JP4160293B2 - Crystal production method - Google Patents

Description

【００８２】
かかる濃度は選択した溶媒によって適宜最適範囲にすればよく、（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの飽和または過飽和状態とすることが結晶の晶出のために好ましい。
【００８３】
酢酸Ｃ_1-4アルキルエステルとしては酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチルなどが挙げられる。好ましくは酢酸エチルまたは酢酸プロピルが用いられる。
【００８４】
晶出は上記（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの酢酸Ｃ_1-4アルキルエステル溶液を、晶出温度約０℃〜約３５℃において放置または自体公知の方法により攪拌することにより行われる。
【００８５】
晶出温度の下限としては、好ましくは約１０℃、より好ましくは約１５℃、さらに好ましくは約２０℃である。一方、晶出温度の上限としては、好ましくは約３０℃である。特に晶出温度としては約２０℃〜約３０℃が好ましい。
【００８６】
晶出時間は約３０分〜約１０時間、好ましくは約３０分〜約４時間であり、特に約１時間〜約２時間が好ましい。
【００８７】
本工程においては、溶液に種晶を加えてもよい。かかる種晶としては、後述するＣ_5-8炭化水素の滴下前、もしくは滴下中に溶液に加えてもよい種晶が挙げられる。
【００８８】
本工程における操作は大気中、不活性ガス雰囲気下、または不活性ガス気流下で行う。ここでいう「不活性ガス」としては後述するＣ_5-8炭化水素の滴下の際に使用され得るものが挙げられる。
【００８９】
本工程により晶出した結晶をろ過、遠心分離などの方法によって分取することができる。
【００９０】
分取した結晶は、必要に応じて酢酸Ｃ_1-4アルキルエステル−Ｃ_5-8炭化水素（１：０〜１：１０）混合液などで洗浄しても良い。なお、ここでいう酢酸Ｃ_1-4アルキルエステルとしては前述したものが挙げられ、また、Ｃ_5-8炭化水素としては後述するものが挙げられる。また分取した結晶は、例えば減圧乾燥、通気乾燥、加熱乾燥、自然乾燥などの方法により乾燥できる。
【００９１】
本工程により得られた結晶は、保存安定性に優れた結晶であり、そのまま後述の医薬品として使用し得るものである。しかしながら、下記の工程（２）をさらに実施することにより、目的とする保存安定性に優れた結晶を収率よく得ることが出来る。
【００９２】
（２）（１）の工程についで同温度で該酢酸Ｃ_1-4アルキルエステル溶液量の７倍量以下のＣ_5-8炭化水素を滴下する工程
【００９３】
上記（１）の工程で晶出した結晶を分取後または分取せずに本工程に付すことによりさらに結晶を晶出させることができる。
【００９４】
本工程は上記（１）の工程において結晶が析出した後に行うことが好ましい。好ましくは原料として加えた（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールのうち少なくとも約２０重量％、より好ましくは約３０重量％〜約９０重量％、特に好ましくは約５０重量％〜約９０重量％が結晶として析出した後に行う。
【００９５】
本工程における結晶の晶出温度は（１）の工程と同様である。
【００９６】
Ｃ_5-8炭化水素としては、ペンタン、イソペンタン、ネオペンタン、ヘキサン、イソヘキサン、３−メチルペンタン、ネオヘキサン、２，３−ジメチルブタン、ヘプタン、２−メチルヘキサン、３−メチルヘキサン、３−エチルペンタン、２，２−ジメチルペンタン、２，３−ジメチルペンタン、２，４−ジメチルペンタン、３，３−ジメチルペンタン、２，２，３−トリメチルブタン、オクタン、イソオクタンなどの直鎖または分枝のＣ_5-8脂肪族炭化水素またはトルエン、キシレンなどのＣ_7-8芳香族炭化水素が挙げられる。好ましくはヘプタンあるいはヘキサンなどの直鎖Ｃ_5-8脂肪族炭化水素が用いられる。
【００９７】
Ｃ_5-8炭化水素の滴下量は、（１）の工程における（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの酢酸Ｃ_1-4アルキルエステル溶液量の７倍量以下、好ましくは５倍量以下、より好ましくは１倍量〜３倍量である。
【００９８】
滴下は、溶液を静置下または攪拌下、例えば約１５分〜約４時間（好ましくは約１時間〜約２時間）かけてほぼ等量づつを逐次滴下することにより行われる。
【００９９】
また、滴下の際の温度も上記晶出温度に調節しておくことが好ましい。
【０１００】
本工程においてはＣ_5-8炭化水素の滴下前、もしくは滴下中に溶液に種晶を加えてもよい。
【０１０１】
かかる種晶としては、例えば、
（１）粉末Ｘ線回折の格子面間隔（ｄ）が５．８８、４．７０、４．３５、３．６６、３．４８オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示す結晶、
（２）粉末Ｘ線回折の格子面間隔（ｄ）が８．３３、６．６３、５．８６、４．８２オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示す結晶、
（３）粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的ピークが現われる粉末Ｘ線回折パターンを有する結晶、
（４）粉末Ｘ線回折の格子面間隔（ｄ）が８．８６、８．０１、６．５８、５．９１、５．６３、５．０２、４．４８オングストロームに特徴的ピークが現われる粉末Ｘ線回折パターンを有する結晶、
（５）粉末Ｘ線回折の格子面間隔（ｄ）が８．３７、４．０７、５．６５、５．５９、５．２１、４．８１、４．２１オングストロームに特徴的ピークが現われる粉末Ｘ線回折パターンを有する結晶、
（６）粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７８、５．８５、５．７３、４．４３、４．０９、３．９４、３．９０、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現われる粉末Ｘ線回折パターンを示す結晶、
（７）前記（１）〜（６）のうち二つ以上の結晶の混合物または（８）溶液中、前記（１）〜（６）に転移する固体が挙げられる。
【０１０２】
滴下後、所望によりさらに約１時間〜約３時間静置または攪拌してもよい。
【０１０３】
本工程における操作は大気中、不活性ガス雰囲気下、または不活性ガス気流下で行う。該「不活性ガス」としては例えば窒素、ヘリウム、ネオン、アルゴンなどが挙げられる。
【０１０４】
本工程により晶出した結晶をろ過、遠心分離などの方法によって分取することができる。
【０１０５】
分取した結晶は、必要に応じて酢酸Ｃ_1-4アルキルエステル−Ｃ_5-8炭化水素（１：０〜１：１０）混合液などで洗浄しても良い。なお、ここでいう酢酸Ｃ_1-4アルキルエステルおよびＣ_5-8炭化水素としては、前述したものが挙げられる。また分取した結晶は、例えば減圧乾燥、通気乾燥、加熱乾燥、自然乾燥などの方法により乾燥できる。
【０１０６】
得られた結晶の解析方法としては、Ｘ線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、機械的な方法または光学的な方法なども挙げられる。
【０１０７】
上記製造方法（工程（１）のみを実施、または工程（１）実施の後、工程（２）を実施）により晶出した結晶は、以下のＤＳＣ測定（昇温速度０．５℃／ｍｉｎ）による融解開始温度を有する。ここでいう「融解開始温度」とは、例えば、後述するＤＳＣ測定条件下で、結晶を加温した場合に結晶の融解が始まる温度をいう。当該結晶は、約１３１℃以上、好ましくは約１３１℃〜約１３７℃、より好ましくは約１３２℃〜約１３５℃、さらに好ましくは約１３３℃〜約１３５℃、特に好ましくは約１３５℃の融解開始温度を有する。例えば、上記工程（１）で得られる結晶の融解開始温度は約１３５℃となり得る。また、上記工程（１）実施の後、工程（２）で得られる結晶の融解開始温度は約１３２℃〜約１３５℃となり得る。
【０１０８】
一方、従来の方法で得られる結晶の融解開始温度は約１３１℃未満である。例えば、後述の参考例３の方法で得られる結晶の融解開始温度は、約１２５℃〜約１３０℃である。
【０１０９】
上記製造方法により得られる融解開始温度が約１３１℃以上である結晶は、従来の方法で得られる融解開始温度が約１３１℃未満である結晶に比べ、非常に優れた保存安定性を有する。例えば、後述する安定性試験（４０℃・一ヶ月残存率、６０℃・一ヶ月残存率）において、本発明の製造方法による結晶は、残存率が９９％以上であるのに対して、先行技術の方法による結晶の残存率は９４％未満である。しかも先行技術の方法による結晶は保存中に顕著な着色が見られる。
【０１１０】
したがって、本発明の製造方法により得られる融解開始温度が約１３１℃以上である結晶は、このような優れた保存安定性を有することにより、従来法により得られる融解開始温度が約１３１℃未満である結晶よりも医薬品として有利に使用することができる。
【０１１１】
本発明の結晶の製造法により得られた（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの結晶は優れた抗潰瘍作用、胃酸分泌抑制作用、粘膜保護作用、抗ヘリコバクターピロリ作用等を有し、また毒性は低いため、医薬品として有用である。（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの乾燥結晶は（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの晶出させた結晶（未乾燥結晶）よりも安定であり、医薬品として用いる場合には（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの乾燥物としての結晶が好ましく用いられる。
【０１１２】
本発明の方法で晶出させた結晶または乾燥結晶は、哺乳動物（例、ヒト、サル、ヒツジ、ウシ、ウマ、イヌ、ネコ、ウサギ、ラット、マウスなど）において、消化性潰瘍（例、胃潰瘍、十二指腸潰瘍、吻合部潰瘍、ゾリンジャー・エリソン（Zollinger-Ellison）症候群等）、胃炎、逆流性食道炎、ＮＵＤ（Non Ulcer Dyspepsia）、胃癌（インターロイキン−１の遺伝子多形によるインターロイキン−１βの産生促進に伴う胃癌を含む）、胃ＭＡＬＴリンパ腫等の治療および予防、ヘリコバクター・ピロリ除菌、消化性潰瘍、急性ストレス潰瘍および出血性胃炎による上部消化管出血の抑制、侵襲ストレス（手術後に集中管理を必要とする大手術や集中治療を必要とする脳血管障害、頭部外傷、多臓器不全、広範囲熱傷から起こるストレス）による上部消化管出血の抑制、非ステロイド系抗炎症剤に起因する潰瘍の治療および予防；手術後ストレスによる胃酸過多および潰瘍の治療および予防、麻酔前投与等に有用である。ヘリコバクター・ピロリ除菌のためには、本発明の方法で晶出させた結晶または乾燥結晶と、ペニシリン系抗生物質（例、アモキシシリン等）およびエリスロマイシン系抗生物質（例、クラリスロマイシン等）とが好ましく用いられる。
【０１１３】
上記した種々の医薬用途に用いる場合、（Ｒ）−ランソプラゾールの結晶が好ましく用いられる。
【０１１４】
本発明の結晶は、そのままあるいは自体公知の方法に従って、薬理学的に許容される担体を混合した医薬組成物、例えば錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆粒剤、カプセル剤（ソフトカプセルを含む）、口腔内崩壊錠、液剤、注射剤、坐剤、徐放剤、貼布剤などとして、経口的または非経口的（例、局所、直腸、静脈投与等）に安全に投与することができる。
【０１１５】
本発明の医薬組成物中の結晶の含有量は、組成物全体の約０．０１ないし１００重量％である。該投与量は、投与対象、投与ルート、疾患などによっても異なるが、例えば抗潰瘍剤として、成人（６０ｋｇ）に対し経口的に投与する場合、有効成分として約０．５〜１５００ｍｇ／日、好ましくは約５〜１５０ｍｇ／日である。本発明の結晶は、１日１回または２〜３回に分けて投与してもよい。
【０１１６】
本発明の医薬組成物の製造に用いられてもよい薬理学的に許容される担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が挙げられ、例えば固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、水溶性高分子、塩基性無機塩；液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤などが挙げられる。また、必要に応じて、通常の防腐剤、抗酸化剤、着色剤、甘味剤、酸味剤、発泡剤、香料などの添加物を用いることもできる。
【０１１７】
該「賦形剤」としては、例えば乳糖、白糖、Ｄ−マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸、酸化チタンなどが挙げられる。
【０１１８】
該「滑沢剤」としては、例えばステアリン酸マグネシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸などが挙げられる。
【０１１９】
該「結合剤」としては、例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、結晶セルロース、αデンプン、ポリビニルピロリドン、アラビアゴム末、ゼラチン、プルラン、低置換度ヒドロキシプロピルセルロースなどが挙げられる。
【０１２０】
