WO2015087853A1 - Crystal form of oxazinane compound and method for preparing same - Google Patents

Crystal form of oxazinane compound and method for preparing same Download PDF

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WO2015087853A1
WO2015087853A1 PCT/JP2014/082497 JP2014082497W WO2015087853A1 WO 2015087853 A1 WO2015087853 A1 WO 2015087853A1 JP 2014082497 W JP2014082497 W JP 2014082497W WO 2015087853 A1 WO2015087853 A1 WO 2015087853A1
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methyl
compound
degrees
triazol
methanone
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PCT/JP2014/082497
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French (fr)
Japanese (ja)
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彩 二村
信隆 服部
洋樹 浦部
有也 尾形
尚人 大崎
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大正製薬株式会社
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Priority to JP2015512427A priority Critical patent/JP5907310B2/en
Priority to CN201480068298.8A priority patent/CN105814042B/en
Publication of WO2015087853A1 publication Critical patent/WO2015087853A1/en

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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Definitions

  • the present invention relates to ( ⁇ )-(2- ⁇ [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-
  • the present invention relates to a crystalline polymorph of methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same.
  • Orexin receptor antagonists expected to be useful as therapeutic and prophylactic agents for orexin (OX) receptor-related diseases such as epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, and other diseases
  • OX orexin receptor-related diseases
  • epilepsy inflammation, immune-related diseases, endocrine-related diseases, hypertension, and other diseases
  • the present invention relates to a polymorph of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same.
  • Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
  • OX-A and OX-B act on the OX receptor.
  • the OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. .
  • the OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
  • the tissue distribution varies depending on the subtype of the OX receptor.
  • the OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves.
  • OX2 receptors are also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
  • Non-patent Documents 6 and 7 When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-patent Documents 6 and 7), the normal behavior is enhanced (see Non-Patent Document 7), and the awakening time is extended (non-patent documents). 6).
  • the effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8).
  • one aspect of the present invention is as follows: (1) having at least one of the following physical properties (a) to (c): ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl-2- It is an anhydrous crystal of (2H-1,2,3-triazol-2-yl) phenyl] methanone.
  • Another aspect of the present invention is as follows: (2) ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) in ethanol -Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried. It is a manufacturing method.
  • another aspect of the present invention is as follows: (3) having at least one of the following physical properties (a) to (c): ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone hydrate crystals.
  • another aspect of the present invention is as follows: (4) (-)-(2- ⁇ [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-in a mixed solvent of lower alcohol or acetone and water Oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried (3 ) For producing a hydrate crystal.
  • crystallization of the anhydride of a compound (A) is shown.
  • crystallization of the anhydride of a compound (A) is shown.
  • crystallization of the anhydride of a compound (A) is shown.
  • 1 shows a powder X-ray diffraction pattern of a hydrate crystal of compound (A).
  • crystallization of the hydrate of a compound (A) is shown.
  • crystallization of the hydrate of a compound (A) is shown.
  • the anhydrous crystals of compound (A) have at least one of the following physical properties (a) to (c).
  • (A) In powder X-ray diffraction (Cu-K ⁇ ), there are peaks at 2 ⁇ 8.1 degrees, 13.4 degrees, 15.6 degrees and 21.6 degrees;
  • the powder X-ray diffraction pattern of the anhydride crystal of compound (A) is as shown in FIG. 1, the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 2, and the infrared absorption spectrum is as shown in FIG.
  • the anhydrous crystals of the present invention can be obtained by the following recrystallization operation. For example, after dissolving the compound (A) in ethanol with heating, the crystals are precipitated by slow cooling, and the precipitated crystals are collected by filtration, separated from a solvent by centrifugation, etc., and then dried to obtain anhydrous crystals. Obtainable. In addition, although recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
  • the concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass.
  • the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension. Crystallization of the anhydride of compound (A) is usually carried out at 0 to 80 ° C. Drying of the anhydride of compound (A) is usually performed at 100 ° C. or lower.
  • the hydrate crystals of compound (A) have at least one of the following physical properties (a) to (c).
  • the melting point is 124-129 ° C .; or
  • (c) in the infrared absorption spectrum the characteristic absorption bands are 1627 cm ⁇ 1 , 1504 cm ⁇ 1 , 1226 cm ⁇ 1 , 1076 cm ⁇ 1 , 822 cm ⁇ 1 and 783 cm ⁇ 1 .
  • the powder X-ray diffraction pattern of the hydrate crystal of compound (A) is as shown in FIG.
  • the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 5
  • the infrared absorption spectrum is as shown in FIG.
  • the hydrate crystals of the compound (A) produced by the production method of the present invention are basically crystals of high purity.
  • the purity of the hydrate crystals is desirably high, and is preferably substantially free from other crystal forms.
  • the hydrate crystals of the compound (A) produced by the production method of the present invention can be obtained as a single crystal having a certain quality with good reproducibility. It can be stably supplied as a drug substance crystal used for the production of raw materials, and has physical properties excellent in storage stability.
  • crystallization of the hydrate of a compound (A) is demonstrated.
  • the hydrate crystals of the present invention can be obtained by the following recrystallization operation. For example, the compound (A) is heated and dissolved in a predetermined solvent, and then slowly cooled to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, and the like, and then dried to obtain a hydrate. Crystals can be obtained.
  • recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
  • the predetermined solvent for dissolving or suspending the raw material compound (A) before recrystallization includes, for example, a mixture of lower alcohol and water, or a mixture of water and an organic solvent having a property to be mixed with water.
  • Examples of the raw material compound (A) before recrystallization include anhydrous and hydrate crystals.
  • lower alcohols examples include methanol, ethanol, 1-propanol, 2-propanol and the like. Preferably, it is methanol or ethanol. More preferably, it is methanol.
  • Examples of the organic solvent having a miscibility with water include acetone, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the like. Acetone is preferred.
  • the concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass.
  • the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension. Crystallization of the hydrate of compound (A) is usually carried out at 0 to 100 ° C.
  • the hydrate of compound (A) is usually dried at 100 ° C. or lower.
  • the “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia.
  • insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
  • the crystals of the compound of the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia).
  • These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
  • These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • the compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • Elemental analysis was measured with a PerkinElmer 2400Z. Powder X-rays were measured with a Rigaku RINT 2200 Ultimate. Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with a Rigaku Thermo plus EvoTG8120. The infrared absorption spectrum was measured with IRAffinity-1 (Shimadzu Corporation). Single crystal X-ray structural analysis was measured by R-AXIS RAPID II (Rigaku). The optical rotation was measured by RUDOLPH RESERCH ANALYTICAL (Systems Engineering).
  • chloroform (1290 mL) was added to a toluene solution (320.69 g) containing 47% of glyoxylate and stirred.
  • molecular sieve 4A manufactured by Sigma-Aldrich, 289 g was added, and then cooled to 10 ° C.
  • a mixture of 3-amino-1-propanol (110.89 g) and chloroform (160 mL) was added dropwise over 20 minutes while maintaining the temperature at 16 ° C. or lower. The mixture was heated to 25 ° C. and stirred for 23 hours.
  • the mixture was cooled to 0 ° C., and a mixture of triethylamine (429.80 g) and chloroform (700 mL) was added dropwise while maintaining the temperature at 0 ° C. or lower.
  • the amine solution was added dropwise to this mixture while keeping the temperature at 7 ° C. or lower, and then the temperature was raised to 5 ° C. and stirred for 30 minutes.
  • Water (1750 mL) was added to the mixture while maintaining the temperature at 21 ° C. or lower.
  • the organic layer and the aqueous layer were separated, and water (1750 mL) was added to the organic layer.
  • NH type silica gel (manufactured by Fuji Silysia Chemical Ltd., 690 g) was added to the separated organic layer and stirred.
  • the suspension was filtered using diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (700 mL).
  • Silica gel on diatomaceous earth was transferred to another container, and chloroform (1400 mL) was added and stirred there. This suspension was filtered through diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (400 mL). The obtained filtrates were mixed and concentrated under reduced pressure.
  • Silica gel (silica gel 60 N (spherical, neutral) 63-210 ⁇ m, 450 g) manufactured by Kanto Chemical Co., Inc.) was added to the residue, and the mixture was concentrated under reduced pressure.
  • the resulting eluate was concentrated under reduced pressure.
  • chloroform (1800 mL) was added to compound (( ⁇ )-D) (200.00 g), and the mixture was cooled to 3 ° C. with stirring. To this mixture was added a mixture of triethylamine (100.55 g) and chloroform (100 mL) at the same temperature. A mixture of mesyl chloride (91.63 g) and chloroform (100 mL) was added dropwise to this mixture while maintaining 19 ° C. or lower. The reaction mixture was warmed to 23 ° C. and stirred for 5 hours. Water (1 L) was added to this mixture, and the organic layer and the aqueous layer were separated.
  • Example 1 ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl Preparation of anhydride of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A))
  • Compound (A) obtained by the method of Reference Example 5 389.00 g
  • Ethanol (7500 mL) was added to and stirred for 1 hour while heating to 60 ° C. to dissolve the solid. The solution was cooled to 2 ° C. over 3 hours with stirring.
  • Example 2 ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl Preparation of Hydrate of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A))
  • Compound (A) (250 g) obtained by the method of Example 1 was obtained.
  • ethanol (5 L) it was dissolved with heating and stirring to 61 ° C., and then filtered while hot.
  • the obtained filtrate was added dropwise to water (15 L) kept at 20-30 ° C. with stirring, and then cooled to 5 ° C.
  • the melting point was measured using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent apparatus at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere. As a result, an endothermic peak derived from melting was observed at 129 to 134 ° C.
  • the infrared spectrum was measured using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the total reflection method (ATR method) 20 times and with a resolution of 4 cm ⁇ 1 . 1626cm -1, 1497cm -1, 1227cm -1 , 1080cm -1, a peak was observed at around 818cm -1 and 785 cm -1.
  • IRAffinity-1 Fourier transform infrared spectrophotometer
  • a powder X-ray diffractometer Ultima III
  • the melting point was measured using a differential thermal balance (Thermo plus EVO TG8120)
  • Test example (measurement of orexin antagonistic activity)
  • the antagonistic activity of the test compound against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) is described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 24,000 cells, 0.1 mM MEM non-essential amino acids, 0.
  • CHO Chinese hamster ovary
  • the cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2 .
  • an assay buffer containing 25 ⁇ M Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 ⁇ L of 200 ⁇ g / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 .
  • test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 ⁇ L was added, and the mixture was incubated for 30 minutes.
  • Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 500 pM for hOX1R and hOX2R The reaction was started by diluting with an assay buffer to 1 nM and adding 50 ⁇ L of this ligand solution.
  • the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration.
  • the antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%.
  • the 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
  • the compound of the present invention is a disease regulated by OX receptor antagonism such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, It can be used as a therapeutic or prophylactic agent for eating disorders, headaches, migraines, pain, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and the like.

