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WO2023068253A1 - Nouvelle forme cristalline de composé de benzothiophène et son procédé de production - Google Patents

Nouvelle forme cristalline de composé de benzothiophène et son procédé de production Download PDF

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Publication number
WO2023068253A1
WO2023068253A1 PCT/JP2022/038720 JP2022038720W WO2023068253A1 WO 2023068253 A1 WO2023068253 A1 WO 2023068253A1 JP 2022038720 W JP2022038720 W JP 2022038720W WO 2023068253 A1 WO2023068253 A1 WO 2023068253A1
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Prior art keywords
crystal
crystals
thiophen
butoxy
quinolin
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PCT/JP2022/038720
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English (en)
Japanese (ja)
Inventor
怜 大塚
亮平 江藤
慎 深名
伸也 森
菜沙 坂本
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel method for producing a benzothiophene compound, a novel crystal form obtained during the method, and the like. It should be noted that the contents of all documents described in this specification (especially Patent Document 1 and Patent Document 2 below) are incorporated herein by reference.
  • brexpiprazole 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as brexpiprazole or compound (I)) is It has dopamine D2 receptor partial agonistic action, serotonin 5- HT2A receptor antagonistic action and adrenergic ⁇ 1 receptor antagonistic action. In addition to these actions, compound (I) is known to have a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) and has a wide therapeutic spectrum for central nervous system diseases (particularly schizophrenia). (Patent Document 1).
  • brexpiprazole or a dihydrate of its salt is stable and is a pharmacologically active substance that is particularly effective when used as an intramuscular injection (Patent Document 2).
  • the brexpiprazole dihydrate is a crystal that can be a better therapeutic drug for central nervous system diseases (hereinafter, the brexpiprazole dihydrate crystal is referred to as "Form I" or "hydrate form I”).
  • the brexpiprazole dihydrate is obtained by dissolving brexpiprazole in an acid (e.g., acetic acid or lactic acid)-containing solvent and neutralizing it with an alkali (e.g., sodium hydroxide) to crystallize (neutralization crystallization), low-temperature aging (for example, 5° C. or less for about 1 hour), and further high-temperature aging (for example, 20-30° C. for about 7 hours).
  • an acid e.g., acetic acid or lactic acid
  • an alkali e.g., sodium hydroxide
  • the present inventors conducted repeated studies to find a method for preparing hydrate form I crystals with a large particle size with good reproducibility. Then, brexpiprazole is dissolved in an alkali (e.g., sodium hydroxide)-containing solvent, cooled to crystallize (cooling crystallization), water is added, and then aged at high temperature to give hydrate I It was found that crystals of this type could be prepared. They also found that hydrate form I crystals having a large particle size can be obtained with good reproducibility by the production method, and that the crystals obtained by the cooling crystallization are novel crystals.
  • an alkali e.g., sodium hydroxide
  • Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 9.
  • An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 1 to 7 is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours.
  • Item 13 The powder X-ray diffraction pattern of the crystal is a pattern measured using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans).
  • EMPYREAN X-ray diffractometer
  • MHC-trans humidification measurement attachment
  • (1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one of Items 2a to 4a.
  • Item 6a Item 5a, wherein the cooling temperature in step (1) is 10 to 40°C.
  • An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 2a to 4a is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours.
  • a production method capable of reproducibly preparing crystals of brexpiprazole dihydrate having a relatively large particle size, and a novel crystal that is a precursor for preparing the stable crystal are provided.
  • the novel crystals are crystals that can be prepared during the production method. can get.
  • the large particle size of the dihydrate crystals can improve filterability and reduce operating time.
  • FIG. 4 shows the infrared absorption spectrum of brexpiprazole hydrate crystals X4 having a water content of 10.4% obtained in Production Example 4.
  • FIG. 1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X3 having a water content of 37.6% obtained in Production Example 3.
  • FIG. 1 shows the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 1.
  • FIG. 2 shows the measurement results of the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 2.
  • 1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X6 having a water content of 50.5% obtained in Production Example 6.
  • FIG. The powder X-ray diffraction pattern of the brexpiprazole hydrate crystals X6 obtained in Preparation Example 6 at 25° C. and each relative humidity (RH), measured by copper radiation with ⁇ 1.5418 ⁇ through a monochromator, is shown in FIG. show.
  • RH relative humidity
  • Crystals encompassed by the present disclosure are 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) or It is a salt hydrate crystal.
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) has the following formula (I):
  • salts of compound (I) include salts described in Patent Document 1, and more specifically, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); , triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine
  • alkali metal salts e.g., sodium salts, potassium salts, etc.
  • Compound (I) or a salt thereof can be produced by a known method (for example, the method described in Patent Document 1 or 2).