該「崩壊剤」としては、（１）クロスポビドン、（２）クロスカルメロースナトリウム（ＦＭＣ−旭化成）、カルメロースカルシウム（五徳薬品）などスーパー崩壊剤と称される崩壊剤、（３）カルボキシメチルスターチナトリウム（例、松谷化学（株）製）、（４）低置換度ヒドロキシプロピルセルロース（例、信越化学（株）製）、（５）コーンスターチ等が挙げられる。該「クロスポピドン」としては、ポリビニルポリピロリドン（ＰＶＰＰ）、１−ビニル−２−ピロリジノンホモポリマーと称されているものも含め、１−エテニル−２−ピロリジノンホモポリマーという化学名を有し架橋されている重合物のいずれであってもよく、具体例としては、コリドンＣＬ（ＢＡＳＦ社製）、ポリプラスドンＸＬ（ＩＳＰ社製）、ポリプラスドンＸＬ−１０（ＩＳＰ社製）、ポリプラスドンＩＮＦ−１０（ＩＳＰ社製）などである。
【０１２１】
該「水溶性高分子」としては、例えばエタノール可溶性水溶性高分子〔例えば、ヒドロキシプロピルセルロース（以下、ＨＰＣと記載することがある）などのセルロース誘導体、ポリビニルピロリドンなど〕、エタノール不溶性水溶性高分子〔例えば、ヒドロキシプロピルメチルセルロース（以下、ＨＰＭＣと記載することがある)、メチルセルロース、カルボキシメチルセルロースナトリウムなどのセルロース誘導体、ポリアクリル酸ナトリウム、ポリビニルアルコール、アルギン酸ナトリウム、グアーガムなど〕などが挙げられる。
【０１２２】
該「塩基性無機塩」としては、例えば、ナトリウム、カリウム、マグネシウムおよび／またはカルシウムの塩基性無機塩が挙げられる。好ましくはマグネシウムおよび／またはカルシウムの塩基性無機塩である。さらに好ましくはマグネシウムの塩基性無機塩である。該ナトリウムの塩基性無機塩としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム、リン酸水素二ナトリウムなどが挙げられる。該カリウムの塩基性無機塩としては、例えば、炭酸カリウム、炭酸水素カリウムなどが挙げられる。該マグネシウムの塩基性無機塩としては、例えば、重質炭酸マグネシウム、炭酸マグネシウム、酸化マグネシウム、水酸化マグネシウム、メタ珪酸アルミン酸マグネシウム、珪酸マグネシウム、アルミン酸マグネシウム、合成ヒドロタルサイト〔Ｍｇ₆Ａｌ₂（ＯＨ）₁₆・ＣＯ₃・４Ｈ₂Ｏ〕および水酸化アルミナ・マグネシウム、好ましくは、重質炭酸マグネシウム、炭酸マグネシウム、酸化マグネシウム、水酸化マグネシウムなどが挙げられる。該カルシウムの塩基性無機塩としては、例えば、沈降炭酸カルシウム、水酸化カルシウムなどが挙げられる。
【０１２３】
該「溶剤」としては、例えば注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油などが挙げられる。
【０１２４】
該「溶解補助剤」としては、例えばポリエチレングリコール、プロピレングリコール、Ｄ−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。
【０１２５】
該「懸濁化剤」としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリンなどの界面活性剤；例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどの親水性高分子などが挙げられる。
【０１２６】
該「等張化剤」としては、例えばブドウ糖、 Ｄ−ソルビトール、塩化ナトリウム、グリセリン、Ｄ−マンニトールなどが挙げられる。
【０１２７】
該「緩衝剤」としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液などが挙げられる。
【０１２８】
該「無痛化剤」としては、例えばベンジルアルコールなどが挙げられる。
【０１２９】
該「防腐剤」としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。
【０１３０】
該「抗酸化剤」としては、例えば亜硫酸塩、アスコルビン酸、α−トコフェロールなどが挙げられる。
【０１３１】
該「着色剤」としては、例えば食用黄色５号、食用赤色２号、食用青色２号などの食用色素；食用レーキ色素、ベンガラなどが挙げられる。
【０１３２】
該「甘味剤」としては、例えばサッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。
【０１３３】
該「酸味剤」としては、例えばクエン酸（無水クエン酸）、酒石酸、リンゴ酸などが挙げられる。
【０１３４】
該「発泡剤」としては、例えば重曹などが挙げられる。
【０１３５】
該「香料」としては、合成物および天然物のいずれでもよく、例えばレモン、ライム、オレンジ、メントール、ストロベリーなどが挙げられる。
【０１３６】
本発明の結晶は、自体公知の方法に従い、例えば賦形剤、崩壊剤、結合剤または滑沢剤などを添加して圧縮成形し、ついで必要により、味のマスキング、腸溶性あるいは持続性の目的のため自体公知の方法でコーティングすることにより経口投与製剤とすることができる。腸溶性製剤とする場合、腸溶層と薬剤含有層との間に両層の分離を目的として、自体公知の方法により中間層を設けることもできる。
【０１３７】
本発明の結晶を口腔内崩壊錠とする場合、例えば、結晶セルロースおよび乳糖を含有する核を、本発明の結晶および塩基性無機塩で被覆し、さらに水溶性高分子を含む被覆層で被覆して組成物を得、得られた組成物をポリエチレングリコールを含有する腸溶性被覆層で被覆し、クエン酸トリエチルを含有する腸溶性被覆層で被覆し、ポリエチレングリコールを含有する腸溶性被覆層で被覆し、さらにマンニトールで被覆して細粒を得、得られた細粒と添加剤とを混合し、成形する方法等が挙げられる。上記「腸溶性被覆層」としては、例えば、セルロースアセテートフタレート(ＣＡＰ)、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネート、メタアクリル酸共重合体〔例えば、オイドラギット(Ｅｕｄｒａｇｉｔ) Ｌ３０Ｄ−５５（商品名;レーム社製）、コリコートＭＡＥ３０ＤＰ（商品名;ＢＡＳＦ社製）、ポリキッドＰＡ３０（商品名;三洋化成社製）など〕、カルボキシメチルエチルセルロース、セラックなどの水系腸溶性高分子基剤；メタアクリル酸共重合体〔例えば、オイドラギットＮＥ３０Ｄ（商品名）、オイドラギットＲＬ３０Ｄ（商品名）、オイドラギットＲＳ３０Ｄ（商品名）など〕などの徐放性基剤；水溶性高分子；クエン酸トリエチル、ポリエチレングリコール、アセチル化モノグリセリド、トリアセチン、ヒマシ油などの可塑剤等の一種または二種以上混合したものなどが挙げられる。上記「添加剤」としては、例えば水溶性糖アルコール（例、ソルビトール、マンニトール、マルチトール、還元澱粉糖化物、キシリトール、還元パラチノース、エリスリトールなど）、結晶セルロース（例、セオラスＫＧ ８０１、アビセルＰＨ １０１、アビセルＰＨ １０２、アビセルＰＨ ３０１、アビセルＰＨ ３０２、アビセルＲＣ−５９１（結晶セルロース・カルメロースナトリウム）など）、低置換度ヒドロキシプロピルセルロース（例、ＬＨ−２２、ＬＨ−３２、ＬＨ−２３、ＬＨ−３３（信越化学（株））およびこれらの混合物など）などが用いられ、さらに結合剤、酸味料、発泡剤、甘味剤、香料、滑沢剤、着色剤、安定化剤、賦形剤、崩壊剤なども用いられる。
【０１３８】
本発明の結晶は、さらに他の１ないし３種の活性成分と併用してもよい。
【０１３９】
該「他の活性成分」としては、例えば、抗ヘリコバクター・ピロリ活性物質、イミダゾール系化合物、ビスマス塩、キノロン系化合物等が挙げられる。このうち、抗ヘリコバクター・ピロリ活性物質、イミダゾール系化合物等が好ましい。該「抗ヘリコバクター・ピロリ活性物質」としては、例えばペニシリン系抗生物質（例、アモキシシリン、ベンジルペニシリン、ピペラシリン、メシリナム等）、セフェム系抗生物質（例、セフィキシム、セファクロル等）、マクロライド系抗生物質（例、エリスロマイシン、クラリスロマイシン等）、テトラサイクリン系抗生物質（例、テトラサイクリン、ミノサイクリン、ストレプトマイシン等）、アミノグリコシド系抗生物質（例、ゲンタマイシン、アミカシン等）、イミペネムなどが挙げられる。中でもペニシリン系抗生物質、マクロライド系抗生物質等が好ましい。特に、ペニシリン系抗生物質、マクロライド系抗生物質および（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの結晶の３剤併用療法が好ましい。該「イミダゾール系化合物」としては、例えばメトロニダゾール、ミコナゾール等が挙げられる。該「ビスマス塩」としては、例えばビスマス酢酸塩、ビスマスクエン酸塩等が挙げられる。該「キノロン系化合物」としては、例えばオフロキサシン、シプロキサシン等が挙げられる。
【０１４０】
該「他の活性成分」と本発明の結晶とを自体公知の方法に従って混合し、ひとつの医薬組成物（例えば錠剤、散剤、顆粒剤、カプセル剤（ソフトカプセルを含む）、液剤、注射剤、坐剤、徐放剤など）中に製剤化して併用してもよく、それぞれを別々に製剤化し、同一対象に対して同時にまたは時間差を置いて投与してもよい。
【０１４１】
【実施例】
以下に参考例および実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。
【０１４２】
粉末Ｘ線回折は、Ｘ−ｒａｙ Ｄｉｆｆｒａｃｔｏｍｅｔｅｒ ＲＩＮＴ Ｕｌｔｉｍａ＋（Ｒｉｇａｋｕ）を用いて測定した。
【０１４３】
融解開始温度は、ＤＳＣ（示差走査熱量計 ＳＥＩＫＯ ＤＳＣ２２０Ｃ）を用いて以下の測定条件により測定した。
【０１４４】
ＤＳＣ測定条件；
温度範囲：室温〜２２０℃
昇温速度：０．５℃／ｍｉｎ．
試料容器：アルミニウムパン（カバーなし）
雰囲気：窒素ガス（１００ｍＬ／ｍｉｎ．）
【０１４５】
鏡像体過剰率（％ｅｅ）は、以下の条件（Ａ）の光学活性カラムを用いる高速液体クロマトグラフィーにより測定した。
【０１４６】
スルフィド体およびスルホン体の存在量は、以下の条件（Ａ）の光学活性カラムを用いる高速液体クロマトグラフィーまたは条件（Ｂ）の高速液体クロマトグラフィーにより測定した。
【０１４７】
高速液体クロマトグラフィー条件（Ａ）；
カラム：ＣＨＩＲＡＬＣＥＬ ＯＤ（４.６×２５０ｍｍ；ダイセル化学工業（株）製）
移動層：ヘキサン／エタノール＝９０／１０
流速：１．０ｍｌ／ｍｉｎ
検出：ＵＶ２８５ｎｍ
【０１４８】
高速液体クロマトグラフィー条件（Ｂ）；
カラム：CAPCELL PAK C18 SG120 ５μｍ ４.６×２５０ｍｍ（資生堂（株）製）
移動層：アセトニトリル：水：トリエチルアミン混液（５０：５０：１）にリン酸を加えて、ｐＨ７．０に調整したもの。
流速：１．０ｍｌ／ｍｉｎ
検出：ＵＶ２８５ｎｍ
【０１４９】
参考例１
不斉酸化による（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールを含む溶液の製造
【０１５０】
２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール一水和物（６ｋｇ，１６．２ｍｏｌ）を８０℃で２１時間減圧乾燥することにより２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール（５．７３ｋｇ，水分含量０．０３６４％）を得た。窒素気流下、２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール（５．００ｋｇ，１４．１ｍｏｌ，水分１．８２ｇを含む）、トルエン（２５Ｌ）、水（１３．１８ｇ，０．７３２ｍｏｌ，全水分量として０．８３３ｍｏｌ）、（＋）−酒石酸ジエチル（５３１ｍＬ，３．１０ｍｏｌ）を混合した。窒素気流下、５０〜６０℃でチタニウム（ＩＶ）イソプロポキシド（４１４ｍｌ，１．４０ｍｏｌ）を添加し、同温度で３０分間攪拌した。窒素気流下、１５〜２５℃で、ジイソプロピルエチルアミン（８１５ｍｌ，４．６８ｍｏｌ）を加えた後、−１０〜５℃でクメンヒドロペルオキシド（７．６５Ｌ，含量８２％、４２．７ｍｏｌ）を加え、−８〜２℃で３時間攪拌することにより反応させた。
【０１５１】
該反応液を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果を示す。
【０１５２】
該反応液中の（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は９６．９％ｅｅであった。
【０１５３】
該反応液を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該反応液中の類縁物質としては、スルフィド体１．０％、スルホン体１．７％が存在し、その他の類縁物質は存在しなかった。
【０１５４】
参考例２
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの精製法
【０１５５】
（１）上記参考例１で得られた反応液に、窒素気流下、３０％チオ硫酸ナトリウム水溶液（１３．５ｋｇ）を加え、残存するクメンヒドロペルオキシドを分解した。液量が約２５Ｌになるまで減圧濃縮した。０〜１０℃を保ちながら、ヘプタン−ｔ−ブチルメチルエーテル（ヘプタン：ｔ−ブチルメチルエーテル＝１：１）（２０Ｌ）を滴下、ついでヘプタン（７０Ｌ）を滴下した。析出結晶を分離し、冷ｔ−ブチルメチルエーテル−トルエン（ｔ−ブチルメチルエーテル：トルエン＝４：１）（５Ｌ）で洗浄した。
【０１５６】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、該結晶中の（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は９８．３％ｅｅであった。
【０１５７】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該結晶中の類縁物質としては、スルフィド体０．４５％、スルホン体１．８％が存在し、その他の類縁物質は存在しなかった。
【０１５８】
（２）上記（１）で得られた湿結晶のアセトン（２０Ｌ）懸濁液を、アセトン（７．５Ｌ）および水（３７．５Ｌ）の混液中に滴下し、ついで水（５２．５Ｌ）を加えた。析出結晶を分離し、冷アセトン−水（アセトン：水＝１：３）（５Ｌ）および水（６．５Ｌ）で洗浄した。
