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WO2022114135A1 - Crystal form of amino acid derivative, and method for producing same - Google Patents

Crystal form of amino acid derivative, and method for producing same Download PDF

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Publication number
WO2022114135A1
WO2022114135A1 PCT/JP2021/043413 JP2021043413W WO2022114135A1 WO 2022114135 A1 WO2022114135 A1 WO 2022114135A1 JP 2021043413 W JP2021043413 W JP 2021043413W WO 2022114135 A1 WO2022114135 A1 WO 2022114135A1
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carbonyl
compound
crystal
degrees
amino
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PCT/JP2021/043413
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French (fr)
Japanese (ja)
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裕子 山内
好博 木村
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大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring

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  • the present invention relates to (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[(tricyclo [). 3.3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy ⁇ carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid or its pharmaceutically acceptable salt crystal polyform and Regarding the manufacturing method. More specifically, for example, mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington chorea, feeding.
  • mood disorders including depression and bipolar disorders
  • anxiety disorders including depression and bipolar disorders
  • cognitive disorders including depression and bipolar disorders
  • cognitive disorders developmental disorders
  • Alzheimer's disease Parkinson's disease
  • motor disorders associated with muscle rigidity sleep disorders
  • sleep disorders Huntington chorea, feeding.
  • Metabolic active glutamate (mGlu) receptor effective for the treatment and prevention of disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases, etc.
  • Bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (hereinafter, also referred to as parent compound or compound (B)) is a prodrug (1R, 2R, 3R, 5R, 6R) -2.
  • bicyclo [3.1.0] hexane-6-carboxylic acid (hereinafter, may be referred to as compound (A)) crystal polymorph and a method for producing the same.
  • the prodrug of the parent compound which is a compound acting on the metabotropic glutamate receptor, enhances mucosal absorbability such as oral absorption and increases the amount of the parent compound exposed in vivo.
  • the present invention relates to a crystal polymorph and a method for producing the same.
  • Metabotropic glutamate receptors are classified into three groups according to their amino acid sequence homology, signal transduction mechanism, and pharmacological properties. Among them, Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 1). In addition, Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thus suppressing excessive release of glutamate (Non-Patent Documents 2 and 3). ).
  • a prodrugization was carried out in which a small modifying group such as an alkyl group or an acyl group is bonded to the carboxy group or amino group of the compound.
  • a prodrug it exists stably as a prodrug before absorption, and absorption is improved by prodrugization, and chemically or enzymatically in the small intestine, liver, and / or plasma during and / or after absorption.
  • a compound that is rapidly converted to an active substance is desired.
  • An object of the present invention is to treat and prevent neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorders, epilepsy, developmental disorders, sleep disorders, as well as drug dependence and cognitive disorders. , Alzheimer's disease, Huntington butoh disease, Parkinson's disease, motor disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders, etc.
  • neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorders, epilepsy, developmental disorders, sleep disorders, as well as drug dependence and cognitive disorders.
  • Alzheimer's disease Huntington butoh disease, Parkinson's disease, motor disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders, etc.
  • the storage stability of prodrugs that enhance mucosal absorbability such as oral absorbability of parent compounds that act on Group 2 metabolic glutamate receptors and increase in vivo exposure.
  • It is an object of the present invention to provide
  • the present inventors have (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6. -(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro as a result of intensive research on prodrugs containing dicarboxylic acid (hereinafter sometimes referred to as compound (B)) as the parent compound.
  • compound (B) dicarboxylic acid
  • one aspect of the present invention is (1) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy) having at least one of the following physical properties (a) to (c). ] -2-( ⁇ (1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6 -It is a D-type crystal of carboxylic acid.
  • another aspect of the present invention is (2) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] in a lower alcohol, acetonitrile, ethyl acetate, an alkylamine or a mixed solvent thereof.
  • the present invention has an excellent group II metabolic glutamate receptor antagonism (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [ 3.1.0]
  • a prodrug of hexane-2,6-dicarboxylic acid (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6- It has become possible to provide crystals of carboxylic acid.
  • the crystal is stable at a temperature near room temperature and has excellent storage stability. Furthermore, it has been confirmed that it is easy to handle and can be a useful raw material for pharmaceuticals because it does not cause metastasis of crystalline form even by a pharmaceutical product operation such as crushing.
  • the powder X-ray diffraction pattern of the D-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the D-type crystal of compound (A) is shown.
  • the infrared absorption spectrum (ATR method) of the D-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the A-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the A-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the B-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the B-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the C-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the C-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) methanesulfonate is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) benzenesulfonate is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) phosphate is shown.
  • the compound of the present invention (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[((1S) -1-[( Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid (Compound (A)) is shown below. It has a chemical structure.
  • the D-type crystal of compound (A) has at least one of the following physical characteristics (a) to (c).
  • the characteristic endothermic bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or
  • the D-type crystal of the compound (A) produced by the production method of the present invention is basically a crystal having high purity. It is desirable that the crystal has a high purity, and preferably it does not substantially contain other crystal forms. As shown in Examples described later, the D-type crystal of the compound (A) produced by the production method of the present invention can be obtained with good reproducibility as a single crystal having a certain quality, and can be used as a raw material for pharmaceuticals and pharmaceuticals. It can be stably supplied as crystals of the drug substance used in production, and has excellent physical properties with excellent storage stability.
  • the D-shaped crystal of the present invention can be obtained by the following recrystallization operation.
  • the compound (A) is heated and dissolved in a predetermined organic solvent and then slowly cooled, or a predetermined poor solvent is added and then slowly cooled to precipitate crystals, and the precipitated crystals are filtered and centrifuged.
  • a D-type crystal of compound (A) can be obtained by separating it from a solvent and then drying it.