Abstract

Provided are: a crystal form of (-)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone, said crystal form being stable in the environment of usage thereof as a medicine; and a method for preparing the same. The present invention is crystals of (-)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which have at least one of characteristics (a) to (c): (a) in powder X-ray diffraction (Cu-Kα), peaks appear at 2θ=11.1º, 12.5º, 20.3º and 24.2º; (b) the melting point is 124 to 129 ºC; and (c) in the infrared absorption spectrum, characteristic absorption bands appear at 1627cm-1, 1504 cm-1, 1226 cm-1, 1076 cm-1, 822 cm-1 and 783 cm-1. The present invention is also a method for preparing the crystals which is characterized by comprising: dissolving (-)-(2-{[3- (5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone in a mixed solvent consisting of water and either a lower alcohol or acetone; and subjecting the solution to crystallization and then drying.

Description

オキサジナン化合物の結晶形及びその製造方法Crystal form of oxazinane compound and process for producing the same
　本発明は、（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの結晶多形及びその製造方法に関する。更に詳しくは、例えば睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患など、オレキシン（ＯＸ）受容体が関与しているとされる疾患の治療剤及び予防剤として有用性が期待されるオレキシン受容体拮抗薬である（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの結晶多形及びその製造方法に関する。 The present invention relates to (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5- The present invention relates to a crystalline polymorph of methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same. More specifically, for example, sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, Orexin receptor antagonists expected to be useful as therapeutic and prophylactic agents for orexin (OX) receptor-related diseases such as epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, and other diseases The drug (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl The present invention relates to a polymorph of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same.
　オレキシンは、視床下部外側野に特異的に発現するプレプロオレキシンからスプライシングされる神経ペプチドである。これまでに、３３個のアミノ酸からなるＯＸ－Ａおよび２８個のアミノ酸からなるＯＸ－Ｂが同定されており、これらはいずれも睡眠・覚醒パターンの調節や摂食の調節に深く関与している。 Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
　ＯＸ－ＡおよびＯＸ－Ｂは、いずれもＯＸ受容体に作用する。ＯＸ受容体は、これまでにＯＸ１およびＯＸ２受容体の２つのサブタイプがクローニングされており、いずれも主として脳内に発現する７回膜貫通Ｇタンパク質共役型受容体であることが知られている。ＯＸ１受容体は、Ｇタンパク質サブクラスのうちＧｑと特異的に共役しており、一方でＯＸ２受容体はＧｑおよびＧｉ／ｏに共役している（非特許文献１及び非特許文献２参照）。
　ＯＸ受容体のサブタイプによって組織分布は異なっており、ＯＸ１受容体はノルアドレナリン作動性神経の起始核である青斑核、ＯＸ２受容体はヒスタミン神経の起始核である結節乳頭核に高密度に発現している（非特許文献３、非特許文献４及び非特許文献５参照）。セロトニン神経の起始核である縫線核や、ドパミン神経の起始核である腹側被蓋野にはＯＸ１受容体とＯＸ２受容体両方の発現がみられる（非特許文献３参照）。オレキシン神経は脳幹と視床下部のモノアミン神経系に投射し、それらの神経に対して興奮性の影響を与えており、さらにＲＥＭ睡眠の制御に関わる脳幹のアセチルコリン神経にもＯＸ２受容体の発現がみられ、これらの神経核の活性にも影響を及ぼしている（非特許文献３及び非特許文献４参照）。 Both OX-A and OX-B act on the OX receptor. The OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. . The OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
The tissue distribution varies depending on the subtype of the OX receptor. The OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves. Furthermore, the expression of OX2 receptors is also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
　近年、ＯＸ１およびＯＸ２受容体と睡眠・覚醒調節との関連が注目されており、ＯＸ受容体拮抗作用を有する化合物の有用性が研究されている。ＯＸ－Ａをラットの脳室内に投与すると、自発運動量の亢進（非特許文献６及び非特許文献７参照）、常同行動の亢進（非特許文献７参照）、覚醒時間の延長（非特許文献６参照）などが認められる。ＯＸ－Ａの投与によるＲＥＭ睡眠時間の短縮作用は、ＯＸ受容体拮抗物質の前処置により完全に拮抗される（非特許文献８参照）。さらに、経口投与が可能なＯＸ１およびＯＸ２受容体を同程度に拮抗する物質の投与により、運動量の減少、入眠潜時の短縮、ｎｏｎ－ＲＥＭ睡眠量およびＲＥＭ睡眠の増加が報告されている（非特許文献９および非特許文献１０参照）。 In recent years, attention has been focused on the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-patent Documents 6 and 7), the normal behavior is enhanced (see Non-Patent Document 7), and the awakening time is extended (non-patent documents). 6). The effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). Furthermore, administration of substances that antagonize OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
　本発明の目的は、ＯＸ受容体拮抗作用を示し、一定の品質を有する単一の結晶として再現性良く得られ、医薬品及び医薬品原料の製造に用いられる原薬の結晶として安定的に供給されることが可能で、保存安定性に優れた物理学的特性を有する新規な化合物の結晶形と製造方法を提供することにある。 It is an object of the present invention to exhibit OX receptor antagonistic activity, be obtained with high reproducibility as a single crystal having a certain quality, and be stably supplied as a crystal of a drug substance used for manufacturing pharmaceuticals and pharmaceutical raw materials. It is possible to provide a crystal form of a novel compound having a physical property excellent in storage stability and a production method thereof.
　本発明者らは、上記課題を達成すべく鋭意研究を重ねた結果、（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン（以下、化合物（Ａ）と記すこともある）が、高いＯＸ受容体拮抗作用を示し、また物理的特性に優れた化合物（Ａ）の結晶を提供することができることを発見し、本発明を完成するに至った。さらに、化合物（Ａ）には無水物及び水和物が存在することを見出した。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl } -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (hereinafter sometimes referred to as compound (A)) Was found to be able to provide a crystal of the compound (A) exhibiting high OX receptor antagonism and excellent physical properties, thereby completing the present invention. Furthermore, it discovered that an anhydride and a hydrate existed in the compound (A).
　すなわち、本願発明の１つの態様は、
（１）下記（ａ）～（ｃ）の物性の少なくとも１つを有する、
（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの無水物の結晶である。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝８．１度、１３．４度，１５．６度及び２１．６度にピークを有する；
（ｂ）融点が１２９～１３４℃である；又は
（ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２６ｃｍ-1、１４９７ｃｍ-1、１２２７ｃｍ-1、１０８０ｃｍ-1、８１８ｃｍ-1及び７８５ｃｍ-1にある。
　また、本願発明の他の態様は、
（２）エタノールに（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンを溶解させた後、結晶化させ、乾燥させることを特徴とする（１）記載の無水物の結晶の製造方法である。
　また、本願発明の他の態様は、
（３）下記（ａ）～（ｃ）の物性の少なくとも１つを有する、
（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの水和物の結晶である。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝１１．１度、１２．５度，２０．３度及び２４．２度にピークを有する；
（ｂ）融点が１２４～１２９℃である；又は
（ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２７ｃｍ-1、１５０４ｃｍ-1、１２２６ｃｍ-1、１０７６ｃｍ-1、８２２ｃｍ-1及び７８３ｃｍ-1にある。
　また、本願発明の他の態様は、
（４）低級アルコールもしくはアセトンと水の混合溶媒に（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンを溶解させた後、結晶化させ、乾燥させることを特徴とする（３）に記載の水和物の結晶の製造方法である。 That is, one aspect of the present invention is as follows:
(1) having at least one of the following physical properties (a) to (c):
(−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- It is an anhydrous crystal of (2H-1,2,3-triazol-2-yl) phenyl] methanone.
(A) In powder X-ray diffraction (Cu-Kα), there are peaks at 2θ = 8.1 degrees, 13.4 degrees, 15.6 degrees and 21.6 degrees;
(B) the melting point is 129-134 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are at 1626 cm −1 , 1497 cm −1 , 1227 cm −1 , 1080 cm −1 , 818 cm −1 and 785 cm −1 . .
In addition, another aspect of the present invention is as follows:
(2) (−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) in ethanol -Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried. It is a manufacturing method.
In addition, another aspect of the present invention is as follows:
(3) having at least one of the following physical properties (a) to (c):
(−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone hydrate crystals.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 11.1 degrees, 12.5 degrees, 20.3 degrees and 24.2 degrees;
(B) the melting point is 124-129 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are 1627 cm −1 , 1504 cm −1 , 1226 cm −1 , 1076 cm −1 , 822 cm −1 and 783 cm −1 . .
In addition, another aspect of the present invention is as follows:
(4) (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-in a mixed solvent of lower alcohol or acetone and water Oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried (3 ) For producing a hydrate crystal.
　（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの水和物の結晶は室温付近の温度で安定な結晶であり、保存安定性に優れている。さらに、粉砕等の製剤操作によっても結晶形の転移を起こさないため、取り扱いやすく、有用な医薬品原料となりうることが確認された。 (−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- Crystals of (2H-1,2,3-triazol-2-yl) phenyl] methanone hydrate are stable at temperatures near room temperature and have excellent storage stability. Furthermore, it was confirmed that the crystal form was not changed even by preparation operations such as pulverization, so that it was easy to handle and could be a useful pharmaceutical raw material.
