HK1130060B

HK1130060B - Novel crystal of substituted phenylalkanoic acid and production process

Info

Publication number: HK1130060B
Application number: HK09110023.1A
Authority: HK
Inventors: 有本雄一; 石井尚之; 正田基
Original assignee: 旭化成制药株式会社
Priority date: 2006-07-20
Filing date: 2007-07-12
Publication date: 2013-01-25

Description

Novel crystal of substituted phenylalkanoic acid and process for producing same

Technical Field

The present invention relates to novel crystals. More particularly, the present invention relates to 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, novel crystals of any of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate and methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate, and processes for producing the crystals.

Background

It has been reported that 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid has a prostaglandin production inhibitory effect and a leukotriene production inhibitory effect, and therefore, these compounds are useful for the prevention and/or treatment of various inflammatory diseases, autoimmune diseases, allergic diseases, and pain caused by lipid mediators, and a method for producing these compounds are disclosed.

Patent document 1: WO No. 03/70686

Disclosure of Invention

It is an object of the present invention to provide a more preferred embodiment and an improved method when using the present compounds as medicaments.

According to the above known production method, 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid (hereinafter, sometimes referred to as "present compound 1") of present compound 1 is obtained as follows: to a methanol solution of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate was added a 2N aqueous sodium hydroxide solution, the mixture was stirred at 60 ℃ for 16 hours, the reaction mixture was concentrated under reduced pressure, the mixture was made acidic with a 5% aqueous hydrochloric acid solution under ice cooling, extracted with ethyl acetate, the organic layer was washed with a saturated saline solution, dried, and the solvent was distilled off under reduced pressure to obtain compound 1 of the present embodiment. In the known production method, the compound of the present invention is obtained as a colorless to brown oily substance. The present inventors have considered that, when the compound 1 is administered as a drug, a new improvement for facilitating the operation is required, and have made various studies to confirm that the compound 1 is crystallized, thereby completing the present invention.

The present invention provides crystals of the present compound 1, and therefore, it is extremely advantageous in that the operation in the formulation step is facilitated and the content of the present compound in each formulation is easily made uniform. Further, the crystals of the present compound are also extremely advantageous in that they can be easily removed from a solvent and the like, can completely remove the solvent and the like, and are suitable for industrial-scale production, as compared with the case of an oily substance.

Further, the present inventors have conducted intensive studies on the above crystals, and as a result, they have found that there are novel a-type crystals and B-type crystals exhibiting the properties described later in the present compound 1, and that they have excellent properties, respectively, and have established a method for selectively obtaining these crystals, thereby completing the present invention.

Further, according to the above known production method, methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate (hereinafter, sometimes referred to as "present compound 2") was obtained as follows: after 2M aqueous sodium carbonate, toluene, and palladium (0) triphenylphosphine were added to an ethanol solution of methyl 3- (3-bromo-4-hydroxy-5-nitrophenyl) propionate and 1-methyl-1H-indazole-5-boronic acid, and the mixture was stirred at 80 ℃ for 16 hours, ethyl acetate was added to the reaction mixture, followed by washing with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and a saturated saline solution in this order, drying the organic layer, removing the solvent by distillation under reduced pressure, and purifying the residue by flash column chromatography, compound 2 of the present invention was obtained. The known production methods do not at all mention the form of the compounds of the present application. In the known manufacturing method, it cannot be said that the handling operation at the time of manufacturing is always easy. The present inventors have also confirmed that there are problems in terms of uniformity of the content and ease of removal of solvents and the like when the compound 2 of the present invention is used as a pharmaceutical. Further, the present inventors have confirmed that compound 2 of the present invention can be obtained as a novel crystal, and have completed the present invention.

Further, according to the above known production method, methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate (hereinafter, sometimes referred to as "present compound 3", and sometimes referred to as "present compound 1", "present compound 2", and "present compound 3" in combination as "present compound") is obtained as follows: raney 2800 nickel (Raney nickel) was added to the ethyl acetate/methanol mixed solution of the present compound 2, and after stirring at room temperature for 6 hours under a hydrogen atmosphere, the reaction mixture was filtered, the solvent of the filtrate was distilled off under reduced pressure, and then the residue was purified by column chromatography to obtain the present compound 3. The known production method does not mention the form of the compound 3 of the present invention at all, and it cannot be said that the handling operation in the production is always easy. The present inventors have also confirmed that the compound 3 of the present invention has problems in terms of uniformity of content and ease of removal of solvents and the like when it is used as a pharmaceutical. Further, the present inventors have confirmed that compound 3 of the present invention can be obtained by forming a novel crystal, and have completed the present invention.

That is, the present invention is as follows.

(1) A crystal which is methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propanoate, methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propanoate, or 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid methyl ester.

(2) A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid.

(3) A crystal which is a crystal of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate.

(4) A crystal which is a crystal of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate.

(5) The crystal according to the above (1) or (2), which is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and which is a form A crystal having 1 or more characteristic peaks at least at 2 θ of 6.9. + -. 0.2 °, 16.4. + -. 0.2 °, 18.2. + -. 0.2 °, 25.0. + -. 0.2 ° or 27.5. + -. 0.2 ° in a powder X-ray diffraction spectrum.

The 2 θ angle in the powder X-ray diffraction spectrum may have some measurement errors that are tolerable due to various factors, and the actual measurement value may vary to the extent of usually ± 0.3 °, typically ± 0.2 °, and more preferably ± 0.1 ° in the measurement. Therefore, in the present specification, the 2 θ angle based on the measured value for a specific sample is understood to mean including these allowable errors.

(5-1) the crystal according to the above (1), (2) or (5), characterized in that the crystal is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and the crystal is a type A crystal having characteristic peaks at 2 θ of 6.9. + -. 0.2 °, 14.4. + -. 0.2 °, 16.4. + -. 0.2 °, 18.2. + -. 0.2 °, 25.0. + -. 0.2 ° and 27.5. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(6) The crystal according to the above (1), (2), (5) or (5-1), which is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and which is a type A crystal having an endothermic peak at about 182 ℃ in differential scanning calorimetry (temperature rising rate of 10 ℃/min).

It should be noted that an endothermic peak in differential scanning calorimetry is an inherent physical property of the crystal of the present compound, but in actual measurement, in addition to measurement errors, a melting point may vary due to incorporation of an allowable amount of impurities or the like, and this possibility cannot be denied. Therefore, the skilled person can fully understand how the actual measurement value of the endothermic peak temperature in the present invention may vary, and for example, the error is assumed to be about ± 5 ℃ in some cases, typically about ± 3 ℃, and about ± 2 ℃ in a preferable measurement.

(7) The crystal according to the above (1), (2), (5-1) or (6),the crystal is prepared from 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl]Propionic acid, and the crystal is an A-type crystal which is 3361cm at a wave number in an infrared absorption spectrum^-1、2938cm^-1、1712cm^-1、1204cm^-1、1011cm^-1And 746cm^-1With a distinct infrared absorption band in the vicinity.

Note that some measurement errors are allowable in the infrared absorption spectrum wavenumber, and it is considered that such errors are included in the present invention. The degree of the error can be fully understood by those skilled in the art, for example, referring to the European pharmacopoeia (ョ - ロッパ)4 th edition, which indicates the degree of error that is consistent within ± 0.5% of the wave number scale value (wave number スケ - ル) compared to a reference spectrum in a confirmation test using infrared absorption spectroscopy. In the present invention, although this is not particularly limited, the error that is generally considered can be referred to, and for example, as one scale, the variation of the measured value with respect to the wave number scale value is about ± 0.8%, preferably about ± 0.5%, and particularly preferably about ± 0.2%.

(7-1) the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (5) to (7), wherein the crystal purity of the crystal is at least 90% by weight or more.

In the above sections, (5) to (7) are written, but they are the meanings of the invention including the branch numbers in the order of arrangement, and specifically, (5) to (7) are (5), (5-1), (6) and (7). The same applies hereinafter.

(8) The crystal according to the above (1) or (2), which is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and which is a B-form crystal having 1 or more characteristic peaks at least at 2 θ of 15.9. + -. 0.2 °, 17.3. + -. 0.2 °, 22.2. + -. 0.2 ° or 22.9. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(8-1) the crystal according to the above (1), (2) or (8), characterized in that the crystal is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and the crystal is a B-type crystal having characteristic peaks at 2 θ of 14.4. + -. 0.2 °, 15.9. + -. 0.2 °, 17.3. + -. 0.2 °, 22.2. + -. 0.2 ° and 22.9. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(9) The crystal according to the above (1), (2), (8) or (8-1), which is composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and which is a B-form crystal having an endothermic peak at about 203 ℃ in differential scanning calorimetry (temperature rising rate of 10 ℃/min).

(10) The crystal according to the above (1), (2), (8-1) or (9), which is characterized by comprising 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl]Propionic acid, and the crystal is a B-type crystal having a wave number of 2939cm in an infrared absorption spectrum^-1、1720cm^-1、1224cm^-1、1016cm^-1And 751cm^-1With a distinct infrared absorption band in the vicinity.

(10-1) the crystal form B of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of (8) to (10), wherein the crystal purity is at least 90% by weight or more.

(10-2) the crystal according to the above (1) or (3), characterized in that the crystal is composed of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate, and the crystal has 1 or more characteristic peaks at least at 2 θ of 7.6 ° ± 0.2 °, 15.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 21.3 ° ± 0.2 ° and 26.9 ° ± 0.2 ° in a powder X-ray diffraction spectrum.

(10-3) the crystal according to the above (1), (3) or (10-2), which is characterized by consisting of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate having characteristic peaks at 2 θ of 7.6. + -. 0.2 °, 15.3. + -. 0.2 °, 18.0. + -. 0.2 °, 21.3. + -. 0.2 ° and 26.9. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(10-4) the crystal according to the above (1) or (4), which is composed of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate and which has 1 or more characteristic peaks at least at 2 θ of 8.6. + -. 0.2 °, 12.7. + -. 0.2 °, 17.2. + -. 0.2 °, 17.6. + -. 0.2 °, 18.9. + -. 0.2 ° and 21.0. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(10-5) the crystal according to the above (1), (4) or (10-4), which is characterized by consisting of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate having characteristic peaks at 2 θ of 8.6. + -. 0.2 °, 12.7. + -. 0.2 °, 17.2. + -. 0.2 °, 17.6. + -. 0.2 °, 18.9. + -. 0.2 ° and 21.0. + -. 0.2 ° in a powder X-ray diffraction spectrum.

(11) A pharmaceutical composition comprising the crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid or the crystal form A or the crystal form B, or the crystal of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate according to any one of the above-mentioned items (1) to (10-5), or the crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-) Any one of the crystals of 5-yl) phenyl ] propionic acid methyl ester as an effective ingredient, and the pharmaceutical composition further contains a pharmaceutically acceptable carrier.

(12) The pharmaceutical composition according to the above (11), wherein the pharmaceutically acceptable carrier is a dried product, and the pharmaceutical composition is a dried preparation.

(13) A pharmaceutical composition comprising, as an active ingredient, form A crystal having a crystal purity of at least 90% by weight, which is 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (5) to (7), and a pharmaceutically acceptable carrier.

(14) A pharmaceutical composition comprising, as an active ingredient, form B crystal having a crystal purity of at least 90% by weight, which is 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (8) to (10), and a pharmaceutically acceptable carrier.

(15) A process for producing the type A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (5) to (7-1), which comprises adding an acid to a solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid in an alkaline condition to produce the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) propionic acid Phenyl) -propionic acid, and then obtaining the crystal.

(16) The process for producing the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to the above (15), wherein the solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid in an alkaline condition is a solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid in the alkaline hydrolysis reaction, and the solution is obtained by subjecting the mixture to alkaline hydrolysis A compound (I) is provided.

(16-1) A crystal form A of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (5) to (7-1), which is characterized in that a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid is subjected to a basic hydrolysis reaction, and then an acid is added to the reaction mixture to produce the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-yloxy) -propionic acid Crystals of H-indazol-5-yl) -phenyl ] propionic acid were formed and then obtained.

(17) The process for producing the B-form crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of the above (8) to (10-1), wherein 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid is dissolved in one or more solvents selected from the group consisting of acetone, dichloromethane, methanol, ethyl acetate, a methanol/acetic acid mixture and acetonitrile, and the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid crystallized.