  • the recrystallization may be repeated not only once but also twice or more, but usually, recrystallization is performed only once.
  • the predetermined organic solvent for dissolving the raw material compound (A) before recrystallization is, for example, general lower alcohol, ethyl acetate, diC 1-4 alkyl ether, acetone, acetonitrile, THF, DMF, DMSO and the like.
  • the organic solvent or alkylamine include organic bases such as triethylamine and diisopropylethylamine, or a mixed solution of these organic solvents.
  • Examples of the predetermined poor solvent to be added after that include water, C 5-8 saturated hydrocarbon, acetic acid and the like.
  • Examples of the lower alcohol include methanol, ethanol, 1-propanol, 2-propanol and the like.
  • Examples of the diC 1-4 alkyl ether include diethyl ether, diisopropyl ether, tbutyl-methyl ether and the like.
  • Examples of the C 5-8 saturated hydrocarbon include pentane, hexane, heptane and octane. Hexane or heptane is preferred.
  • the concentration at which the compound (A) is dissolved is 1 to 50% by mass.
  • the mass% is the mass percent of the D-type crystal of the compound (A) in the solution or the suspension. Crystallization of the D-type crystal of compound (A) is usually carried out at 0 to 100 ° C. Drying of the D-type crystal of compound (A) is usually carried out at 100 ° C. or lower.
  • 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 specified in the 17th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, body weight, and purpose of treatment.
  • compositions containing the compounds of the invention are pharmacologically acceptable carriers for compositions containing the compounds of the invention, ie, excipients (eg, crystalline cellulose, starch, lactose, mannitol), binders (eg, hydroxypropyl cellulose). , Polyvinylpyrrolidone), lubricants (eg, magnesium stearate, talc), disintegrants (eg, carboxymethyl cellulose calcium), and various other pharmacologically acceptable additives can be blended and produced.
  • excipients eg, crystalline cellulose, starch, lactose, mannitol
  • binders eg, hydroxypropyl cellulose
  • Polyvinylpyrrolidone eg, polyvinylpyrrolidone
  • lubricants eg, magnesium stearate, talc
  • disintegrants eg, carboxymethyl cellulose calcium
  • various other pharmacologically acceptable additives can be blended and produced
  • Powder X-rays were measured by SmartLab (Rigaku). Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with Thermo plus EvoTG8120 (Rigaku). The infrared absorption spectrum was measured by IRAfitity-1 (Shimadzu Corporation). The water vapor adsorption measurement was measured by DVS-1 Advantage (Surface Measurement Systems). In the reference example and the example, the room temperature is around 25 ° C.
  • the infrared spectrum was measured by a total reflection method (ATR method) using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the conditions of total integration 45 times and resolution: 2 cm -1 .
  • the product was dried at 60 ° C for 2 hours, the relative humidity was increased from 0% RH to 95% RH, and then the mass change in the process of decreasing the relative humidity to 5% RH was measured at 5% intervals.
  • the equilibrium condition was set when the mass change of 0.01% disappeared in 1 minute, and the humidity was set to the next.
  • the hygroscopicity (DVS) measurement the D-type crystal of compound (A) had no hygroscopicity and the crystal form did not change due to humidity.
  • the D-form crystal of compound (A) was 65 ° C. for 4 weeks, 40 ° C.
  • Disorders including depression and bipolar disorder
  • anxiety disorders including depression and bipolar disorder
  • cognitive disorders developmental disorders
  • Alzheimer's disease Parkinson's disease
  • motor disorders associated with muscle rigidity sleep disorders
  • Huntington chorea eating disorders
  • drug addiction epilepsy It can be used as a therapeutic and preventive drug for cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Provided are: a crystal form that is stable in a use environment where a prodrug compound of an amino acid derivative exhibiting group 2 metabotropic glutamate receptor antagonism is used as a pharmaceutical product; and a method for producing the same.　Specifically, provided are: a crystal of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.13,7]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid having at least one among the following physical properties (a)-(c); and a method for producing the same. (a) The crystal has a peak at 2θ of 10.8 degrees, 14.5 degrees, 19.4 degrees, and 21.8 degrees in the powder X‐ray diffraction (Cu-Kα); (b) the characteristic absorption band is 3,310 cm-1, 1,762 cm-1, 1,731 cm-1, 1,583 cm-1, and 1,236 cm-1 in the infrared absorption spectrum (ATR method); or (c) the endothermic peak is 225-235ºC in the differential thermal analysis/thermogravimetry (TG/DTA).

Description

アミノ酸誘導体の結晶形及びその製造方法Crystal form of amino acid derivative and its manufacturing method
　本発明は、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸又はその医薬上許容される塩の結晶多形及びその製造方法に関する。さらに詳しくは、例えば、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、筋硬直に伴う運動障害、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳不全、脳浮腫、脊髄障害、頭部外傷、炎症、免疫関連疾患等の治療及び予防に有効な代謝活性型グルタミン酸（ｍＧｌｕ）受容体のサブグループＩＩに属するｍＧｌｕ２およびｍＧｌｕ３受容体のアンタゴニストとして作用する化合物である（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸（以下、親化合物又は化合物（Ｂ）と記すこともある）のプロドラッグである（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（以下、化合物（Ａ）と記すこともある）の結晶多形及びその製造方法に関する。
また、本発明は、代謝型グルタミン酸受容体に作用する化合物である親化合物のプロドラッグ化により、経口吸収性等の粘膜吸収性が高められ、親化合物の生体内暴露量が増大したプロドラッグの結晶多形及びその製造方法に関する。 The present invention relates to (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [). 3.3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid or its pharmaceutically acceptable salt crystal polyform and Regarding the manufacturing method. More specifically, for example, mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington chorea, feeding. Metabolic active glutamate (mGlu) receptor effective for the treatment and prevention of disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases, etc. A compound that acts as an antagonist of mGlu2 and mGlu3 receptors belonging to subgroup II of (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy]. Bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (hereinafter, also referred to as parent compound or compound (B)) is a prodrug (1R, 2R, 3R, 5R, 6R) -2. -Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl)) Oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid (hereinafter, may be referred to as compound (A)) crystal polymorph and a method for producing the same.