【０１５９】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、該結晶中の（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は１００％ｅｅであった。
【０１６０】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該結晶中の類縁物質としては、スルフィド体０．１９％、スルホン体０．０８％が存在し、その他の類縁物質は存在しなかった。
【０１６１】
（３）上記（２）で得られた湿結晶を酢酸エチル（５０Ｌ）に懸濁後、硫酸マグネシウム（２．５ｋｇ）を加えた。硫酸マグネシウムを分離し、酢酸エチル（３．５Ｌ）で洗浄した。トリエチルアミン（２５０ｍＬ）添加した後、減圧下で液量が約１０Ｌになるまで濃縮した。濃縮液にメタノール（２．５Ｌ）、約５０℃の約１２．５％アンモニア水（２５．５Ｌ）、約５０℃のｔ−ブチルメチルエーテル（２４．５Ｌ）を加え、分液した。有機層に約５０℃の約１２．５％アンモニア水（１２Ｌ）を加え、分液した（本操作をもう一回繰り返した）。水層を合わせ、酢酸エチル（２４．５Ｌ）を加え、２０℃以下で、酢酸を滴下し、ｐＨを約８に調整した。分液し、水層を酢酸エチル（２４．５Ｌ）で抽出した。有機層を合わせ、約２０％食塩水（２４．５Ｌ）で洗浄した。トリエチルアミン（２５０ｍＬ）添加後、有機層を減圧濃縮した。濃縮物にアセトン（５．５５Ｌ）を加え、減圧濃縮した。濃縮物をアセトン（１０Ｌ）に溶解させ、同液をアセトン（５Ｌ）および水（２５Ｌ）の混合液へ滴下し、ついで得られた混合液に水（２０Ｌ）を滴下した。析出結晶を分離し、冷アセトン−水（１：３）（４Ｌ）、水（１３Ｌ）で順次洗浄した。
【０１６２】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、該結晶中の（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は１００％ｅｅであった。
【０１６３】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該結晶中の類縁物質としては、スルフィド体０．０１８％、スルホン体０．０１６％が存在し、その他の類縁物質は存在しなかった。
【０１６４】
参考例３
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの精製法
【０１６５】
上記参考例２の方法で得られた湿結晶を酢酸エチル（４３Ｌ）に溶解した。分離した水層を分液操作により分離し、得られた有機層を、液量が約１９Ｌになるまで減圧濃縮した。残留液に酢酸エチル（４８Ｌ）を加えた後、液量が約１９Ｌになるまで減圧濃縮した。残留液に酢酸エチル（４８Ｌ）および活性炭（３６０ｇ）を加え、攪拌した後、活性炭をろ過により除去した。ろ液を液量が約１９Ｌになるまで減圧濃縮した。約４０℃でヘプタン（１５０Ｌ）を残留液物に滴下した。同温度で約３０分間攪拌後、結晶を分離し、約４０℃の酢酸エチル−ヘプタン（１：８、８Ｌ）で洗浄した。乾燥し、表記化合物を４．５ｋｇ得た。
【０１６６】
該結晶を粉末Ｘ線回折により分析した結果を以下に示す。
【０１６７】
該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１６８】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶中の類縁物質として、スルホン体０．０２％が存在し、スルフィド体およびその他の類縁物質は存在しなかった。該結晶中の（Ｒ）−ランソプラゾールの鏡像体過剰率は、１００％ｅｅであった。
【０１６９】
また、該結晶の融解開始温度は１２７．５℃であった。
【０１７０】
参考例４
（Ｓ）−ランソプラゾールの製造
【０１７１】
（１）窒素雰囲気下、２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール（５０．０ｇ，０．１４ｍｏｌ，水分２０ｍｇを含む）、トルエン（２５０ｍｌ）、水（１３０ｍｇ，０．００７２ｍｏｌ，全水分量として０．００８３ｍｏｌ）および（−）−酒石酸ジエチル（５．３１ｍｌ，０．０３１ｍｏｌ）を混合した。窒素雰囲気下、５０℃で混合物にチタニウム（ＩＶ）イソプロポキシド（４．１４ｍｌ，０．０１４ｍｏｌ）を添加し、５０〜５５℃で１時間攪拌した。窒素雰囲気下、冷却下で、得られた混合液にジイソプロピルエチルアミン（８．１３ｍｌ，０．０４７ｍｏｌ）を加えた後、−１０〜０℃でクメンヒドロペルオキシド（７６．５０ｍｌ，含量８２％、０．４２ｍｏｌ）を加え、−５〜５℃で３．５時間攪拌し、反応液を得た。
【０１７２】
反応液を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、反応液中の（Ｓ）−ランソプラゾールの鏡像体過剰率は９６．５％ｅｅであった。
【０１７３】
該反応液を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、反応液中の類縁物質として、スルホン体１．９０％およびスルフィド体１．５０％が存在し、その他の類縁物質は存在しなかった。
【０１７４】
（２）上記（１）で得られた反応液に、窒素気流下、３０％チオ硫酸ナトリウム水溶液（１８０ｍｌ）を加え、残存するクメンヒドロペルオキシドを分解した。分液し、得られた有機層に、水（５０ｍｌ）、ヘプタン（１５０ｍｌ）、ｔ−ブチルメチルエーテル（２００ｍｌ）およびヘプタン（３００ｍｌ）を順次加え、晶出させた。結晶を分離し、ｔ−ブチルメチルエーテル−トルエン（ｔ−ブチルメチルエーテル：トルエン＝４：１）（４５ｍｌ）で洗浄し、以下の粉末Ｘ線回折の格子面間隔（ｄ）を有する（Ｓ）−ランソプラゾールを湿結晶として得た。
【０１７５】
該湿結晶を粉末Ｘ線回折により分析した結果、該湿結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が５．８８、４．７０、４．３５、３．６６、３．４８オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１７６】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶の鏡像体過剰率は、１００％ｅｅであった。
【０１７７】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、結晶中の類縁物質として、スルホン体０．７２％が存在し、スルフィド体およびその他の類縁物質は存在しなかった。
【０１７８】
（３）上記（２）で得られた湿結晶のアセトン（２２０ｍｌ）懸濁液を、アセトン（７５ｍｌ）および水（３７０ｍｌ）の混液中に滴下し、ついで水（５２０ｍｌ）を加えた。析出結晶を分離し、アセトン−水（アセトン：水＝１：３）（４４ｍｌ）および水（１３０ｍｌ）で洗浄し、以下の粉末Ｘ線回折の格子面間隔（ｄ）を有する（Ｓ）−ランソプラゾールを湿結晶として得た。
【０１７９】
該湿結晶を粉末Ｘ線回折により分析した結果、粉末Ｘ線回折の格子面間隔（ｄ）が８．３３、６．６３、５．８６、４．８２オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１８０】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶の鏡像体過剰率は、１００％ｅｅであった。
【０１８１】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、結晶中の類縁物質として、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。
【０１８２】
参考例５
（Ｓ）−ランソプラゾールの製造
【０１８３】
参考例４に準じて得られた湿結晶（表題化合物３５．３７ｇ含有，類縁物質存在量：０％，鏡像体過剰率：１００％ｅｅ）を酢酸エチル（３４０ｍｌ）に溶解した。分離した水層を分液操作により分離し、得られた有機層を、液量が約１００ｍｌになるまで減圧濃縮した。残留液に酢酸エチル（４００ｍｌ）および活性炭（３ｇ）を加え、攪拌した後、活性炭をろ過により除去した。ろ液を、液量が約１００ｍｌになるまで減圧濃縮した。約４０℃でヘプタン（１０００ｍｌ）を残留液物に滴下した。同温度で約３０分間攪拌後、結晶を分離し、約４０℃の酢酸エチル−ヘプタン（１：８，６３ｍｌ）で洗浄した。乾燥し、表題化合物を３５．０８ｇ（収率：９９．２％）得た。
【０１８４】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１８５】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶中の類縁物質として、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。該結晶中の（Ｓ）−ランソプラゾールの鏡像体過剰率は、１００％ｅｅであった。
【０１８６】
また、該結晶の融解開始温度は１２７．０℃であった。
【０１８７】
参考例６
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（１．５ｇ、４．０６ｍｍｏｌ）を酢酸エチル（３０ｍＬ）に溶解させた後、外温約２５℃で６ｍＬまで減圧濃縮した。約−５℃でヘプタン（２４ｍＬ）を約３０分間で滴下した。約２．５時間の攪拌の後、析出結晶を分離し、乾燥し、題記化合物（１．４６ｇ、収率：９７．３％）を得た。
【０１８８】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１８９】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶中の類縁物質として、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。該結晶中の（Ｒ）−ランソプラゾールの鏡像体過剰率は、１００％ｅｅであった。
【０１９０】
また、該結晶の融解開始温度は１３０．０℃であった。
【０１９１】
参考例７
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（１．５ｇ、４．０６ｍｍｏｌ）を酢酸エチル（３０ｍＬ）に溶解させた後、外温約２５℃で２０ｍＬまで減圧濃縮した。約２５℃でヘプタン（９０ｍＬ）を約３０分間で滴下した。約２．５時間の攪拌の後、析出結晶を分離し、乾燥し、題記化合物（１．４０ｇ、収率：９３．３％）を得た。
【０１９２】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１９３】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶中の類縁物質として、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。該結晶中の（Ｒ）−ランソプラゾールの鏡像体過剰率は、１００％ｅｅであった。また、該結晶の融解開始温度は１２８．５℃であった。
【０１９４】
実施例１
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの高融点結晶の製造法
【０１９５】
上記参考例２の方法で得られた湿結晶を酢酸エチル（５０Ｌ）に溶解させた後、分液した。有機層を減圧下で液量が約２５Ｌになるまで濃縮した。残留物に酢酸エチル（３０Ｌ）を加えた後、減圧下で液量が約１５Ｌになるまで濃縮した。残留物に酢酸エチル（３０Ｌ）および活性炭（１５０ｇ）を加えた。活性炭を除去し、酢酸エチル（１．５Ｌ）で洗浄した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの濃度が約０．２８ｇ／ｍＬになるまで、ろ洗液を減圧下で濃縮した（１２．５Ｌ）。窒素気流下、約２５℃で約２時間攪拌し、結晶の析出を確認後、ヘプタン（２５Ｌ）を約１．５時間かけて滴下、ついで約１．５時間攪拌した。析出結晶を分離し、酢酸エチル−ヘプタン（酢酸エチル：ヘプタン＝１：５）（６Ｌ）で洗浄後、乾燥し、題記化合物（３．６６ｋｇ，２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール基準の収率：７０％）を得た。
【０１９６】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０１９７】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、該結晶中の（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は１００％ｅｅであった。
【０１９８】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該結晶中の類縁物質としては、スルホン体０．０１％が存在し、スルフィド体およびその他の類縁物質は存在しなかった。また該結晶の融解開始温度は、１３４．０℃であった。
【０１９９】
実施例２
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（３ｇ、８．１２ｍｍｏｌ）を酢酸エチル（１２ｍＬ）に約５０℃で溶解させた後、約２５℃で約６時間攪拌した。析出結晶を分離し、酢酸エチル−ヘプタン（酢酸エチル：ヘプタン＝１：５）（３ｍＬ）で洗浄後、乾燥し、題記化合物（１．５５ｇ、収率：５２％）を得た。
【０２００】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０２０１】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、結晶中の類縁物質として、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。該結晶中の（Ｒ）−ランソプラゾールの鏡像体過剰率は、１００％ｅｅであった。
【０２０２】
該結晶の融解開始温度は、１３５．０℃であった。
【０２０３】
実施例３