(18) The method for producing a crystal according to any one of (8) to (10-1) above, characterized in that an acid is added to a solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid under basic conditions, immediately before the formation of the crystal formed from the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid, the form B crystal of the compound is added as a seed crystal, thereby obtaining the form B crystal of the compound.

(18-1) the process for producing form B crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to the above (18), wherein the solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid in an alkaline condition is a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid An alkaline hydrolysate.

(18-2) the process for producing a crystal according to any one of the above (8) to (10-1), wherein after the basic hydrolysis reaction of the lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, an acid is added to the reaction mixture, and a B-type crystal of the compound is added as a seed crystal to the reaction mixture immediately before the crystal composed of the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid is produced, thereby obtaining form B crystals of the compound.

(19) A process for producing a crystal of methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate, which comprises dissolving methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate in one or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane and methanol, and adding a solvent selected from the group consisting of heptane, diisopropyl ether, isopropanol, tert-butyl methyl ether, ethyl acetate, methyl acetate, and methyl acetate to the solution obtained by dissolving the above solvents, Water, and a solvent selected from the group consisting of water, and water.

(19-1) the production method according to the above (19), wherein the crystal has at least 1 or more characteristic peaks in the powder X-ray diffraction spectrum, wherein 2 θ is 7.6. + -. 0.2 °, 15.3. + -. 0.2 °, 18.0. + -. 0.2 °, 21.3. + -. 0.2 ° and 26.9. + -. 0.2 °, typically the crystal has all of these peaks.

(20) A process for producing a crystal of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate, which comprises dissolving methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate in one or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran and acetone, adding one or more solvents selected from the group consisting of heptane, isopropanol, methanol and water to the solution obtained by dissolving the methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionate in the other solvent, crystals are formed.

(20-1) the production method according to the above (20), wherein the crystal has at least 1 or more characteristic peaks in a powder X-ray diffraction spectrum, wherein 2 θ is 8.6. + -. 0.2 °, 12.7. + -. 0.2 °, 17.2. + -. 0.2 °, 17.6. + -. 0.2 °, 18.9. + -. 0.2 ° and 21.0. + -. 0.2 °, typically the crystal has all of the peaks.

The crystals of the present compound 1 have a great advantage in the process of preparation, for example, the content of the present compound in each preparation can be easily made uniform, and the crystals are advantageous in that the solvent and the like can be easily removed as compared with the case of an oily substance, and are suitable for industrial-scale production.

As the crystal of the present compound 1 used in a specific embodiment of the present invention, an a-type crystal is cited as a preferable example. The a-type crystal of the compound 1 of the present embodiment is a crystal defined by any one or a combination of two or more of the following various characteristics, which are confirmed in the above-described technical aspects (5) to (7-1) or in the examples, experimental examples and the like of the present specification. It was confirmed that, in addition to the advantages of the crystals of compound 1 of the present invention, the a-type crystals exhibit certain properties and thus exhibit excellent properties not only in the pharmaceutical preparation or the pharmaceutical effect but also in the production process, etc., as compared with the conventional crystals which are not controlled. The above-mentioned type a crystal is also preferable from the viewpoint that it has higher solubility in an aqueous solvent than, for example, the type B crystal described later.

In order to maximize the excellent effects of the a-type crystal, it is preferable to use the a-type crystal which is substantially the a-type crystal, and the a-type crystal has a crystal purity (percentage) of usually about 90% by weight or more, preferably 95% by weight or more, more preferably 97% by weight or more, further preferably 99% by weight or more, and particularly preferably about 100% by weight. In some cases, the content is preferably 93% by weight or more, more preferably 98% by weight or more, and particularly preferably 99.5% by weight or more. When used as the drug of the present invention, the content is usually 80% by weight or more. Further, as a preferable embodiment of the a-type crystal, there can be mentioned a crystal which does not substantially contain a crystal type other than the a-type crystal. "substantially not containing" means as follows: the content of the crystal other than the a-type crystal is preferably 10% by weight or less, more preferably 5% by weight or less, further preferably 3% by weight or less, particularly preferably 1% by weight or less, and most preferably no crystal other than the a-type crystal is contained.

Further, as the crystal used in another embodiment of the present invention, B-type crystal is also cited as a preferable example. The form B crystal of Compound 1 of the present application is a crystal defined by any one or a combination of two or more of the following various characteristics, which are confirmed in the above-mentioned technical aspects (8) to (10-1) or in the examples, test examples and the like of the present specification. In addition to the advantages of the crystals of compound 1 of the present invention, the B-form crystals exhibit certain properties and thus exhibit excellent properties as a pharmaceutical preparation, a pharmaceutical effect, a production process, and the like, as compared with the uncontrolled conventional crystals (mono なる). Further, the B-type crystal has higher filterability and further improved flow characteristics as compared with the a-type crystal, and therefore, it is expected that the time required for the filtration step and/or dehydration step, for example, can be shortened when producing a large amount of the B-type crystal. Further, the form B crystal is more preferable in the production of a dry preparation or a solid preparation. It has been also confirmed that the water content of the type B crystal after the filtration and dehydration is lower than that of the type a crystal after the filtration and dehydration, and particularly in the case of mass production, the type B crystal is expected to shorten the time required for drying and to reduce the heat energy, and the type B crystal is considered to be preferable. Further, it is considered that the form B crystal has substantially better morphological stability than the form a crystal. In order to maximize the advantageous effects of the B-type crystal, it is preferable to use the B-type crystal which is substantially a B-type crystal, and the purity (percentage) of the B-type crystal is usually about 90% by weight or more, preferably 95% by weight or more, more preferably 97% by weight or more, further preferably 99% by weight or more, and particularly preferably about 100% by weight. In some cases, the content is preferably 93% by weight or more, more preferably 98% by weight or more, and particularly preferably 99.5% by weight or more. When used as the drug of the present invention, the content is usually 80% by weight or more. Further, as a preferable embodiment of the B-type crystal, a crystal substantially not containing a crystal type other than the B-type crystal can be cited. "substantially not containing" means as follows: the content of crystals other than the B-type crystals is preferably 10% by weight or less, more preferably 5% by weight or less, further preferably 3% by weight or less, particularly preferably 1% by weight or less, and most preferably none at all.

The purity (percentage) of the crystals of the form a crystals may be obtained by dividing the weight of the crystals of the form a crystals by the weight of the compound 1 present in this case and multiplying the result by 100. Here, as the method for measuring the weight of crystals present in the a-type crystal and the weight of compound 1 present in the present case, any of the following methods may be used, and a measurement method in which these methods are further appropriately modified may be used.

Incidentally, in some measurement methods, an unnecessary measurement error may occur, and in this case, it is preferable to use a known amount of standard substance to confirm the magnitude of the error and correct it. For example, in the present invention, it is particularly preferable to express the crystal purity by dividing a measured value of the crystal calculated by a measurement method based on differential scanning calorimetry (particularly, specific measurement conditions described in the present specification can be given as a particularly preferable example) by a value obtained by multiplying a measured value of the compound 1 of the present invention by 100 times, and to express the measured value of the compound 1 of the present invention calculated by a measurement based on HPLC (particularly, specific measurement conditions described in the present specification can be given as a particularly preferable example). The crystal purity (percentage) of the B-type crystal is also the same as that described above, and the measurement method thereof may be appropriately changed, and it is particularly preferable to express the crystal purity by dividing the measurement value of the crystal calculated by the measurement method of differential scanning calorimetry (particularly, specific measurement conditions described in the present specification may be given as a particularly preferable example) by the measurement value of the compound 1 of the present application, and to express the crystal purity by multiplying the measurement value by 100 times, and the measurement value of the compound 1 of the present application is calculated by the measurement of HPLC (particularly, specific measurement conditions described in the present specification may be given as a particularly preferable example).

In general, each crystal can be present in an amount determined by differential scanning calorimetry analysis or by measuring powder X-ray diffraction spectrum, infrared absorption spectrum, solid state¹³The intensity of a characteristic peak in a C-NMR spectrum, a Raman spectrum or the like is determined, and particularly when the presence ratio of the A-type crystal and the B-type crystal of the present compound 1 is measured as described above, a method of measurement by differential scanning calorimetry is cited as a preferable example. Specifically, taking the a-type crystal of compound 1 of the present case as an example, in differential scanning calorimetry (as an appropriate temperature rise rate, for example, 50 ℃/min) using an appropriate temperature rise rate, a pure a-type crystal is used as a standard for the crystal, the weight (mg) of the standard is plotted against the area (mJ) of the endothermic peak at about 185 ℃ due to the melting of the a-type crystal to prepare a calibration curve, and the area (mJ) of the endothermic peak at about 185 ℃ of the sample is substituted into the calibration curve to determine the amount of the a-type crystal. The amount of the B-form crystal of Compound 1 can be determined in the same manner as described above. That is, as for the crystal, a pure B-type crystal may be used as a standard, and an endothermic peak at about 205 ℃ in general, for example, may be measured as an endothermic peak of a differential scanning calorimetry analysis of the B-type crystal.

In other measuring methods than differential scanning calorimetry, i.e. in powder X-ray diffraction spectra, infrared absorption spectra, solids¹³In the measurement methods such as C-NMR spectroscopy and raman spectroscopy, the amount of the target crystal form present may be determined by preparing a calibration curve using a standard substance in the same manner as in differential scanning calorimetry.

In particular, the measurement method other than the differential scanning calorimetry, i.e., the powder X-ray diffraction spectrum, the infrared absorption spectrum, and the solid¹³When the amount of the target crystal form to be present is calculated by a measurement method such as C-NMR spectroscopy or raman spectroscopy, the amount of the target crystal form to be present can be determined by appropriately selecting characteristic peaks of the respective crystal forms and preparing a calibration curve.

The optical system for the measurement using the powder X-ray diffraction spectrum includes a general focusing optical system and a parallel beam optical system. The optical system used is not particularly limited, and when the decomposition energy and the intensity are to be ensured, the measurement is preferably performed using a focusing optical system. When the orientation (i.e., a phenomenon that crystals are oriented in a certain direction due to their shape (needle-like shape, sheet-like shape, etc.)) is to be suppressed, it is preferable to perform the measurement using a parallel beam method optical system. Examples of the measuring apparatus for the focusing optical system include XRD-6000 (manufactured by Shimadzu corporation) and MultiFlex (manufactured by Rigaku corporation). Further, as a measuring apparatus of the parallel beam method optical system, XRD-7700 (manufactured by Shimadzu corporation), RINT2200Ultima +/PC (manufactured by Shikoku corporation), and the like can be mentioned.

In addition, when the amount of the present compound 1 in the present invention in the preparation needs to be measured, HPLC is generally used for convenience and is preferable. That is, for example, with respect to the present compound 1, a standard sample of the present compound 1 having a known chemical purity can be used and measured by the HPLC method to prepare a standard curve of the present compound 1, and the amount of the present compound 1 present in a sample can be quantified based on the standard curve.