Further, in the present invention, the prodrug of the parent compound, which is a compound acting on the metabotropic glutamate receptor, enhances mucosal absorbability such as oral absorption and increases the amount of the parent compound exposed in vivo. The present invention relates to a crystal polymorph and a method for producing the same.
代謝型グルタミン酸受容体は、アミノ酸配列の相同性、シグナル伝達機構及び薬理学的な特性から３つのグループに分類される。この中で、グループＩＩ代謝型グルタミン酸受容体（ｍＧｌｕ２およびｍＧｌｕ３受容体）は、Ｇタンパク質共役型受容体であり、アデニルサイクラーゼと結合し、サイクリックアデノシン１リン酸（ｃＡＭＰ）のホルスコリン刺激性の蓄積を抑制する（非特許文献１）。また、グループＩＩ代謝型グルタミン酸受容体は、主にグルタミン酸神経系のプレシナプスに存在し、自己受容体として機能するため、グルタミン酸の過剰遊離を抑制している（非特許文献２、非特許文献３）。グループＩＩ代謝型グルタミン酸受容体に拮抗する化合物は急性及び慢性の精神医学的疾患並びに神経学的疾患の治療または予防に有効であると考えられ、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－アルコキシビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸誘導体は、グループＩＩ代謝型グルタミン酸受容体に対して強い拮抗作用を有する化合物である。 Metabotropic glutamate receptors are classified into three groups according to their amino acid sequence homology, signal transduction mechanism, and pharmacological properties. Among them, Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 1). In addition, Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thus suppressing excessive release of glutamate (Non-Patent Documents 2 and 3). ). Compounds that antagonize Group II metabolic glutamate receptors are believed to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders, (1R, 2R, 3R, 5R, 6R) -2. -Amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative is a compound having a strong antagonism to group II metabolite-type glutamate receptors.
しかしながら、これらの化合物はサルでの経口吸収性が悪く、ヒトにおいても経口吸収性が悪いことが予想された。そこで、化合物の経口吸収性等の膜透過性を改善するため、化合物のカルボキシ基やアミノ基に、アルキル基やアシル基などの小さな修飾基を結合させるプロドラッグ化が行われた。
プロドラッグとしては、吸収前はプロドラッグ体として安定に存在し、プロドラッグ化により吸収が改善され、吸収時及び／又は吸収後には小腸、肝臓、及び／又は血漿で、化学的または酵素的に速やかに活性体に変換される化合物が望まれる。
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－アルコキシビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸誘導体のプロドラッグ化について、検討を重ねた結果、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－アルコキシビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸誘導体の２位カルボン酸にエステル結合を有するプロドラッグにすることで、経口吸収性を大幅に改善した理想的な化合物が得られたことが報告されており、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸をプロドラッグ化した（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸についても報告されている（特許文献１）。 However, these compounds were expected to have poor oral absorbability in monkeys and poor oral absorbability in humans. Therefore, in order to improve the membrane permeability of the compound such as oral absorbability, a prodrugization was carried out in which a small modifying group such as an alkyl group or an acyl group is bonded to the carboxy group or amino group of the compound.
As a prodrug, it exists stably as a prodrug before absorption, and absorption is improved by prodrugization, and chemically or enzymatically in the small intestine, liver, and / or plasma during and / or after absorption. A compound that is rapidly converted to an active substance is desired.
(1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-alkoxybicyclo [3.1.0] Hexan-2,6-dicarboxylic acid derivative prodrugization has been studied repeatedly. As a result, (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative ester bond to the 2-position carboxylic acid. It has been reported that an ideal compound with significantly improved oral absorbability was obtained by using a prodrug having (1R, 2R, 3R, 5R, 6R) -2-amino-6-. Fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid prodrugized (1R, 2R, 3R, 5R, 6R) -2-amino- 6-Fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [ 3.3.1.113,7 ] decane-1-carbonyl) oxy] ethoxy} A carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid has also been reported (Patent Document 1).
また、医薬品の観点からは、工業的規模における取扱いがし易く、保存安定性に優れた物理的特性を有する化合物が望まれている。 Further, from the viewpoint of pharmaceutical products, a compound that is easy to handle on an industrial scale and has excellent storage stability and physical properties is desired.
ＷＯ２０１７／１８３７３４WO2017 / 183734
本発明の目的は、例えば統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患の治療及び予防、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患など、グループ２代謝型グルタミン酸受容体が関与しているとされる疾患の治療剤又は予防剤として、グループ２代謝型グルタミン酸受容体に作用する親化合物の経口吸収性等の粘膜吸収性を高め、生体内暴露量を増大させるプロドラッグの保存安定性や取り扱いのし易さ等の点で医薬品や医薬品原料としての使用環境で好ましい結晶形とその製造方法を提供することである。 An object of the present invention is to treat and prevent neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorders, epilepsy, developmental disorders, sleep disorders, as well as drug dependence and cognitive disorders. , Alzheimer's disease, Huntington butoh disease, Parkinson's disease, motor disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders, etc. As a therapeutic or prophylactic agent for diseases that are said to be present, the storage stability of prodrugs that enhance mucosal absorbability such as oral absorbability of parent compounds that act on Group 2 metabolic glutamate receptors and increase in vivo exposure. It is an object of the present invention to provide a crystalline form and a method for producing the same, which are preferable in the environment of use as a pharmaceutical product or a raw material for a pharmaceutical product in terms of ease of handling and the like.
