WO2003008388A1 - I-form crystal of n-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-n'-propylurea and process for producing the same - Google Patents

Abstract

Crystals of N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-propylurea which are suitable for use in preparing a medicine.

Description

 Specification

N- {2-chloro-1,4-[(6,7-dimethoxy_4-quinazolinyl) oxy] phenyl} -N'-propyl perylene type I crystal and its manufacturing process

 Field of the invention

 The present invention relates to a crystal of N- {2-clomouth-4-1 [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} -N'-propylperia suitable for a pharmaceutical preparation and a method for producing the same. In the research and development of the treatment of diseases such as tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and positron sarcoma, many drugs using various approaches are used in clinical practice. However, treatment with chemotherapeutic agents has problems such as side effects due to the drug and individual differences between patients, and a better drug is desired. Furthermore, considering the QOL (quality 'op' life) of patients, there is a need for a variety of drug administration forms.

 For example, when formulated in tablets, capsules, powders, granules, suspensions, or suppositories, tapes, and ointments for parenteral administration, the drug substance must meet the pharmaceutical requirements. That is, it is required to have a specific crystal form (crystal form) that can realize a formulation that satisfies certain quality and effect expression. In addition, the method of manufacturing the drug substance as a drug must be a method that can be manufactured stably on an industrial scale and a method that is suitable for mass production on an industrial scale.

WO 00/43366 states that N— {2—black mouth—4-1— [6,1 is effective in treating diseases such as tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and positiosarcoma. 7-dimethoxy-14-quinazolinyl) oxy] phenyl} 1-N′-propylperylene and a method for producing the same are disclosed. However, WO 00/43366 states that the crystal form of N- {2-chloro-41-[(6,7-dimethoxy-4'-quinazolinyl) oxy] phenyl} —N'-propyl Not disclosed. Overview of the invention

 The present inventors have found that the crystal form of N— {2-chloro-1,4-[(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} —N′—propylperylene has several polymorphs, One of them was found to have the properties required for pharmaceutical preparations, that is, it was thermodynamically stable and stable to physical and thermal stress.

 The present inventors also dissolve N- {2-chloro-1-4-[(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl] -1-N'-propylurea in an aprotic polar organic solvent. It has been found that the compound can produce a crystal of this compound. The present inventors have further found that crystals can be produced on an industrial scale by adding an alcoholic solvent and stirring after dissolution in an aprotic polar organic solvent. The present invention relates to a crystal of N— {2-cyclomouth—41-[(6,7-dimethoxy—4-quinazolinyl) oxy] phenyl} —N′-propylperia suitable for a pharmaceutical preparation and a method for producing the same. Its purpose is to provide a manufacturing method suitable for industrial production.

 The crystal according to the present invention is a crystal of N— {2-cyclomouth—4 — [(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} ——′- propylperia suitable for pharmaceutical preparation (hereinafter referred to as “I Type crystal).

 The method for producing the type I crystal according to the present invention comprises an aprotic solution prepared by dissolving {-{2-chloro-41-[(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl] -1-N'-propylurea. Comprising a step of precipitating crystals from a polar organic solvent.

The type I crystal according to the present invention is used as a medicament, in particular, a therapeutic agent for a disease selected from the group consisting of malignant tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and power-positive sarcoma. Can be. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a DSC chart of a type I crystal of N— {2-chloro-4 -— [(6,7-dimethoxy—4-quinazolinyl) oxy] phenyl} —N′-propylperrea obtained in Example 1. is there.

 Figure 2 shows the DSC curve of the type II crystal of N- {2-chloro-1-4-[(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} —N'-propylperia obtained in Reference Example 1. It is one.

 Fig. 3 shows the DSC of the type III crystal of N- {2-chloro- 4-([6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} —N'-propylperia obtained in Reference Example 2. It is a chart.

 FIG. 4 is a DSC chart of the type IV crystal of N— {2-chloro-41-[(6,7-dimethoxy—4-quinazolinyl) oxy] phenyl} —N, —propyl-peryl obtained in Reference Example 3. is there.