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（１．５ｇ、４．０６ｍｍｏｌ）をｎ−酢酸プロピル（３０ｍＬ）に溶解させた後、外温約２５℃で６ｍＬまで減圧濃縮した。約２．５時間の攪拌の後、析出結晶を分離し、乾燥し、題記化合物（０．９４ｇ、収率：６３％）を得た。該結晶の融解開始温度は、１３４．５℃であった。
【０２０４】
実施例４
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（３．０ｇ、８．１２ｍｍｏｌ）を酢酸エチル（１２ｍＬ）に約５０℃で溶解させた後、約２５℃で約２．５時間攪拌した。結晶の析出を確認後、これにヘプタン（６０ｍＬ）を約１５分かけて滴下した後、析出結晶を分離し、酢酸エチル−ヘプタン（酢酸エチル：ヘプタン＝１：５）（３ｍＬ）で洗浄後、乾燥し、題記化合物（２．８４ｇ、収率：９５％）を得た。
【０２０５】
該結晶の融解開始温度は、１３３．５℃であった。
【０２０６】
実施例５
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（３．０ｇ、８．１２ｍｍｏｌ）を酢酸エチル（１２ｍＬ）に約５０℃で溶解させた後、約２５℃で約２時間攪拌した。結晶の析出を確認後、これにヘキサン（２４ｍＬ）を約２０分かけて滴下した後、析出結晶を分離し、酢酸エチル−ヘキサン（酢酸エチル：ヘキサン＝１：５）（３ｍＬ）で洗浄後、乾燥し、題記化合物を得た。
【０２０７】
該結晶の融解開始温度は、１３３．５℃であった。
【０２０８】
実施例６
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（２．０ｇ、５．４１ｍｍｏｌ）をｎ−酢酸プロピル（３０ｍＬ）に約３０℃で溶解させた後、外温約２５℃で８ｍＬまで減圧濃縮した。約１．５時間の攪拌の後、結晶の析出を確認し、ついでヘプタン（１６ｍＬ）を約２０分かけて滴下した。析出結晶を分離し、ｎ−酢酸プロピル−ヘプタン（ｎ−酢酸プロピル：ヘプタン＝１：５）（６ｍＬ）で２回洗浄後、乾燥し、題記化合物（１．８６ｇ、収率：９３％）を得た。
【０２０９】
該結晶の融解開始温度は、１３４．０℃であった。
【０２１０】
実施例７
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（２．０ｇ、５．４１ｍｍｏｌ）をｉ−酢酸プロピル（４０ｍＬ）に約３５℃で溶解させた後、外温約３５℃で８ｍＬまで減圧濃縮した。約１．５時間の攪拌の後、結晶の析出を確認し、ついでヘプタン（１６ｍＬ）を約２０分かけて滴下した。析出結晶を分離し、ｉ−酢酸プロピル−ヘプタン（ｉ−酢酸プロピル：ヘプタン＝１：５）（６ｍＬ）で２回洗浄後、乾燥し、題記化合物（１．８９ｇ、収率：９５％）を得た。該結晶の融解開始温度は、１３３．０℃であった。
【０２１１】
実施例８
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（２．０ｇ、５．４１ｍｍｏｌ）をｎ−酢酸ブチル（４０ｍＬ）に約３５℃で溶解させた後、外温約３５℃で８ｍＬまで減圧濃縮した。約１時間の攪拌の後、結晶の析出を確認し、ついでヘプタン（１６ｍＬ）を約２０分かけて滴下した。析出結晶を分離し、ｎ−酢酸ブチル−ヘプタン（ｎ−酢酸ブチル：ヘプタン＝１：５）（６ｍＬ）で２回洗浄後、乾燥し、題記化合物（１．８７ｇ、収率：９３％）を得た。該結晶の融解開始温度は、１３３．０℃であった。
【０２１２】
実施例９
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（２．０ｇ、５．４１ｍｍｏｌ）を酢酸メチル（１５ｍＬ）に溶解させた後、外温約２５℃で８ｍＬまで減圧濃縮した。約１．５時間の攪拌の後、結晶の析出を確認し、ついでヘプタン（１６ｍＬ）を約２０分かけて滴下した。析出結晶を分離し、酢酸メチル−ヘプタン（酢酸メチル：ヘプタン＝１：５）（６ｍＬ）で２回洗浄後、乾燥し、題記化合物（１．７１ｇ、収率：８６％）を得た。該結晶の融解開始温度は、１３４．０℃であった。
【０２１３】
実施例１０
上記参考例４の方法で得られた湿結晶を酢酸エチル（５０Ｌ）に溶解させた後、分液した。有機層を減圧下で液量が約２７Ｌになるまで濃縮した。残留物に酢酸エチル（３０Ｌ）を加えた後、減圧下で液量が約１６Ｌになるまで濃縮した。残留物に酢酸エチル（３０Ｌ）および活性炭（１５０ｇ）を加えた。活性炭を除去し、酢酸エチル（１．５Ｌ）で洗浄した。（Ｓ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの濃度が約０．２７ｇ／ｍＬになるまで、ろ洗液を減圧下で濃縮した（１２．５Ｌ）。窒素気流下、約２５℃で約２時間攪拌後、結晶の析出を確認し、ついでヘプタン（２５Ｌ）を約１．５時間かけて滴下し、ついで約１．５時間攪拌した。析出結晶を分離し、酢酸エチル−ヘプタン（酢酸エチル：ヘプタン＝１：５）（６Ｌ）で洗浄後、乾燥し、題記化合物（３．７６ｋｇ，２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］チオ］−１Ｈ−ベンズイミダゾール基準の収率：７２％）を得た。
【０２１４】
該結晶を粉末Ｘ線回折により分析した結果、該結晶は、粉末Ｘ線回折の格子面間隔（ｄ）が１１．６８、６．７７、５．８４、５．７３、４．４３、４．０９、３．９４、３．８９、３．６９、３．４１、３．１１オングストロームに特徴的なピークが現れる粉末Ｘ線回折パターンを示した。
【０２１５】
該結晶を高速液体クロマトグラフィー（条件（Ａ））にて分析した結果、該結晶中の（Ｓ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの鏡像体過剰率は１００％ｅｅであった。
【０２１６】
該結晶を高速液体クロマトグラフィー（条件（Ｂ））にて分析した結果、該結晶中の類縁物質としては、スルホン体、スルフィド体およびその他の類縁物質は存在しなかった。
【０２１７】
該結晶の融解開始温度は、１３３．５℃であった。
【０２１８】
実施例１１
（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（１．５ｇ、４．０６ｍｍｏｌ）を酢酸エチル（３０ｍＬ）に溶解させた後、外温約２５℃で６ｍＬまで減圧濃縮した。同温度で約２時間撹拌した後、結晶の析出を確認し、ついでヘプタン（２４ｍＬ）を約３０分間で滴下した。約２．５時間の攪拌の後、析出結晶を分離し、乾燥し、題記化合物（１．４６ｇ、収率：９７．３％）を得た。該結晶の融解開始温度は、１３３．５℃であった。
【０２１９】
試験例 安定性試験（融解開始温度と安定性との関係）
上記参考例および実施例で得られた各種（Ｒ）−ランソプラゾール結晶について６０℃・一ヶ月の安定性試験を実施した結果の一例を下表１に示す。
【０２２０】
【表１】

【０２２１】
本発明の方法による結晶は６０℃・一ヶ月の安定性試験において９９％以上の残存率を示すが、従来法による結晶は、約９０〜９４％の残存率まで低下することがわかった。
【０２２２】
また、（Ｒ）−ランソプラゾールの結晶について４０℃・一ヶ月の安定性試験を実施した結果の一例を下表２に示す。
【０２２３】
【表２】

【０２２４】
本発明の方法では４０℃・一ヶ月の安定性試験において分解が認められないが、従来法では、外観が悪化、含量が低下、類縁物質量が増加することがわかった。
【０２２５】
また、図１に、融解開始温度が約１３４℃の結晶（実施例１）および融解開始温度が約１３０℃の結晶（参考例６）の安定性試験前と、４０℃・２週間、５０℃・２週間および６０℃・２週間の安定性試験後の外観を示す。融解開始温度が約１３４℃の結晶では外観に変化が生じていないが、融解開始温度が約１３０℃の結晶では明らかに外観が悪化することがわかった。
【０２２６】
以上の結果より、（Ｒ）−ランソプラゾールおよび（Ｓ）―ランソプラゾールの結晶の場合、融解開始温度と安定性には明確な関係があり、融解開始温度が約１３１℃以上の結晶は、安定であるが、融解開始温度が約１３１℃未満の結晶は、不安定であることがわかった。
【０２２７】
製剤例１
カプセル剤の製造
下記〔表３〕の仕込量−１で、以下に示す方法に従って、１５ｍｇカプセル剤を得た（〔表４〕には１カプセル当りの処方量を示す）。
【０２２８】
（１）実施例１で得られた（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジニル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールの結晶（以下、化合物Ａと略称する）および（３）から（６）の成分をよく混合して散布剤とした。遠心流動型コーティング造粒装置中に、（２）ノンパレルを入れ、（７）ヒドロキシプロピルセルロースを精製水に溶解した水溶液をスプレーしながら、上記の散布剤をコーティングした。該球状顆粒を４０℃で１６〜２０時間真空乾燥し、篩（６００μｍ、１１８０μｍ）で篩過して主薬粒を得た。主薬粒を転動流動型コーティング機に入れ、（８）メタアクリル酸コポリマーＬＤ〜（１２）ポリソルベート８０を精製水に懸濁させた懸濁液をコーティングした。このコーティングした粒を篩（７１０μｍ、１４００μｍ）で篩過し、４０℃で１６〜２０時間真空乾燥して腸溶性粒を得た。腸溶性粒に（１３）タルクおよび（１４）軽質無水ケイ酸を加えてタンブラー混合機を用い、混合粒とした。混合粒をカプセル充填機により、（１７）ＨＰＭＣカプセル２号に充填して、１５ｍｇカプセルとした。
【０２２９】
さらに、上記の混合粒の充填量を調整することにより２０ｍｇおよび１０ｍｇカプセルとした。
【０２３０】
【表３】

【０２３１】
【表４】

【０２３２】
製剤例２
カプセル剤の製造
下記〔表５〕の仕込量−２で、以下に示す方法に従って１５ｍｇカプセル剤を得た（〔表６〕には１カプセル当りの処方量を示す）。（１）化合物Ａおよび（３）から（６）の成分をよく混合して主薬散布剤とした。（７）から（９）の成分をよく混合して上掛散布剤とした。遠心流動型コーティング造粒装置中に、（２）ノンパレルを入れ、（１０）ヒドロキシプロピルセルロースを精製水に溶解した水溶液をスプレーしながら、上記の主薬散布剤、上掛散布剤をその順にコーティングした。該球状顆粒を４０℃で１６〜２０時間真空乾燥し、篩（６００μｍ、１１８０μｍ）で篩過して主薬粒を得た。主薬粒を転動流動型コーティング機に入れ、（１１）メタアクリル酸コポリマーＬＤ〜（１５）ポリソルベート８０を精製水に懸濁させた懸濁液をコーティングした。このコーティングした粒を篩（７１０μｍ、１４００μｍ）で篩過し、４０℃で１６〜２０時間真空乾燥して腸溶性粒を得た。腸溶性粒に（１６）タルクおよび（１７）軽質無水ケイ酸を加えてタンブラー混合機を用い、混合粒とした。混合粒をカプセル充填機により、（１８）ＨＰＭＣカプセル２号に充填して１５ｍｇカプセルとした。
【０２３３】
【表５】

【０２３４】
【表６】

【０２３５】
【発明の効果】
本発明の製造法によれば、保存安定性に優れる（Ｒ）−ランソプラゾールまたは（Ｓ）−ランソプラゾールの結晶を効率よく工業的大量規模で製造することができる。
【０２３６】
【図面の簡単な説明】
【図１】融解開始温度が約１３４℃の結晶（実施例１）および融解開始温度が約１３０℃の結晶（参考例６）の安定性試験前（イニシャル）と、４０℃・２週間、５０℃・２週間および６０℃・２週間の安定性試験後の外観を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an optically active sulfoxide compound having an anti-ulcer activity, crystals of the optically active sulfoxide compound with significantly improved stability, and the like.
[0002]
[Prior art]
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole [hereinafter referred to as (R) ) -Lansoprazole] or (S) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole As a method for producing [hereinafter also referred to as (S) -lansoprazole], for example, Japanese Patent Publication No. 11-508590 (WO 97/02261) discloses (+)-enantiomer or (-)- A preparation of a compound enriched in one of the enantiomers, i.e. one enantiomer, is treated with a solvent and the racemic crystallization of this compound is utilized to obtain the The semi-compound is selectively precipitated from the solvent and the precipitated racemate is filtered off followed by removal of the solvent to give a single enantiomer with increased optical purity of the corresponding compound, such as lansoprazole, A method for optical purification of a preparation of one enantiomerically enriched compound and a crystallization method by solvent removal are described.