　本発明者らは、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸（以下、化合物（Ｂ）と記すこともある）を親化合物としたプロドラッグについて鋭意研究を重ねた結果、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（以下、化合物（Ａ）と記すこともある）が、プロドラッグとして、経口吸収性等の粘膜吸収性を高め、親化合物の生体内暴露量を高めることを見出し、さらに、物理的特性に優れた該化合物又はその医薬上許容される塩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。 The present inventors have (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6. -(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro as a result of intensive research on prodrugs containing dicarboxylic acid (hereinafter sometimes referred to as compound (B)) as the parent compound. -3-[(4-Fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) Bicyclo [3.1.0] hexane-6-carboxylic acid (hereinafter, also referred to as compound (A)) enhances mucosal absorbability such as oral absorbability as a prodrug, and in vivo exposure of the parent compound. We have found that the amount is increased, and further discovered that it is possible to provide crystals of the compound having excellent physical properties or a pharmaceutically acceptable salt thereof, which has led to the completion of the present invention.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　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、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸のＤ形結晶である。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝１０．８度、１４．５度、１９．４度、及び２１．８度にピークを有する；
（ｂ）赤外線吸収スペクトル（ＡＴＲ法）において、特性吸収帯が、３３１０ｃｍ－１，　１７６２ｃｍ－１，　１７３１ｃｍ－１，　１５８３ｃｍ－１及び１２３６ｃｍ－１にある；又は
（ｃ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが２２５～２３５℃にある。
また、本願発明の他の態様は、
（２）低級アルコール、アセトニトリル、酢酸エチル、アルキルアミン又はこれらの混合溶媒に（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸を溶解させた後、Ｃ５－８飽和炭化水素、または水を加えて１５－４０℃で結晶化させ、得られた結晶を乾燥させることを特徴とする（１）に記載の化合物（Ａ）のＤ形結晶の製造方法である。 That is, one aspect of the present invention is
(1) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy) having at least one of the following physical properties (a) to (c). ] -2-({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6 -It is a D-type crystal of carboxylic acid.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 10.8 degrees, 14.5 degrees, 19.4 degrees, and 21.8 degrees;
(B) In the infrared absorption spectrum (ATR method), the characteristic absorption bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or (c) Differential thermal analysis / thermal mass measurement. In (TG / DTA), the endothermic peak is at 225 to 235 ° C.
Further, another aspect of the present invention is
(2) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] in a lower alcohol, acetonitrile, ethyl acetate, an alkylamine or a mixed solvent thereof. -2-({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6- The compound according to (1), wherein after dissolving the carboxylic acid, C 5-8 saturated hydrocarbon or water is added to crystallize at 15-40 ° C., and the obtained crystal is dried. A) is a method for producing a D-type crystal.
　本発明により、優れたグループＩＩ代謝型グルタミン酸受容体拮抗作用を有する（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸のプロドラッグである（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸の結晶を提供することが可能となった。該結晶は、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。 According to the present invention, it has an excellent group II metabolic glutamate receptor antagonism (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [ 3.1.0] A prodrug of hexane-2,6-dicarboxylic acid (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6- It has become possible to provide crystals of carboxylic acid. The crystal is stable at a temperature near room temperature and has excellent storage stability. Furthermore, it has been confirmed that it is easy to handle and can be a useful raw material for pharmaceuticals because it does not cause metastasis of crystalline form even by a pharmaceutical product operation such as crushing.
化合物（Ａ）のＤ形結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the D-type crystal of compound (A) is shown. 化合物（Ａ）のＤ形結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the D-type crystal of compound (A) is shown. 化合物（Ａ）のＤ形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 D-type crystal of compound (A) is shown. 化合物（Ａ）のＡ形結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the A-type crystal of compound (A) is shown. 化合物（Ａ）のＡ形結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the A-type crystal of compound (A) is shown. 化合物（Ａ）のＢ形結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the B-type crystal of compound (A) is shown. 化合物（Ａ）のＢ形結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the B-type crystal of compound (A) is shown. 化合物（Ａ）のＣ形結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the C-type crystal of compound (A) is shown. 化合物（Ａ）のＣ形結晶の示差熱分析／熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of the C-type crystal of compound (A) is shown. 化合物（Ａ）メタンスルホン酸塩の結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the crystal of the compound (A) methanesulfonate is shown. 化合物（Ａ）ベンゼンスルホン酸塩の結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the crystal of the compound (A) benzenesulfonate is shown. 化合物（Ａ）リン酸塩の結晶の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the crystal of the compound (A) phosphate 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（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））は、下記に示す化学構造を有している。 Hereinafter, embodiments for carrying out the present invention will be specifically described.
The compound of the present invention (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[((1S) -1-[( Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid (Compound (A)) is shown below. It has a chemical structure.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　化合物（Ａ）のＤ形結晶は、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＝１０．８度、１４．５度、１９．４度、及び２１．８度にピークを有する；又は
（ｂ）赤外線吸収スペクトル（ＡＴＲ法）において、特性吸収帯が、３３１０ｃｍ－１，　１７６２ｃｍ－１，　１７３１ｃｍ－１，　１５８３ｃｍ－１及び１２３６ｃｍ－１にある；又は
（ｃ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが２２５～２３５℃にある。
　化合物（Ａ）のＤ形結晶の粉末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。
図１～３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Ｄ形結晶は、基本的に純度の高い結晶であることが分かる。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。
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Ｄ形結晶は、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。 The D-type crystal of compound (A) has at least one of the following physical characteristics (a) to (c).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 10.8 degrees, 14.5 degrees, 19.4 degrees, and 21.8 degrees; or (b) infrared absorption spectrum (ATR). In method), the characteristic endothermic bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or (c) heat absorption in differential thermal analysis / thermal mass measurement (TG / DTA). The peak is at 225 to 235 ° C.