 Fig. 5 shows the DSC of the V-type crystal of N- {2-chloro-1-4-[(6,7-dimethoxy-4--4-quinazolinyl) oxy] phenyl} -N, -propylperia obtained in Reference Example 4. It is a chart.

 FIG. 6 shows the N- {2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl] —Ν′-propylurea type I crystal obtained in Example 1 after the pulverization treatment. It is a DSC chart.

 Fig. 7 shows the Ν- {2-clocloth-4 — [(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl] —Ν'-propylurea II obtained in Reference Example 1 after the pulverization treatment. It is a DSC chart of a type crystal.

 Fig. 8 shows the type III of Ν- {2-chloro- 4 — [(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —} '-propylurea obtained in Reference Example 2 after the pulverization treatment. It is a DSC chart of a crystal.

 FIG. 9 shows the I of {Ν {2-cloclo—4 — [(6,7—dimethoxy-4-quinazolinyl) oxy] phenyl} —Ν′-propylurea obtained in Example 1 after the heating treatment. It is a DSC chart of a type crystal.

Figure 10 shows the results of Ν— {2—black mouth— 4— [(6, 7-Dimethoxy-14-quinazolinyl) oxy] phenyl} -N'-propylurea is a type II crystal DSC chart.

 FIG. 11 shows the N— {2-cloclo—4-1 [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl] —Ν′-propylurea obtained in Reference Example 2 after the heating treatment. 3 is a DSC chart of the type III crystal. Specific invention of the invention

 I 华 crystal

 The type I crystal according to the present invention can be produced by the method described in Example 1, Example 2, or Example 3. The obtained type I crystal is characterized by exhibiting a powder X-ray diffraction pattern shown in Table 1 of Example 1. The type I crystal according to the present invention is also characterized by exhibiting the differential scanning calorie chart shown in FIG.

 {— {2-chloro-1--4 — [(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —N′-propylurea is not only type I crystal but also type II, III, IV, and It can have a V-shaped crystal form.

 The II type crystal can be produced by the method described in Reference Example 1, and the obtained II type crystal shows the powder X-ray diffraction pattern described in Reference Example 5.

 The III type crystal can be produced by the method described in Reference Example 2, and the obtained III type crystal shows the powder X-ray diffraction pattern described in Reference Example 6.

 The IV type crystal can be produced by the method described in Reference Example 3, and the obtained IV type crystal shows the powder X-ray diffraction pattern described in Reference Example 7.

 The V-type crystal can be produced by the method described in Reference Example 4, and the obtained V-type crystal shows the powder X-ray diffraction pattern described in Reference Example 8.

The results of the differential scanning calorimeter measurement described in Test Example 1 indicate that Form I crystal is a thermodynamically stable crystal form as compared with Form II, Form III, Form IV and Form V crystals. Form I crystals have a single peak (thermal change) on the DSC chart measured by differential scanning calorimetry at a higher temperature (2 3 1) than forms II, III, IV, and V crystals. ~ 235 ° C). In addition, type II, III, IV, and V crystals have peaks that are thought to be derived from phase transition, while type I crystals have Only the endothermic peak due to melting is observed.

 The result of the differential scanning calorimeter measurement described in Test Example 2 shows that the type I crystal is a crystal form that is more stable to physical stress than the type II and type III crystals. Each sample was pulverized in an agate mortar and the sample before and after the treatment was compared on a DSC chart measured by a differential scanning calorimeter. As a result, no change in the peak shape was observed before and after the treatment for the type I crystal. On the other hand, the peak shape of the type I crystal changed before and after the treatment, and the peak shape after the treatment matched the peak shape of the type I crystal. Before and after the treatment, the ratio of the calorific value of the endothermic peak considered to be due to the phase transition to the calorific value of the endothermic peak after the phase transition changed in the III type crystal. From these results, it was suggested that the type I crystal exhibited resistance to physical stress, but that the properties of the type II and II I crystals changed due to the physical stress. i