[0003]
In addition, Japanese Patent Publication No. 10-504290 (WO 96/02535) discloses a method for producing an optically active sulfoxide compound by subjecting a thio compound to an oxidation reaction, and crystallization of omeprazole by concentration of acetonitrile solution (Example 11). ).
[0004]
Lansoprazole is currently marketed worldwide as a pharmaceutical with excellent anti-ulcer activity. The lansoprazole crystals are racemic and excellent in storage stability.
[0005]
[Problems to be solved by the invention]
The optically active (R) -lansoprazole and (S) -lansoprazole crystals obtained by the conventional methods as described above cannot be said to be sufficiently satisfactory in storage stability, and the purity decreases during storage. It was impossible to deny the possibility of increasing the amount of related substances or coloring.
[0006]
There is a demand for a method for producing crystals of (R) -lansoprazole or (S) -lansoprazole, which are sufficiently excellent in storage stability.
[0007]
[Means for Solving the Problems]
The inventors of the present invention have studied various methods for producing crystals of (R) -lansoprazole and (S) -lansoprazole, and by crystallizing (R) -lansoprazole and (S) -lansoprazole under specific conditions. Surprisingly, extremely stable crystals were obtained, and it was found for the first time that this method was a satisfactory production method on an industrial scale, and earnestly researched based on these findings, thereby completing the present invention.
[0008]
That is, the present invention
[1] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2- [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole at a concentration of about 0.1 g / ml to about 0.5 g / ml Acetic acid C contained in _1-4 (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2, characterized by crystallization from an alkyl ester solution at a temperature of about 0 ° C. to about 35 ° C. -Pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H A method for producing crystals of benzimidazole,
[2] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2- [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole at a concentration of about 0.1 g / ml to about 0.5 g / ml Acetic acid C contained in _1-4 Crystallization from the alkyl ester solution at a temperature of about 0 ° C. to about 35 ° C., followed by the acetic acid C at the same temperature. _1-4 C less than 7 times the amount of alkyl ester solution _5-8 (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole, characterized by dropping hydrocarbons Or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystal production method,
[3] The production method according to the above [1] or [2], wherein the crystallization temperature is about 20 ° C to about 30 ° C.
[4] The production method according to the above [1] or [2], wherein the crystallization time is about 30 minutes to about 4 hours,
[5] Acetic acid C _1-4 The production method according to the above [1] or [2], wherein the alkyl ester is ethyl acetate or propyl acetate,
[6] Acetic acid C _1-4 C less than 5 times the amount of alkyl ester solution _5-8 The production method according to the above [2], wherein hydrocarbons are dropped.
[7] C _5-8 The production method of the above-mentioned [2], wherein the hydrocarbon is heptane or hexane,
[8] C _5-8 The production method according to the above [2], wherein the dropping time of the hydrocarbon is about 15 minutes to about 4 hours,
[9] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] produced by the production method described in [1] or [2] above Methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole Crystals of the
[10] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] produced by the production method described in [1] or [2] above Methyl] sulfinyl] -1H-benzimidazole crystals,
[11] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H having a melting start temperature of about 131 ° C. or higher -Crystals of benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole,
[12] The crystal according to the above [11], wherein the melting start temperature is about 135 ° C.
[13] A pharmaceutical composition comprising the crystal of [9] or [11] above,
[14] Peptic ulcer; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MALT lymphoma; upper gastrointestinal bleeding; ulcer caused by nonsteroidal anti-inflammatory drugs; The pharmaceutical composition according to [13] above, which is an agent for preventing or treating ulcers or diseases caused by Helicobacter pylori,
[15] The crystal according to [9] or [11] is administered to a human and peptic ulcer; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MLT lymphoma; upper gastrointestinal bleeding; Ulcers caused by steroidal anti-inflammatory drugs; gastric hyperacidity and ulcers due to post-operative stress; or methods for preventing or treating diseases caused by Helicobacter pylori,
[16] Peptic ulcer; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MALT lymphoma; upper gastrointestinal bleeding; ulcers caused by nonsteroidal anti-inflammatory agents; Use of the crystal according to the above [9] or [11] for producing a pharmaceutical composition for prevention / treatment against an ulcer or a disease caused by Helicobacter pylori,
[17] (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2- [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole at a concentration of about 0.1 g / ml to about 0.5 g / ml Acetic acid C contained in _1-4 (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2, characterized by crystallization from an alkyl ester solution at a temperature of about 0 ° C. to about 35 ° C. -Pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H -It relates to a method for stabilizing crystals of benzimidazole.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The “(R) -lansoprazole” or “(S) -lansoprazole” used as a raw material in the method for producing a crystal of the present invention is a method known per se, for example, JP 10-504290 A (WO 96/02535). Or a method analogous thereto, or a method described in the following production method 1 or 2, etc.
[0010]
(1) Production method 1
2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole and an excess amount (about 1.5 to 10 molar equivalents). Oxidizing agents (eg, peroxides such as hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, etc.) and asymmetric induction catalysts (eg, optically active diols, titanium (IV) alkoxides, water complexes, etc.) ), Organic solvents [eg, alcohols such as methanol, ethanol, propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, butyl methyl ether, dioxane and tetrahydrofuran; Esters such as ethyl acetate and methyl acetate; acetone and methyl isobuty Ketones such as ruketone; halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride and carbon tetrachloride; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; acetic acid and the like] and bases (eg, Inorganic bases such as alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride; sodium methoxide, Alkali metal alkoxides such as sodium ethoxide, alkali metal carboxylates such as sodium acetate, piperidine, piperazine, pyrrolidine, morpholine, triethylamine, tripropylamine, tributylamine, trioctylamine, di In the presence of amines such as sopropylethylamine and dimethylphenylamine, pyridines such as pyridine and dimethylaminopyridine; basic amino acids such as arginine, lysine and ornithine] at about -20 to 20 ° C, It can be obtained by reacting for about 0.1 to 50 hours.
[0011]
The obtained compound is isolated by means of separation and purification known per se, for example, concentration, solvent extraction, crystallization, phase transfer, chromatography, or a combination thereof.
[0012]
(2) Production method 2
2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole can be subjected to optical resolution to give an isomer. .
[0013]
Examples of the optical resolution method include methods known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method, and the like.
[0014]
The “fractional recrystallization method” includes a racemate and an optically active compound [eg, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1 -Phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization or the like, and optionally subjected to a neutralization step. The method of obtaining the optical isomer of this is mentioned.
[0015]
Examples of the “chiral column method” include a method in which a racemate or a salt thereof is applied to an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, a racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corp.) or CHIRAL series (manufactured by Daicel Corp.), and water, buffer solution (eg, phosphate buffer solution), organic solvent (eg, hexane) , Ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate optical isomers. For example, in the case of gas chromatography, a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) can be mentioned.
[0016]
In the “diastereomer method”, a racemate and an optically active reagent are reacted (preferably, an optically active reagent is reacted at the 1-position of a benzimidazole group) to obtain a mixture of diastereomers, After obtaining one diastereomer by separation means (eg, fractional recrystallization, chromatography method, etc.), it is subjected to chemical reaction (eg, acid hydrolysis reaction, basic hydrolysis reaction, hydrogenolysis reaction, etc.). And an optically active reagent site is obtained to obtain the desired optical isomer. Examples of the “optically active reagent” include optically active organic acids such as MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid] and (−)-menthoxyacetic acid; (1R-endo) -2 And optically active alkoxymethyl halides such as-(chloromethoxy) -1,3,3-trimethylbicyclo [2.2.1] heptane.
[0017]
The above 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole is disclosed in JP-A-61-50978, USP. 4,628,098, JP-A-10-195068, WO 98/22101, etc., or a method analogous thereto.
[0018]
Further, 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole is disclosed in JP-A-61-50978, USP. 4,628,098 or the like, or a method analogous thereto.
[0019]
(R) -lansoprazole or (S) -lansoprazole produced by the above method may be either solid (crystalline, amorphous) or oily, and may not be isolated and purified.
[0020]
Furthermore, the crystals of (R) -lansoprazole or (S) -lansoprazole may be hydrated or non-hydrated.
[0021]
Examples of the “hydrate” include 0.5 hydrate to 5.0 hydrate. Among these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate, and 2.5 hydrate are preferable. Particularly preferred are 0.5 hydrate, 1.0 hydrate and 1.5 hydrate.
[0022]
When (R) -lansoprazole or (S) -lansoprazole obtained by the above method is obtained, for example, as a crystal (hereinafter sometimes referred to as crystal (1)), and then subjected to the method for producing a crystal of the present invention, Examples of the crystallization method for obtaining (1) include methods known per se, such as crystallization from a solution, crystallization from a vapor, and crystallization from a melt.
[0023]
Examples of the “crystallization from solution” include a concentration method, a cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a flux method, and the like. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acid amides (Eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like are used. These solvents are used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100).
[0024]
Examples of the “crystallization from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
[0025]
Examples of the “crystallization from melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). And liquid phase epitaxy method).
[0026]
Examples of the crystal of (R) -lansoprazole or (S) -lansoprazole used as a raw material in the crystal production method of the present invention include, for example,
(1) Powder X-ray diffraction in which the lattice spacing (d) of powder X-ray diffraction of the undried crystals has a characteristic peak at 5.88, 4.70, 4.35, 3.66, 3.48 angstroms Crystal showing pattern,
(2) A crystal showing a powder X-ray diffraction pattern in which a peak characteristic of a lattice distance (d) of powder X-ray diffraction of 8.33, 6.63, 5.86, 4.82 angstroms appears in an undried crystal. ,
(3) A mixture of the crystals of (1) and (2) above,
(4) The lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69. It is a crystal showing a powder X-ray diffraction pattern in which a characteristic peak appears at 3.41, 3.11 angstroms.
[0027]
The enantiomeric excess of (R) -lansoprazole or (S) -lansoprazole subjected to the method for producing a crystal of the present invention is, for example, about 80% ee or more, preferably about 90% ee or more.
[0028]
More preferred (R) -lansoprazole is one that is substantially free of (S) -lansoprazole. “Substantially free” means (R) -lansoprazole containing 0-3%, preferably 0-1% (S) -lansoprazole. Further, more preferable (S) -lansoprazole does not substantially contain (R) -lansoprazole. “Substantially free” means (S) -lansoprazole containing 0-3%, preferably 0-1% (R) -lansoprazole.
[0029]
After (R) -lansoprazole or (S) -lansoprazole is obtained by the above-described production method, it is preferably subjected to a step of improving optical purity described later.
[0030]
In order to improve the optical purity of (R) -lansoprazole or (S) -lansoprazole obtained by the above-mentioned production method, for example, the method described in JP-T-11-508590 (WO 97/02261) or It is carried out by a similar method or the following method [1] or [2].
[0031]
[1] By selectively crystallizing crystals of (R) -lansoprazole from a solution containing more (R) -lansoprazole than (S) -lansoprazole, and fractionating the crystallized crystals (S Crystals of (R) -lansoprazole substantially free of) -lansoprazole can be produced.
[0032]
[2] From a solution containing more (S) -lansoprazole than (R) -lansoprazole, (S) -lansoprazole crystals are selectively crystallized, and the crystallized crystals are separated (R Crystals of (S) -lansoprazole substantially free of) -lansoprazole can be produced.
[0033]
After the above operation [1] or [2], the crystallized crystal may be collected and further subjected to one or more recrystallizations.
[0034]
Examples of the method of “selectively crystallizing” include, for example, a method of stirring the solution, a method of adding seed crystals to the solution, a method of changing the temperature of the solution, a method of changing the solvent composition of the solution, Examples thereof include a method for reducing the liquid volume of the solution, a method for combining two or more of these methods, and the like.
[0035]
As the “method of stirring the solution”, for example, a solution rich in either (R) -lansoprazole or (S) -lansoprazole is used at about −80 to 120 ° C., preferably about −20 to 60 ° C., about 0 A method of stirring for 0.01 to 100 hours, preferably about 0.1 to 10 hours can be mentioned.
[0036]
As the “method of adding seed crystals to a solution”, for example, in a solution containing either (R) -lansoprazole or (S) -lansoprazole, (1) the lattice spacing (d) of powder X-ray diffraction is 5 .88, 4.70, 4.35, 3.66, 3.48 angstrom crystals showing a powder X-ray diffraction pattern, (2) lattice spacing (d) of powder X-ray diffraction 8. A crystal showing a powder X-ray diffraction pattern in which a peak characteristic in 8.33, 6.63, 5.86, 4.82 angstroms appears, (3) a mixture of the crystals of (1) and (2) or (4 ) Solids (1) to (3) in the solution (for example, powder X-ray diffraction lattice spacing (d) is 11.68, 6.77, 5.84, 5.73, 4.43) 4.09, 3.94, 3.89, 3.69, 3.41 A crystal having a powder X-ray diffraction pattern in which a characteristic peak appears at 3.11 Å, and a lattice spacing (d) of powder X-ray diffraction is 8.86, 8.01, 6.58, 5.91, and 5.63. , 5.02, 4.48 angstrom, a crystal having a powder X-ray diffraction pattern, and the lattice spacing (d) of powder X-ray diffraction is 8.37, 4.07, 5.65, 5. A crystal having a powder X-ray diffraction pattern with characteristic peaks appearing at 59, 5.21, 4.81, 4.21 angstroms, and a lattice spacing (d) of powder X-ray diffraction of 11.68, 6.78, 5 .85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11 angstroms showing a powder X-ray diffraction pattern in which a characteristic peak appears Etc.) as seed crystals How to, and the like.