The HPLC-based quantitative method and the crystal measurement method for the compound 1 are also applicable to the compound 2 or the compound 3 described later. For example, HPLC conditions may be the same as those described above, and a measurement method based on differential scanning calorimetry may be used to perform measurement using characteristic endothermic peaks thereof. The respective crystal purities may be determined by the same measurement as described above. Pure a-type crystals and B-type crystals of the present compound 1 used as a standard in the above measurement and pure a-type crystals and B-type crystals of the present compound 1 used as seed crystals in the below-described crystal production method can be obtained as follows: preferably, after each of the crystals obtained by the methods of examples 3, 4 or 5 of the present application, a crystal having an excellent shape is particularly selected from the crystals, and then a crystal showing a single endothermic peak characteristic to each of the crystals is selected by differential scanning calorimetry, thereby obtaining each of the crystals. The B-form crystals obtained by the methods of examples 6 to 7 can also be used as a standard. Further, the B-form crystals obtained by the methods of examples 6 to 7 can be used as seed crystals for obtaining pure B-form crystals. In addition, in the case where the type a crystal is mixed with the type B crystal, the quantitative value of the type a crystal obtained by the differential scanning calorimetry analysis may be measured to be lower than that of the normal standard type a crystal. The degree of the decrease varies depending on the mixing ratio of the type B crystal in the type A crystal, and for example, when the mixing ratio of the type B crystal is 10% or less, the quantitative value of the type A crystal may have an error of about 10% as usual. Further, when the mixing ratio of the B-type crystal is close to 50%, there is a possibility that an error of about 20% at the maximum is caused. Conversely, when the type a crystal is mixed in the type B crystal, the quantitative value may be higher than that of the standard type B crystal, and the degree of increase varies depending on the mixing ratio of the type a crystal in the type B crystal, and similarly, for example, when the mixing ratio of the type a crystal is 10% or less, the quantitative value of the type B crystal may have an error of about 10% as usual, and when the mixing ratio of the type a crystal is close to 50%, the error may be about 20% at maximum. In a normal state where the mutual mixing ratio is not particularly high, the crystal purity of the a-type crystal or the B-type crystal includes an error of about 10%. In the case of quantitative determination, a method of preparing a calibration curve from a standard sample of a desired mixing ratio and performing quantitative determination is used. In order to further clearly judge the mixing ratio, a mixture of the type a crystal standard and the type B crystal standard at known mixing ratios is appropriately prepared, a calibration curve is prepared from the mixing ratio (percentage) of the target crystal and the percentage of the area (mJ) of the endothermic peak generated by melting of the crystal relative to the total peak area, and the mixing ratio of the crystal in the sample is known from the calibration curve.

In addition, in the measurement method other than differential scanning calorimetry, that is, in powder X-ray diffraction spectrum, infrared absorption spectrum, solid state¹³In the measurement method such as C-NMR spectroscopy and Raman spectroscopy, a standard curve may be prepared by using a standard mixture having a known mixing ratioLine, from which the mixing ratio is clearly judged.

Drawings

Fig. 1 is a powder X-ray diffraction spectrum of the crystal of the present compound 2. In the figure, the vertical axis represents intensity (CPS) and the horizontal axis represents 2 θ (°).

Fig. 2 is a powder X-ray diffraction spectrum of the crystal of the present compound 3. In the figure, the vertical axis represents intensity (CPS) and the horizontal axis represents 2 θ (°).

Fig. 3 is a powder X-ray diffraction spectrum of the a-type crystal of the present compound 1. In the figure, the vertical axis represents intensity (CPS) and the horizontal axis represents 2 θ (°).

Fig. 4 is a differential scanning calorimetry analysis of the a-type crystal of the present case compound 1. In the figure, the vertical axis represents mW, and the horizontal axis represents temperature (. degree. C.).

Fig. 5 shows an infrared absorption spectrum of a type a crystal of the present compound 1. In the figure, the vertical axis represents transmittance (%), and the horizontal axis represents cm^-1。

Fig. 6 is a powder X-ray diffraction spectrum of the B-type crystal of present compound 1. In the figure, the vertical axis represents intensity (CPS) and the horizontal axis represents 2 θ (°).

Fig. 7 is a differential scanning calorimetry analysis of the B-form crystals of compound 1 of the present case. In the figure, the vertical axis represents mW, and the horizontal axis represents temperature (. degree. C.).

Fig. 8 shows an infrared absorption spectrum of a B-type crystal of the present compound 1. In the figure, the vertical axis represents transmittance (%), and the horizontal axis represents cm^-1。

Fig. 9 shows a calibration curve in differential scanning calorimetry of the a-type crystal of the present compound 1. In the figure, the vertical axis represents the area (mJ) and the horizontal axis represents the weight (mg).

Fig. 10 shows a calibration curve in differential scanning calorimetry of the B-form crystal of the present compound 1. In the figure, the vertical axis represents the area (mJ) and the horizontal axis represents the weight (mg).

Fig. 11 is a photograph serving as an accompanying drawing showing the crystal shape of the a-type crystal of compound 1 of the present case, and fig. 11 is a Scanning Electron Microscope (SEM) photograph.

Fig. 12 is a photograph serving as an accompanying drawing showing the crystal shape of the B-type crystal of compound 1 of the present case, and fig. 12 is a Scanning Electron Microscope (SEM) photograph.

Detailed Description

[ Process for producing A-type crystals of Compound 1 ]

The following methods can be mentioned as a method for producing the a-type crystal of compound 1: adding an acid into a solution of the compound 1 in the scheme under an alkaline condition to generate crystals consisting of the compound 1 in the scheme, and then obtaining the crystals.

That is, the solution of the present compound 1 used in the present invention under alkaline conditions is not particularly limited as long as the compound is dissolved under alkaline conditions, and the compound to be dissolved may be any one of an oil, a solid (including various crystalline forms and amorphous forms), and a mixture thereof. The compound 1 of the present invention can be prepared according to the method disclosed in international publication No. WO 03/70686.

As the base used for preparing the solution under the above-mentioned alkaline condition, an inorganic base is preferable. That is, for example, an alkali metal base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium tert-butoxide, etc., is mentioned, sodium hydroxide, potassium hydroxide, etc. are preferred, and sodium hydroxide is particularly preferred. These bases may be used as an alkali solution in the form of a solution of water or an alcohol such as methanol, ethanol, or tert-butanol, and when an aqueous solution containing a base at a certain concentration is prepared and used, such an operation is particularly preferable because the amount of addition can be easily determined. Further, when a concentrated alkaline solution is used, a highly preferable example is a case where an aqueous solution of 0.5 to 2N alkali is used, because it is considered that a high heat of neutralization is generated when an acid is added later.

The lower limit of the amount of the base to be added is usually 0.8 equivalent or more, preferably 0.9 equivalent or more, and more preferably 1.0 equivalent or more to 1 equivalent of the compound. The upper limit is usually 3.0 equivalents or less, preferably 2.0 equivalents or less, relative to 1 equivalent of the compound.

The solvent for dissolving the compound together with the base is preferably a polar solvent, and specifically, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; acetone, etc., and these may be used in combination as necessary. Among these, water, methanol, ethanol, tetrahydrofuran, and the like are preferable, and water, methanol, ethanol, and the like are particularly preferable. In addition, when water and methanol are mixed and used, the mixing ratio of water to methanol after the alkali-containing solution is prepared is 1: 20 to 10: 1, preferably 1: 10 to 1: 1.

In the solution under the above-mentioned alkaline condition, the heating may be carried out at a temperature not higher than the boiling point of the solvent, and when insoluble substances are present, the insoluble substances are preferably removed by an operation such as filtration.

The acid added to the solution may be in any of a liquid state, a solid state, and a gas state as long as it does not enter a precipitate of crystals generated by the addition of the acid, and a solution state or a gas is preferable.

Further, various organic acids and inorganic acids can be mentioned as the kind of the acid, but the acid used for neutralizing the base must have a higher acidity than that of the present compound, and inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid are preferable, and hydrochloric acid is particularly preferable. These acids may be used in the form of a solution prepared in advance from water or alcohols such as methanol, ethanol, and tert-butanol, and when an aqueous solution containing an acid at a constant concentration is prepared in advance and used, it is preferable to use such a solution because the amount of the acid added can be easily determined. In addition, when a concentrated acidic solution is used, a particularly preferable example is a case where an acidic aqueous solution of 0.5 to 2N is used, because high heat of neutralization is generated.

The amount of the acid to be added is not particularly limited as long as the acid is added to the crystals to sufficiently form crystals, and the amount is usually 0.8 equivalent or more, preferably 0.9 equivalent or more, based on 1 equivalent of the base. And, particularly preferably, about 1 equivalent is added. The upper limit is not particularly limited, and the amount of the base to be added is usually 1.5 equivalents or less, and preferably 1.2 equivalents or less, based on 1 equivalent of the base.

Examples of the method of adding the acid include: (1) the addition is preferably carried out by a method of adding the components at once, (2) adding the components in several portions, (3) continuously adding the components for a long time by a method such as dropwise addition, and the like, and continuously adding the components for a long time by a method such as dropwise addition is preferable. Stirring is preferably performed when the acid is added. The addition rate varies depending on the amount of the compound to be used, the alkali concentration in the solution under an alkaline condition, the kind of the acid to be used, and the concentration of the acidic solution, and when 0.5 to 2N hydrochloric acid is used, the total amount is added over a period of 1 to 6 hours.

The upper limit of the temperature at the time of adding the acid is preferably 60 ℃ or lower, more preferably 50 ℃ or lower, further preferably 45 ℃ or lower, and the lower limit is preferably 0 ℃ or higher, more preferably 10 ℃ or higher, further preferably 25 ℃ or higher.

When the crystal to be formed is to be obtained, it is usually carried out within 24 hours, preferably within 20 hours, particularly preferably within 10 hours after the addition of the acid. Further, although the crystal may be obtained immediately after the addition of the acid, the crystal is preferably obtained after 1 hour, particularly preferably after 3 hours after the addition.

As a method for collecting precipitated crystals, crystals can be obtained by a known method such as filtration and decantation, and filtration is generally preferred. After the crystals are collected by filtration, the crystals can be washed with a polar solvent (e.g., water, methanol, ethanol, or a mixture thereof), which is effective as an operation for removing impurities. As the cleaning method, a method of rinsing the crystals on the filter with a polar solvent is preferable. Also, the following method is also preferable: the crystals are added to a polar solvent (e.g., water, methanol, ethanol, or a mixture thereof) to prepare a suspension, and the suspension is stirred sufficiently and then filtered again to obtain crystals. Further, the above 2 cleaning methods are particularly preferably performed. The obtained crystals can be dried by a commonly used drying method (for example, drying under reduced pressure and heating, drying under normal pressure and heating, air drying, etc.).

The final deposition concentration of the compound after addition of the acid varies depending on the kind of the solvent used and the ratio of the solvent in the case of a mixed solvent, and the lower limit of the deposition concentration is generally 1 w/v% or more, preferably 5 w/v% or more. The upper limit is preferably 30 w/v% or less, preferably 20 w/v% or less.

It is considered that a mode in which a small amount of a crystal is added as a seed crystal when the crystal is generated is also a preferable mode.

Among the above-mentioned production methods, the following methods are preferred. In the following 3 production method examples, the above preferred examples of the amount of the base used, the stirring temperature before the addition of the acid, the amount of the acid added, and the stirring time after the addition of the acid can be adopted.

A method in which 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid is dissolved in a solvent comprising 0.8 to 3.0 equivalents of sodium hydroxide or potassium hydroxide in water, methanol, ethanol, tetrahydrofuran, or a mixture thereof to obtain a solution, and an aqueous solution of hydrochloric acid, sulfuric acid, or phosphoric acid in an amount of 0.8 to 1.5 equivalents relative to 1 equivalent of a base is continuously added to the obtained solution for a long period of time at a temperature of 10 to 50 ℃ under stirring, for example, by a method such as dropwise addition, and the solution is further stirred for 1 to 24 hours to obtain crystals.

A method comprising dissolving the above compound in water, methanol, ethanol or a mixed solvent thereof containing 0.9 to 2.0 equivalents of sodium hydroxide to 1 equivalent of the above compound to obtain a solution, adding 0.5 to 2N aqueous hydrochloric acid solution to the obtained solution at a temperature of 25 to 45 ℃ for 1 to 6 hours while stirring, and further stirring for 3 to 24 hours to obtain crystals, wherein the amount of the aqueous hydrochloric acid solution is 0.9 to 1.2 equivalents relative to 1 equivalent of a base.

A method comprising dissolving the above compound in a solution containing 0.5 to 2N aqueous sodium hydroxide solution and methanol in an amount of 0.9 to 2.0 equivalents based on 1 equivalent of the above compound, adding 0.5 to 2N aqueous hydrochloric acid solution in an amount of 0.9 to 1.2 equivalents based on 1 equivalent of a base at a temperature of 25 to 45 ℃ for 1 to 6 hours under stirring, and further stirring for 3 to 24 hours to obtain crystals.

Also, the solution of compound 1 of the present case under basic conditions described above may be a basic hydrolysate of a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propanoic acid. That is, as another method for producing the a-type crystal, the following method can be mentioned.

A method in which a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid is subjected to basic hydrolysis in a solvent, and then an acid is added to the solution under basic conditions, thereby obtaining crystals.

Examples of the "lower alkyl ester" include carboxylic acid esters of an alkyl group having 1 to 4 carbon atoms, and examples of the alkyl group having 1 to 4 carbon atoms include any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Among them, methyl and ethyl are particularly preferable.

The lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid can be prepared according to the method of International publication WO 03/70686.

As the base used for preparing the basic hydrolysate of the above compound, the above-mentioned base for making the solution under basic conditions can be used.

The amount of the base to be used is usually 1 equivalent or more to 1 equivalent of the compound. The upper limit is usually 10 equivalents or less, preferably 3 equivalents or less, and particularly preferably 2 equivalents or less, to 1 equivalent of the compound.

The solvent is generally an inert medium which does not hinder the reaction, and the reaction is preferably carried out in a polar solvent. The polar solvent may be water, methanol, ethanol, tetrahydrofuran, dioxane, or the like, although the above conditions may be applied, and these solvents may be used in combination as necessary. Among these, water, methanol, ethanol, tetrahydrofuran, and the like are preferable, and water, methanol, ethanol, and the like are particularly preferable. In addition, it is very preferable to use water and methanol in combination, and the mixing ratio of water to methanol is, for example, 1: 20 to 10: 1, preferably 1: 10 to 1: 1, as the reaction solution after addition of the alkali.

The reaction temperature of the basic hydrolysis may be selected from a suitable temperature, for example, from room temperature to the reflux temperature of the solvent, and particularly preferred examples thereof include conditions of 50 to 70 ℃. The reaction time is usually 0.5 to 72 hours, preferably 1 to 24 hours, more specifically, the upper limit is preferably within 24 hours, more preferably within 20 hours, further preferably within 10 hours, and the lower limit is preferably 0.5 hours or more, more preferably 1 hour or more, further preferably 3 hours or more, and the reaction process can be followed by Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), and the like, and therefore, the reaction is usually appropriately terminated when the yield of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid reaches the maximum.

The acid to be added to the solution under the alkaline condition after the alkaline hydrolysis reaction, the conditions for producing crystals, the collection method, and the like are as described above.

Preferable examples of the above-mentioned production method include the following. In the following 3 production method examples, the preferred examples described above can be employed for the amount of the base used in the alkaline hydrolysis, the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before the addition of the acid, the amount of the acid added, and the stirring time after the addition of the acid.

A method comprising reacting a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid in the presence of 1 to 3 equivalents of sodium hydroxide or potassium hydroxide to 1 equivalent of the lower alkyl ester in water, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof at 50 to 70 ℃ for 1 to 24 hours, then continuously adding an aqueous solution of hydrochloric acid, sulfuric acid, or phosphoric acid to 1 equivalent of a base by dropwise addition at a temperature of 10 to 50 ℃ for a long time while stirring, and further stirring for 1 to 24 hours to obtain crystals.

And a method comprising reacting a methyl ester or ethyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid at 50 to 70 ℃ for 1 to 24 hours in the presence of 1 to 2 equivalents of sodium hydroxide to 1 equivalent of the methyl ester or ethyl ester in water, methanol, ethanol or a mixed solvent thereof, adding 0.5 to 2N aqueous hydrochloric acid solution at 0.9 to 1.2 equivalents of a base to the mixture at 25 to 45 ℃ for 1 to 6 hours under stirring, and further stirring the mixture for 3 to 24 hours to obtain crystals.

Further, a method in which a 0.5 to 2N aqueous sodium hydroxide solution and methanol are added to a methyl ester or an ethyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid in an amount of 1 to 2 equivalents based on 1 equivalent of the methyl ester or ethyl ester, the mixture is reacted at 50 to 70 ℃ for 1 to 24 hours, then a 0.5 to 2N aqueous hydrochloric acid solution in an amount of 0.9 to 1.2 equivalents based on 1 equivalent of a base is added thereto at 25 to 45 ℃ for 1 to 6 hours with stirring, and the mixture is further stirred for 3 to 24 hours to obtain crystals.

[ Process for producing B-form crystals of Compound 1 of the present invention ]

The following methods can be mentioned as a method for producing the B-type crystal of compound 1: the compound 1 is dissolved in any one or more solvents selected from the group consisting of acetone, dichloromethane, methanol, ethyl acetate, a methanol/acetic acid mixed solution, and acetonitrile, and the dissolved compound 1 is crystallized from the solution.

As described above, compound 1 of the present invention can be produced by the method disclosed in International publication WO 03/70686.

Examples of the solvent used include acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, nitrobenzene, 2, 2, 2-trifluoroethanol, N-dimethylformamide, and N, N-dimethylacetamide, and these solvents may be mixed and used. Further, tetrahydrofuran/water, N-dimethylformamide/water, N-dimethylacetamide/water, tetrahydrofuran/methanol, diisopropyl ether/acetic acid, methanol/acetic acid, and the like can be given. Among these, acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, methanol/acetic acid and the like are preferable, and acetone, dichloromethane and the like are particularly preferable.

When the compound is dissolved in a solvent, it is preferable to heat the mixture at a temperature equal to or lower than the boiling point of the solvent from the viewpoint of the yield of the obtained crystals, and when insoluble substances are present, it is preferable to remove the insoluble substances by filtration or the like.

The amount of the solvent to be added varies depending on the kind of the solvent to be used and the ratio of the solvent in the case of mixing the solvents, and the amount of the solvent to be added is preferably an amount in which the compound is dissolved at a temperature equal to or lower than the boiling point of the solvent to be used, and further, from the viewpoint of the yield of the crystals to be obtained, the amount of the solvent to be added in which the compound is dissolved at a concentration near the boiling point of the solvent to reach a saturation concentration is particularly preferably used. Specifically, for example, when acetone is used as the solvent, it is preferably 15 to 25ml, more preferably about 15ml, based on 1g of the compound. When dichloromethane is used, the amount of dichloromethane is preferably 30 to 50ml, and more preferably about 30ml, based on 1g of the compound.

As a method of cooling the solution of the compound prepared by heating, there may be mentioned a method of rapid cooling, stepwise cooling, natural cooling, etc., and a stepwise cooling method or a natural cooling method is preferable.

The cooling temperature differs depending on the amount of the solvent used, the type of the solvent used, and the ratio of the solvent in the case of a mixed solvent, and also differs depending on the temperature at which the compound is dissolved, and it is preferable to cool the compound to a temperature at which the compound becomes a saturated concentration or higher.

The cooling operation may be carried out under stirring or in a static state, and is preferably carried out under stirring from the viewpoint of accelerating the precipitation of crystals and shortening the operation time.

When crystals are formed by the above method, it is also a preferable embodiment to add a small amount of B crystals as seed crystals.

The precipitated crystals are usually collected by filtration. After collecting the crystals by filtration, the crystals can be washed with a solvent for dissolving the compound, a solvent for not dissolving the crystals significantly, or a mixture thereof, and this is effective as an operation for removing impurities.

The obtained crystals can be dried by a commonly used drying method (for example, drying under reduced pressure and heating, drying under normal pressure and heating, air drying, etc.).

Among the above-mentioned production methods, the following methods are preferred.

Adding 15-25 ml of acetone or 30-50 ml of dichloromethane to 1g of the compound 1, heating to a temperature near the boiling point to dissolve the compound, filtering the insoluble matter if necessary, and stirring at room temperature for several hours to several days to obtain the formed crystals.

Further, as another method for producing the B-type crystal of compound 1 of the present invention, there can be mentioned the following methods: an acid is added to a solution of the present compound 1 under alkaline conditions, in the process, B-type crystals of the present compound 1 are added as seed crystals to generate B-type crystals of the present compound 1 immediately before the start of crystallization of the present compound 1, and then the crystals are obtained.

The present compound 1 used in the present invention, its form and the method for obtaining the same are the same as those described in the above "method for producing a type a crystal of the present compound 1". The method for preparing a solution of the present compound 1 under alkaline conditions is also the same as described above. The basic solution may be a basic hydrolysate of a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, and the same applies to the above.

The kind and amount of the base used for preparing the solution under alkaline conditions, the kind and amount of the solvent used for dissolving the compound together with the base, the kind and amount of the acid to be added, the method of addition, the rate of addition, the temperature at the time of addition, and the like can be as described above. As a method of adding the seed crystal of the B-type crystal, it is preferable that no crystal is present in the mixed liquid at the stage of adding the seed crystal, and it is preferable that the seed crystal after addition is present in an undissolved state. In this case, it is preferable to add the seed crystal of the B-type crystal at a stage after the addition of the equivalent or more of the base is neutralized by the added acid, from the viewpoint of avoiding the dissolution of the seed crystal. In this case, it is also a preferable method to confirm the neutralization state of the alkali by using a device such as a pH meter. That is, when the compound is dissolved using 1.5 equivalents of a base with respect to the compound, preferable examples thereof include the following methods: adding 0.5 equivalent of acid, and adding seed crystal at a stage when the pH in the system is slightly alkaline about 7-9. Further, it is preferable to add a seed crystal before the crystal is generated by adding the acid. In the case of adding 2N hydrochloric acid for 1 to 6 hours, after the neutralization of the above-mentioned compound with an equivalent or more of a base is completed, the crystallization is likely to start in a stage where the pH in the system is weakly acidic by adding 0.1 to 0.2 equivalent of an acid, and therefore, it is preferable to add a B-type seed crystal at a stage earlier than this stage.

The amount of the B-type crystal to be added is not particularly limited as long as the amount of the B-type crystal added is an amount in which the crystal after addition is insoluble, and it is usually 0.01% or more, preferably 0.05% or more, and particularly preferably about 0.1% to the compound. The upper limit is not particularly limited, and the amount of the compound added is usually 2% or less, preferably 1.5% or less, more preferably 1.0% or less, and particularly preferably 0.3% or less. The method of collecting the precipitated crystals, the method of drying the collected crystals, the concentration of the precipitated compound at the end after addition of an acid, and the like can be carried out under the same conditions as in the above-mentioned "method for producing a type a crystal of compound 1 of the present application".

Among the above-mentioned production methods, the following methods are preferred. In the following 3 production method examples, the above preferred examples can be employed for the amount of the base used, the stirring temperature before the acid addition, the amount of the acid added, the amount of the B-type seed crystal added, and the stirring time after the acid addition.

A method comprising dissolving the compound 1 in water, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof containing 0.8 to 3.0 equivalents of sodium hydroxide or potassium hydroxide per 1 equivalent of the compound 1 to obtain a solution, adding an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid in an amount of 0.8 to 1.5 equivalents based on 1 equivalent of a base to the obtained solution continuously for a long time at a temperature of 10 to 50 ℃ by, for example, dropwise addition under stirring, adding a B-type seed crystal in an amount of 0.01 to 2% based on the compound at a stage at which the pH in the system shows weak basicity of 7 to 9, and further stirring for 1 to 24 hours to obtain crystals.

Further, a method comprising dissolving the compound 1 in water, methanol, ethanol or a mixed solvent thereof containing 0.9 to 2.0 equivalents of sodium hydroxide to 1 equivalent of the compound 1 to obtain a solution, adding 0.5 to 2N hydrochloric acid aqueous solution to 1 equivalent of base in an amount of 0.9 to 1.2 equivalents to the obtained solution at a temperature of 25 to 45 ℃ for 1 to 6 hours under stirring, adding 0.05 to 1.5% of B-type seed crystal to the compound at a stage at which the pH in the system shows weak alkalinity of 7 to 9, and further stirring for 1 to 5 hours to obtain crystals.

And a method in which 0.5 to 2N aqueous sodium hydroxide solution and methanol are added to 1 equivalent of the compound 1 in this case in an amount of 0.9 to 2.0 equivalents, and the mixture is dissolved in the solvent, 0.9 to 1.2 equivalents of 0.5 to 2N aqueous hydrochloric acid solution is added to the above solution at a temperature of 25 to 45 ℃ for 1 to 6 hours under stirring, 0.9 to 1.2 equivalents based on 1 equivalent of alkali is added at a stage in which the pH in the system shows weak alkalinity of 7 to 9, and then, after that, 0.1% of B-type seed crystal is added to the above compound, the mixture is further stirred for 1 to 5 hours, thereby obtaining crystals.

Further, as preferable examples of the production method, the following modes can be given. In the following 3 production method example, the above-mentioned preferable examples can be adopted for the amount of the base used in the alkaline hydrolysis, the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before the acid addition, the amount of the acid added, the amount of the B-type seed crystal added, and the stirring time after the acid addition.