 The result of the differential scanning calorimeter measurement described in Test Example 3 indicates that the type I crystal is a crystal form that is more stable to thermal stress than the type II and type III crystals. Each sample was placed in a glass container sealed with Teflon (registered trademark) packing and left at 73 ° C for 1 week before and after the treatment. The samples before and after the treatment were compared using a DSC chart measured by a differential scanning calorimeter. . As a result, no change in the peak shape was observed before and after the treatment in type I crystal. On the other hand, the peak pattern of the type I crystal changed before and after the treatment. The peak shape of the I-I type crystal changed before and after the treatment, and the peak shape after the treatment matched the peak shape of the I-type crystal. These results suggest that type I crystals exhibit resistance to thermal stress, but that properties of type II and II I crystals change due to thermal stress.

 When formulating a pharmaceutical compound, a specific crystal form that can maintain a certain quality of the pharmaceutical compound and exhibit a certain effect, that is, it is thermodynamically stable and physically and thermally It is required to be formulated in a crystal form that is stable against stress. The type I crystal according to the present invention is thermodynamically stable, exhibits resistance to physical stress, and exhibits resistance to thermal stress. . The properties of this type I crystal have the properties required for the crystalline form of a pharmaceutical compound formulated as a pharmaceutical preparation.

^ Notice of T In the production method according to the present invention, a non-proton polar solvent in which N- {2-chloro-41-[(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl] -1-N'-propylurea is dissolved Form I crystal can be precipitated from N- {2-chloro-1-4-((6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —N′-propylurea by about 60%. A type I crystal can be precipitated by dissolving in a nonprotonic polar organic solvent in a temperature range from ° C to the boiling point, and then cooling the solvent, preferably to room temperature.

 The aprotic polar organic solvent is about 5 times to about 50 times that of N— {2 —clo— 4— [(6,7-dimethoxy—4-quinazolinyl) oxy] phenyl} — N '—propylperyl It can be an amount of times V / W, preferably about 10 to about 20 times VZW.

 The aprotic polar organic solvent can preferably be N, N-dimethylformamide or N, N-dimethylacetamide. More preferably, N, N-dimethylformamide or N, N-dimethylacetamide in a temperature range of about 80 to about 100 ° C. is added in an amount of about 10 to about 20 times VZW. it can. In the production method according to the present invention, a crystal is produced in good yield by adding an alcoholic solvent after the precipitation step from the aprotic organic solvent, preferably by adding the alcoholic solvent and stirring. be able to. The alcoholic solvent is N— {2-chloro—4 — [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} 1-N'-propyl-peryl about 5 times to about 50 times V / W, preferably about 10 to about 30 times V / W.

 An alcoholic solvent is one in which one or more hydrogens of a hydrocarbon have been replaced by hydroxyl groups, and may be methanol, ethanol, 1-propanol, 2-propanol, or butanol, preferably methanol. it can. More preferably, methanol can be added in an amount of about 10 to about 30 times V / W.

 In the production method according to the present invention, N, N-dimethylformamide is preferably used as the aprotic polar organic solvent, and methanol can be used as the alcoholic solvent.

In the production method according to the present invention, 1 kg scale (Example 1), 3 g scale (Example 2) It is possible to stably produce I-type crystals on large and small scales. Further, the yields of the crystallization step are 92% (Example 1) and 90% (Example 2), and are stable and high in large and small scales.

 The method described in Example 3 is different from the methods of Examples 1 and 2 in that an alcoholic solvent is not added and stirring is performed. By this method, type I crystals can be obtained with a yield of 50%.

 The methods described in Reference Examples 1 and 3 are based on N- {2-chloro-41-[(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl] —N'-propylurea, 10 times V / W pyridine. This is a crystallization method in which the solution dissolved by heating to the boiling point of the solvent is stirred and cooled. In this production method, on the 22 g scale, EI type crystal (Reference Example 1) was obtained, and on the lg scale, type IV crystal (Reference Example 3) was obtained. In these production methods, the morphology to be crystallized changed due to the difference in scale.