化合物（Ａ）の無水物の結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the crystal | crystallization of the anhydride of a compound (A) is shown. 化合物（Ａ）の無水物の結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the crystal | crystallization of the anhydride of a compound (A) is shown. 化合物（Ａ）の無水物の結晶の赤外吸収スペクトル（ＡＴＲ法）を示す。The infrared absorption spectrum (ATR method) of the crystal | crystallization of the anhydride of a compound (A) is shown. 化合物（Ａ）の水和物の結晶の粉末Ｘ線回折パターンを示す。1 shows a powder X-ray diffraction pattern of a hydrate crystal of compound (A). 化合物（Ａ）の水和物の結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the crystal | crystallization of the hydrate of a compound (A) is shown. 化合物（Ａ）の水和物の結晶の赤外吸収スペクトル（ＡＴＲ法）を示す。The infrared absorption spectrum (ATR method) of the crystal | crystallization of the hydrate of a compound (A) is shown.
　以下、本発明を実施するための形態を具体的に説明する。
　本発明の化合物である（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン（以下、化合物（Ａ）と記すことがある）は、下記に示す化学構造を有している。 Hereinafter, the form for implementing this invention is demonstrated concretely.
(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) which is a compound of the present invention [ 5-Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (hereinafter sometimes referred to as compound (A)) has the following chemical structure.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　化合物（Ａ）の無水物の結晶は、次の（ａ）～（ｃ）の物性の少なくとも１つを有する。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝８．１度、１３．４度，１５．６度及び２１．６度にピークを有する；
（ｂ）融点が１２９～１３４℃である；又は
（ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２６ｃｍ-1、１４９７ｃｍ-1、１２２７ｃｍ-1、１０８０ｃｍ-1、８１８ｃｍ-1及び７８５ｃｍ-1にある。
　化合物（Ａ）の無水物の結晶の粉末Ｘ線回折パターンは図１に、示差熱分析／熱質量測定カーブは図２に、赤外線吸収スペクトルは図３に示した通りである。 The anhydrous crystals of compound (A) have at least one of the following physical properties (a) to (c).
(A) In powder X-ray diffraction (Cu-Kα), there are peaks at 2θ = 8.1 degrees, 13.4 degrees, 15.6 degrees and 21.6 degrees;
(B) the melting point is 129-134 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are at 1626 cm −1 , 1497 cm −1 , 1227 cm −1 , 1080 cm −1 , 818 cm −1 and 785 cm −1 . .
The powder X-ray diffraction pattern of the anhydride crystal of compound (A) is as shown in FIG. 1, the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 2, and the infrared absorption spectrum is as shown in FIG.
　次に、化合物（Ａ）の無水物の結晶の製造方法について説明する。本発明の無水物の結晶は、以下のような再結晶操作により得られる。たとえば、エタノールに化合物（Ａ）を加熱溶解させた後、徐冷することにより結晶を析出させ、析出した結晶をろ取、遠心分離等により溶媒と分離した後に乾燥させることにより無水物の結晶を得ることができる。なお、再結晶は、１度のみならず２度以上繰り返してもよいが、通常は１度のみ再結晶を行う。
　化合物（Ａ）を溶解させる濃度は１～５０質量％、好ましくは５～２５質量％である。ここで質量％とは、溶液中または懸濁液中の化合物（Ａ）の無水物の質量パーセントである。
　化合物（Ａ）の無水物の結晶化は、通常０～８０℃で行う。
　化合物（Ａ）の無水物の乾燥は、通常１００℃以下で行う。 Next, a method for producing an anhydride crystal of compound (A) will be described. The anhydrous crystals of the present invention can be obtained by the following recrystallization operation. For example, after dissolving the compound (A) in ethanol with heating, the crystals are precipitated by slow cooling, and the precipitated crystals are collected by filtration, separated from a solvent by centrifugation, etc., and then dried to obtain anhydrous crystals. Obtainable. In addition, although recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
The concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass. Here, the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension.
Crystallization of the anhydride of compound (A) is usually carried out at 0 to 80 ° C.
Drying of the anhydride of compound (A) is usually performed at 100 ° C. or lower.
　化合物（Ａ）の水和物の結晶は、次の（ａ）～（ｃ）の物性少なくとも１つを有する。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝１１．１度、１２．５度，２０．３度及び２４．２度にピークを有する；
（ｂ）融点が１２４～１２９℃である；又は
（ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２７ｃｍ-1、１５０４ｃｍ-1、１２２６ｃｍ-1、１０７６ｃｍ-1、８２２ｃｍ-1及び７８３ｃｍ-1にある。
　化合物（Ａ）の水和物の結晶の粉末Ｘ線回折パターンは図４に、示差熱分析／熱質量測定カーブは図５に、赤外線吸収スペクトルは図６に示した通りである。
　図４～図６から分かるように、本発明の製造方法により製造される化合物（Ａ）の水和物の結晶は、基本的に純度の高い結晶であることが分かる。水和物の結晶の純度は高いものが望ましく、好ましくは他の結晶形のものを実質的に含まないものである。 The hydrate crystals of compound (A) have at least one of the following physical properties (a) to (c).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 11.1 degrees, 12.5 degrees, 20.3 degrees and 24.2 degrees;
(B) the melting point is 124-129 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are 1627 cm −1 , 1504 cm −1 , 1226 cm −1 , 1076 cm −1 , 822 cm −1 and 783 cm −1 . .
The powder X-ray diffraction pattern of the hydrate crystal of compound (A) is as shown in FIG. 4, the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 5, and the infrared absorption spectrum is as shown in FIG.
As can be seen from FIGS. 4 to 6, the hydrate crystals of the compound (A) produced by the production method of the present invention are basically crystals of high purity. The purity of the hydrate crystals is desirably high, and is preferably substantially free from other crystal forms.
　後述の実施例に示されるように、本発明の製造方法により製造される化合物（Ａ）の水和物の結晶は、一定の品質を有する単一の結晶として再現性良く得られ、医薬品及び医薬品原料の製造に用いられる原薬の結晶として安定的に供給されることが可能で、保存安定性に優れた物理学的特性を有する。
　次に、化合物（Ａ）の水和物の結晶の製造方法について説明する。本発明の水和物の結晶は、以下のような再結晶操作により得られる。たとえば、所定の溶媒に化合物（Ａ）を加熱溶解させた後、徐冷することにより結晶を析出させ、析出した結晶をろ過、遠心分離等により溶媒と分離した後に乾燥させることにより水和物の結晶を得ることができる。なお、再結晶は、１度のみならず２度以上繰り返してもよいが、通常は１度のみ再結晶を行う。 As shown in the examples below, the hydrate crystals of the compound (A) produced by the production method of the present invention can be obtained as a single crystal having a certain quality with good reproducibility. It can be stably supplied as a drug substance crystal used for the production of raw materials, and has physical properties excellent in storage stability.
Next, the manufacturing method of the crystal | crystallization of the hydrate of a compound (A) is demonstrated. The hydrate crystals of the present invention can be obtained by the following recrystallization operation. For example, the compound (A) is heated and dissolved in a predetermined solvent, and then slowly cooled to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, and the like, and then dried to obtain a hydrate. Crystals can be obtained. In addition, although recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
　再結晶前の原料の化合物（Ａ）を溶解、又は懸濁させる所定の溶媒とは、例えば低級アルコールと水の混液又は水と混和する性質を有する有機溶媒と水の混液が挙げられる。 The predetermined solvent for dissolving or suspending the raw material compound (A) before recrystallization includes, for example, a mixture of lower alcohol and water, or a mixture of water and an organic solvent having a property to be mixed with water.
　再結晶前の原料の化合物（Ａ）としては、無水物及び水和物の結晶が挙げられる。 Examples of the raw material compound (A) before recrystallization include anhydrous and hydrate crystals.
　低級アルコールとしては、メタノール、エタノール、１－プロパノール、２-プロパノールなどが挙げられる。好ましくは、メタノールもしくはエタノールである。さらに好ましくは、メタノールである。 Examples of lower alcohols include methanol, ethanol, 1-propanol, 2-propanol and the like. Preferably, it is methanol or ethanol. More preferably, it is methanol.
　水と混和する性質を有する有機溶媒としては、アセトン、アセトニトリル、テトラヒドロフラン（ＴＨＦ）、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、などが挙げられる。好ましくは、アセトンである。
　化合物（Ａ）を溶解させる濃度は１～５０質量％、好ましくは５～２５質量％である。ここで質量％とは、溶液中または懸濁液中の化合物（Ａ）の無水物の質量パーセントである。
　化合物（Ａ）の水和物の結晶化は、通常０～１００℃で行う。
　化合物（Ａ）の水和物の乾燥は、通常１００℃以下で行う。 Examples of the organic solvent having a miscibility with water include acetone, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the like. Acetone is preferred.
The concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass. Here, the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension.
Crystallization of the hydrate of compound (A) is usually carried out at 0 to 100 ° C.
The hydrate of compound (A) is usually dried at 100 ° C. or lower.
　本明細書中における「睡眠障害」とは、入眠時、睡眠持続相又は覚醒時の障害であり、例えば、不眠症等を挙げることができる。また、不眠症の分類としては、入眠障害、中途覚醒、早朝覚醒、熟眠障害等を挙げることができる。
　本発明の化合物の結晶は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、皮膚貼付剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術（例えば、第１５改正日本薬局方に規定する方法等）によって製造することができる。これらの投与剤型は、患者の症状、年齢、体重、及び治療の目的に応じて適宜選択することができる。
　これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤（例えば、結晶セルロース、デンプン、乳糖、マンニトール）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム）、その他薬理学的に許容される各種添加剤を配合し、製造することができる。
　本発明の化合物は、成人患者に対して１回の投与量として０．００１～５００ｍｇを１日１回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状等により適宜増減することができる。 The “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia. Examples of insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
The crystals of the compound of the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
　次に、参考例、実施例及び試験例によって本発明をさらに詳細に説明するが、本発明はこれらの内容に限定されるものではない。
　元素分析は、ＰｅｒｋｉｎＥｌｍｅｒ　２４００Ｚにて測定した。
　粉末Ｘ線は、Ｒｉｇａｋｕ　ＲＩＮＴ２２００Ｕｌｔｉｍａｌｌｌにて測定した。