The powder X-ray diffraction pattern of the D-type crystal of compound (A) is as shown in FIG. 1, the differential thermal analysis / thermal mass measurement curve is shown in FIG. 2, and the infrared absorption spectrum is shown in FIG.
As can be seen from FIGS. 1 to 3, the D-type crystal of the compound (A) produced by the production method of the present invention is basically a crystal having high purity. It is desirable that the crystal has a high purity, and preferably it does not substantially contain other crystal forms.
As shown in Examples described later, the D-type crystal of the compound (A) produced by the production method of the present invention can be obtained with good reproducibility as a single crystal having a certain quality, and can be used as a raw material for pharmaceuticals and pharmaceuticals. It can be stably supplied as crystals of the drug substance used in production, and has excellent physical properties with excellent storage stability.
　次に、化合物（Ａ）のＤ形結晶の製造方法について説明する。本発明のＤ形結晶は、以下のような再結晶操作により得られる。たとえば、所定の有機溶媒に化合物（Ａ）を加熱溶解させた後、徐冷する、または所定の貧溶媒を加えた後で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化合物（Ａ）のＤ形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。
　再結晶前の原料の化合物（Ａ）を溶解させる所定の有機溶媒とは、例えば、低級アルコール、酢酸エチル、ジＣ１－４アルキルエーテル、アセトン、アセトニトリル、ＴＨＦ、ＤＭＦ、ＤＭＳＯなどの一般的な有機溶媒又はアルキルアミンとしてトリエチルアミン、ジイソプロピルエチルアミンなどの有機塩基、又はこれらの有機溶媒の混合溶液が挙げられる。そのあとに加える所定の貧溶媒とは、例えば、水、Ｃ５－８飽和炭化水素、酢酸などが挙げられる。 Next, a method for producing a D-type crystal of compound (A) will be described. The D-shaped crystal of the present invention can be obtained by the following recrystallization operation. For example, the compound (A) is heated and dissolved in a predetermined organic solvent and then slowly cooled, or a predetermined poor solvent is added and then slowly cooled to precipitate crystals, and the precipitated crystals are filtered and centrifuged. A D-type crystal of compound (A) can be obtained by separating it from a solvent and then drying it. The recrystallization may be repeated not only once but also twice or more, but usually, recrystallization is performed only once.
The predetermined organic solvent for dissolving the raw material compound (A) before recrystallization is, for example, general lower alcohol, ethyl acetate, diC 1-4 alkyl ether, acetone, acetonitrile, THF, DMF, DMSO and the like. Examples of the organic solvent or alkylamine include organic bases such as triethylamine and diisopropylethylamine, or a mixed solution of these organic solvents. Examples of the predetermined poor solvent to be added after that include water, C 5-8 saturated hydrocarbon, acetic acid and the like.
　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。
　ジＣ１－４アルキルエーテルとしては、ジエチルエーテル、ジイソプロピルエーテル、ｔブチル－メチルエーテルなどが挙げられる。 Examples of the lower alcohol include methanol, ethanol, 1-propanol, 2-propanol and the like.
Examples of the diC 1-4 alkyl ether include diethyl ether, diisopropyl ether, tbutyl-methyl ether and the like.
　Ｃ５－８飽和炭化水素としては、ペンタン、ヘキサン、ヘプタン及びオクタンなどが挙げられる。好ましくは、ヘキサンもしくはヘプタンである。　 Examples of the C 5-8 saturated hydrocarbon include pentane, hexane, heptane and octane. Hexane or heptane is preferred.
化合物（Ａ）を溶解させる濃度は１～５０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Ｄ形結晶の質量パーセントである。
　化合物（Ａ）のＤ形結晶の結晶化は、通常０～１００℃で行う。
　化合物（Ａ）のＤ形結晶の乾燥は、通常１００℃以下で行う。 The concentration at which the compound (A) is dissolved is 1 to 50% by mass. Here, the mass% is the mass percent of the D-type crystal of the compound (A) in the solution or the suspension.
Crystallization of the D-type crystal of compound (A) is usually carried out at 0 to 100 ° C.
Drying of the D-type crystal of compound (A) is usually carried out at 100 ° C. or lower.
　　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１７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 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 specified in the 17th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, body weight, and purpose of treatment.
These formulations are pharmacologically acceptable carriers for compositions containing the compounds of the invention, ie, excipients (eg, crystalline cellulose, starch, lactose, mannitol), binders (eg, hydroxypropyl cellulose). , Polyvinylpyrrolidone), lubricants (eg, magnesium stearate, talc), disintegrants (eg, carboxymethyl cellulose calcium), and various other pharmacologically acceptable additives can be blended and produced.
The compound of the present invention can be administered orally or parenterally to an adult patient in a single dose of 0.001 to 500 mg once or divided into several times a day. This dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, body weight, symptoms and the like 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。
　粉末Ｘ線は、ＳｍａｒｔＬａｂ（リガク）にて測定した。
　示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）は、Ｔｈｅｒｍｏ　ｐｌｕｓ　ＥｖｏＴＧ８１２０（リガク）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。
　水蒸気吸着測定はDVS-1 Advantage（Surface Measurement Systems）にて測定した。
　参考例及び実施例中、室温とは２５℃付近を示す。
　参考例及び実施例で用いた（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））は、例えば特許文献１（ＷＯ２０１７／１８３７３４）の実施例４と同様の方法で得ることができる。 Next, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to these contents.