 The method described in Reference Examples 2 and 4 is as follows: N— {2-—Mouth—4 — [(6,7-Dimethoxy-4-quinazolinyl) succinyl] phenyl} —N′-propylurea 150-170 times This is a crystallization method in which a solution dissolved in V / W 2-propanol by heating to the boiling point of the solvent is stirred and cooled. In this production method, II-I type crystals (Reference Example 2) were obtained on the 22 g scale, and V-type crystals (Reference Example 4) were obtained on the 2 g scale. In these production methods, the crystal morphology to be crystallized changed due to the difference in scale.

 Use of T-type crystals / Chemicals

 N— {2—Black mouth 41-1 [(6,7-Dimethoxy-4-quinazolinyl) oxy] phenyl} _Ν'-Propylurea is a tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, atheromatous It is effective for the treatment of arteriosclerosis, cystic sarcoma, and metastasis of solid cancer (see WO 00/43366). Therefore, type I crystals of —— {2—clo mouth—4 — [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} —Ν′—propylperrea are malignant tumors, diabetic retinopathy, rheumatoid arthritis, It is effective in treating psoriasis, atherosclerosis, positron sarcoma, and metastasis of solid cancer.

According to the present invention there is provided a pharmaceutical composition comprising a Form I crystal according to the present invention. Pharmaceutical compositions according to the present invention include malignant tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, It can be used to treat atherosclerosis, cystic sarcoma, and metastasis of solid cancer.

 According to the present invention, there is also provided a method for administering a type I crystal according to the present invention to a mammal together with a pharmaceutically acceptable carrier, which comprises a malignant tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, and atherosclerotic artery. Treatments for sclerosis, cystic sarcoma, and metastasis of solid cancers are provided.

 The type I crystal according to the present invention can be administered to humans and non-human animals by any of oral and parenteral (for example, rectal and transdermal) administration methods. Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is formulated into an appropriate dosage form according to the administration route.

 Specifically, the oral preparations include tablets, capsules, powders, granules and suspensions, and the parenteral preparations include suppositories, tapes, ointments and the like. These various preparations can be produced by a conventional method using commonly used excipients, disintegrants, binders, lubricants, coloring agents, diluents and the like.

 Excipients include, for example, lactose, pudose, corn starch, sorbitol, crystalline cellulose, and the like.Disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, and the like. For example, dimethylcellulose, polyvinyl alcohol, polyvinylether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone, etc., as lubricants, for example, talc, magnesium stearate, Examples include polyethylene glycol and hydrogenated vegetable oil.

 In the pharmaceutical composition according to the present invention, the content of the compound according to the present invention varies depending on the dosage form, but is usually 0.5 to 50% by weight, preferably 1 to 20% by weight in the whole composition. is there.

The dosage is appropriately determined depending on the individual case in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, etc., for example, 0.1 to 100 mg / kg, preferably Is in the range of 1 to 5 O mg g Kg, which is administered once or several times a day. The type I crystals according to the invention can be administered in combination with other medicaments. Administration can be simultaneous or sequential. For example, when the target disease is malignant tumor, the compound according to the present invention can be used to regress a tumor, and then the tumor can be effectively eliminated by administering an anticancer drug. The type and administration interval of the anticancer drug can be determined depending on the type of cancer, the condition of the patient, and the like. Diseases other than malignancy can be treated similarly.