　示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）は、Ｒｉｇａｋｕ　Ｔｈｅｒｍｏ　ｐｌｕｓ　ＥｖｏＴＧ８１２０にて測定した。
　赤外線吸収スペクトルは、ＩＲＡｆｆｉｎｉｔｙ－１（島津製作所）にて測定した。
　単結晶Ｘ線構造解析は、Ｒ－ＡＸＩＳ　ＲＡＰＩＤ　ＩＩ　（Ｒｉｇａｋｕ）にて測定した。
　旋光度は、ＲＵＤＯＬＰＨ　ＲＥＳＥＲＣＨ　ＡＮＡＬＹＴＩＣＡＬ　（Ｓｙｓｔｅｍｓ　Ｅｎｇｉｎｅｅｒｉｎｇ）にて測定した。
　以下の参考例および実施例において、高速液体クロマトグラフィーマススペクトル（ＬＣＭＳ）は以下の条件により測定した。
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ２９００及びＡｇｉｌｅｎｔ６１５０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝８０／２０）、１．２～１．４分（Ａ液／Ｂ液＝１／９９）
流速：０．８ｍＬ／ｍｉｎ、検出法：ＵＶ　２５４ｎｍ
イオン化法：エレクトロンスプレー法（ＥＳＩ：Ｅｌｅｃｔｒｏｎ　Ｓｐｒａｙ　Ｉｏｎｉｚａｔｉｏｎ）
　参考例及び実施例中、室温とは２５℃付近を示す。 Next, the present invention will be described in more detail with reference examples, examples and test examples, but the present invention is not limited to these contents.
Elemental analysis was measured with a PerkinElmer 2400Z.
Powder X-rays were measured with a Rigaku RINT 2200 Ultimate.
Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with a Rigaku Thermo plus EvoTG8120.
The infrared absorption spectrum was measured with IRAffinity-1 (Shimadzu Corporation).
Single crystal X-ray structural analysis was measured by R-AXIS RAPID II (Rigaku).
The optical rotation was measured by RUDOLPH RESERCH ANALYTICAL (Systems Engineering).
In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under the following conditions.
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 80/20), 1.2 to 1.4 minutes (A solution / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)
In Reference Examples and Examples, room temperature indicates around 25 ° C.
　参考例１　エチル　３－［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）ベンゾイル］－１，３－オキサジナン－２－カルボキシラート　（化合物（Ｂ））の製造　 Reference Example 1 Production of ethyl 3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxylate (compound (B))
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　窒素気流下、グリオキシル酸エチルを４７％含有したトルエン溶液（３２０．６９ｇ）に、クロロホルム（１２９０ｍＬ）を加え、攪拌した。この混合物に、モレキュラーシーブ４Ａ（シグマアルドリッチ社製、２８９ｇ）を加えた後、１０℃まで冷却した。この冷却した混合物に、１６℃以下に保ちながら３－アミノ－１－プロパノール（１１０．８９ｇ）とクロロホルム（１６０ｍＬ）の混合液を２０分かけて滴下した。この混合物を２５℃まで昇温し２３時間攪拌した。この混合物を、珪藻土を用いてろ過した後、珪藻土をクロロホルム（１６０ｍＬ）で洗浄した。得られたろ液を－７℃まで冷却した。このアミン溶液を次の反応に供した。
　窒素気流下、５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）安息香酸（３４５．００ｇ）にクロロホルム（６２１０ｍＬ）を注ぎ入れ、２４℃付近で攪拌した。この混合物に、同温度を保ちながらオキサリルクロリド（２５８．６１ｇ）とクロロホルム（１７３ｍＬ）の混合液を滴下し、１４時間攪拌した。この混合物を０℃まで冷却し、トリエチルアミン（４２９．８０ｇ）とクロロホルム（７００ｍＬ）の混合液を０℃以下に保ちながら滴下した。この混合物に、７℃以下を保ちながら上記アミン溶液を滴下した後、５℃まで昇温し３０分攪拌した。この混合物に２１℃以下を保ちながら水（１７５０ｍＬ）を加えた。有機層と水層を分離し、有機層に水（１７５０ｍＬ）を加えた。分離した有機層にＮＨ型シリカゲル（富士シリシア化学社製、６９０ｇ）を加えて攪拌した。この懸濁液を珪藻土を用いてろ過した後、クロロホルム（７００ｍＬ）で珪藻土上のシリカゲルを洗浄した。珪藻土上のシリカゲルを別容器に移し、そこにクロロホルム（１４００ｍＬ）を入れて攪拌した。この懸濁液を珪藻土でろ過し、クロロホルム（４００ｍＬ）で珪藻土上のシリカゲルを洗浄した。得られたろ液を混合し、減圧濃縮した。得られた残渣（６２６．９ｇ）にエタノール（９００ｍＬ）を加え、２４℃付近で攪拌することで結晶化させた後、５℃まで冷却した。結晶をろ取した後、冷却したエタノール（２００ｍＬ）で洗浄した。窒素気流下２５℃付近で吸引乾燥した。得られた固体を５０℃で減圧下乾燥し、無色固体の化合物（Ｂ）（４７１．８６ｇ）を得た。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　３４５　［Ｍ＋Ｈ］＋ Under a nitrogen stream, chloroform (1290 mL) was added to a toluene solution (320.69 g) containing 47% of glyoxylate and stirred. To this mixture, molecular sieve 4A (manufactured by Sigma-Aldrich, 289 g) was added, and then cooled to 10 ° C. To this cooled mixture, a mixture of 3-amino-1-propanol (110.89 g) and chloroform (160 mL) was added dropwise over 20 minutes while maintaining the temperature at 16 ° C. or lower. The mixture was heated to 25 ° C. and stirred for 23 hours. The mixture was filtered using diatomaceous earth, and the diatomaceous earth was washed with chloroform (160 mL). The resulting filtrate was cooled to -7 ° C. This amine solution was subjected to the next reaction.
Under nitrogen stream, chloroform (6210 mL) was poured into 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (345.00 g), and the mixture was stirred at around 24 ° C. A mixture of oxalyl chloride (258.61 g) and chloroform (173 mL) was added dropwise to this mixture while maintaining the same temperature, and the mixture was stirred for 14 hours. The mixture was cooled to 0 ° C., and a mixture of triethylamine (429.80 g) and chloroform (700 mL) was added dropwise while maintaining the temperature at 0 ° C. or lower. The amine solution was added dropwise to this mixture while keeping the temperature at 7 ° C. or lower, and then the temperature was raised to 5 ° C. and stirred for 30 minutes. Water (1750 mL) was added to the mixture while maintaining the temperature at 21 ° C. or lower. The organic layer and the aqueous layer were separated, and water (1750 mL) was added to the organic layer. NH type silica gel (manufactured by Fuji Silysia Chemical Ltd., 690 g) was added to the separated organic layer and stirred. The suspension was filtered using diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (700 mL). Silica gel on diatomaceous earth was transferred to another container, and chloroform (1400 mL) was added and stirred there. This suspension was filtered through diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (400 mL). The obtained filtrates were mixed and concentrated under reduced pressure. Ethanol (900 mL) was added to the resulting residue (626.9 g), and the mixture was crystallized by stirring at around 24 ° C., and then cooled to 5 ° C. The crystals were collected by filtration and washed with cooled ethanol (200 mL). Suction drying was performed at around 25 ° C. under a nitrogen stream. The obtained solid was dried under reduced pressure at 50 ° C. to obtain a colorless solid compound (B) (471.86 g).
MS (ESI pos.) M / z: 345 [M + H] +
　参考例２　［２－（ヒドロキシメチル）－１，３－オキサジナン－３－イル］［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン　（化合物（Ｃ））の製造 Reference Example 2 [2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (compound (C ))Manufacturing of
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　窒素気流下、化合物（Ｂ）（４４５．００ｇ）に０．０１Ｍ　ＮａＯＨのメタノール溶液（１６００ｍＬ）を加え、２０℃付近で攪拌した。この混合物に、２７℃以下を保ちながら、ＮａＢＨ４（９７．８ｇ）を０．０１Ｍ　ＮａＯＨ　メタノール溶液（１０００ｍＬ）に溶かした混合溶液を滴下した。この混合物を２５℃付近で２０時間攪拌した後、２０℃付近において、塩化アンモニウム（１３３．５ｇ）を加え、さらにＮａ２ＳＯ４の１０水和物（８０．２ｇ）を加えた。この混合物をろ過し、酢酸エチル（４００ｍＬ）で洗い流した。ろ液に水（２００ｍＬ）を加え、減圧濃縮した。残渣に水（３００ｍＬ）、クロロホルム（１１００ｍＬ）を加え攪拌した。析出した固体をろ別し、得られたろ液を分液し、有機層と水層に分離した。得られた水層にクロロホルム（３００ｍＬ）を加え同様に分液操作した。得られた有機層を混合し、Ｎａ２ＳＯ４（１００ｇ）を用いて乾燥した後、乾燥剤をろ別し減圧濃縮した。残渣にシリカゲル（関東化学社製　シリカゲル６０　Ｎ（球状、中性）　６３－２１０μｍ、４５０ｇ）を加え、減圧濃縮した。得られた残渣を、シリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ社製ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－Ｓｉｌを使用し、ヘキサン／酢酸エチル／アセトン＝５０：５０：０→０：１００：０→０：０：１００溶液にて溶出）で精製し、得られた溶出液を減圧濃縮した。残渣にアセトン（２００ｍＬ）を加えた後、減圧濃縮し、無色非晶質として化合物（Ｃ）（４４９ｇ）を得た。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　３０３　［Ｍ＋Ｈ］＋ Under a nitrogen stream, 0.01M NaOH methanol solution (1600 mL) was added to compound (B) (445.00 g), and the mixture was stirred at around 20 ° C. To this mixture, a mixed solution in which NaBH 4 (97.8 g) was dissolved in 0.01 M NaOH methanol solution (1000 mL) was dropped while maintaining the temperature at 27 ° C. or lower. After the mixture was stirred at around 25 ° C. for 20 hours, ammonium chloride (133.5 g) was added at around 20 ° C., and Na 2 SO 4 decahydrate (80.2 g) was further added. The mixture was filtered and rinsed with ethyl acetate (400 mL). Water (200 mL) was added to the filtrate and concentrated under reduced pressure. Water (300 mL) and chloroform (1100 mL) were added to the residue and stirred. The precipitated solid was separated by filtration, and the obtained filtrate was separated, and separated into an organic layer and an aqueous layer. Chloroform (300 mL) was added to the obtained aqueous layer, and liquid separation was performed in the same manner. The obtained organic layers were mixed and dried using Na 2 SO 4 (100 g), and then the desiccant was filtered off and concentrated under reduced pressure. Silica gel (silica gel 60 N (spherical, neutral) 63-210 μm, 450 g) manufactured by Kanto Chemical Co., Inc.) was added to the residue, and the mixture was concentrated under reduced pressure. The obtained residue was eluted with a silica gel column chromatography (SNAPCartridge KP-Sil manufactured by Biotage, Inc., hexane / ethyl acetate / acetone = 50: 50: 0 → 0: 100: 0 → 0: 0: 100). The resulting eluate was concentrated under reduced pressure. Acetone (200 mL) was added to the residue, and the mixture was concentrated under reduced pressure to give Compound (C) (449 g) as a colorless amorphous substance.
MS (ESI pos.) M / z: 303 [M + H] +
　参考例３　（－）－［２－（ヒドロキシメチル）－１，３－オキサジナン－３－イル］［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン　（化合物（（－）－Ｄ））の製造　 Reference Example 3 (-)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone Production of (compound ((-)-D))