[0037]
As the “method for changing the temperature of the solution”, for example, the temperature of the solution containing either (R) -lansoprazole or (S) -lansoprazole is changed, preferably cooling (eg, the liquid temperature is adjusted to 5 to 100). A method of lowering the temperature).
[0038]
Examples of the “method for changing the solvent composition of a solution” include, for example, a solution containing either one of (R) -lansoprazole or (S) -lansoprazole, water, a low-polar organic solvent (eg, esters, ethers). , Aromatic hydrocarbons, hydrocarbons, halogenated hydrocarbons, or a mixture of two or more thereof) or a method of adding a mixture of two or more of these.
[0039]
Examples of the “method for reducing the liquid volume of the solution” include a method of evaporating and evaporating the solvent from a solution containing either one of (R) -lansoprazole or (S) -lansoprazole.
[0040]
Of these, preferably
(I) a method of stirring the solution,
(Ii) a method of performing both a method of stirring the solution and a method of adding seed crystals to the solution;
(Iii) a method of performing both a method of stirring the solution and a method of changing the temperature of the solution;
(Iv) a method of performing both a method of stirring the solution and a method of changing the solvent composition of the solution;
(V) a method of performing both a method of stirring the solution and a method of reducing the liquid volume of the solution,
(Vi) a method of stirring the solution, a method of changing the temperature of the solution, and a method of adding seed crystals to the solution,
(Vii) a method of stirring the solution, a method of changing the solvent composition of the solution, and a method of adding seed crystals to the solution,
(Viii) a method of stirring the solution, a method of reducing the liquid volume of the solution, and a method of adding seed crystals to the solution,
(Ix) a method of stirring the solution, a method of changing the temperature of the solution, and a method of changing the solvent composition of the solution,
(X) a method of stirring the solution, a method of changing the temperature of the solution, a method of changing the solvent composition of the solution, and a method of adding seed crystals to the solution,
(Xi) a method of stirring the solution, a method of changing the temperature of the solution, and a method of reducing the amount of the solution,
(Xii) A method of stirring the solution, a method of changing the temperature of the solution, a method of reducing the amount of the solution, and a method of adding seed crystals to the solution.
[0041]
The crystallized crystals can be collected by a method such as filtration or centrifugation.
[0042]
The crystals thus obtained may be dried as they are or, if necessary, and then subjected to a recrystallization step as necessary.
[0043]
Examples of the “drying” include reduced pressure drying, ventilation drying, heat drying, and natural drying.
[0044]
For example, when (R) -lansoprazole or (S) -lansoprazole obtained by asymmetric synthesis is used, it is subjected to the above-mentioned method [1] or [2] or, if necessary, one or more recrystallizations. Related substances (e.g. 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole and ( Or) the amount of 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfonyl] -1H-benzimidazole, etc.) can be reduced.
[0045]
Specifically, the obtained crystal or its dried crystal is converted into a solvent (eg, water, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons). Nitriles, halogenated hydrocarbons, pyridines, or a mixture of two or more of these, and then subjected to a dehydration step if necessary, and then crystals are crystallized.
[0046]
The “dehydration” may be any ordinary dehydration method, and examples thereof include a concentration method and a method using a dehydrating agent [eg, anhydrous magnesium sulfate, anhydrous sodium sulfate, molecular sieve (trade name)]. .
[0047]
Examples of the “crystallization” method include the crystallization methods described above.
[0048]
As the crystals obtained after the recrystallization,
(1) Powder X-ray diffraction in which the lattice spacing (d) of powder X-ray diffraction of the undried crystals has a characteristic peak at 5.88, 4.70, 4.35, 3.66, 3.48 angstroms Crystal showing pattern,
(2) A crystal showing a powder X-ray diffraction pattern in which a peak characteristic of a lattice distance (d) of powder X-ray diffraction of 8.33, 6.63, 5.86, 4.82 angstroms appears in an undried crystal. ,
(3) a mixture of the crystals of (1) and (2) above, or
(4) The lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69. Examples include crystals having a powder X-ray diffraction pattern in which characteristic peaks appear at 3.41 and 3.11 angstroms.
[0049]
The amount of the related substance in the crystal is less than 1% by weight, preferably less than 0.4% by weight.
[0050]
Crystals crystallized in the recrystallization step can be separated by a method such as filtration or centrifugation.
[0051]
The crystals thus obtained may be dried as they are or, if necessary, and then subjected to a second recrystallization step as necessary.
[0052]
Examples of the “drying” include the same method as the above “drying”.
[0053]
Specifically, the obtained crystals are mixed with a solvent (eg, water, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons, nitriles. , Halogenated hydrocarbons, pyridines, or a mixture of two or more thereof, and then subjected to a dehydration step as necessary, and then crystals are crystallized, separated, and dried.
[0054]
Examples of the “dehydration” include the same methods as the “dehydration method” described above.
[0055]
Examples of the “crystallization” method include the crystallization methods described above.
[0056]
As the crystals obtained in the second recrystallization step, the lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84, 5.73, 4.43, 4.09. Examples include crystals of (R)-or (S) -lansoprazole having a powder X-ray diffraction pattern in which characteristic peaks appear at 3.94, 3.89, 3.69, 3.41, 3.11 angstroms.
[0057]
The crystals crystallized in the second recrystallization step can be separated by a method such as filtration or centrifugation.
[0058]
The collected crystal can be dried by a method such as vacuum drying, aeration drying, heat drying, or natural drying.
[0059]
Examples of the “esters” include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethyl formate.
[0060]
Examples of the “ketones” include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, and the like.
[0061]
Examples of the “phenols” include anisole.
[0062]
Examples of the “alcohols” include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, pentanol, 3-methyl-1-butanol, 2 -Methoxyethanol, 2-ethoxyethanol, ethylene glycol, etc. are mentioned.
[0063]
Examples of the “ethers” include t-butyl methyl ether, diethyl ether, 1,1-diethoxypropane, 1,1-dimethoxypropane, 2,2-dimethoxypropane, isopropyl ether, tetrahydrofuran, methyltetrahydrofuran and the like. Can be mentioned.
[0064]
Examples of the “aromatic hydrocarbons” include chlorobenzene, toluene, xylene, cumene and the like.
[0065]
Examples of the “amides” include formamide, N, N-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone and the like.
[0066]
Examples of the “sulfoxides” include dimethyl sulfoxide.
[0067]
Examples of the “hydrocarbons” include propane, hexane, pentane, octane, isooctane and the like.
[0068]
Examples of the “nitriles” include acetonitrile.
[0069]
Examples of the “halogenated hydrocarbons” include chloroform, dichloromethane, dichloroethene, trichloroethene and the like.
[0070]
Examples of the “pyridines” include pyridine.
[0071]
The crystal crystallized by the above method or its dry crystal is substantially free of other enantiomers.
[0072]
(R) -lansoprazole or (S) -lansoprazole obtained by the various methods described above is subjected to the method for producing a crystal of the present invention.
[0073]
The manufacturing method of the crystal | crystallization of this invention is explained in full detail below.
[0074]
(1) Acetic acid C containing (R) -lansoprazole or (S) -lansoprazole in a concentration of about 0.1 g / ml to about 0.5 g / ml _1-4 Crystallization from an alkyl ester solution at a temperature of about 0 ° C. to about 35 ° C.
[0075]
First, (R) -lansoprazole or (S) -lansoprazole is acetic acid C _1-4 About 0.1 g / ml to about 0.5 g / ml (preferably about 0.1 g / ml to about 0.35 g / ml, more preferably about 0.2 g / ml to about 0.3 g / ml), Particularly preferably, a state of being present at a concentration of about 0.25 g / ml to about 0.28 g / ml is realized.
[0076]
For example, (R) -lansoprazole or (S) -lansoprazole and acetic acid C _1-4 An excess amount of alkyl ester is added, and if desired, dissolved at about 30 ° C. to 60 ° C. with heating, and then concentrated under reduced pressure to give a predetermined concentration (about 0.1 g / ml to about 0.5 g / ml). ).
[0077]
Here, the concentration is measured by an area comparison method with a standard solution using high performance liquid chromatography. The measurement method will be described in detail below.
[0078]
Measurement condition
Column: Shiseido CAPCELL PAK C18 SG120 5μm 4.6 × 250mm
Column Temp .: 25 ℃
Mobile Phase: H ₂ O: CH _Three CN: Et _Three N = 50: 50: 1 (pH adjusted to 7.0 with phosphoric acid)
Flow rate: 1.0 ml / min.
Inject. Vol .: 10μl
Wave length: 285nm
[0079]
Sample preparation
Standard solution: Weigh accurately about 75 mg of the standard product, and add the mobile phase to make 100 ml.
Sample solution: Add the mobile phase to 1 ml of ethyl acetate solution to make 100 ml.
[0080]
Concentration measurement method
The standard solution and 10 μl of the sample solution were tested by liquid chromatography under the above HPLC conditions, and the peak area A of (R) -lansoprazole or (S) -lansoprazole in the standard solution _S , (R) -lansoprazole or (S) -lansoprazole peak area A of the sample solution _T Is measured by an automatic integration method, and the concentration of (R) -lansoprazole or (S) -lansoprazole is calculated by the following formula.
[0081]
[Expression 1]

[0082]
The concentration may be appropriately adjusted depending on the selected solvent, and (R) -lansoprazole or (S) -lansoprazole is preferably saturated or supersaturated for crystallization.
[0083]
Acetic acid C _1-4 Examples of the alkyl ester include methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like. Preferably, ethyl acetate or propyl acetate is used.
[0084]
Crystallization was achieved by the above-mentioned (R) -lansoprazole or (S) -lansoprazole acetate C _1-4 The alkyl ester solution is allowed to stand at a crystallization temperature of about 0 ° C. to about 35 ° C. or stirred by a method known per se.
[0085]
The lower limit of the crystallization temperature is preferably about 10 ° C, more preferably about 15 ° C, and further preferably about 20 ° C. On the other hand, the upper limit of the crystallization temperature is preferably about 30 ° C. In particular, the crystallization temperature is preferably about 20 ° C to about 30 ° C.
[0086]
The crystallization time is about 30 minutes to about 10 hours, preferably about 30 minutes to about 4 hours, and particularly preferably about 1 hour to about 2 hours.
[0087]
In this step, seed crystals may be added to the solution. Such seed crystals include C described later. _5-8 Examples include seed crystals that may be added to the solution before or during the dropping of the hydrocarbon.
[0088]
The operation in this step is performed in air, under an inert gas atmosphere, or under an inert gas stream. As used herein, “inert gas” refers to C described later. _5-8 The thing which can be used in the case of dripping of a hydrocarbon is mentioned.
[0089]
Crystals crystallized in this step can be collected by methods such as filtration and centrifugation.
[0090]
The collected crystals can be added with acetic acid C if necessary. _1-4 Alkyl ester-C _5-8 You may wash | clean with a hydrocarbon (1: 0 to 1:10) liquid mixture. In addition, acetic acid C here _1-4 Examples of the alkyl ester include those described above, and C _5-8 Examples of the hydrocarbon include those described later. The collected crystals can be dried by a method such as reduced pressure drying, aeration drying, heat drying, or natural drying.
[0091]
The crystal obtained by this step is a crystal excellent in storage stability and can be used as it is as a pharmaceutical product described later. However, the target crystal | crystallization excellent in the storage stability can be obtained with a sufficient yield by further implementing the following process (2).
[0092]
(2) Following the step (1), the acetic acid C at the same temperature _1-4 C less than 7 times the amount of alkyl ester solution _5-8 Step of dripping hydrocarbon
[0093]
Crystals crystallized in the step (1) can be further crystallized by subjecting them to this step after or without fractionation.
[0094]
This step is preferably performed after crystals are precipitated in the step (1). Preferably, at least about 20% by weight of (R) -lansoprazole or (S) -lansoprazole added as a raw material, more preferably about 30% to about 90% by weight, particularly preferably about 50% to about 90% by weight. Is carried out after precipitation as crystals.
[0095]
The crystal crystallization temperature in this step is the same as in step (1).