 According to the present invention, there is further provided a method for treating the type I crystal of the present invention by bringing the same into contact with a tissue causing a disease (eg, tumor tissue, retinopathy tissue, rheumatoid arthritis tissue). The contact of the compound according to the present invention with a tissue causing a disease can be carried out, for example, by systemic administration (such as oral administration) or topical administration (such as transdermal administration). Example

Production example: N— · Γ2—Black mouth 4-— ((6.7-Dimethoxy-4-quinazolinyl) oxy-phenyl) — Production of N'-propyl-peryl

 (1) Cyclization step

メチル 2—ァミノ一 （4， 5—ジメトキシ） ベンゾエート (750. 0 g) にホルムアミ ド （ 5250ml) を加え、 150〜 155°Cにて 12時間攪拌し た。 室温まで放冷し、 3時間攪拌した後、 5°Cにて 3時間攪拌した。 析出物を濾 過し、 水 （1500ml).にて洗浄した。 濾過物を減圧乾燥して、 6, 7—ジメ トキシ一 4—キナゾロン （670. 4 g) を取得した。 （収率 =91. 6%) — NMR (400MH z , DMS 0— d₆/ppm) ； 7. 97 ( 1 H, s) 、 7. 43 ( 1 H, s) 、 7. 12 (1H, s) 、 3. 89 (3H, s) 、 3. 86 (3H, s) (2) クロ口化工程

Formamide (5250 ml) was added to methyl 2-amino (4,5-dimethoxy) benzoate (750.0 g), and the mixture was stirred at 150 to 155 ° C for 12 hours. After allowing to cool to room temperature and stirring for 3 hours, the mixture was stirred at 5 ° C for 3 hours. The precipitate was filtered off and washed with water (1500 ml). The filtrate was dried under reduced pressure to obtain 6,7-dimethoxy-14-quinazolone (670.4 g). (Yield = 91.6%) — NMR (400 MHz, DMS 0—d ₆ / ppm); 7.97 (1H, s), 7.43 (1H, s), 7.12 (1H, s), 3.89 (3H, s), 3.86 (3H, s) (2) Closing process

6, 7-dimethyl butoxy one 4- quinazolone a (670. 4 g) in toluene (3350 ml) and POC 1 ₃ (86 1), and stirred for 5 hours 7. at reflux. ice

(15 kg) and a 48% aqueous NaOH solution (1982 g) were added to the reaction solution so that the temperature did not exceed 15 ° C. The reaction solution (suspension) was filtered, and the cake collected by filtration was washed with water (2 L). The cake collected by filtration was repulped and washed with water (6.5 L) for 30 minutes, filtered, and washed with water (2 L). The filtrate was dried under reduced pressure to obtain 4-chloro-6: 7-dimethoxyquinazoline (69.2.lg). (Yield = 94.7%) — NMR (400 MHz, DMS 0-d ₆ / ppm); 8.86 (1 H, s), 7.43 (1 H, s), 7.37 (1 H, s), 4.00 (3H, s), 3.98 (3H, s)

 (3) Phenol site introduction process

48% NaOH aqueous solution (25 96 g) in water (2110 m 1), 4-amino-3-chloro phenol 'HC 1 (644 g), 2-butynone (1 380 ml), 4 chlor One 6,7-dimethoxyquinazoline (692.1 g), tetrabutylan Monidopromide (192 g) was added, and the mixture was stirred at reflux for 2 hours. After the reaction, 2-butane was distilled off. After filtration, the residue was washed with water (12 L). The cake was washed with methanol (140 Oml). The filtrate was dried under reduced pressure to obtain 4-[(4-amino-3-chlorophenyl) oxy] -6,7-dimethoxyquinazoline (944.6 g). (Yield = 92.4%)

— NMR (400 MHz, DMS 0-d ₆ / ppm); 8.52 (1 H, s), 7.50 (1 H, s), 7.35 (1 H, s), 7.20 (1 H, d, J = 2.68 Hz) 6.98 (1 H, dd, J = 2.68, 8.78 Hz), 684 (1 H, d, J = 8.78 Hz) ), 5.33 (2 H, brs), 3.97

(3H, s), 3.95 (3H, s)

 (4) Urea conversion ''

4-[(4-Amino-3-chlorophenyl) oxy] —6,7-dimethoxyquinazoline (944.6 g) plus N, N-dimethylacetamide (4720 ml), pyridine (1350 g), Phenyl carbonate (888 g) was added, and the mixture was stirred at room temperature for 2 hours. n-Propylamine (7 19 g) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Methanol (924 Oml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 5 ° C overnight. After the precipitate was collected by filtration, the precipitate was washed with methanol (1900 ml). The filtrate was dried under reduced pressure to give the title compound (1.098 Kg). (Yield = 92.5%)