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　窒素気流下、化合物（Ｃ）（２００．５０ｇ）、酢酸ビニルモノマー（１６０４ｍＬ）、メチルｔ―ブチルエーテル（６４１６ｍＬ）の混合物に、ブタ膵臓由来リパーゼ（商品名　Ｌｉｐａｓｅ　ｆｒｏｍ　ｐｏｒｃｉｎｅ　ｐａｎｃｒｅａｓ　Ｔｙｐｅ　ＩＩ、ＳＩＧＭＡ社製、４０１．００ｇ）を加えて２５℃付近で２１時間撹拌した。不溶物はＫＣフロック（日本製紙ケミカル社製、１００ｇ）を使用してろ別し、酢酸エチル（２００５ｍＬ）で洗い流した後、ろ液を減圧濃縮した。残渣にシリカゲル（関東化学社製　シリカゲル６０　Ｎ（球状、中性）　６３－２１０μｍ、３００ｇ）を加え、減圧濃縮した。得られた残渣を、シリカゲルカラムクロマトグラフィー（Ｇｒａｃｅ社Ｒｅｖｅｌｅｒｉｓ　Ｓｉｌｉｃａ　Ｆｌａｓｈ　Ｃａｒｔｒｉｄｇｅを使用し、ヘキサン／酢酸エチル／アセトン＝５０：５０：０→０：１００：０→０：０：１００溶液にて溶出）で精製した。先に溶出した溶液を減圧濃縮し、褐色固体として酢酸｛３－［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）ベンゾイル］－１，３－オキサジナン－２－イル｝メチル（１３２．９６ｇ）を得た。後に溶出した溶液を減圧濃縮し、残渣にアセトンを加え減圧濃縮することにより、化合物（（－）－Ｄ）とアセトン混合物である褐色油状物質（１６１．６９ｇ）を得た。この褐色油状物質には、１Ｈ　ＮＭＲの解析結果から、化合物（（－）－Ｄ）（９６．８３ｇ、＞９９．５％ｅｅ）であった。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　３０３　［Ｍ＋Ｈ］＋
［α］Ｄ ２０　＝　－４０．６０　（ｃ　＝　１．０１，　ＣＨＣｌ３） Under a nitrogen stream, a mixture of compound (C) (200.50 g), vinyl acetate monomer (1604 mL) and methyl t-butyl ether (6416 mL) was added to porcine pancreatic lipase (trade name Lipase from porcine pancreas Type II, manufactured by SIGMA, 401.00 g) was added and the mixture was stirred at around 25 ° C. for 21 hours. The insoluble material was filtered off using KC Flock (manufactured by Nippon Paper Chemical Co., Ltd., 100 g), washed with ethyl acetate (2005 mL), and the filtrate was concentrated under reduced pressure. Silica gel (silica gel 60 N (spherical, neutral) 63-210 μm, 300 g, manufactured by Kanto Chemical Co., Inc.) was added to the residue, and the mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution with hexane / ethyl acetate / acetone = 50: 50: 0 → 0: 100: 0 → 0: 0: 100, using Grace Revelelis Silica Flash Cartridge). Purified. The previously eluted solution was concentrated under reduced pressure, and acetic acid {3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2- Ir} methyl (132.96 g) was obtained. The solution eluted later was concentrated under reduced pressure, and acetone was added to the residue and concentrated under reduced pressure to obtain a brown oily substance (161.69 g) which is a mixture of the compound ((−)-D) and acetone. This brown oily substance was a compound ((−)-D) (96.83 g,> 99.5% ee) from the analysis result of 1 H NMR.
MS (ESI pos.) M / z: 303 [M + H] +
[Α] D 20 = −40.60 (c = 1.01, CHCl 3 )
　参考例４　（－）－［２－（クロロメチル）－１，３－オキサジナン－３－イル］［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン　（化合物（（－）－Ｅ））の製造 Reference Example 4 (-)-[2- (Chloromethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone Production of (compound ((-)-E))
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　窒素気流下、化合物（（－）－Ｄ）（２００．００ｇ）にクロロホルム（１８００ｍＬ）を加え、攪拌しながら３℃まで冷却した。この混合物に、同温度でトリエチルアミン（１００．５５ｇ）とクロロホルム（１００ｍＬ）の混合液を加えた。この混合物に、１９℃以下を保ちながら、メシルクロリド（９１．６３ｇ）とクロロホルム（１００ｍＬ）の混合液を滴下した。反応混合物を２３℃まで昇温し、５時間攪拌した。この混合物に水（１Ｌ）を加え、有機層と水層を分離した。水層をクロロホルム（５００ｍＬ）で抽出した後、合わせた有機層をＮａ2ＳＯ4（２００ｇ）にて乾燥した。乾燥剤をろ別した後、乾燥剤をクロロホルム（５００ｍＬ）で洗浄した。得られた溶液を減圧濃縮し、残渣にジイソプロピルエーテル（ＩＰＥ、５００ｍＬ）及び酢酸エチル（５０ｍＬ）を加え１２時間攪拌した。析出した固体をろ取し、ＩＰＥ（４００ｍＬ）で洗浄した。得られた固体を４０℃で減圧下乾燥し、無色固体として化合物（（－）－Ｅ）（１９３ｇ）を得た。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　３２１　［Ｍ＋Ｈ］＋
［α］D 20　＝　－４１．３６　（ｃ　＝　１．００，　ＣＨＣｌ3） Under a nitrogen stream, chloroform (1800 mL) was added to compound ((−)-D) (200.00 g), and the mixture was cooled to 3 ° C. with stirring. To this mixture was added a mixture of triethylamine (100.55 g) and chloroform (100 mL) at the same temperature. A mixture of mesyl chloride (91.63 g) and chloroform (100 mL) was added dropwise to this mixture while maintaining 19 ° C. or lower. The reaction mixture was warmed to 23 ° C. and stirred for 5 hours. Water (1 L) was added to this mixture, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with chloroform (500 mL), and then the combined organic layers were dried over Na 2 SO 4 (200 g). After the desiccant was filtered off, the desiccant was washed with chloroform (500 mL). The resulting solution was concentrated under reduced pressure, and diisopropyl ether (IPE, 500 mL) and ethyl acetate (50 mL) were added to the residue and stirred for 12 hours. The precipitated solid was collected by filtration and washed with IPE (400 mL). The obtained solid was dried under reduced pressure at 40 ° C. to obtain compound ((−)-E) (193 g) as a colorless solid.
MS (ESI pos.) M / z: 321 [M + H] +
[Α] D 20 = −41.36 (c = 1.00, CHCl 3 )
　参考例５　（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン　（化合物（Ａ））の製造 Reference Example 5 (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (compound (A))
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　窒素気流下、ｔ－ＢｕＯＮａ（８０．４５ｇ）にＤＭＳＯ（７３０ｍＬ）を加え、２８℃で攪拌した。この混合物に、別途調製した５－フルオロ－２－（１Ｈ－ピラゾール－３－イル）ピリジン（１２４．５８ｇ）のＤＭＳＯ（７３０ｍＬ）溶液を滴下した後、８２℃まで加熱させ１時間攪拌した。この混合物に、別途調製した化合物（（－）－Ｅ）（２４４．００ｇ）のＤＭＳＯ（９８０ｍＬ）溶液を滴下した後、３０分間攪拌した。この時、溶液の温度は８７℃まで上昇した。反応混合物を３５℃まで冷却し、酢酸エチル（４８８０ｍＬ）を加えた。反応混合物に水（２４４０ｍＬ）を加え、有機層と水層を分離した。水層を酢酸エチル（２４００ｍＬ）で抽出し、合わせた有機層に水（３６００ｍＬ）を加えた。有機層と水層を分離した後、有機層を１５％　ＮａＣｌ水溶液（３６００ｍＬ）で洗浄した後、有機層を減圧濃縮した。残渣にエタノール（２０００ｍＬ）を加え、１℃まで冷却しながら攪拌した。析出した固体をろ取した後、冷却したエタノール（４８０ｍＬ）で洗浄した。得られた固体を窒素気流下、２５℃付近で吸引乾燥した。その後４０℃で減圧乾燥することにより、無色固体として化合物（Ａ）（１８３．１４ｇ）を得た。本発明の化合物（Ａ）の絶対立体配置は、化合物（Ａ）の１塩酸塩の単結晶Ｘ線構造解析により（Ｓ）体であることを決定した。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　４４８　［Ｍ＋Ｈ］＋ Under a nitrogen stream, DMSO (730 mL) was added to t-BuONa (80.45 g), and the mixture was stirred at 28 ° C. To this mixture, a separately prepared solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (124.58 g) in DMSO (730 mL) was added dropwise, followed by heating to 82 ° C. and stirring for 1 hour. To this mixture was added dropwise a separately prepared solution of the compound ((−)-E) (244.00 g) in DMSO (980 mL), and the mixture was stirred for 30 minutes. At this time, the temperature of the solution rose to 87 ° C. The reaction mixture was cooled to 35 ° C. and ethyl acetate (4880 mL) was added. Water (2440 mL) was added to the reaction mixture, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate (2400 mL), and water (3600 mL) was added to the combined organic layers. After separating the organic layer and the aqueous layer, the organic layer was washed with 15% NaCl aqueous solution (3600 mL), and then the organic layer was concentrated under reduced pressure. Ethanol (2000 mL) was added to the residue and stirred while cooling to 1 ° C. The precipitated solid was collected by filtration and washed with cooled ethanol (480 mL). The obtained solid was sucked and dried at around 25 ° C. under a nitrogen stream. Thereafter, it was dried under reduced pressure at 40 ° C. to obtain Compound (A) (183.14 g) as a colorless solid. The absolute configuration of the compound (A) of the present invention was determined to be the (S) form by single crystal X-ray structural analysis of the monohydrochloride salt of the compound (A).
MS (ESI pos.) M / z: 448 [M + H] +
　実施例１　（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン（化合物（Ａ））の無水物の製造
　参考例５の方法で得られた化合物（Ａ）（３８９．００ｇ）にエタノール（７５００ｍＬ）を加え、６０℃まで加熱しながら１時間攪拌し、固体を溶解した。この溶液を攪拌しながら３時間かけて２℃まで冷却した。析出した固体をろ取した後、冷却したエタノール（７９０ｍＬ）で洗浄した。得られた結晶を窒素気流下、２５℃付近で吸引乾燥した。その後４０℃で２０時間、減圧乾燥することで、化合物（Ａ）の無水物の結晶（３５６．４６ｇ）を得た。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　４４８　［Ｍ＋Ｈ］＋
［α］Ｄ ２０　＝　－３２．３４　（ｃ　＝　１．００，　ＣＨＣｌ３） Example 1 (−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl Preparation of anhydride of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A)) Compound (A) obtained by the method of Reference Example 5 (389.00 g) Ethanol (7500 mL) was added to and stirred for 1 hour while heating to 60 ° C. to dissolve the solid. The solution was cooled to 2 ° C. over 3 hours with stirring. The precipitated solid was collected by filtration and washed with cooled ethanol (790 mL). The obtained crystals were sucked and dried at around 25 ° C. under a nitrogen stream. Thereafter, it was dried under reduced pressure at 40 ° C. for 20 hours to obtain an anhydride crystal (356.46 g) of compound (A).
MS (ESI pos.) M / z: 448 [M + H] +
[Α] D 20 = −32.34 (c = 1.00, CHCl 3 )
　実施例２　（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン（化合物（Ａ））の水和物の製造