  • a hydrate crystal of compound (I) or a salt thereof included in the present disclosure has at least one of the following characteristics (i) and (ii), and more preferably has both characteristics.
  • the crystal may be referred to as "the crystal of the present disclosure”.
  • diffraction angles 2 ⁇ (°) 11.4 ⁇ 0.2, 12.4 ⁇ 0.2, 15.8 ⁇ 0.2, 18.2 ⁇ 0.2, and 22.8 ⁇ 0.2
  • the crystals of the present disclosure preferably have the 5 or 6 peaks when the water content of the crystals is 30-45%, more preferably 30-40%.
  • Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS).
  • the specific peaks of these diffraction angles 2 ⁇ may shift slightly depending on the water content (moisture content).
  • the diffraction angle tends to shift slightly to the high angle side.
  • the table below shows the values of the above-mentioned specific peaks when the water values of the crystals of the present disclosure are between 30 and 45%, as well as the above-mentioned specific peak values when the water values of the crystals of the present disclosure are between 45-55%. Peak values are indicated.
  • the water content value of the crystal is the value (% by weight) measured by the Karl Fischer method (coulometric titration method).
  • Karl Fischer method coulometric titration method
  • it can be measured using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
  • Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans)).
  • EMPYREAN X-ray diffractometer manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans)
  • the measurement under a specific relative humidity means that the crystal of the present disclosure is allowed to stand under the specific temperature and relative humidity, the mass is observed, and the measurement is performed when the mass change has stabilized. means to do
  • the infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
  • an infrared spectrophotometer for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation.
  • one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption band wavenumbers (cm -1 ) may be ⁇ 10, ⁇ 9, ⁇ 8, ⁇ 7, ⁇ 6, ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1.
  • the present inventors dissolved brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent, crystallized it by cooling (cooling crystallization), added water, and then dissolved at high temperature. It was found that hydrate form I crystals can be prepared by aging, and that the production method yields hydrate form I crystals having a large particle size with good reproducibility.
  • the crystals of the present disclosure were found as crystals obtained by the cooling crystallization.
  • the crystal of the present disclosure can be preferably used as a precursor of hydrate form I crystal. By the method for preparing hydrate form I crystals using the crystals of the present disclosure, hydrate form I crystals can be obtained with good reproducibility. Furthermore, it is also possible to efficiently obtain hydrate form I crystals having a large particle size.
  • brexpiprazole can be prepared by a known method, for example, by the method described in Patent Document 1 or 2.
  • the crystals of the present disclosure are prepared, for example, by dissolving brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent and crystallizing it by cooling (cooling crystallization). can do.
  • alkali e.g., sodium hydroxide
  • the present disclosure preferably also includes methods for producing the crystals of the present disclosure.
  • the method for producing crystals of the present disclosure preferably includes (1) cooling an aqueous alcohol solution in which brexpiprazole and an alkali are dissolved.
  • the cooling temperature here is a temperature lower than the temperature at which brexpiprazole is dissolved, specifically 40° C. or less. About 10 to 40°C is preferable, and about 15 to 40°C is more preferable. Furthermore, it is preferably about 15 to 35°C.
  • alkalis examples include sodium hydroxide and potassium hydroxide, with sodium hydroxide being particularly preferred.
  • alcohols include monohydric alkyl alcohols having 1 to 4 carbon atoms, such as ethanol and propanol (n-propanol, isopropanol), with ethanol being particularly preferred.
  • the alcohol content of the alcohol aqueous solution here is preferably about 45 to 55% by mass.
  • the content of brexpiprazole is about 1 to 10% by mass, more preferably about 3 to 6% by mass, and the content of alkali is preferably about 1 to 5% by mass, more preferably about 1 to 3% by mass. is.
  • the method for producing crystals of the present disclosure includes (0) mixing brexpiprazole, alkali, alcohol, and water to obtain a solution in which brexpiprazole is dissolved before step (1).
  • the mixing ratio of each component can be the same mixing ratio as described in step (1) above.
  • brexpiprazole when dissolving brexpiprazole in an alkali-containing solvent, add 4 to 6 equivalents of sodium hydroxide to 50 to 60% by volume ethanol aqueous solution, and add an appropriate amount of brexpiprazole (for example, to the aqueous ethanol solution). about 1 to 5% by mass), mixed (preferably at a temperature of about 80 to 85° C. and stirred under reflux) to prepare a brexpiprazole solution, and the solution is cooled (dissolved at a temperature lower than the temperature at which the crystals of the present disclosure were obtained.
  • the cooling temperature is, for example, about 10 to 40.degree. C., more preferably about 15 to 40.degree.
  • the upper or lower limit of the cooling temperature may be 15, 20, 25, 30, or 35°C, for example.
  • the cooling temperature may be about 15-35°C.
  • step (1) with or without isolation of the crystals of the present disclosure, (2) further water is added to the cooled aqueous solution, and (3) high temperature aging.
  • a method for producing the dihydrate of siprazole or a salt thereof is also preferably included in the present disclosure.