Reacting a lower alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid in the presence of 1 to 3 equivalents of sodium hydroxide or potassium hydroxide to 1 equivalent of the lower alkyl ester in water, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof at 50 to 70 ℃ for 1 to 24 hours, then continuously adding an aqueous solution of hydrochloric acid, sulfuric acid, or phosphoric acid to 1 equivalent of a base by a method such as dropwise addition at a temperature of 10 to 50 ℃ while stirring, and adding 0.01 to 2% of a B-type seed crystal to the compound at a stage where the pH in the system shows weak basicity of 7 to 9, and further stirring for 1-24 hours to obtain crystals.

And in the presence of 1 to 2 equivalents of sodium hydroxide relative to 1 equivalent of the methyl or ethyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, reacting the methyl ester or ethyl ester in water, methanol, ethanol or a mixed solvent thereof at 50 to 70 ℃ for 1 to 24 hours, then, 0.5 to 2N hydrochloric acid aqueous solution is added to the solution at a temperature of 25 to 45 ℃ for 1 to 6 hours under stirring in an amount of 0.9 to 1.2 equivalents relative to the alkali, and adding 0.05-1.5% of B-type seed crystal relative to the compound at a stage when the pH value in the system shows alkalescence of 7-9 in the process, and further stirring for 3-24 hours to obtain crystals.

Further, a method in which a 0.5 to 2N aqueous sodium hydroxide solution and methanol are added to 1 equivalent of methyl or ethyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propanoic acid ester or ethyl ester, and the methyl or ethyl ester is reacted at 50 to 70 ℃ for 1 to 24 hours, then 0.9 to 1.2 equivalents of 0.5 to 2N aqueous hydrochloric acid solution is added to 1 equivalent of base at 25 to 45 ℃ for 1 to 6 hours under stirring, and in this process, 0.1% of a B-type seed crystal is added to the compound at a stage where the pH in the system shows weak alkalinity of 7 to 9, and then the mixture is stirred for 3 to 24 hours to obtain crystals.

[ Process for producing crystals of Compound 2 ]

Further, the crystals of the present compound 2 of the present invention are advantageous in the process of preparation, for example, the content of the present compound in each preparation can be easily made uniform, and the crystals are advantageous in that the solvent can be easily removed as compared with the case of an oily substance, and a method for producing the crystals has been found, and therefore, the crystals have an advantage that the present compound having excellent purity can be obtained without purification by column chromatography in the above known production methods, and are suitable for industrial-scale production, and thus, the crystals are very preferable.

As a method for producing the crystal of compound 2 of the present embodiment, the following method can be mentioned: the compound 2 of the present application is dissolved in a good solvent which is easily soluble to prepare a solution, a poor solvent which is difficult to dissolve the compound is added to the prepared solution to generate crystals composed of the compound, and then the crystals are obtained. Compound 2 of the present invention can be prepared according to the method disclosed in International publication WO 03/70686.

Examples of the good solvent for dissolving the compound include toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol, etc., acetone, toluene, tetrahydrofuran, etc. are preferable, and acetone is particularly preferable. Examples of the poor solvent to be added for forming crystals of the compound include heptane, diisopropyl ether, isopropanol, tert-butyl methyl ether, water, etc., and when acetone is used as the good solvent, water is preferably used, and when toluene or tetrahydrofuran is used as the good solvent, heptane is preferably used. A particularly preferable example is a combination of acetone as a good solvent and water as a poor solvent.

The concentration of the solution prepared using the good solvent is preferably 20 w/v% or less at the upper limit, more preferably 10 w/v% or less at the lower limit, and preferably 5 w/v% or more at the lower limit. The amount of the poor solvent to be added is preferably 2.0 times or less, more preferably 1.5 times or less, and still more preferably 1.1 times or less in the upper limit, and preferably 0.8 times or more, and more preferably 0.9 times or more in the lower limit, relative to the good solvent. Particularly, the amount of the compound is preferably 1.0 times. In some cases, the amount of the compound added is particularly preferably 1.05 times. As a method of adding the poor solvent, a method of continuously adding for a long time by a method such as dropwise addition is preferable. Stirring is preferably performed when the poor solvent is added. The addition rate varies depending on the amount of the compound to be used, the concentration of the compound in the solution, the kind of the good solvent and the poor solvent to be used, and when water is added to the acetone solution of the compound as the poor solvent, a method of adding water over a period of 1 to 3 hours is exemplified.

The temperature at the time of adding the poor solvent is preferably 50 ℃ or lower, more preferably 40 ℃ or lower, and still more preferably 30 ℃ or lower, and preferably 0 ℃ or higher, more preferably 10 ℃ or higher, and still more preferably 20 ℃ or higher.

The crystals to be obtained are usually obtained from 1 to 24 hours, preferably from 1 to 5 hours after the addition of the poor solvent.

As a method for collecting precipitated crystals, crystals can be obtained by a known method such as filtration and decantation, and filtration is generally preferred. After the crystals are collected by filtration, the crystals can be washed with a polar solvent (e.g., water, acetone, or a mixture thereof), and this is effective as an operation for removing impurities.

[ Process for producing crystals of Compound 3 ]

Further, the crystals of the present compound 3 of the present invention are advantageous in the process of preparation, for example, the content of the present compound in each preparation can be easily made uniform, and the crystals are advantageous in that the solvent can be easily removed as compared with the case of an oily substance, and a method for producing the crystals has been found, and therefore, the crystals have an advantage that the present compound having excellent purity can be obtained without purification by column chromatography in the above known production methods, and are suitable for industrial-scale production, and thus, the crystals are very preferable.

As a method for producing the crystal of compound 3 of the present embodiment, the following method can be mentioned: the compound 3 of the present application is dissolved in a good solvent which is easily soluble to prepare a solution, a poor solvent which is difficult to dissolve the compound is added to the prepared solution to generate crystals composed of the compound, and then the crystals are obtained.

Compound 3 of the present invention can be prepared according to the method disclosed in International publication WO 03/70686. The compound can also be produced by a usual methyl esterification reaction such as methyl esterification of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid in a methanol solvent under acidic conditions.

Examples of the good solvent for dissolving the compound include toluene, ethyl acetate, tetrahydrofuran, and acetone, with acetone and tetrahydrofuran being preferred, and tetrahydrofuran being particularly preferred. The poor solvent includes heptane, isopropanol, methanol, water, etc., and when acetone is used as the good solvent, water or heptane is preferably used, and when tetrahydrofuran is used as the good solvent, heptane, isopropanol, and water are preferably used. A particularly preferable example is a combination of tetrahydrofuran as a good solvent and water as a poor solvent.

The concentration of the solution prepared using the good solvent is preferably 20 w/v% or less at the upper limit, more preferably 10 w/v% or less at the lower limit, and preferably 5 w/v% or more at the lower limit. The amount of the poor solvent to be added is preferably 2.0 times or less, more preferably 1.5 times or less, and still more preferably 1.1 times or less in the upper limit, and preferably 0.8 times or more, and more preferably 0.9 times or more in the lower limit, relative to the good solvent. Particularly, the amount of the compound is preferably 1.0 times. In some cases, the amount of the compound added is particularly preferably 1.05 times. As a method of adding the poor solvent, a method of continuously adding for a long time by a method such as dropwise addition is preferable. Stirring is preferably performed when the poor solvent is added. The addition rate varies depending on the amount of the compound to be used, the concentration of the compound in the solution, the kind of the good solvent and the poor solvent to be used, and when water is added to a tetrahydrofuran solution of the compound as the poor solvent, the addition may be carried out over a period of 1 to 3 hours.

The temperature at the time of adding the poor solvent is preferably 50 ℃ or lower, more preferably 40 ℃ or lower, and still more preferably 35 ℃ or lower, and preferably 0 ℃ or higher, more preferably 10 ℃ or higher, and still more preferably 25 ℃ or higher at the lower limit.

When the formed crystal is obtained, it is generally obtained by adding a poor solvent and then subjecting the mixture to ice cooling for 1 to 24 hours, preferably 1 to 5 hours.

Since the compound can inhibit inflammatory edema, allergic edema, acetic writhing reaction and rat adjuvant arthritis in mice when administered orally at 0.1 to 500mg/kg, and no death is observed even when administered orally at 500 mg/kg/day for 3 days, the compound is a safe compound as a drug for mammals (preferably pets such as humans, dogs and cats, companion animals or livestock), and is a useful substance as an active ingredient of the drug. As a drug to be used in mammals (preferably, pets such as humans, dogs and cats, companion animals, and livestock), any of a variety of prophylactic and/or therapeutic agents for various diseases or pathological conditions (i.e., inflammatory diseases, allergic diseases, autoimmune diseases, and pain) in which a state of various acute or chronic inflammatory reactions due to the production of prostaglandins and/or leukotrienes is confirmed can be cited as a preferable example.

When the compound is used as the above-mentioned drug, an effective amount of the compound may be used as it is or mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition, and as the carrier, for example, a suspending agent such as carboxymethyl cellulose or other known carriers may be used. As an example, a method of suspending the compound of the present invention in purified water containing 0.5% of carboxymethylcellulose and using it is mentioned.

Examples of dosage forms used for the preparation of the pharmaceutical composition include tablets, powders, granules, syrups, suspensions, capsules, injections, and the like, and in view of the properties of crystals of the present compound, the pharmaceutical composition is particularly preferably a dry preparation. For this production, various carriers corresponding to these preparations can be used. Examples of carriers for oral preparations include excipients, binders, lubricants, flowability improvers, and colorants.

When the compound of the present invention is formulated into a non-oral preparation such as an injection, distilled water for injection, physiological saline, an aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, or the like is generally used as a diluent. Further, a bactericide, a preservative, a stabilizer, an isotonic agent, a soothing agent, and the like may be added as necessary.

When the compound of the present invention is administered to mammals (e.g., humans), the compound may be administered orally in the form of tablets, powders, granules, suspensions, capsules, or parenterally in the form of injections (including drops), suppositories, gels, lotions, ointments, creams, or sprays. The dosage varies depending on the indication of application, the administration method, the age, body weight, and degree of symptoms of the patient, and is generally 1 to 1000mg per day for an adult, and is administered in 1 to 3 divided doses. The administration period is generally several days to 2 months of continuous daily administration, but the amount and period of daily administration may be increased or decreased depending on the symptoms of the patient.

Further, as analogous compounds to the compounds of the present application, the following compounds can be cited, and these compounds can also be produced by the method of International publication WO 03/70686 or the production method described in the present specification.

3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (1, 2-indan-2-yloxy) phenyl ] propionic acid;

3- [4- (1, 2-indan-2-yloxy) -3- (N-methylamino) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [4- (1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) -3- (N-methylamino) phenyl ] propionic acid;

3- [5- (1-ethyl-1H-indazol-5-yl) -4- (1, 2-indan-2-yloxy) -3- (N-methylamino) phenyl ] propionic acid;

3- [ 3-amino-4- (4-fluoro-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5-fluoro-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-difluoro-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (1-hydroxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (4-hydroxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5-hydroxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dihydroxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (4-methoxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5-methoxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dimethoxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (4-benzyloxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dibenzyloxy-1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (4-fluoro-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5-fluoro-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-difluoro-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (1-hydroxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (4-hydroxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5-hydroxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dihydroxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-5- (1H-indazol-5-yl) -4- (4-methoxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-5- (1H-indazol-5-yl) -4- (5-methoxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dimethoxy-1, 2-indan-2-yloxy) -5- (-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (4-benzyloxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dibenzyloxy-1, 2-indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (4-fluoro-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (5-fluoro-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-difluoro-1, 2-indan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (1-hydroxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (4-hydroxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (5-hydroxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dihydroxy-1, 2-indan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (4-methoxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (5-methoxy-1, 2-indan-2-yloxy) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dimethoxy-1, 2-indan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid;

3- [ 3-amino-4- (4-benzyloxy-1, 2-indan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid and isomers thereof;

3- [ 3-amino-4- (5, 6-dibenzyloxy-1, 2-indan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid.

Examples

The present invention will be described in further detail with reference to examples and test examples, but the present invention is not limited to these examples.