　実施例１の方法で得られた化合物（Ａ）（２５０ｇ）をエタノール（５Ｌ）に加え、６１℃まで加熱攪拌しながら溶解させた後、熱時ろ過した。得られたろ液を、２０～３０℃に保った水（１５Ｌ）に攪拌しながら滴下した後、５℃まで冷した。析出した固体をろ取し、得られた結晶を２５℃付近で吸引乾燥した。その後４０℃で５時間、減圧乾燥することで、無色結晶（２３５．４７ｇ）を得た。この結晶の粉末Ｘ線を測定したところ、化合物（Ａ）の水和物の結晶であった。 Example 2 (−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl Preparation of Hydrate of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A)) Compound (A) (250 g) obtained by the method of Example 1 was obtained. In addition to ethanol (5 L), it was dissolved with heating and stirring to 61 ° C., and then filtered while hot. The obtained filtrate was added dropwise to water (15 L) kept at 20-30 ° C. with stirring, and then cooled to 5 ° C. The precipitated solid was collected by filtration, and the obtained crystals were sucked and dried at around 25 ° C. Then, colorless crystals (235.47 g) were obtained by drying under reduced pressure at 40 ° C. for 5 hours. When powder X-rays of this crystal were measured, it was a hydrate crystal of compound (A).
　実施例３　（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノン（化合物（Ａ））の水和物の製造　
　化合物（Ａ）の無水物（１０．０１ｇ）にメタノール（６０．０ｇ）を加え、６５℃まで加熱しながら１時間攪拌し、固体を溶解した。この溶液にメタノール（１０．０ｇ）、水（９．０ｇ）を加えたのち、実施例２の方法で得られた化合物（Ａ）の水和物の種晶を加え、９時間かけて０℃まで冷却した。析出した固体をろ取した後、水（５７．７ｇ）で洗浄した。得られた結晶を５０℃で４時間、減圧乾燥することで、化合物（Ａ）の水和物の結晶（９．０５ｇ）を得た。化合物（Ａ）の水和物の結晶は、単結晶Ｘ線構造解析により、１／４水和物であることを決定した。
ＭＳ　（ＥＳＩ　ｐｏｓ．）　ｍ／ｚ　：　４４８　［Ｍ＋Ｈ］＋
［α］Ｄ ２０　＝　－３２．２１　（ｃ　＝　１．０１，　ＣＨＣｌ３） Example 3 (−)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl Preparation of hydrate of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (compound (A))
Methanol (60.0 g) was added to the anhydride of compound (A) (10.01 g), and the mixture was stirred for 1 hour while heating to 65 ° C. to dissolve the solid. Methanol (10.0 g) and water (9.0 g) were added to this solution, and then seed crystals of the hydrate of compound (A) obtained by the method of Example 2 were added. Until cooled. The precipitated solid was collected by filtration and washed with water (57.7 g). The obtained crystals were dried under reduced pressure at 50 ° C. for 4 hours to obtain hydrate crystals (9.05 g) of compound (A). The hydrate crystals of compound (A) were determined to be ¼ hydrate by single crystal X-ray structural analysis.
MS (ESI pos.) M / z: 448 [M + H] +
[Α] D 20 = −32.21 (c = 1.01, CHCl 3 )
　実施例４
　実施例１の方法で得られた化合物（Ａ）の無水物の結晶の粉末Ｘ線回折パターンをリガク製の粉末Ｘ線回折装置（Ｕｌｔｉｍａ　ＩＩＩ）を用い、Ｃｕ―Ｋα線をＸ線源として測定した。２θ＝８．１度、１３．４度，１５．６度及び２１．６度付近にピークが認められた。
　融点をリガク製の示差熱天秤（Ｔｈｅｒｍｏ　ｐｌｕｓ　ＥＶＯ　ＴＧ８１２０）及び同等の装置を用い、大気下にて、室温から約２５０℃まで１０℃／分の昇温速度で測定した。その結果、１２９～１３４℃に融解に由来する吸熱ピークが認められた。
　赤外スペクトルを島津製作所製のフーリエ変換赤外分光光度計（ＩＲＡｆｆｉｎｉｔｙ－１）を用い、全反射法（ＡＴＲ法）にて積算回数２０回、分解能：４ｃｍ－１の条件で測定した。１６２６ｃｍ－１、１４９７ｃｍ－１、１２２７ｃｍ－１、１０８０ｃｍ－１、８１８ｃｍ－１及び７８５ｃｍ－１付近にピークが認められた。 Example 4
The powder X-ray diffraction pattern of the anhydride crystal of the compound (A) obtained by the method of Example 1 was measured using a powder X-ray diffractometer (Ultima III) manufactured by Rigaku and using Cu-Kα ray as an X-ray source. did. Peaks were observed in the vicinity of 2θ = 8.1 degrees, 13.4 degrees, 15.6 degrees, and 21.6 degrees.
The melting point was measured using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent apparatus at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere. As a result, an endothermic peak derived from melting was observed at 129 to 134 ° C.
The infrared spectrum was measured using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the total reflection method (ATR method) 20 times and with a resolution of 4 cm −1 . 1626cm -1, 1497cm -1, 1227cm -1 , 1080cm -1, a peak was observed at around 818cm -1 and 785 cm -1.
　実施例５
　実施例３の方法で得られた化合物（Ａ）の水和物の結晶の粉末Ｘ線回折パターンをリガク製の粉末Ｘ線回折装置（Ｕｌｔｉｍａ　ＩＩＩ）を用い、Ｃｕ―Ｋα線をＸ線源として測定した。２θ＝１１．１度、１２．５度，２０．３度及び２４．２度付近にピークが認められた。
　融点をリガク製の示差熱天秤（Ｔｈｅｒｍｏ　ｐｌｕｓ　ＥＶＯ　ＴＧ８１２０）及び同等の装置を用い、大気下にて、室温から約２５０℃まで１０℃／分の昇温速度で測定した。その結果、１２４～１２９℃に融解に由来する吸熱ピークがあること、熱質量測定にて１２４～１２９℃で０．５～１．５％の重量減少があることが認められた。
　赤外スペクトルを島津製作所製のフーリエ変換赤外分光光度計（ＩＲＡｆｆｉｎｉｔｙ－１）を用い、全反射法（ＡＴＲ法）にて積算回数２０回、分解能：４ｃｍ－１の条件で測定した。１６２７ｃｍ－１、１５０４ｃｍ－１、１２２６ｃｍ－１、１０７６ｃｍ－１、８２２ｃｍ－１及び７８３ｃｍ－１付近にピークが認められた。 Example 5
The powder X-ray diffraction pattern of the hydrate crystal of compound (A) obtained by the method of Example 3 was measured using a powder X-ray diffractometer (Ultima III) manufactured by Rigaku, and Cu—Kα ray as an X-ray source. It was measured. Peaks were observed around 2θ = 11.1 degrees, 12.5 degrees, 20.3 degrees and 24.2 degrees.
The melting point was measured using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent apparatus at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere. As a result, it was recognized that there was an endothermic peak derived from melting at 124 to 129 ° C., and that a weight loss of 0.5 to 1.5% was observed at 124 to 129 ° C. by thermal mass measurement.
The infrared spectrum was measured using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the total reflection method (ATR method) 20 times and with a resolution of 4 cm −1 . 1627cm -1, 1504cm -1, 1226cm -1 , 1076cm -1, a peak was observed at around 822cm -1 and 783 cm -1.
　試験例　（オレキシン拮抗活性の測定）
　試験化合物のヒトオレキシン１型受容体（ｈＯＸ１Ｒ）、オレキシン２型受容体（ｈＯＸ２Ｒ）に対する拮抗活性は文献（Ｔｏｓｈｉｋａｔｓｕ　Ｏｋｕｍｕｒａ　ｅｔ　ａｌ．，Ｂｉｏｃｈｅｍｉｃａｌ　ａｎｄ　Ｂｉｏｐｈｙｓｉｃａｌ　Ｒｅｓｅａｒｃｈ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ　２８０，９７６－９８１，２００１）に記載された方法を改変して行った。ｈＯＸ１Ｒ、ｈＯＸ２Ｒを強制発現させたＣｈｉｎｅｓｅ　ｈａｍｓｔｅｒ　ｏｖａｒｙ（ＣＨＯ）細胞を９６ｗｅｌｌのＢｌａｃｋ　ｃｌｅａｒ　ｂｏｔｔｏｍプレート（Ｎｕｎｃ）の各ウェルに２４，０００個となるように播種し、０．１ｍＭ　ＭＥＭ非必須アミノ酸、０．５ｍｇ／ｍｌ　Ｇ４１８、１０％　牛胎児血清を含むＨａｍ’ｓ　Ｆ－１２培地（以上インビトロジェン）で、３７℃、５％　ＣＯ２の条件下で１６時間培養した。培地を除去後、０．５μＭ　Ｆｌｕｏ－３ＡＭ　エステル（同仁）を含むアッセイ用緩衝液（２５ｍＭ　ＨＥＰＥＳ（同仁）、Ｈａｎｋｓ’　ｂａｌａｎｃｅｄ　ｓａｌｔ　ｓｏｌｕｔｉｏｎ（インビトロジェン）、０．１％　牛血清アルブミン、２．５ｍＭ　プロベネシド、２００μｇ／ｍｌ　Ａｍａｒａｎｔｈ（以上Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）、ｐＨ７．４）を１００μＬ添加し６０分間、３７℃、５％　ＣＯ２にインキュベートした。Ｆｌｕｏ－３ＡＭ　エステルを含むアッセイ用緩衝液を除去したのち、試験化合物は１０ｍＭとなるようにジメチルスルホキシドで溶解してアッセイ用緩衝液で希釈後、１５０μＬを添加し、３０分間インキュベートした。
　リガンドであるヒトオレキシン－Ａの２アミノ酸を置換したペプチド（Ｐｙｒ－Ｐｒｏ－Ｌｅｕ－Ｐｒｏ－Ａｓｐ－Ａｌａ－Ｃｙｓ－Ａｒｇ－Ｇｌｎ－Ｌｙｓ－Ｔｈｒ－Ａｌａ－Ｓｅｒ－Ｃｙｓ－Ａｒｇ－Ｌｅｕ－Ｔｙｒ－Ｇｌｕ－Ｌｅｕ－Ｌｅｕ－Ｈｉｓ－Ｇｌｙ－Ａｌａ－Ｇｌｙ－Ａｓｎ－Ｈｉｓ－Ａｌａ－Ａｌａ－Ｇｌｙ－Ｉｌｅ－Ｌｅｕ－Ｔｈｒ－Ｌｅｕ－ＮＨ２；ペプチド研究所）はｈＯＸ１Ｒに対しては終濃度５００ｐＭ、ｈＯＸ２Ｒに対しては１ｎＭとなるようにアッセイ用緩衝液で希釈し、このリガンド溶液５０μＬを添加して反応を開始した。反応はＦｕｎｃｔｉｏｎａｌ　Ｄｒｕｇ　Ｓｃｒｅｅｎｉｎｇ　Ｓｙｓｔｅｍ（ＦＤＳＳ；浜松ホトニクス社製）を用いて各ｗｅｌｌの蛍光値を１秒毎に３分間測定し、最大蛍光値を細胞内Ｃａ２＋濃度の指標として拮抗活性を求めた。試験化合物の拮抗活性は希釈緩衝液のみを添加したウェルの蛍光値を１００％、リガンドおよび化合物を含まない緩衝液を添加したウェルの蛍光値を０％として算出し、種々の濃度の試験化合物を添加した際の蛍光値から、５０％阻害濃度（ＩＣ５０値）を求めた。
　本発明の化合物（Ａ）の、ヒトオレキシン１型受容体に対する拮抗活性はＩＣ５０＝０．７ｎＭ、オレキシン２型受容体に対する拮抗活性はＩＣ５０＝１．２ｎＭであった。 Test example (measurement of orexin antagonistic activity)
The antagonistic activity of the test compound against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) is described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 24,000 cells, 0.1 mM MEM non-essential amino acids, 0. The cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2 . After removing the medium, an assay buffer containing 25 μM Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 μL of 200 μg / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 . After removing the assay buffer containing Fluo-3AM ester, the test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 μL was added, and the mixture was incubated for 30 minutes.
Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 500 pM for hOX1R and hOX2R The reaction was started by diluting with an assay buffer to 1 nM and adding 50 μL of this ligand solution. For the reaction, the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration. The antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%. The 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
The antagonistic activity of the compound (A) of the present invention against human orexin type 1 receptor was IC 50 = 0.7 nM, and the antagonistic activity against orexin type 2 receptor was IC 50 = 1.2 nM.
　本発明の（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンは、ＯＸ受容体拮抗作用を有することが示された。従って、本発明化合物は、ＯＸ受容体拮抗作用によって調節される病気、例えば、睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の治療又は予防薬として使用することが可能である。また、本発明により、（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの水和物の結晶は、優れた保存安定性、その他の物性を有しており、医薬品原体として有用である。 (-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl of the present invention -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone has been shown to have OX receptor antagonism. Therefore, the compound of the present invention is a disease regulated by OX receptor antagonism such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, It can be used as a therapeutic or prophylactic agent for eating disorders, headaches, migraines, pain, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and the like. According to the present invention, (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [ The crystal of 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone hydrate has excellent storage stability and other physical properties. Useful as.