  • the amount of water to be added in (2) is, for example, 0.3 to 3 times the volume of the cooled aqueous solution.
  • the upper or lower limit of the range may be, for example, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, or 2.5.
  • the range may be 0.4 to 1 volume, or 0.4 to 0.8 volume.
  • the temperature of the water to be added is preferably about the same as that of the cooled aqueous solution, such as 10 to 40°C, more preferably 15 to 40°C, and even more preferably 15 to 35°C.
  • water may be added and further stirred.
  • the stirring time can be appropriately set, for example, about 1 to 72 hours.
  • the high-temperature aging in (3) can be carried out by standing or stirring at a temperature higher than the cooling temperature (for example, 35 to 50°C, more preferably 35 to 45°C).
  • the standing or stirring time is preferably 10 minutes or longer, more preferably about 10 minutes to 19 hours.
  • the upper or lower limit of the stirring time (10 minutes to 19 hours) may be, for example, about 1, 2, 3, 5, 10, or 15 hours.
  • Dihydrate crystals (hydrate form I crystals) of brexpiprazole or a salt thereof having a large average particle size can be obtained with good reproducibility.
  • the dihydrate crystals of brexpiprazole or a salt thereof prepared as described above are sometimes referred to as "hydrate Form I crystals of the present disclosure.” It can also be said that the hydrate Form I crystals of the present disclosure can be prepared using the crystals of the present disclosure as precursors.
  • the hydrate form I crystal of the present disclosure preferably has an average particle size of 26 ⁇ m or more, more preferably 35 or 45 ⁇ m or more.
  • the upper limit is not particularly limited, for example, 60 ⁇ m or less is exemplified, and 55 or 50 ⁇ m or less may be exemplified.
  • the average particle size in this specification is the volume average size measured by a laser diffraction method.
  • an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
  • FT-IR IRAffinity-1S Fourier transform infrared spectrophotometer
  • the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc. .
  • the water content of crystal X3 obtained in Production Example 3 was 37.6%. Moreover, the powder X-ray diffraction pattern measurement results are shown in FIG. 1 and Table 1b. Table 1b shows characteristic peaks.
  • the crystal X4 obtained in Production Example 4 was placed in a desiccator adjusted to a relative humidity of about 7%, left to stand for 16 hours, and further dried.
  • the moisture content of the dried crystals obtained in this manner was measured in the same manner as described above and found to be 10.4%.
  • the infrared absorption spectrum of this dried crystal was also measured in the same manner as described above.
  • Figures 3a to 3b show the measurement results of the infrared absorption spectrum.
  • the moisture values for crystals X3 and X4 whose results are shown in Figures 3a-3b are given in the table below.
  • Powder X-ray diffraction pattern measurement confirms that the dihydrate crystals obtained in the above "Preparation of brexpiprazole hydrate crystals" are the same crystals as the hydrate form I crystals obtained in Patent Document 2. It was confirmed from the results and infrared absorption spectrum measurement.
  • the average particle size of the hydrate form I crystals obtained in Production Example 1 was measured using a particle size distribution analyzer (MASTERSIZER 3000) manufactured by Malvern Panalytical Co., Ltd., by a particle size measurement method based on a laser diffraction method. bottom.
  • the average particle size of the hydrate form I crystals obtained in Production Example 1 was 45.6 ⁇ m.
  • the average particle diameter here means a volume average diameter.
  • FIG. 5b the infrared absorption spectrum measurement result is shown in FIG. 5b.
  • absorption was observed near wavenumbers of 3505 cm ⁇ 1 , 2934 cm ⁇ 1 , 2810 cm ⁇ 1 , 1653 cm ⁇ 1 , 1624 cm ⁇ 1 , 1447 cm ⁇ 1 , 1223 cm ⁇ 1 and 839 cm ⁇ 1 .
  • the water content (% by weight) of the hydrate I crystals obtained in Production Example 2 was measured by the Karl Fischer method (coulometric titration method) using a water content analyzer (MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. bottom.
  • the average particle size was measured by a particle size measurement method based on a laser diffraction method using a particle size distribution analyzer (MT3300EX) manufactured by Nikkiso Co., Ltd.
  • the average particle diameter here means a volume average diameter.
  • an X-ray diffractometer (SmartLab) manufactured by Rigaku Corporation and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
  • FT-IR IRAffinity-1S Fourier transform infrared spectrophotometer
  • the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
  • the water content of crystal X6 was 50.5%.
  • 6a and Table 3 show the powder X-ray diffraction pattern measurement results. Table 3 shows characteristic peaks. Furthermore, the infrared absorption spectrum measurement result is shown in FIG. 6b.
  • the measurement was performed by a transmission method using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans).
  • Crystal X6 was allowed to stand for 24 hours in an atmosphere of 25° C. and 95% relative humidity, and subjected to powder X-ray diffraction measurement. After that, the humidity was further lowered in stages, and the relative humidity was allowed to stand for 5 hours in an atmosphere of 90% relative humidity. 3 hours each at 38, 33, and 28% humidity, 2 hours at 16% relative humidity, 3 hours at 11% relative humidity, and 5 hours at 6% relative humidity.
  • Powder X-ray diffraction measurements were performed after standing at each relative humidity.
  • Fig. 7 and Table 4 show the measurement results at relative humidity of 90%, 75%, 53%, and 33%. Table 4 shows characteristic peaks.