(example 1)

Preparation example 1 of crystalline methyl 3- [4- (1, 2-indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl ] propionate (Compound 2 herein)

THF (40ml) was added to methyl 3- [ 3-bromo-4- (1, 2-indan-2-yloxy) -5-nitrophenyl ] propionate (14.00g, prepared by the method of International publication WO 03/70686), 1-methyl-1H-indazole-5-boronic acid (7.62g, prepared by the method of International publication WO 03/70686), palladium acetate (75mg, manufactured by Wako pure chemical industries, Ltd.), triphenylphosphine (0.17g, manufactured by Wako pure chemical industries, Ltd.), and after stirring, a solution in which tripotassium phosphate (16.97g, manufactured by Wako pure chemical industries, Ltd.) was dissolved in water (27ml) was added to replace the system with nitrogen. Then, the mixture was stirred at 60 ℃ for 4 hours to effect a reaction. After completion of the reaction, liquid separation was carried out to obtain an upper layer, and the upper layer was cooled to room temperature, and then ethyl acetate (40ml) and activated carbon (2.8g, manufactured by Nippon environmental chemical Co., Ltd.) were added and stirred at room temperature for 1 hour. The suspension was filtered to give a filtrate, and the residue on the filter was washed with ethyl acetate (20ml) to give a washing solution, and the filtrate and the washing solution were combined and concentrated under reduced pressure to give a concentrated solution (44 g). Acetone (140ml) was then added to the concentrated solution, followed by stirring, followed by addition of water (140ml) at room temperature for 1 hour with stirring, and further stirring at room temperature for 1 hour. Then, the mixture was filtered, and the solid matter on the filter was further washed with water (70ml) to obtain a wet solid matter. The wet solid was dried under reduced pressure at 50 ℃ to obtain crystals of the title compound (15.7 g).

(examples 1 to A, B)

Preparation example 2 of crystals of Compound 2 of the present case

Crystals of the compound were obtained by using toluene instead of acetone and heptane instead of water in the subsequent operations of obtaining the concentrated solution in example 1.

Further, by using tetrahydrofuran instead of acetone in example 1 and heptane instead of water, the crystals of compound 2 of the present application can be obtained.

(example 2)

Preparation example 1 of methyl 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propanoate (Compound 3 in this case)

THF (138ml), stabilized nickel ((stabilized ニッケル) (4.42 g, manufactured by Nikkiso Co., Ltd.), and water (4ml) were added to compound 2(13.0g) prepared in the present case according to example 1, followed by stirring, replacement with hydrogen gas in the system, and stirring at 50 ℃ for 7 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was purged with nitrogen, filtered to obtain a filtrate, and the residue on the filter was washed with THF (34ml) to obtain a washing solution. The filtrate and the washing solution were combined, and activated carbon (2.6g, manufactured by Nippon environmental chemical Co., Ltd.) was added to the combined solution, followed by stirring at room temperature for 1 hour. The suspension was filtered to give a filtrate, and the residue on the filter was washed with THF (34ml) to give a washing solution. The filtrate and the washing solution were combined, and water (207ml) was added to the combined solution at room temperature for 1 hour, followed by stirring under ice cooling for 1 hour. Then, the mixture was filtered, and the solid matter on the filter was further washed with water (68ml) to obtain a wet solid matter. The wet solid was dried under reduced pressure at 50 ℃ to obtain crystals of the title compound (10.3 g).

(example 2-A, B)

Preparation example 2 of Compound 3 of the present case

By using heptane instead of water added to the mixed solution of the filtrate and the washing reagent in example 2, crystals of the present compound 3 were obtained.

By using isopropanol as the solvent, crystals of the present compound 3 can be obtained.

(example 3)

Preparation example 1 of A-type crystals of Compound 1 of the present case

Methanol (45ml) was added to the present compound 3(10.0g) obtained in example 2, followed by stirring, then, 2N aqueous sodium hydroxide solution (17.0ml) was added thereto, and basic hydrolysis was performed at 60 ℃ for 3 hours under stirring. After the reaction, the reaction mixture was cooled to 35 ℃ and 2N aqueous hydrochloric acid (17.0ml) was added thereto over 2 hours, followed by stirring at 35 ℃ for 16 hours. Then, the mixture was filtered, and the solid matter on the filter was washed with a mixture of water (27ml) and methanol (13ml) to obtain a wet solid matter. The wet solid was dried under reduced pressure at 50 ℃ to obtain 9.2g of crystals.

(example 4)

Preparation example 1 of B-form Crystal of Compound 1 of this example

Acetone (17ml) was added to the a-type crystal (1.0g) of compound 1 of the present case prepared according to example 3, and the mixture was dissolved by heating in a water bath at 60 ℃. The solution was then stirred at room temperature overnight. The resulting precipitate was filtered to give a solid on the filter. Then, drying was performed at 50 ℃ under reduced pressure, thereby obtaining 0.55g of crystals.

(example 5)

Preparation example 2 of B-form Crystal of Compound 1 of this example

Methylene chloride (31ml) was added to the form A crystal (1.0g) of compound 1 of the present application prepared in example 3, and the mixture was dissolved by heating in a water bath at 40 ℃. The solution was then stirred at room temperature overnight. The resulting precipitate was filtered to give a solid on the filter. Then, drying was performed at 50 ℃ under reduced pressure, thereby obtaining 0.81g of crystals.

This crystal was confirmed to be a B-type crystal of compound 1 of this example by showing a spectrum substantially the same as that of fig. 7 by differential scanning calorimetry analysis in test example 4 described later.

(example 6)

Preparation example 3 of B-form Crystal of Compound 1 of this case

Methanol (45ml) was added to the A-type crystal (10.0g) of compound 1 of the present case prepared according to example 3, followed by stirring, and then 2N aqueous sodium hydroxide solution (17.0ml) was added thereto, followed by stirring at 60 ℃ for 1 hour. After the mixture was cooled to 35 ℃ and a 2N aqueous hydrochloric acid solution (7.0ml) was added for 30 minutes to confirm that the pH of the mixture was 7 to 9, seed crystals (0.1g) of B-type crystals of Compound 1 prepared in example 4 were rapidly added and stirred for 10 minutes. Then, a 2N aqueous hydrochloric acid solution (10.0ml) was added to the mixture over 1 hour, and the mixture was stirred at 35 ℃ for 2 hours. The mixture was then filtered, and the solid material on the filter was washed with a mixture of water (27ml) and methanol (13ml) to obtain a wet solid material. The wet solid was dried under reduced pressure at 50 ℃ to obtain 9.7g of white crystals.

The crystal showed substantially the same spectrum as that in fig. 6 by powder X-ray diffraction measurement in test example 3 described later, and it was confirmed that the crystal was a B-type crystal of compound 1 of this example. The crystal showed substantially the same spectrum as that in fig. 7 by differential scanning calorimetry analysis in test example 4 described later, and was confirmed to be a B-type crystal.

(example 7)

Preparation example 4 of B-form Crystal of Compound 1 of the present case

Methanol (360.0ml) was added to compound 3 of the present application (80.0g) obtained by the method of example 2, followed by stirring, addition of water (36.2ml) and a 2N aqueous solution of sodium hydroxide (99.7ml), and alkaline hydrolysis at 60 ℃ for 3 hours under stirring. After the reaction, insoluble matter such as dust in the reaction mixture was filtered, and water (180.2ml) was added to the filtrate to adjust the temperature to 35 ℃. After a 2N aqueous hydrochloric acid solution (10.7ml) was added to the mixture over 8 minutes and the pH of the mixture was confirmed to be 7.9, seed crystals (0.08g) of B-type crystals of compound 1 of the present application prepared according to example 4 were quickly added thereto and stirred for 4 minutes. Then, a 2N aqueous hydrochloric acid solution (89.0ml) was added to the mixture over 111 minutes, and the mixture was stirred at 35 ℃ for 14.3 hours. The mixture was then filtered, and the solid matter on the filter was washed with a mixture of water (213.4ml) and methanol (106.7ml) to obtain a wet solid matter. To the wet solid, water (213.4ml) and methanol (106.7ml) were added to prepare a mixed solution again, and the mixed solution was stirred at 18 to 20 ℃ for 37 minutes. Then, the mixture was filtered, and the solid matter on the filter was washed with a mixture of water (21.3ml) and methanol (10.7ml) to obtain a wet solid matter. The wet solid was dried under reduced pressure at 50 ℃ to obtain 76.28g of white crystals.

(example 8)

Preparation example 1 of Mixed crystals of Compound 1

0.9g of the form A crystal of the present case of Compound 1 prepared according to example 3 was mixed with 0.1g of the form B crystal prepared according to example 4 using a mortar and pestle to obtain a mixture of 90% of the form A crystal and 10% of the form B crystal.

(example 9)

Preparation example 2 of mixed crystals of Compound 1 of the present case

0.1g of the form A crystal of the present case of Compound 1 prepared according to example 3 and 0.9g of the form B crystal prepared according to example 4 were mixed using a mortar and pestle to obtain a mixture of 10% of the form A crystal and 90% of the form B crystal.

(example 10)

Preparation example 2 of A-type crystals of Compound 1 of the present case

Compound 3(3.92kg) of the present application obtained by the method of example 2 was charged into a reaction apparatus A (model: BD-1, 30L Lift type reaction apparatus, manufactured by Asahi Techno Glass Co., Ltd.), methanol (14.08kg) was added thereto and stirred. After a 2N aqueous solution of sodium hydroxide (6.76kg) was added, the mixture was heated to 60.6 ℃ over 27 minutes. After stirring at about 60 ℃ for 4 hours and 9 minutes, the reaction mixture was cooled to 35 ℃ over 19 minutes, and the reaction mixture was filtered through a membrane filter to prepare reaction mixture 1. Further, compound 3(3.92kg) of the present application obtained in example 2 was charged into a reaction apparatus a, and methanol (14.25kg) was added thereto and stirred. After a 2N aqueous solution of sodium hydroxide (6.70kg) was added, the mixture was heated to 60.0 ℃ over 30 minutes. After stirring at about 60 ℃ for 4 hours and 30 minutes, the reaction mixture was cooled to 34.6 ℃ for 17 minutes, filtered through a membrane filter, and combined with reaction mixture 1 in reaction apparatus B (model: BD-2, 100L Lift type reaction apparatus, manufactured by Asahi Techno Glass Co., Ltd.) to prepare reaction mixture 2. The reaction solution 2 was kept at 30 to 35 ℃ and stirred for 48 minutes, and a 2N hydrochloric acid aqueous solution (13.30kg) was added dropwise thereto over 5 hours to precipitate crystals, thereby preparing a crystallization solution. Further, the resulting crystallization solution was stirred for 10 hours and 5 minutes while maintaining the temperature at about 35 ℃ and then charged into a filter (model F-9, 600mm vacuum filter, manufactured by ASAHI ENGINEERING Co., Ltd.) and filtered by suction to obtain wet crystals. A mixture of water (20.00kg) and methanol (7.88kg) was sprayed on the wet crystals on the filter, and the wet crystals were washed by suction. Then, the suction was continued and sufficient dehydration was carried out to obtain wet crystals (15.571kg) of the A-type crystals of Compound 1. In this case, the time required for obtaining wet crystals from the crystallization liquid by filtration was 1 hour and 5 minutes, the time required for washing the wet crystals on the filter with a mixed solution of water and methanol was 1 hour and 44 minutes, and the time required for dehydration was 50 minutes. The wet crystals were spread on a tray, and dried under reduced pressure at 50 ℃ for 3 days (65 hours and 52 minutes) in a dryer (model: BM-6, lamellar vacuum dryer, VAC-300PR, Espec Co., Ltd.) to obtain A-type crystals (7.402kg) of Compound 1 of the present invention.

This crystal showed substantially the same spectrum as that in fig. 3 by powder X-ray diffraction measurement in test example 3 described later, and it was confirmed that this crystal was a type a crystal of present compound 1. The crystal was confirmed to be a type a crystal of the present compound 1 by showing a spectrum substantially the same as that of fig. 4 by differential scanning calorimetry analysis in test example 4 described later.