— NMR (DMSO— d ₆ , 40 OMH z): δ 0.91 (t, J = 7. 1Z

3 Hz, 3H), 1.41-1.53 (m, 2H), 3.05-3.12 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.99 (t, J = 5.4Hz, 1H), 7.22 (dd, J = 2.7Hz, 9.0Hz, 1H), 7.38 (s, 1 H), 7. 46 (d, J = 2. 9 Hz 3 1 H), 7. 54 (s, 1 H), 8. 04 (s, 1 H), 8. 20 (d, J = 9.3 Hz, 1 H), 8.55 (s, 1 H)

 Mass spectrometry value (ESI-MS, m / z): 4 17 (M ++ 1) Example 1: Production of T crystal (NN-ditylformamide '+ methanol medium) Produced as described in Production Examples N— {2-—Mouth—4 — [(6,7—Dimethoxy—4-quinazolinyl) oxy] phenyl} —Ν′—Propylurea (1,098 g) is converted to N, N—dimethylformamide (11 L) was heated to 80 ° C. to dissolve, and the solution was stirred and cooled to room temperature, then methanol (22 L) was added, and the mixture was stirred at room temperature for 2 hours. After solid-liquid separation by filtration, the wet crystal was dried under reduced pressure at 60 ° C. to obtain a crystal (1.010 g).

 Using a powder X-ray diffractometer (X-ray diffraction RINT DMAX-2000, manufactured by Rigaku Denki Co., Ltd.), use Cu-α radiation (40 kV, 40 mA, S = 1.541 A) as described above. The X-ray diffraction pattern of the obtained crystal was measured (scan speed: 5./min, scanning range: 5.000 to 40.000 °, filter: K filter).

Table 1 shows the peak positions and relative intensities (%) of the peaks having a relative intensity of> 20% in the crystal obtained in Example 1.

2 θ relative intensity (> 20%)

 6. 99 66

 10. 25 100

 14. 02 39

 14. 97 45

 16. 68 84

 20.03 44

 20. 61 41

 23. 55 40

 25.63 23

 26.91 29

 28. 29 36 蓥 Example 2: Preparation of Τ-type crystal (Ν. Ν—dimethylformamide + methanol ^ vehicle) Ν— {2-chloro-1--4-((6,7-dimethoxy-1-4-) Quinazolinyl) oxy] phenyl} —Ν'-Propylurea (3.0 g) was dissolved in N, N-dimethylformamide (30 ml) by heating to 80 ° C, and the solution was allowed to reach room temperature. After cooling with stirring, methanol (60 ml) was added, and the mixture was stirred at room temperature for 2 hours. After solid-liquid separation by filtration, the wet crystals were dried under reduced pressure at 60 ° C to obtain crystals (2.7 g). As a result of measuring the powder X-ray diffraction pattern of the obtained crystal, it was confirmed that the crystal was an I-type crystal (details omitted). Example 3: Production of T-type crystal (N-N-dimethylacetamide catalyst)

N— {2-—Mouth—4 — [(6,7-Dimethoxy-14-quinazolinyl) oxy] phenyl} —Ν′—Propylurea (1.0 g) is added to N, N-dimethylacetamide ( (10 ml) was heated to 150 ° C. and dissolved, and the solution was stirred and cooled to room temperature, and further stirred at room temperature overnight. After solid-liquid separation by filtration, the solid content was washed with N, N-dimethylacetamide (4 ml), and the wet crystal was dried at 60 ° C. under reduced pressure to obtain a crystal (0.5 g). The obtained results of measurement of the powder X-ray diffraction pattern of the crystals, probability ¾ ^r to be a I-form crystal, the (de Isseki omitted). Participant example 1: Production of T T¾J crystal