Powder X-rays were measured by SmartLab (Rigaku).
Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with Thermo plus EvoTG8120 (Rigaku).
The infrared absorption spectrum was measured by IRAfitity-1 (Shimadzu Corporation).
The water vapor adsorption measurement was measured by DVS-1 Advantage (Surface Measurement Systems).
In the reference example and the example, the room temperature is around 25 ° C.
(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-] used in Reference Examples and Examples [(Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) Bicyclo [3.1.0] hexane-6-carboxylic acid (compound (A)) is, for example, It can be obtained by the same method as in Example 4 of Patent Document 1 (WO2017 / 183734).
実施例１　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））のＤ形結晶の製造法 Example 1 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic acid (Compound (A)) Method for producing D-type crystals
　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（４６６ｇ）に酢酸エチル（１．８７ｋｇ）及びトリエチルアミン（４６２ｇ）を加え、外温５４℃にて加熱溶解させた。溶液をカートリッジフィルターに通して異物ろ過をし、酢酸エチル（０．４８ｋｇ）で洗浄した。外温７５℃付近に保ちながら、ろ液にヘプタン（２．３９ｋｇ）を滴下して加えた。外温７５℃付近で３０分以上攪拌させた後、徐々に２０℃付近まで冷却しながら約２０時間撹拌した。懸濁液をろ過した後、酢酸エチル／ヘプタン（１／９、１．９３ｋｇ）混合溶液にて洗浄した。得られた固体を減圧下乾燥することにより、化合物（Ａ）のＤ形結晶（４１７ｇ、白色固体）を得た。 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3. 1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (466 g) with ethyl acetate (1.87 kg) and triethylamine (462 g) In addition, it was heated and dissolved at an outside temperature of 54 ° C. The solution was passed through a cartridge filter to filter for foreign matter and washed with ethyl acetate (0.48 kg). Heptane (2.39 kg) was added dropwise to the filtrate while keeping the outside temperature at around 75 ° C. After stirring at an outside temperature of around 75 ° C. for 30 minutes or more, the mixture was gradually cooled to around 20 ° C. and stirred for about 20 hours. The suspension was filtered and then washed with a mixed solution of ethyl acetate / heptane (1/9, 1.93 kg). The obtained solid was dried under reduced pressure to obtain D-type crystals (417 g, white solid) of compound (A).
実施例２
実施例１の方法で得られた化合物（Ａ）のＤ形結晶の粉末Ｘ線回折パターンをリガク製の粉末Ｘ線回折装置（ＳｍａｒｔＬａｂ）を用い、Ｃｕ―Ｋα線をＸ線源として測定した。２θ＝１０．８度、１４．５度、１９．４度、及び２１．８度付近にピークが認められ、Ｄ形結晶の結晶性が良好であることが確認された。
　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４５回、分解能：２ｃｍ－１の条件で測定した。３３１０ｃｍ－１，　１７６２ｃｍ－１，　１７３１ｃｍ－１，　１５８３ｃｍ－１及び１２３６ｃｍ－１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、２２５～２３５℃に融解に由来する吸熱ピークが認められた。
　吸湿性をSurface Measurement Systems製の水蒸気吸着測定装置（DVS-1 Advantage）を用い、 室温、常圧、窒素フロー条件下で測定した。測定前に60℃で2時間乾燥し、相対湿度を0％RH から 95%RHまで上げた後、5%RHまで下げた過程の質量変化を5%間隔で測定した。平衡条件は、1分間に0.01%の質量変化がなくなった時とし、次の湿度に移るように設定した。
　吸湿性(DVS)測定により、化合物（Ａ）のＤ形結晶は、吸湿性は無く、湿度による結晶形の変化も無かった。
　固体安定性試験の結果、化合物（Ａ）のＤ形結晶は固体状態では65℃ 4週、40℃75％RH3ヶ月、光照射（FL3000 lx、室温3週）後の定量値は99.8％、99.4％、100.4％（対初期値）と安定であった。
　また、化合物（Ａ）のＤ形結晶は粉砕や打錠による結晶形、結晶性の変化はなかった。 Example 2
The powder X-ray diffraction pattern of the D-type crystal of the compound (A) obtained by the method of Example 1 was measured using a powder X-ray diffractometer (SmartLab) manufactured by Rigaku using Cu—Kα rays as an X-ray source. Peaks were observed around 2θ = 10.8 ° C, 14.5 ° C, 19.4 ° C, and 21.8 ° C, confirming that the crystallinity of the D-shaped crystal was good.
The infrared spectrum was measured by a total reflection method (ATR method) using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the conditions of total integration 45 times and resolution: 2 cm -1 . Peaks were observed near 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 .
The melting point was measured at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent device. As a result, an endothermic peak derived from melting was observed at 225 to 235 ° C.
Hygroscopicity was measured using a water vapor adsorption measuring device (DVS-1 Advantage) manufactured by Surface Measurement Systems under room temperature, normal pressure, and nitrogen flow conditions. Before the measurement, the product was dried at 60 ° C for 2 hours, the relative humidity was increased from 0% RH to 95% RH, and then the mass change in the process of decreasing the relative humidity to 5% RH was measured at 5% intervals. The equilibrium condition was set when the mass change of 0.01% disappeared in 1 minute, and the humidity was set to the next.
According to the hygroscopicity (DVS) measurement, the D-type crystal of compound (A) had no hygroscopicity and the crystal form did not change due to humidity.
As a result of the solid stability test, the D-form crystal of compound (A) was 65 ° C. for 4 weeks, 40 ° C. for 75% RH for 3 months, and the quantitative values after light irradiation (FL3000 lx, room temperature for 3 weeks) were 99.8% and 99.4. It was stable at% and 100.4% (vs. initial value).