(example 11)

Preparation example 5 of B-form Crystal of Compound 1 of this example

Compound 3(3.90kg) of the present application obtained by the method of example 2 was charged into a reaction apparatus A (model: BD-1, 30L lift type reaction apparatus, manufactured by Asahi Techno Glass Co., Ltd.), methanol (13.75kg) was added thereto and stirred. After a 2N aqueous sodium hydroxide solution (5.20kg) and water (1.75kg) were added, the mixture was heated to 60 ℃ over 42 minutes. After stirring at about 60 ℃ for 2 hours and 29 minutes, the reaction mixture was cooled to 35.0 ℃ over 13 minutes, and the reaction mixture was filtered through a membrane filter to prepare reaction mixture 1. Further, the compound 3(3.90kg) of the present application obtained in example 2 was charged into the reaction apparatus a, and methanol (13.97kg) was added thereto and stirred. After a 2N aqueous sodium hydroxide solution (5.20kg) and water (1.75kg) were added, the mixture was heated to 60 ℃ over 40 minutes. After stirring at about 60 ℃ for 2 hours and 34 minutes, the reaction mixture was cooled to 35.0 ℃ for 19 minutes, filtered through a membrane filter, and combined with reaction mixture 1 in reaction apparatus B (model: BD-2, 100L Lift type reaction apparatus, manufactured by Asahi Techno Glass Co., Ltd.) to prepare reaction mixture 2. After water (17.36kg) was added to the reaction solution 2, the solution was kept at 30 to 35 ℃, and a 2N aqueous hydrochloric acid solution (0.92kg) was added dropwise over 38 minutes with stirring, and the dropwise addition was stopped when the pH reached 7.90. Then, after adding B-type crystal (7.795g) of Compound 1 of this example, a 2N aqueous hydrochloric acid solution (9.08kg) was added dropwise over 3 hours and 50 minutes to precipitate a crystal, thereby preparing a crystallization solution. The resulting crystallization solution was stirred for 8 hours and 42 minutes while maintaining the temperature at about 35 ℃ and then charged into a filter (model F-9, 600mm vacuum suction filter, manufactured by ASAHIENGINEERING Co., Ltd.), and filtered by suction in the same manner as in example 10 to obtain wet crystals. A mixed solution of water (20.78kg) and methanol (8.10kg) was sprayed on the wet crystals obtained on the filter, and the wet crystals were washed by suction. Further, the suction was continued to sufficiently dehydrate the crystals, thereby obtaining wet crystals of the B-form crystals of the compound 1 of the present invention. In this case, the time required for obtaining wet crystals from the crystallization liquid by filtration was 8 minutes, the time required for washing the wet crystals on the filter with a mixed solution of water and methanol was 10 minutes, and the time required for dehydration was 37 minutes. To increase the purity of the wet crystals, the wet crystals were put into a mixed solution of water (21.00kg) and methanol (8.18kg) to prepare a suspension, and after washing the crystals by stirring for 34 minutes, the crystals were put into a filter (model F-9,. phi.600 mm vacuum suction filter, manufactured by ASAHI ENGINEERING K.K.). Then, a mixed solution of water (2.10kg) and methanol (0.80kg) was introduced into the filter, and the mixture was filtered by suction to obtain wet crystals, which were further continuously sucked to sufficiently dehydrate the crystals to obtain wet crystals (12.211kg) of the B-form crystal of compound 1. At this time, the time required for obtaining wet crystals from the suspension by filtration was 4 minutes, and the time required for dehydration was 16 minutes. The wet crystals were spread on a tray, and dried under reduced pressure at 50 ℃ for 3 days (71 hours and 3 minutes) in a dryer (model: BM-6, vacuum plate dryer, VAC-300PR, Espec Co., Ltd.) to obtain B-form crystals of the present compound 1 (7.412 kg).

The crystal showed substantially the same spectrum as that in fig. 6 by powder X-ray diffraction measurement in test example 3 described later, and it was confirmed that the crystal was a B-type crystal of compound 1 of this example. The crystal showed substantially the same spectrum as that of fig. 7 by differential scanning calorimetry analysis in test example 4 described later, and was confirmed to be a B-form crystal of compound 1 of this example.

(test example 1)

Measurement of filtration Rate 1

A mixture of methanol and water (mixing ratio: 1: 2) (50ml) was added to the A-type crystal (5.0g) of Compound 1 of the present application prepared in example 3, and after stirring at 25 ℃ for 30 minutes, filtration was carried out using a Kikura funnel (Kikura ロ - ト) (inner diameter: 40mm, filter paper No.3 for Kikura funnel) and a suction apparatus. At this time, it took 2 minutes 37 seconds to obtain 10ml of filtrate, 7 minutes 45 seconds to obtain 20ml of filtrate, 15 minutes 14 seconds to obtain 30ml of filtrate, and finally 25 minutes 24 seconds to obtain 40ml of filtrate. Further, the wet solid on the funnel was dried under reduced pressure at 50 ℃ to obtain 4.9g of crystals.

Then, a mixture (50ml) of methanol/water (1: 2) was added to the type B crystal (5.0g) of Compound 1 of the present invention prepared in example 4, and the mixture was stirred at 25 ℃ for 30 minutes, followed by filtration using a Fukusan funnel (inner diameter: 40mm, filter paper No.3 for Fukusan funnel) and a suction apparatus. It took 8 seconds to obtain 10ml of filtrate, 17 seconds to obtain 20ml of filtrate, 28 seconds to obtain 30ml of filtrate, and finally 2 minutes to obtain 42ml of filtrate. The wet solid on the funnel was dried under reduced pressure at 50 ℃ to obtain 4.7g of crystals.

As shown in the above examples, the time required to obtain B-type crystals may be 10 to 1 times less than the time required to obtain substantially the same amount of a-type crystals, and thus it was confirmed that the B-type crystals of the present invention have excellent filterability.

(test examples 1-2)

Measurement of filtration Rate 2

The filterability of the a-type crystal of the present compound 1 in example 10 and the filterability of the B-type crystal of the present compound 1 in example 11 were compared. For each crystal, the time required for (1) putting the crystallization liquid into a filter and sucking it to separate it into wet crystals and a mother liquid was compared with the time required for the following 3 stages; (2) then putting the mixed liquid of water and methanol into a filter with wet crystals, sucking, and cleaning the wet crystals for a certain time; (3) finally, pumping was continued until a time sufficient to reduce the water content of the wet crystals after washing, and as a result, the type a crystals were: (1)1 hour 5 minutes, (2)1 hour 44 minutes, and (3)50 minutes, whereas the B-type crystal is: (1) the excellent filterability of the B-form crystal of the present invention was confirmed in 8 minutes, (2)10 minutes, and (3)37 minutes.

(test examples 1 to 3)

Measurement of Water content after filtration

The water content of each of the crystals obtained in examples 10 and 11 was calculated from the weight of the wet crystal and the weight of the crystal after drying, and as a result, 52.5% of the a-type crystal and 39.3% of the B-type crystal were obtained, and it was confirmed that the B-type crystal of the present invention was also excellent in drying property. The results are shown in Table 1. Although examples 10 and 11 were dried for 3 days, it can be easily estimated that the B-form crystals having a low water content are low in terms of the time and energy required for actual drying.

[ TABLE 1 ]

Table 1: water content measurement results

Crystallization of	Weight of Wet crystals (kg)	Weight of crystals after drying (kg)	Water content (%)
				Type A crystal (example 10)	15.571	7.402	52.5
Form B crystals (example 11)	12.211	7.412	39.3

(test example 2)

Solubility test

10mg of the A-type crystal of the present compound 1 prepared according to example 3 and 10mg of the B-type crystal of the present compound 1 prepared according to example 4 were measured in 10mL centrifuge tubes, respectively, 3mL of the No. 1 solution (pH1.2) of the Japanese pharmacopoeia disintegration test solution was added, and the mixture was shaken at 37 ℃ for 24 hours, and then the solution was filtered, 1mL of the filtrate was measured accurately, and 1mL of acetonitrile was added accurately to prepare a sample solution.

The sample solution was measured for concentration using a standard solution having a known concentration under the following HPLC conditions to determine the solubility.

The same test was carried out for the Japanese pharmacopoeia disintegration test solution No. 2 (pH6.8) to determine the solubility.

The results are shown in Table 3.

[ TABLE 2 ]

Condition

Injection amount: 10 μ L

A detector: ultraviolet absorption photometer (measuring wavelength: 235nm)

Mobile phase: 50mmol/L sodium dihydrogen phosphate/acetonitrile mixture (55: 45)

Column: YMC-Pack Pro C18 having an inner diameter of 4.6mm and a length of 15cm (manufactured by YMC)

Column temperature: 40 deg.C

Flow rate: 1.0 mL/min

[ TABLE 3 ]

Table 3: results of solubility test

Crystallization of	Solubility (mg/mL) in the Japanese pharmacopoeia disintegration test solution No. 1 solution (pH1.2)	Solubility (mg/mL) in the Japanese pharmacopoeia disintegration test solution No. 2 solution (pH6.8)
			A type crystal	0.03	0.06
B type crystal	0.01	0.02

As shown in table 3, the solubility of the a-type crystal was 3 times that of the B-type crystal in the japanese pharmacopoeia disintegration test solution 1 (ph1.2) and the japanese pharmacopoeia disintegration test solution 2 (ph6.8), and it was confirmed that the a-type crystal of the present invention had high solubility.

(test example 3)

Powder X-ray diffraction

The crystals obtained in the examples of the present specification were subjected to powder X-ray diffraction.

[ TABLE 4 ]

Measurement conditions

An X-ray diffraction apparatus: XRD-6000 manufactured by Shimadzu corporation

An X-ray source: CuK alpha (40kV30mA)

Scanning mode: continuous

Scanning speed: 2 °/min

Scanning interval: 0.02 degree

Scanning drive shaft: theta-2 theta

Scanning range: 5-40 degree

Scattering slit: 1 degree

Light receiving slit: 0.30mm

The results of this measurement are as follows.

The crystals of the present compound 2 obtained in example 1 were measured, and the spectrum shown in fig. 1 was obtained. Characteristic peaks at 2 θ of 7.6 °, 15.3 °, 18.0 °, 21.3 ° and 26.9 ° were confirmed in the powder X-ray diffraction spectrum of the crystal of the present compound 2. Further, a peak is also observed at any one or all of 16.3 °, 20.4 °, 23.0 °, or 30.5 °, and a peak at any one of these 2 θ may be regarded as at least a characteristic peak. Further, a peak is also observed at any one or all of 11.5 °, 19.1 °, 25.1 ° or 25.8 °, and a peak at any one of these 2 θ may be regarded as at least a characteristic peak. The crystal was also judged to be a crystal by shape observation with the naked eye, and it was confirmed from the above analysis data that it was indeed a crystal.

The crystal of the present compound 3 obtained in example 2 was measured, and the spectrum shown in fig. 2 was obtained. In the powder X-ray diffraction spectrum of the crystal of the present compound 3, characteristic peaks were confirmed at 8.6 °, 12.7 °, 17.2 °, 17.6 °, 18.9 °, and 21.0 ° 2 θ. Further, a peak is also observed at any one or all of 14.7 °, 18.4 °, 19.4 ° or 22.1 °, and a peak at any one of these 2 θ may be regarded as at least a characteristic peak. Further, a peak is also observed at any one or all of 11.9 °, 14.2 °, 23.0 °, 24.7 °, 26.1 °, 26.8 °, or 32.6 °, and a peak at any one of these 2 θ may be considered to be at least a characteristic peak. The crystal was also judged to be a crystal by shape observation with the naked eye, and it was confirmed from the above analysis data that it was indeed a crystal.

Then, the a-type crystal of the present compound 1 obtained in example 3 was measured, and the spectrum shown in fig. 3 was obtained. In the powder X-ray diffraction spectrum of the a-type crystal of the present compound 1, characteristic peaks were confirmed at 6.9 °, 14.4 °, 16.4 °, 18.2 °, 25.0 ° and 27.5 ° 2 θ. Further, a peak is also observed at any one or all of 20.0 °, 20.7 °, 22.9 °, or 25.4 °, and a peak at any one of these 2 θ may be regarded as at least a characteristic peak. Further, a peak is also observed at any one or all of 10.2 °, 12.7 °, 15.0 ° or 23.8 °, and a peak at any one of these 2 θ may be considered to be at least a characteristic peak.