Claims (4)

  1. 　下記（ａ）～（ｃ）の物性の少なくとも１つを有する、（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの無水物の結晶。
    （ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝８．１度、１３．４度，１５．６度及び２１．６度にピークを有する；
    （ｂ）融点が１２９～１３４℃である；又は
    （ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２６ｃｍ－１、１４９７ｃｍ－１、１２２７ｃｍ－１、１０８０ｃｍ－１、８１８ｃｍ－１及び７８５ｃｍ－１にある。     (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl}-having at least one of the following physical properties (a) to (c) Anhydrous crystals of 1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.
    (A) In powder X-ray diffraction (Cu-Kα), there are peaks at 2θ = 8.1 degrees, 13.4 degrees, 15.6 degrees and 21.6 degrees;
    (B) the melting point is 129-134 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are at 1626 cm −1 , 1497 cm −1 , 1227 cm −1 , 1080 cm −1 , 818 cm −1 and 785 cm −1 . .
  2. 　エタノールに（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンを溶解させた後、結晶化させ、乾燥させることを特徴とする請求項１に記載の無水物の結晶の製造方法。 (-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl- The method for producing an anhydride crystal according to claim 1, wherein 2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried. .
  3. 　下記（ａ）～（ｃ）の物性の少なくとも１つを有する、（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンの水和物の結晶。
    （ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝１１．１度、１２．５度，２０．３度及び２４．２度にピークを有する；
    （ｂ）融点が１２４～１２９℃である；又は
    （ｃ）赤外線吸収スペクトルにおいて、特性吸収帯が１６２７ｃｍ-1、１５０４ｃｍ-1、１２２６ｃｍ-1、１０７６ｃｍ-1、８２２ｃｍ-1及び７８３ｃｍ-1にある。     (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl}-having at least one of the following physical properties (a) to (c) Crystals of hydrates of 1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.
    (A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 11.1 degrees, 12.5 degrees, 20.3 degrees and 24.2 degrees;
    (B) the melting point is 124-129 ° C .; or (c) in the infrared absorption spectrum, the characteristic absorption bands are 1627 cm −1 , 1504 cm −1 , 1226 cm −1 , 1076 cm −1 , 822 cm −1 and 783 cm −1 . .
  4. 　低級アルコールもしくはアセトンと水の混合溶媒に（－）－（２－｛［３－（５－フルオロピリジン－２－イル）－１Ｈ－ピラゾール－１－イル］メチル｝－１，３－オキサジナン－３－イル）［５－メチル－２－（２Ｈ－１，２，３－トリアゾール－２－イル）フェニル］メタノンを溶解させた後、結晶化させ、乾燥させることを特徴とする請求項３に記載の水和物の結晶の製造方法。 (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinane-3 in a mixed solvent of lower alcohol or acetone and water 4. The method according to claim 3, wherein -yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried. Method for producing hydrate crystals of
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WO2019013244A1 (en) 2017-07-13 2019-01-17 大正製薬株式会社 Method for producing (2s)-2-[(1h-pyrazol-1-yl)methyl]-1,3-oxazinane derivative