 N— {2-Chloro-4-1 [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} —N′-propylurea (22.0 g) was heated to reflux temperature in pyridine (220 m 1). After dissolution, the solution was stirred and cooled to room temperature, and further stirred at room temperature for one hour. After solid-liquid separation by filtration, the solid content was washed with pyridine (30 ml), and the diet crystal was dried under reduced pressure at 60 ° C to obtain II type crystal (17.4 g). Example 2: Report of Τ Τ Τ¾ΰ

 Ν— {2_chloro-1-4-((6,7-dimethoxy-4-quinazolinyl) oxy] phenyl} — ヱ '-Propylurea (22.0 g) is refluxed into 2-propanol (3.75 L) After warming to a temperature and dissolving, the solution was stirred and cooled to room temperature, and further stirred at 5 ° C overnight. After solid-liquid separation by filtration, the wet crystals were dried under reduced pressure at room temperature to obtain II I type crystals (21.6 g). Example 3: Production of TV type crystal

 N— {2-chloro-1-4-[(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —N'-propylurea (1.0 g) is heated to reflux temperature in pyridine (10 ml). Then, the solution was stirred and cooled to room temperature, and further stirred at room temperature overnight. After solid-liquid separation by filtration, the ether crystal was dried under reduced pressure at 60 ° C. to obtain a type IV crystal (0.8 g). Participant example 4: Production of V-type crystal

N— {2-chloro-4 -— [(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —Reflux N, 1-propylurea (2.0 g) to 2-propanol (300 ml) After heating to dissolve, the solution was stirred and cooled to room temperature, and further stirred at 5 ° C. for one hour. After solid-liquid separation by filtration, the wet crystal was dried under reduced pressure at room temperature to obtain a V-type crystal (1.5 g). Example 5: TT¾J crystal powder X-ray diffraction ^!

 The powder X-ray diffraction pattern was measured under the same conditions as in Example 1. .

 Table 2 shows peak positions and relative intensities (%) of peaks having a relative intensity of> 35% in the type II crystal obtained in Reference Example 1.

 Table 2

Example 6: T T T¾j crystal powder X source 间: {ff ^ l

 The powder X-ray diffraction pattern was measured under the same conditions as in Example 1.

 Table 3 shows the peak positions and relative intensities (%) of peaks having a relative intensity of> 30% in the II type I crystal obtained in Reference Example 2.

 Table 3

 2 Θ relative strength (> 30%)

 7.42 56

 7.88 100

 9. 66 54

 10. 49 32

 10.6 1 35

 14. 58 57

 14. 81 56

15. 16 55 尜 Example 7: Powder removal of TV-type crystal X 綈 ιιι 折 ^!

 The powder X-ray diffraction pattern was measured under the same conditions as in Example 1.

 Table 4 shows that the crystals having a relative intensity of> 50% in the type IV crystal obtained in Reference Example 3 were obtained.

The peak position and relative intensity (%) are shown.

 Table 4

 2 Θ Relative strength (> 50%)

 6. 26 100

1 1.93 72

14. 75 56

15. 12 82

16. 13 60

2 1.12 55

22. 1 9 62

22. 77 58

23. 19 54

23. 28 55

23. 66 56

24.49 63

24.63 63

24. 81 5 1

25. 58 55

25. 75 67

25.92 76

26.48 54

Participant example 8: V¾J crystal! ^ Main X bundle [I ^ I l

 The powder X-ray diffraction pattern was measured under the same conditions as in Example 1.

 Table 5 shows peak positions and relative intensities (%) of peaks having a relative intensity of> 20% in the V-type crystal obtained in Reference Example 4.