Then, the B-type crystal of the present compound 1 obtained in example 6 was measured, and the spectrum shown in fig. 6 was obtained. In the powder X-ray diffraction spectrum of the B-type crystal of the present compound 1, characteristic peaks were identified at 14.4 °, 15.9 °, 17.3 °, 22.2 ° and 22.9 ° 2 θ. Further, a peak is also observed at any one or all of 8.6 °, 9.8 °, 21.2 °, 23.6 ° or 28.4 °, and a peak at any one of these 2 θ may be regarded as at least a characteristic peak. Furthermore, a peak is also observed at any one or all of 12.6 °, 18.0 °, 18.3 °, 18.8 °, 19.2 °, 19.8 °, 20.4 °, 25.3 °, 26.6 °, or 31.8 °, and a peak at any one of these 2 θ points may be considered to be at least a characteristic peak.

(test example 3-2)

Method for measuring crystal purity

When the incorporation ratio in the case of different crystal forms in which the present compound 1 is incorporated is calculated, for example, the incorporation ratio is measured under the following conditions using a parallel beam method optical system using a rotating sample stage for powder X-ray diffraction spectroscopy. Taking the case where the type a crystal is mixed in the type B crystal as an example, a suitable peak (for example, a peak of 6.9 ± 0.2 ° as a suitable peak) is selected from the characteristic peaks of the type a crystal by using a pure type a crystal as a standard crystal, and the peak intensity of the standard crystal and the peak intensity of the sample are compared with each other for the selected peak, that is, the mixing ratio of the type a crystal in the sample can be determined by dividing the peak intensity of the sample by the peak intensity of the standard crystal.

[ TABLE 5 ]

Measurement conditions

An X-ray diffraction apparatus: RINT2200Ultima +/PC manufactured by Physics corporation

The determination method comprises the following steps: parallel beam method using a rotating sample table

An X-ray source: CuK alpha (40kV50mA)

Scanning mode: continuous

Scanning speed: 2 °/min

Scanning interval: 0.02 degree

Scanning drive shaft: theta-2 theta

Scanning range: 3-40 degree

Scattering slit: open and open

Light receiving slit: open and open

Rotating speed of a sample table: 120rpm

(test example 4)

Differential scanning calorimetry

1 to 3mg of the crystals obtained in examples 3 and 4 described herein were placed on an open aluminum pan, and measured at 50 to 220 ℃ at a temperature rising rate of 10 ℃/min under a dry nitrogen atmosphere using a PYRIS Diamond DSC differential scanning calorimeter manufactured by Perkinelmer. Alternatively, the measurement was carried out at a temperature rise rate of 10 ℃ per minute from 50 ℃ to 220 ℃ using a DSC3200DSC differential scanning calorimeter manufactured by Bruker AXS.

The results are as follows.

The a-type crystal of the present compound 1 obtained in example 3 was measured, and the results obtained gave a graph shown in fig. 4. In differential scanning calorimetry analysis of the a-type crystal of compound 1 of the present application, an endothermic peak was observed at about 182 ℃. Note that no peak showing a hydrate or a solvate was particularly observed.

Further, the B-form crystal of compound 1 of the present invention obtained in example 4 was measured, and the results obtained were shown in fig. 7. In the differential scanning calorimetry analysis of the form B crystal of Compound 1 of the present application, an endothermic peak was observed at about 203 ℃. Note that no peak showing a hydrate or a solvate was particularly observed.

The crystal prepared in example 10 also has substantially the same pattern as that of fig. 4, and the description thereof is similar to that of the a-type crystal. The crystal patterns of examples 5 to 7 and 11 are substantially the same as those of FIG. 7, and the B-form crystal will be described.

In the present invention, although it cannot be said that the compound of the present invention becomes a hydrate or solvate, it is preferably a non-hydrate (a hydrate), or more preferably a non-solvate (a hydrate).

(test example 5)

Infrared absorption spectrum analysis

The crystals obtained in examples 3 and 6 according to the present specification were measured by potassium bromide tableting method.

The results are as follows.

The a-type crystal of the present compound 1 obtained in example 3 was measured, and the spectrum shown in fig. 5 was obtained. As a result, the A-type crystal of Compound 1 of the present invention absorbs infrared lightIn the spectrum, at a wave number of 3361cm^-1、2938cm^-1、1712cm^-1、1204cm^-1、1011cm^-1And 746cm^-1A distinct infrared absorption band was confirmed. And, also at 3443cm^-1、3349cm^-1、1620cm^-1、1515cm^-1、1480cm^-1Or 1278cm^-1An infrared absorption band is observed at any one or all of these wave numbers, and a peak at any one of these wave numbers can be considered to be at least a characteristic peak. Further, 3473cm^-1、1585cm^-1、1432cm^-1、1343cm^-1、1159cm^-1、781cm^-1Or 615cm^-1An infrared absorption band is observed at any one or all of these wave numbers, and a peak at any one of these wave numbers can be considered to be at least a characteristic peak.

Then, the B-type crystal of the present compound 1 obtained in example 6 was measured, and the spectrum shown in fig. 8 was obtained. In the infrared absorption spectrum of the B-type crystal, the wavenumber is 2939cm^-1、1720cm^-1、1224cm^-1、1016cm^-1And 751cm^-1A distinct infrared absorption band was confirmed. And, also at 3407cm^-1、3358cm^-1、1513cm^-1、1476cm^-1Or 852cm^-1An infrared absorption band is observed at any one or all of these wave numbers, and a peak at any one of these wave numbers can be considered to be at least a characteristic peak. Further, 3447cm^-1、3325cm^-1、1615cm^-1、1339cm^-1、1157cm^-1、945cm^-1、783cm^-1And 617cm^-1An infrared absorption band is observed at any one or all of these wave numbers, and a peak at any one of these wave numbers can be considered to be at least a characteristic peak.

(test example 6)

Quantitative determination of crystallization

A standard curve for the quantification of type A crystals was prepared by placing 0.4mg, 0.8mg, 1.2mg, 1.6mg, 2.0mg, 2.4mg, 2.8mg, and 3.2mg of a type A crystal standard of the present compound 1 in an open aluminum pan, measuring the temperature from 50 ℃ to 220 ℃ at a temperature rise rate of 50 ℃/min in a dry nitrogen atmosphere using a PYRIS Diamond DSC differential scanning calorimeter manufactured by Perkinelmer, and determining the area (mJ) of the endothermic peak at about 185 ℃.

Then, 0.4mg, 0.8mg, 1.2mg, 1.6mg, 2.0mg, 2.4mg, 2.8mg, and 3.2mg of a B-type crystal standard of the present compound 1 were placed on an open aluminum pan, and measured from 50 ℃ to 220 ℃ at a temperature rise rate of 50 ℃/min in a dry nitrogen atmosphere using a PYRIS Diamond DSC differential scanning calorimeter manufactured by Perkinelmer, to obtain the area (mJ) of the endothermic peak at about 205 ℃ to prepare a calibration curve for the quantification of B-type crystal.

The standard curve for form A is shown in FIG. 9.

And, the standard curve of the B-type crystal is shown in FIG. 10.

It was confirmed that both the A-type crystal and the B-type crystal can be quantified.

As a type a crystal standard, a crystal obtained by the method according to example 3 of the present application, which has a particularly preferable shape and shows a characteristic single endothermic peak by differential scanning calorimetry, was used. Further, as a type B crystal standard, a crystal obtained by the method according to example 4 of the present application, which has a particularly preferable shape and shows a characteristic single endothermic peak by differential scanning calorimetry, was used.

(test example 7)

Quantification of the Compounds of the present case

The compounds of the present invention were detected and quantified by the following HPLC conditions.

[ TABLE 6 ]

Condition

Sample concentration: 0.2mg/mL (Compounds 1 and 3 in this case: dissolving Compound 2 in a Water/acetonitrile mixture (1: 1): acetonitrile)

Injection amount: 10 μ L

A detector: ultraviolet absorption photometer (measuring wavelength: 235nm)

Column temperature: 40 deg.C

Mobile phase A: 50mmol/L sodium dihydrogen phosphate

Mobile phase B: acetonitrile

Liquid feeding procedure: the mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 7 to control the concentration gradient

Flow rate: 1.0 mL/min

[ TABLE 7 ]

Table 7: liquid feeding procedure

Time after injection (minutes)	Mobile phase A (%)	Mobile phase B (%)
			0～45	65→20	35→80
45～60	65	35

As a result, as the retention time, a peak was observed at about 15 minutes for compound 1 of the present application, at about 30 minutes for compound 2 of the present application, and at about 25 minutes for compound 3 of the present application.

Standard curves were obtained using known amounts of each standard of the present compounds. The standard curve is linear.

This HPLC confirmed that the present compound can be quantitatively measured.

(test example 8)

PGE in stimulation of MG-63 cells with IL-1 beta₂Inhibition of production of

The compound of the present invention was examined for PGE caused by Interleukin (IL) -1. beta. as an inflammatory stimulant according to the method of International publication WO 03/70686₂Resulting in the inhibition effect.

As a result, any of the compounds obtained by the methods described in examples 1 to 9 inhibited PGE induced by IL-1. beta. by 50% or more at a concentration of 0.1. mu.M₂Is generated. In addition, at this concentration, each test compound showed no cytotoxic effect. Therefore, the compound is useful as a drug having an inhibitory effect on the production of inflammatory prostaglandins.

(test example 9)

Preventive and therapeutic effects on adjuvant arthritis in rats

The inhibitory effect of the compound of this example on foot edema in rat adjuvant arthritis, which is a pathological model of chronic rheumatoid arthritis, a chronic inflammatory disease as one of autoimmune diseases, was examined according to the method of international publication No. WO 03/70686. The test compound is suspended in purified water containing 0.5% methylcellulose, and administered orally to the test animal in an amount of 0.1 to 50mg/0.2 ml/kg.

The results showed that any of the compounds obtained in examples 3 and 6 had inhibitory effects on foot edema in adjuvant arthritis, compared to the positive control group.

In addition, no dead cases of test animals were observed in this test. Therefore, the compounds of the present invention are useful as prophylactic and/or therapeutic agents for chronic rheumatoid arthritis and autoimmune diseases.

(test example 10)

Scanning Electron Microscope (SEM) Observation

The crystals obtained in examples 3 and 4 described in the present specification were observed by SEM.

As a result of measuring the a-type crystal of the present compound 1 of example 3, an SEM photograph shown in fig. 11 was obtained.

As a result of measuring the B-form crystal of the present compound 1 of example 4, an SEM photograph shown in fig. 12 was obtained.

However, these are given for reference purposes only, and the characteristics of any crystal of the present invention are not limited to the electron microscope image and are not necessarily limited to these.

Claims

1. A crystal composed of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid, which is a type a crystal having characteristic peaks at 2 θ of 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° in a powder X-ray diffraction spectrum, and further having characteristic peaks at 2 θ of 20.0 ± 0.2 °, 20.7 ± 0.2 °, 22.9 ± 0.2 ° and 25.4 ± 0.2 °.

2. The crystal according to claim 1, further having characteristic peaks at 10.2 ± 0.2 °, 12.7 ± 0.2 °, 15.0 ± 0.2 ° and 23.8 ± 0.2 ° in 2 Θ.

3. The crystal of claim 1 or 2, having a powder X-ray diffraction spectrum substantially as shown in figure 3.

4. The crystal of claim 1 or 2, wherein the form a crystal has an endotherm at about 182 ℃ in differential scanning calorimetry at a temperature rise rate of 10 ℃/min.

5. The crystal according to claim 1 or 2, wherein the form A crystal has a wavenumber of 3361cm in the infrared absorption spectrum^-1、2938cm^-1、1712cm^-1、1204cm^-1、1011cm^-1And 746cm^-1With an infrared absorption band in the vicinity.

6. A pharmaceutical composition comprising the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of claims 1 to 5 as an active ingredient, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier is a dry substance and the pharmaceutical composition is a dry formulation.

8. A pharmaceutical composition comprising the form A crystal having a crystal purity of at least 90% by weight, which is the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of claims 1 to 5, as an active ingredient, and a pharmaceutically acceptable carrier.

9. The process for producing the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to any one of claims 1 to 5, wherein the 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid solution is prepared from 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid by adding an acid to the solution under basic conditions Propionic acid, and then obtaining the crystal.

10. The method for producing the form A crystal of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid according to claim 9, wherein the solution of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl ] propionic acid in the presence of the base is an alkyl ester of 3- [ 3-amino-4- (1, 2-indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid having 1 to 4 carbon atoms The alkaline hydrolysate of (2).