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004533440A (en) * 2001-05-05 2004-11-04 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー N-aroyl cyclic amine
JP2004534026A (en) * 2001-05-05 2004-11-11 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー N-aroyl cyclic amine derivatives as orexin receptor antagonists
JP2005501026A (en) * 2001-06-28 2005-01-13 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー Compound
JP2012506376A (en) * 2008-10-21 2012-03-15 メルク・シャープ・エンド・ドーム・コーポレイション 2,5-disubstituted morpholine orexin receptor antagonist
WO2013068935A1 (en) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists
WO2013187467A1 (en) * 2012-06-15 2013-12-19 大正製薬株式会社 Heteroaromatic methyl cyclic amine derivative

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8410142B2 (en) * 2007-03-02 2013-04-02 Merck Sharp & Dohme Corp. Bipyridine carboxamide orexin receptor antagonists
RU2010130087A (en) * 2007-12-20 2012-01-27 Технише Университет Эйндховен (Nl) METHOD FOR OBTAINING CARRYING TRACKS
RU2011119217A (en) * 2008-10-14 2012-11-27 Актелион Фармасьютикалз Лтд DERIVATIVES OF PHENETHYLAMIDE AND THEIR HETEROCYCLIC ANALOGUES
MX2011004551A (en) * 2008-10-30 2011-05-25 Merck Sharp & Dohme Isonicotinamide orexin receptor antagonists.
JP5930010B2 (en) * 2013-12-13 2016-06-08 大正製薬株式会社 Medicament containing heteroaromatic methyl cyclic amine derivative

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004533440A (en) * 2001-05-05 2004-11-04 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー N-aroyl cyclic amine
JP2004534026A (en) * 2001-05-05 2004-11-11 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー N-aroyl cyclic amine derivatives as orexin receptor antagonists
JP2005501026A (en) * 2001-06-28 2005-01-13 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー Compound
JP2012506376A (en) * 2008-10-21 2012-03-15 メルク・シャープ・エンド・ドーム・コーポレイション 2,5-disubstituted morpholine orexin receptor antagonist
WO2013068935A1 (en) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists
WO2013187467A1 (en) * 2012-06-15 2013-12-19 大正製薬株式会社 Heteroaromatic methyl cyclic amine derivative

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019013244A1 (en) 2017-07-13 2019-01-17 大正製薬株式会社 Method for producing (2s)-2-[(1h-pyrazol-1-yl)methyl]-1,3-oxazinane derivative
JPWO2019013244A1 (en) * 2017-07-13 2020-05-07 大正製薬株式会社 Process for producing (2S) -2-[(1H-pyrazol-1-yl) methyl] -1,3-oxazinane derivative
US11198690B2 (en) 2017-07-13 2021-12-14 Taisho Pharmaceutical Co., Ltd. Method for producing (2S)-2-[(1H-pyrazol-1-yl)methyl]-1,3-oxazinane derivative
JP7178002B2 (en) 2017-07-13 2022-11-25 大正製薬株式会社 Method for producing (2S)-2-[(1H-pyrazol-1-yl)methyl]-1,3-oxazinane derivative

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