 Table 5

 2 Θ relative strength (> 20%)

 7. 58 45

7.90 100

14. 13 36

1 5. 18 52

22. 16 27

24. 24 33

ΜΜ 1 ： Difference 击

 Using a differential scanning calorimeter (Pyr isl manufactured by PerkinElmer Inc.), place l to 5 mg of sample in an aluminum shallow dish container and measure (under nitrogen stream, heating rate: 5 ° C / min, measurement range 30 ° C-250 ° C). The results were as shown in FIGS. umm? ,: Ni ϋ ^ ¾ ^ ι¾¾ΐί no ^^ J

 For crushing with a mortar, 50 Omg of each sample was ground in an agate mortar. The DSC chart measurement of the sample before and after pulverization by a differential scanning calorimeter was performed under the same conditions as in Test Example 1. The results were as shown in FIGS. mm 3: rn um (7 ° oma ま tn)> sc chart measurement.

 1.2 g of each sample was placed in a glass container and sealed with Teflon (registered trademark) packing. This was left for one week in a thermostat set at 73 ° C. The DSC chart measurement by a differential scanning calorimeter of the sample before and after the treatment was performed under the same conditions as in Test Example 1. The results were as shown in FIGS.

Claims

The scope of the claims 1. Crystals of N- {2-chloro-1-4-((6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} 1-N'-propyl-peryl suitable for pharmaceutical preparations.  2. The crystal according to claim 1, which exhibits the following diffraction angle (20) and relative intensity in powder X-ray diffraction using Cu-Kor radiation.  table 1

3. The crystal according to claim 1 or 2, wherein a single peak at 231 to 235 is observed in a DSC chart measurement by a differential scanning calorimeter.  4. N- {2-chloro-4-1 [(6,7-dimethoxy-4-quinazolinyl) oxy] phenyl] -1-N'-propylurea dissolved in aprotic polar organic solvent A method for producing a crystal of N— {2-chloro—41-[(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} —Ν′-propylurea.  5. The process of precipitating the crystals is as follows. The production method according to claim 4, comprising a step of dissolving in an aprotic polar organic solvent in a temperature range up to and then cooling the solvent. 6. When the aprotic polar organic solvent is N- {2-chloro- 4— [(6,7-dimethoxy-4-quinazolinyl) thioxy] phenyl} — N'-propyl The method according to claim 4, wherein the amount is about 5 times to about 50 times V / W.  7. The aprotic polar organic solvent is N, N-dimethylformamide or N, N-dimethylacetamide, in a temperature range of about 80 ° C to about 100 ° C, and N— { 2-—Mouth 4 -— [(6,7-Dimethoxy-1-quinazolinyl) oxy] phenyl} —N / V-W The method according to any one of claims 4 to 6, characterized in that:  8. The method according to any one of claims 4 to 7, further comprising a step of adding an alcoholic solvent after the step of precipitating crystals.  9. Alcoholic solvent is added about 5 times to about 50 times with respect to N— {2-chloro- 4 — [(6,7-dimethoxy—4-quinazolinyl) oxy] phenyl} 9. The production method according to claim 8, wherein the addition is performed in an amount of twice VZW.  10. The alcoholic solvent is methanol, and about N- {2-chloro-4-1-[(6,7-dimethoxy-14-quinazolinyl) oxy] phenyl} -N'-propyl The method according to claim 8 or 9, wherein the addition is performed in an amount of 10 to about 30 times VZW.  11. The process according to any one of claims 8 to 10, wherein the aprotic polar organic solvent is N, N-dimethylformamide and the alcoholic solvent is methanol. Law.  12. N- {2-chloro-4-[(6,7-dimethoxy-14-quinazolinyl) oxy] which can be obtained by the production method according to any one of claims 4 to 11. Fe-nil} — N'-propyl perylene crystals.  13. A pharmaceutical composition comprising the crystal according to claim 1, 2, 3, or 12.  14. The pharmaceutical composition according to claim 13, which is used for treating malignant tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, or positron sarcoma. 15. For the manufacture of a medicament for the treatment of malignant tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, or positron sarcoma, claims 1, 2, 3, Or use of the crystal according to 12.  16. Malignant tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, comprising administering to a mammal a therapeutically effective amount of the crystal of claim 1, 2, 3, or 12. How to treat atherosclerosis or positron sarcoma.