In addition, the D-type crystals of compound (A) did not change in crystal form or crystallinity due to pulverization or tableting.
参考例１　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））のＡ形結晶の製造法 Reference Example 1 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic acid (Compound (A)) A method for producing A-type crystals
　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（１ｇ）をシリカゲルカラムクロマトグラフィー（ＹＭＣ　Ｃ１８、Ｈ２Ｏ／ＭｅＣＮ＝９５／５～５／９５）にて精製した。目的物を含む画分を減圧下濃縮し、再びアセトニトリルを加えて撹拌した。析出物をろ取することにより、化合物（Ａ）のＡ形結晶（０．８５ｇ）を得た。 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3. 1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (1 g) by silica gel column chromatography (YMC C18, H 2 O / MeCN) = 95/5 to 5/95). The fraction containing the desired product was concentrated under reduced pressure, acetonitrile was added again, and the mixture was stirred. The precipitate was collected by filtration to obtain A-type crystals (0.85 g) of compound (A).
参考例２
参考例１の方法で得られた化合物（Ａ）のＡ形結晶の粉末Ｘ線回折パターンを測定し、２θ＝１２．２度及び１２．６度付近にピークが認められた。
示差熱分析／熱質量測定を行い、２２５～２３５℃に融解に由来する吸熱ピークが認められた。 Reference example 2
The powder X-ray diffraction pattern of the A-type crystal of the compound (A) obtained by the method of Reference Example 1 was measured, and peaks were observed near 2θ = 12.2 degrees and 12.6 degrees.
Differential thermal analysis / thermogravimetric analysis was performed, and an endothermic peak derived from melting was observed at 225 to 235 ° C.
参考例３　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））のＢ形結晶の製造法 Reference Example 3 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic acid (Compound (A)) B-type crystal production method
　参考例１で得られた（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸のＡ形結晶（３０　ｍｇ）に２－プロパノール（１　ｍＬ）を加え、２５℃で１週間振とうした。遠心分離（３０００　ｒｐｍ，　１０分）後、上清を取り除き、室温で減圧乾燥させることにより、化合物（Ａ）のＢ形結晶を得た。 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1- [] obtained in Reference Example 1 (Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic acid A-form crystal (30 mg) 2 -Propanol (1 mL) was added and shaken at 25 ° C. for 1 week. After centrifugation (3000 rpm, 10 minutes), the supernatant was removed and dried under reduced pressure at room temperature to obtain B-type crystals of compound (A).
参考例４
参考例３の方法で得られた化合物（Ａ）のＢ形結晶の粉末Ｘ線回折パターンを測定し、２θ＝７．４度及び１１．６度付近にピークが認められた。
　また示差熱分析／熱質量測定を行い、２２５～２３５℃に融解に由来する吸熱ピークが認められた。 Reference example 4
The powder X-ray diffraction pattern of the B-type crystal of the compound (A) obtained by the method of Reference Example 3 was measured, and peaks were observed near 2θ = 7.4 ° C and 11.6 ° C.
In addition, differential thermal analysis / thermogravimetric analysis was performed, and an endothermic peak derived from melting was observed at 225 to 235 ° C.
参考例５　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））のＣ形結晶の製造法 Reference Example 5 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic acid (Compound (A)) C-shaped crystal production method
　参考例１で得られた（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸のＡ形結晶（３０　ｍｇ）に酢酸エチル（１　ｍＬ）を加え、２５℃で１週間振とうした。遠心分離（３０００　ｒｐｍ，　２５℃，　１０分）後、上清を取り除き、室温で減圧乾燥させることにより、化合物（Ａ）のＣ形結晶を得た。 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1- [] obtained in Reference Example 1 (Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid A-form crystals (30 mg) acetic acid Ethyl (1 mL) was added and shaken at 25 ° C. for 1 week. After centrifugation (3000 rpm, 25 ° C., 10 minutes), the supernatant was removed and dried under reduced pressure at room temperature to obtain C-type crystals of compound (A).
参考例６
参考例５の方法で得られた化合物（Ａ）のＣ形結晶の粉末Ｘ線回折パターンを測定し、２θ＝７．０度、９．９度，１２．０度及び１３．５度付近にピークが認められた。
　示差熱分析／熱質量測定を行い、２２５～２３５℃に融解に由来する吸熱ピークが認められた。 Reference example 6
The powder X-ray diffraction pattern of the C-type crystal of the compound (A) obtained by the method of Reference Example 5 was measured and measured at around 2θ = 7.0 degrees, 9.9 degrees, 12.0 degrees and 13.5 degrees. A peak was observed.
Differential thermal analysis / thermogravimetric analysis was performed, and an endothermic peak derived from melting was observed at 225 to 235 ° C.
参考例７　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））メタンスルホン酸塩の結晶の製造法 Reference Example 7 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-Carboxylic Acid (Compound (A)) Preparation of Crystals of Methanesulfonate Law
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（０．５ｇ）にＴＨＦ（１．９ｍＬ）を加えた。氷冷下メタンスルホン酸（０．０６９ｍＬ）を加えて１時間撹拌後、減圧下溶媒を留去した。残渣にアセトンおよびヘキサンを加え、室温にて撹拌した。析出した固体をろ取することにより、化合物（Ａ）のメタンスルホン酸塩結晶（０．４１２ｇ）を得た。 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3. 1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (0.5 g) was added with THF (1.9 mL). Methanesulfonic acid (0.069 mL) was added under ice-cooling, and the mixture was stirred for 1 hour, and then the solvent was distilled off under reduced pressure. Acetone and hexane were added to the residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain methanesulfonate crystals (0.412 g) of compound (A).