[0096]
C _5-8 As hydrocarbons, pentane, isopentane, neopentane, hexane, isohexane, 3-methylpentane, neohexane, 2,3-dimethylbutane, heptane, 2-methylhexane, 3-methylhexane, 3-ethylpentane, 2,2 Linear or branched C such as dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 2,2,3-trimethylbutane, octane, isooctane, etc. _5-8 Aliphatic hydrocarbon or C such as toluene, xylene _7-8 Aromatic hydrocarbons are mentioned. Preferably linear C such as heptane or hexane _5-8 Aliphatic hydrocarbons are used.
[0097]
C _5-8 The dripping amount of the hydrocarbon is the acetic acid C of (R) -lansoprazole or (S) -lansoprazole in the step (1). _1-4 The amount is 7 times or less, preferably 5 times or less, more preferably 1 to 3 times the amount of the alkyl ester solution.
[0098]
The dropping is carried out by dropping the solution in an equal amount successively over a period of about 15 minutes to about 4 hours (preferably about 1 hour to about 2 hours) while standing or stirring.
[0099]
Moreover, it is preferable to adjust the temperature at the time of dripping to the said crystallization temperature.
[0100]
In this process, C _5-8 A seed crystal may be added to the solution before or during the dropping of the hydrocarbon.
[0101]
As such seed crystals, for example,
(1) A crystal showing a powder X-ray diffraction pattern in which the lattice spacing (d) of powder X-ray diffraction shows a characteristic peak at 5.88, 4.70, 4.35, 3.66, 3.48 angstroms ,
(2) A crystal showing a powder X-ray diffraction pattern in which the lattice spacing (d) of powder X-ray diffraction shows a characteristic peak at 8.33, 6.63, 5.86, 4.82 angstroms,
(3) The lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69. Crystals having a powder X-ray diffraction pattern with characteristic peaks appearing at 3.41, 3.11 angstroms,
(4) Powder with characteristic peaks appearing in the lattice spacing (d) of powder X-ray diffraction is 8.86, 8.01, 6.58, 5.91, 5.63, 5.02, 4.48 angstroms. A crystal having an X-ray diffraction pattern,
(5) Powder in which a characteristic peak appears at a lattice spacing (d) of powder X-ray diffraction of 8.37, 4.07, 5.65, 5.59, 5.21, 4.81, 4.21 angstroms A crystal having an X-ray diffraction pattern,
(6) The lattice spacing (d) of powder X-ray diffraction is 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69. A crystal showing a powder X-ray diffraction pattern in which a characteristic peak appears at 3.41, 3.11 angstrom,
(7) The solid which transfers to said (1)-(6) in the mixture of two or more crystals among said (1)-(6) or (8) solution is mentioned.
[0102]
After dropping, if desired, the mixture may be allowed to stand for about 1 hour to about 3 hours or stirred.
[0103]
The operation in this step is performed in air, under an inert gas atmosphere, or under an inert gas stream. Examples of the “inert gas” include nitrogen, helium, neon, and argon.
[0104]
Crystals crystallized in this step can be collected by methods such as filtration and centrifugation.
[0105]
The collected crystals can be added with acetic acid C if necessary. _1-4 Alkyl ester-C _5-8 You may wash | clean with a hydrocarbon (1: 0 to 1:10) liquid mixture. In addition, acetic acid C here _1-4 Alkyl esters and C _5-8 Examples of the hydrocarbon include those described above. The collected crystals can be dried by a method such as reduced pressure drying, aeration drying, heat drying, or natural drying.
[0106]
As a method for analyzing the obtained crystal, a crystal analysis method by X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
[0107]
The crystals crystallized by the above production method (only step (1) or step (1) followed by step (2)) are crystallized by the following DSC measurement (heating rate 0.5 ° C./min) Has a melting start temperature. The “melting start temperature” here refers to, for example, a temperature at which the crystal starts to melt when the crystal is heated under the DSC measurement conditions described later. The crystal starts melting at about 131 ° C. or more, preferably about 131 ° C. to about 137 ° C., more preferably about 132 ° C. to about 135 ° C., more preferably about 133 ° C. to about 135 ° C., particularly preferably about 135 ° C. Have temperature. For example, the melting start temperature of the crystal obtained in the step (1) can be about 135 ° C. In addition, after the implementation of the above step (1), the melting start temperature of the crystals obtained in the step (2) can be about 132 ° C. to about 135 ° C.
[0108]
On the other hand, the melting start temperature of the crystal obtained by the conventional method is less than about 131 ° C. For example, the melting start temperature of the crystal obtained by the method of Reference Example 3 described later is about 125 ° C. to about 130 ° C.
[0109]
A crystal having a melting start temperature of about 131 ° C. or higher obtained by the above production method has very excellent storage stability compared to a crystal having a melting start temperature of less than about 131 ° C. obtained by a conventional method. For example, in the stability test described later (40 ° C./month residual rate, 60 ° C./month residual rate), the crystal produced by the production method of the present invention has a residual rate of 99% or more, whereas the prior art The residual ratio of crystals by the method is less than 94%. Moreover, the crystals produced by the prior art method show significant coloration during storage.
[0110]
Therefore, the crystal having a melting start temperature of about 131 ° C. or higher obtained by the production method of the present invention has such excellent storage stability, so that the melting start temperature obtained by the conventional method is less than about 131 ° C. It can be advantageously used as a pharmaceutical rather than a certain crystal.
[0111]
The crystal of (R) -lansoprazole or (S) -lansoprazole obtained by the method for producing a crystal of the present invention has an excellent anti-ulcer action, gastric acid secretion inhibitory action, mucosal protective action, anti-Helicobacter pylori action, etc. Since toxicity is low, it is useful as a medicine. Dry crystals of (R) -lansoprazole or (S) -lansoprazole are more stable than crystallized crystals of (R) -lansoprazole or (S) -lansoprazole (undried crystals), and when used as pharmaceuticals ( Crystals of R) -lansoprazole or (S) -lansoprazole as a dried product are preferably used.
[0112]
Crystals or dry crystals crystallized by the method of the present invention can be used in mammals (eg, humans, monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, mice, etc.) peptic ulcers (eg, gastric ulcers). Duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, etc., gastritis, reflux esophagitis, NUD (Non Ulcer Dyspepsia), gastric cancer (interleukin-1β polymorphism of interleukin-1) Treatment and prevention of gastric cancer associated with production promotion, gastric MALT lymphoma, Helicobacter pylori eradication, peptic ulcer, suppression of upper gastrointestinal bleeding due to acute stress ulcer and hemorrhagic gastritis, invasive stress (intensive management after surgery) Cerebrovascular disorder requiring major surgery or intensive care, head trauma, multiple organ failure, stress resulting from extensive burns) Inhibition of tubes bleeding, treatment and prevention of ulcer caused by non-steroidal anti-inflammatory agent; treatment of hyperacidity and ulcer due to postoperative stress and prevention, useful for anesthesia prior to administration. For eradication of Helicobacter pylori, crystals crystallized by the method of the present invention or dried crystals, penicillin antibiotics (eg, amoxicillin, etc.) and erythromycin antibiotics (eg, clarithromycin, etc.) Preferably used.
[0113]
When used for the above-described various pharmaceutical uses, crystals of (R) -lansoprazole are preferably used.
[0114]
The crystal of the present invention can be used as it is or according to a method known per se, a pharmaceutical composition mixed with a pharmacologically acceptable carrier, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (soft capsules). Orally disintegrating tablets, liquids, injections, suppositories, sustained release agents, patches, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) Can do.
[0115]
The content of crystals in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight of the total composition. The dosage varies depending on the administration subject, administration route, disease, etc., but for example, when administered orally to an adult (60 kg) as an anti-ulcer agent, the active ingredient is preferably about 0.5 to 1500 mg / day, preferably Is about 5-150 mg / day. The crystal of the present invention may be administered once a day or divided into 2 to 3 times a day.
[0116]
Examples of the pharmacologically acceptable carrier that may be used in the production of the pharmaceutical composition of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials, such as excipients and lubricants in solid formulations. Agents, binders, disintegrants, water-soluble polymers, basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffering agents, soothing agents and the like in liquid preparations. In addition, additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, sour agents, foaming agents, and fragrances can be used as necessary.
[0117]
Examples of the “excipient” include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
[0118]
Examples of the “lubricant” include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
[0119]
Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, α-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropylcellulose, and the like.
[0120]
Examples of the “disintegrant” include (1) crospovidone, (2) disintegrants called super disintegrants such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical), (3) carboxymethyl Examples include starch sodium (eg, Matsutani Chemical Co., Ltd.), (4) low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd.), (5) corn starch and the like. The “crospovidone” is crosslinked with a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinyl polypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer. Specific examples include Kollidon CL (manufactured by BASF), Polyplaston XL (manufactured by ISP), Polyplaston XL-10 (manufactured by ISP), and Polyplastidone. For example, INF-10 (manufactured by ISP).
[0121]
Examples of the “water-soluble polymer” include ethanol-soluble water-soluble polymers [eg, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers. [For example, hydroxypropyl methylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like].
[0122]
Examples of the “basic inorganic salt” include basic inorganic salts of sodium, potassium, magnesium and / or calcium. Preferred is a basic inorganic salt of magnesium and / or calcium. More preferred is a basic inorganic salt of magnesium. Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like. Examples of the basic inorganic salt of potassium include potassium carbonate and potassium hydrogen carbonate. Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg ₆ Al ₂ (OH) ₁₆ ・ CO _Three ・ 4H ₂ O] and alumina / magnesium hydroxide, preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
[0123]
Examples of the “solvent” include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
[0124]
Examples of the “dissolution aid” include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
[0125]
Examples of the “suspending agent” include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Examples thereof include hydrophilic polymers such as pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
[0126]
Examples of the “isotonic agent” include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
[0127]
Examples of the “buffering agent” include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
[0128]
Examples of the “soothing agent” include benzyl alcohol.
[0129]
Examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
[0130]
Examples of the “antioxidant” include sulfite, ascorbic acid, α-tocopherol and the like.
[0131]
Examples of the “coloring agent” include edible pigments such as edible yellow No. 5, edible red No. 2 and edible blue No. 2; edible lake pigments and red peppers.
[0132]
Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
[0133]
Examples of the “acidulant” include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
[0134]
Examples of the “foaming agent” include sodium bicarbonate.
[0135]
The “fragrance” may be a synthetic product or a natural product, and examples thereof include lemon, lime, orange, menthol, and strawberry.
[0136]
The crystal of the present invention is compression-molded according to a method known per se, for example, by adding an excipient, a disintegrant, a binder or a lubricant, and then, if necessary, for the purpose of taste masking, enteric property or sustainability. Therefore, an oral preparation can be obtained by coating by a method known per se. In the case of an enteric preparation, an intermediate layer may be provided between the enteric layer and the drug-containing layer by a method known per se for the purpose of separating both layers.
[0137]
When the crystal of the present invention is an orally disintegrating tablet, for example, a core containing crystalline cellulose and lactose is coated with the crystal of the present invention and a basic inorganic salt, and further coated with a coating layer containing a water-soluble polymer. The composition obtained is coated with an enteric coating layer containing polyethylene glycol, coated with an enteric coating layer containing triethyl citrate, and coated with an enteric coating layer containing polyethylene glycol. Further, a method of coating with mannitol to obtain fine particles, mixing the obtained fine particles with an additive, and molding is included. Examples of the “enteric coating layer” include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and a methacrylic acid copolymer [for example, Eudragit L30D-55 (trade name; Rame Co., Ltd.), Kollicoat MAE30DP (trade name; manufactured by BASF), Polykid PA30 (trade name; manufactured by Sanyo Kasei Co., Ltd.), etc.], water-based enteric polymer bases such as carboxymethyl ethyl cellulose and shellac; Sustained release bases such as coalescent [eg Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.]; water-soluble polymer; triethyl citrate, polyethylene glycol, aceto Le monoglycerides, triacetin, and the like a mixture plasticizer one or two or more of castor oil. Examples of the “additives” include water-soluble sugar alcohols (eg, sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (eg, Theolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose / carmellose sodium), etc., low-substituted hydroxypropyl cellulose (eg, LH-22, LH-32, LH-23, LH- 33 (Shin-Etsu Chemical Co., Ltd.) and mixtures thereof, etc.), binders, acidulants, foaming agents, sweeteners, fragrances, lubricants, colorants, stabilizers, excipients, disintegration Agents are also used.
[0138]
The crystal of the present invention may be used in combination with 1 to 3 other active ingredients.
