ray diffraction.   The crystal according to claim 2, which has a heat absorption peak at 237 to 247 ° C in simultaneous differential thermothermal weight measurement.   In powder X-ray diffraction, peaks at diffraction angles 2θ (°) of 5.7, 6.1, 7.9, 12.2, 12.3, 12.9, 13.4, 16.2, and 17.0 ° The crystal according to claim 1, wherein   In powder X-ray diffraction, it has peaks at diffraction angles 2θ (°) 5.5, 5.9, 7.6, 12.0, 12.5, 13.2, 16.6, and 23.1 °. Item 1. The crystal according to Item 1.   The simultaneous measurement of X-ray diffraction differential scanning calorimetry has peaks at diffraction angles 2θ (°) of 12.0, 13.8, 18.1, 19.3, 19.9, and 22.8 °. crystal.   The crystal according to claim 1, which has peaks at diffraction angles 2θ (°) 11.6, 12.0 and 17.1 ° in powder X-ray diffraction.   The powder X-ray diffraction has peaks at diffraction angles 2θ (°) of 5.7, 6.2, 10.9, 11.5, 13.3, 17.0, and 19.6 °. crystal.   The crystal according to claim 1, wherein the salt is a potassium salt.   In powder X-ray diffraction, it has peaks at diffraction angles 2θ (°) of 4.1, 7.6, 8.2, 8.8, 10.0, 14.2, 15.2, and 19.2 °. Item 10. The crystal according to Item 9.   The crystal according to claim 9 or 10, which is a hydrate crystal.   The pharmaceutical which contains the crystal | crystallization as described in any one of Claims 1-11 as an active ingredient.   A therapeutic or prophylactic agent for inflammatory bowel disease, allergic dermatitis, multiple sclerosis or leukemia, comprising the crystal according to any one of claims 1 to 11 as an active ingredient.

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