参考例８
参考例７の方法で得られた化合物（Ａ）メタンスルホン酸塩の結晶の粉末Ｘ線回折パターンを測定し、２θ＝７．７度及び１５．２度付近にピークが認められた。 Reference example 8
The powder X-ray diffraction pattern of the crystal of the compound (A) methanesulfonate obtained by the method of Reference Example 7 was measured, and peaks were observed near 2θ = 7.7 ° C and 15.2 ° C.
参考例９　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））ベンゼンスルホン酸塩の結晶の製造法 Reference Example 9 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (Compound (A)) Preparation of benzenesulfonate crystals Law
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（０．０５ｇ）にＴＨＦ（０．３ｍＬ）を加えた。氷冷下ベンゼンスルホン酸（０．０１８ｍＬ）を加えて１時間撹拌後、減圧下溶媒を留去した。残渣にジイソプロピルエーテルを加え、室温にて１６時間撹拌した。析出した固体をろ取することにより、化合物（Ａ）のベンゼンスルホン酸塩結晶（０．０２５ｇ）を得た。 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3. 1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (0.05 g) was added with THF (0.3 mL). Benzenesulfonic acid (0.018 mL) was added under ice-cooling, and the mixture was stirred for 1 hour, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration to obtain benzenesulfonate crystals (0.025 g) of compound (A).
参考例１０
参考例９の方法で得られた化合物（Ａ）ベンゼンスルホン酸塩の結晶の粉末Ｘ線回折パターンを測定し、２θ＝５．６度及び７．９度付近にピークが認められた。 Reference example 10
The powder X-ray diffraction pattern of the crystal of the compound (A) benzenesulfonate obtained by the method of Reference Example 9 was measured, and peaks were observed near 2θ = 5.6 degrees and 7.9 degrees.
参考例１１　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（化合物（Ａ））リン酸塩の結晶の製造法 Reference Example 11 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3]) 3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexan-6-carboxylic acid (Compound (A)) Method for producing phosphate crystals
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸（０．０２０ｇ）のＴＨＦ（１．０ｍＬ）溶液にリン酸（０．００２ｍＬ）を加え、室温にて１６時間撹拌した。減圧下溶媒を留去後、ＩＰＥを加えて室温にて撹拌した。析出した固体をろ取することにより、化合物（Ａ）のリン酸塩結晶（０．０１１ｇ）を得た。 (1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [3.3. 1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid (0.020 g) in a THF (1.0 mL) solution with phosphoric acid (1.0 mL) 0.002 mL) was added, and the mixture was stirred at room temperature for 16 hours. After distilling off the solvent under reduced pressure, IPE was added and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain phosphate crystals (0.011 g) of compound (A).
参考例１２
参考例１１の方法で得られた化合物（Ａ）リン酸塩の結晶の粉末Ｘ線回折パターンを測定し、２θ＝４．２度及び１３．３度付近にピークが認められた。 Reference example 12
The powder X-ray diffraction pattern of the crystal of the compound (A) phosphate obtained by the method of Reference Example 11 was measured, and peaks were observed near 2θ = 4.2 degrees and 13.3 degrees.
　本発明により、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸の保存安定性や取り扱いのし易さ等の点で医薬品や医薬品原料としての使用環境で好ましい結晶形とその製造方法を提供することが可能となり、本発明の結晶形は、グループＩＩ代謝型グルタミン酸受容体拮抗作用によって調節される病気、例えば、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、筋硬直に伴う運動障害、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳不全、脳浮腫、脊髄障害、頭部外傷、炎症、免疫関連疾患等の治療及び予防薬として使用することが可能である。 According to the present invention, (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1S) -1-[(tricyclo [) 3.3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy} carbonyl) Bicyclo [3.1.0] hexane-6-carboxylic acid storage stability and ease of handling It is possible to provide a preferable crystal form and a method for producing the same in a drug or a pharmaceutical raw material environment, and the crystal form of the present invention is a disease regulated by group II metabolic glutamate receptor antagonism, for example, mood. Disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington chorea, eating disorders, drug addiction, epilepsy It can be used as a therapeutic and preventive drug for cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases and the like.

Claims (2)

  1. 　下記（ａ）～（ｃ）の物性の少なくとも１つを有する、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸の結晶。
    （ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝１０．８度、１４．５度、１９．４度、及び２１．８度にピークを有する；
    （ｂ）赤外線吸収スペクトル（ＡＴＲ法）において、特性吸収帯が、３３１０ｃｍ－１，　１７６２ｃｍ－１，　１７３１ｃｍ－１，　１５８３ｃｍ－１及び１２３６ｃｍ－１にある；又は、
    （ｃ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが２２５～２３５℃にある。     (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2 having at least one of the following physical properties (a) to (c). -({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid Crystal.
    (A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 10.8 degrees, 14.5 degrees, 19.4 degrees, and 21.8 degrees;
    (B) In the infrared absorption spectrum (ATR method), the characteristic absorption bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or
    (C) In differential thermal analysis / thermal mass measurement (TG / DTA), the endothermic peak is at 225 to 235 ° C.
  2. 　低級アルコール、アセトニトリル、酢酸エチル、アルキルアミン又はこれらの混合溶媒に、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸を溶解させた後、Ｃ５－８飽和炭化水素または水を加えて徐冷することにより結晶化させ、得られた結晶を乾燥させることを特徴とする請求項１に記載の結晶の製造方法。 In lower alcohol, acetonitrile, ethyl acetate, alkylamine or a mixed solvent thereof, (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2 -({(1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid The method for producing a crystal according to claim 1, wherein the crystal is crystallized by adding C 5-8 saturated hydrocarbon or water and slowly cooling, and the obtained crystal is dried.
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