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Abstract

L'invention concerne un moyen grâce auquel un cristal stable dihydraté de 7-[4-(4-benzo[b]thiophèn-4-yl-pipérazin-1-yl)butoxy]-1H-quinolin-2-one ou un sel de celui-ci peut être produit de manière efficace. Plus particulièrement, l'invention concerne un procédé de production d'un cristal de dihydrate de 7-[4-(4-benzo[b]thiophèn-4-yl-pipérazin-1-yl)butoxy]-1H-quinolin-2-one ou un sel de celui-ci, le procédé comprenant les étapes consistant à : (1) refroidir une solution aqueuse d'alcool dans laquelle du 7-[4-(4-benzo [b]thiophèn-4-yl-pipérazin-1-yl)butoxy]-1H-quinolin-2-one et un alcali sont dissous ; (2) ajouter en outre de l'eau à la solution aqueuse refroidie ; et (3) laisser au repos ou agiter le résultat pendant 10 minutes à 19 heures à une température supérieure à la température de refroidissement.
PCT/JP2022/038720 2021-10-18 2022-10-18 Nouvelle forme cristalline de composé de benzothiophène et son procédé de production Ceased WO2023068253A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006316052A (ja) * 2005-04-14 2006-11-24 Otsuka Pharmaceut Co Ltd 複素環化合物
JP2015514677A (ja) * 2012-04-23 2015-05-21 大塚製薬株式会社 ベンゾチオフェン化合物又はその塩の、二水和物、及びその製造方法
US20170320862A1 (en) * 2016-05-03 2017-11-09 Cadila Healthcare Limited Process for the preparation of brexpiprazole and intermediates thereof
WO2017208251A1 (fr) * 2016-05-31 2017-12-07 Cipla Limited Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation
WO2018015354A1 (fr) * 2016-07-19 2018-01-25 Adamed Sp. Z O.O. Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé
WO2018087775A1 (fr) * 2016-11-09 2018-05-17 Msn Laboratories Private Limited, R&D Center Procédés de préparation de 7-{4-[4-(1-benzothiophén-4-yl)pipérazin-1-yl]butoxy}quinolin-2(1h)-one
WO2018172463A1 (fr) * 2017-03-22 2018-09-27 Amneal Pharmaceuticals Company Gmbh Procédé de préparation de brexpiprazole

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20200109A1 (ar) * 2012-04-23 2017-06-16 Otsuka Pharma Co Ltd مستحضر قابل للحقن

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006316052A (ja) * 2005-04-14 2006-11-24 Otsuka Pharmaceut Co Ltd 複素環化合物
JP2015514677A (ja) * 2012-04-23 2015-05-21 大塚製薬株式会社 ベンゾチオフェン化合物又はその塩の、二水和物、及びその製造方法
US20170320862A1 (en) * 2016-05-03 2017-11-09 Cadila Healthcare Limited Process for the preparation of brexpiprazole and intermediates thereof
WO2017208251A1 (fr) * 2016-05-31 2017-12-07 Cipla Limited Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation
WO2018015354A1 (fr) * 2016-07-19 2018-01-25 Adamed Sp. Z O.O. Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé
WO2018087775A1 (fr) * 2016-11-09 2018-05-17 Msn Laboratories Private Limited, R&D Center Procédés de préparation de 7-{4-[4-(1-benzothiophén-4-yl)pipérazin-1-yl]butoxy}quinolin-2(1h)-one
WO2018172463A1 (fr) * 2017-03-22 2018-09-27 Amneal Pharmaceuticals Company Gmbh Procédé de préparation de brexpiprazole

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