[0139]
Examples of the “other active ingredients” include anti-Helicobacter pylori active substances, imidazole compounds, bismuth salts, quinolone compounds, and the like. Of these, anti-Helicobacter pylori active substances and imidazole compounds are preferred. Examples of the “anti-Helicobacter pylori active substance” include penicillin antibiotics (eg, amoxicillin, benzylpenicillin, piperacillin, mesilinum, etc.), cephem antibiotics (eg, cefixime, cefaclor, etc.), macrolide antibiotics (eg Examples include erythromycin, clarithromycin, etc.), tetracycline antibiotics (eg, tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (eg, gentamicin, amikacin, etc.), imipenem and the like. Of these, penicillin antibiotics and macrolide antibiotics are preferred. In particular, a triple combination therapy of penicillin antibiotics, macrolide antibiotics and (R) -lansoprazole or (S) -lansoprazole crystals is preferred. Examples of the “imidazole compound” include metronidazole, miconazole and the like. Examples of the “bismuth salt” include bismuth acetate and bismuth citrate. Examples of the “quinolone compound” include ofloxacin, cyproxacin and the like.
[0140]
The “other active ingredient” and the crystal of the present invention are mixed according to a method known per se, and a single pharmaceutical composition (eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository) is prepared. Preparations, sustained release preparations, etc.) may be formulated and used together, or each may be formulated separately and administered to the same subject simultaneously or with a time difference.
[0141]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Examples, but the present invention is not limited thereto.
[0142]
Powder X-ray diffraction was measured using an X-ray Diffractometer RINT Ultimate + (Rigaku).
[0143]
The melting start temperature was measured under the following measurement conditions using a DSC (differential scanning calorimeter SEIKO DSC220C).
[0144]
DSC measurement conditions;
Temperature range: room temperature to 220 ° C
Temperature increase rate: 0.5 ° C./min.
Sample container: Aluminum pan (without cover)
Atmosphere: Nitrogen gas (100 mL / min.)
[0145]
The enantiomeric excess (% ee) was measured by high performance liquid chromatography using an optically active column under the following condition (A).
[0146]
The abundance of sulfide and sulfone was measured by high performance liquid chromatography using an optically active column under the following conditions (A) or high performance liquid chromatography under conditions (B).
[0147]
High performance liquid chromatography conditions (A);
Column: CHIRALCEL OD (4.6 × 250 mm; manufactured by Daicel Chemical Industries, Ltd.)
Moving bed: hexane / ethanol = 90/10
Flow rate: 1.0 ml / min
Detection: UV285nm
[0148]
High performance liquid chromatography conditions (B);
Column: CAPCELL PAK C18 SG120 5 μm 4.6 × 250 mm (manufactured by Shiseido Co., Ltd.)
Moving layer: A mixture adjusted to pH 7.0 by adding phosphoric acid to a mixture of acetonitrile: water: triethylamine (50: 50: 1).
Flow rate: 1.0 ml / min
Detection: UV285nm
[0149]
Reference example 1
Preparation of a solution containing (R) -2-[[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole by asymmetric oxidation
[0150]
2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole monohydrate (6 kg, 16.2 mol) was added at 80 ° C. And dried under reduced pressure for 21 hours to give 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole (5.73 kg, moisture A content of 0.0364%) was obtained. 2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole (5.00 kg, 14.1 mol, moisture) under nitrogen flow 1.82 g included), toluene (25 L), water (13.18 g, 0.732 mol, 0.833 mol as the total water content), and (+)-diethyl tartrate (531 mL, 3.10 mol) were mixed. Titanium (IV) isopropoxide (414 ml, 1.40 mol) was added at 50 to 60 ° C. under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. After adding diisopropylethylamine (815 ml, 4.68 mol) at 15 to 25 ° C. under a nitrogen stream, cumene hydroperoxide (7.65 L, content 82%, 42.7 mol) was added at −10 to 5 ° C., − It was made to react by stirring at 8-2 degreeC for 3 hours.
[0151]
The result of having analyzed this reaction liquid by the high performance liquid chromatography (condition (A)) is shown.
[0152]
Enantiomeric excess of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole in the reaction solution Was 96.9% ee.
[0153]
As a result of analyzing the reaction solution by high performance liquid chromatography (condition (B)), as a related substance in the reaction solution, 1.0% of a sulfide body and 1.7% of a sulfone body exist, and other related substances. There was no material present.
[0154]
Reference example 2
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole purification method
[0155]
(1) A 30% aqueous sodium thiosulfate solution (13.5 kg) was added to the reaction solution obtained in Reference Example 1 under a nitrogen stream to decompose the remaining cumene hydroperoxide. It concentrated under reduced pressure until the liquid volume was set to about 25L. While maintaining 0 to 10 ° C., heptane-t-butyl methyl ether (heptane: t-butyl methyl ether = 1: 1) (20 L) was added dropwise, and then heptane (70 L) was added dropwise. The precipitated crystals were separated and washed with cold t-butyl methyl ether-toluene (t-butyl methyl ether: toluene = 4: 1) (5 L).
[0156]
The crystals were analyzed by high performance liquid chromatography (conditions (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)- The enantiomeric excess of 2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole was 98.3% ee.
[0157]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), as a related substance in the crystal, a sulfide form 0.45% and a sulfone form 1.8% existed, and other related substances were Did not exist.
[0158]
(2) The acetone (20 L) suspension of the wet crystals obtained in (1) above is dropped into a mixture of acetone (7.5 L) and water (37.5 L), and then water (52.5 L) Was added. The precipitated crystals were separated and washed with cold acetone-water (acetone: water = 1: 3) (5 L) and water (6.5 L).
[0159]
The crystals were analyzed by high performance liquid chromatography (conditions (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)- The enantiomeric excess of 2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole was 100% ee.
[0160]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), as a related substance in the crystal, there were 0.19% sulfide and 0.08% sulfone, and other related substances were Did not exist.
[0161]
(3) The wet crystals obtained in (2) above were suspended in ethyl acetate (50 L), and magnesium sulfate (2.5 kg) was added. Magnesium sulfate was separated and washed with ethyl acetate (3.5 L). After adding triethylamine (250 mL), the mixture was concentrated under reduced pressure until the liquid volume became about 10 L. Methanol (2.5 L), about 12.5% aqueous ammonia (25.5 L) at about 50 ° C., and t-butyl methyl ether (24.5 L) at about 50 ° C. were added to the concentrate to separate the layers. About 12.5% aqueous ammonia (12 L) at about 50 ° C. was added to the organic layer for liquid separation (this operation was repeated once more). The aqueous layers were combined, ethyl acetate (24.5 L) was added, and acetic acid was added dropwise at 20 ° C. or lower to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with ethyl acetate (24.5 L). The organic layers were combined and washed with about 20% brine (24.5 L). After adding triethylamine (250 mL), the organic layer was concentrated under reduced pressure. Acetone (5.55 L) was added to the concentrate, and the mixture was concentrated under reduced pressure. The concentrate was dissolved in acetone (10 L), the same solution was added dropwise to a mixture of acetone (5 L) and water (25 L), and then water (20 L) was added dropwise to the resulting mixture. The precipitated crystals were separated and washed successively with cold acetone-water (1: 3) (4 L) and water (13 L).
[0162]
The crystals were analyzed by high performance liquid chromatography (conditions (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)- The enantiomeric excess of 2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole was 100% ee.
[0163]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), as a related substance in the crystal, there are 0.018% of a sulfide body and 0.016% of a sulfone body, and other related substances are Did not exist.
[0164]
Reference example 3
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole purification method
[0165]
The wet crystals obtained by the method of Reference Example 2 were dissolved in ethyl acetate (43 L). The separated aqueous layer was separated by a liquid separation operation, and the obtained organic layer was concentrated under reduced pressure until the liquid volume became about 19 L. Ethyl acetate (48 L) was added to the residual liquid, followed by concentration under reduced pressure until the liquid volume reached about 19 L. Ethyl acetate (48 L) and activated carbon (360 g) were added to the residual liquid and stirred, and then the activated carbon was removed by filtration. The filtrate was concentrated under reduced pressure until the liquid volume was about 19 L. At about 40 ° C. heptane (150 L) was added dropwise to the remaining liquid. After stirring at the same temperature for about 30 minutes, the crystals were separated and washed with ethyl acetate-heptane (1: 8, 8 L) at about 40 ° C. Drying gave 4.5 kg of the title compound.
[0166]
The results of analyzing the crystals by powder X-ray diffraction are shown below.
[0167]
The crystal has a lattice spacing (d) of powder powder X-ray diffraction of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3. A powder X-ray diffraction pattern showing a characteristic peak at 69, 3.41, 3.11 angstroms was shown.
[0168]
As a result of analyzing the crystal by high performance liquid chromatography (condition (A)), 0.02% of the sulfone compound was present as an analogous substance in the crystal, and no sulfide substance and other related substances were present. The enantiomeric excess of (R) -lansoprazole in the crystals was 100% ee.
[0169]
The melting start temperature of the crystals was 127.5 ° C.
[0170]
Reference example 4
Production of (S) -lansoprazole
[0171]
(1) 2-[[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole (50.0 g,. 14 mol, containing 20 mg of water), toluene (250 ml), water (130 mg, 0.0072 mol, 0.0083 mol as total water content) and (-)-diethyl tartrate (5.31 ml, 0.031 mol) were mixed. Titanium (IV) isopropoxide (4.14 ml, 0.014 mol) was added to the mixture at 50 ° C. under a nitrogen atmosphere, and the mixture was stirred at 50 to 55 ° C. for 1 hour. Under a nitrogen atmosphere and under cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added to the resulting mixture, and then cumene hydroperoxide (76.50 ml, content 82%, 0.8%) at −10 to 0 ° C. 42 mol) was added, and the mixture was stirred at −5 to 5 ° C. for 3.5 hours to obtain a reaction solution.
[0172]
As a result of analyzing the reaction solution by high performance liquid chromatography (condition (A)), the enantiomeric excess of (S) -lansoprazole in the reaction solution was 96.5% ee.
[0173]
As a result of analyzing the reaction solution by high performance liquid chromatography (condition (B)), as a related substance in the reaction liquid, 1.90% sulfone and 1.50% sulfide were present, and other related substances were Did not exist.
[0174]
(2) A 30% aqueous sodium thiosulfate solution (180 ml) was added to the reaction solution obtained in (1) above under a nitrogen stream to decompose the remaining cumene hydroperoxide. Liquid separation was performed, and water (50 ml), heptane (150 ml), t-butyl methyl ether (200 ml) and heptane (300 ml) were sequentially added to the obtained organic layer to cause crystallization. The crystals are separated and washed with t-butyl methyl ether-toluene (t-butyl methyl ether: toluene = 4: 1) (45 ml) and have the following lattice spacing (d) of powder X-ray diffraction (S) -Lansoprazole was obtained as wet crystals.
[0175]
As a result of analyzing the wet crystal by powder X-ray diffraction, the wet crystal had a lattice spacing (d) of 5.88, 4.70, 4.35, 3.66, 3.48 angstroms in powder X-ray diffraction. Shows a powder X-ray diffraction pattern in which a characteristic peak appears.
[0176]
As a result of analyzing the crystal by high performance liquid chromatography (condition (A)), the enantiomeric excess of the crystal was 100% ee.
[0177]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), 0.72% of the sulfone compound was present as an analogous substance in the crystal, and no sulfide substance and other related substances were present.
[0178]
(3) A suspension of the wet crystals obtained in (2) above in acetone (220 ml) was dropped into a mixture of acetone (75 ml) and water (370 ml), and then water (520 ml) was added. The precipitated crystals were separated, washed with acetone-water (acetone: water = 1: 3) (44 ml) and water (130 ml), and (S) -lansoprazole having the following lattice spacing (d) of powder X-ray diffraction Was obtained as wet crystals.
[0179]
As a result of analyzing the wet crystal by powder X-ray diffraction, powder X in which the lattice spacing (d) of powder X-ray diffraction shows a characteristic peak at 8.33, 6.63, 5.86, 4.82 angstroms. A line diffraction pattern was shown.
[0180]
As a result of analyzing the crystal by high performance liquid chromatography (condition (A)), the enantiomeric excess of the crystal was 100% ee.
[0181]
The crystals were analyzed by high performance liquid chromatography (condition (B)), and as a result, sulfones, sulfides and other related substances did not exist as related substances in the crystals.
[0182]
Reference Example 5
Production of (S) -lansoprazole
[0183]
Wet crystals obtained according to Reference Example 4 (containing 35.37 g of the title compound, abundance of related substances: 0%, enantiomeric excess: 100% ee) were dissolved in ethyl acetate (340 ml). The separated aqueous layer was separated by a liquid separation operation, and the obtained organic layer was concentrated under reduced pressure until the liquid volume became about 100 ml. Ethyl acetate (400 ml) and activated carbon (3 g) were added to the residual liquid, and after stirring, the activated carbon was removed by filtration. The filtrate was concentrated under reduced pressure until the liquid volume was about 100 ml. At about 40 ° C. heptane (1000 ml) was added dropwise to the residual liquid. After stirring at the same temperature for about 30 minutes, the crystals were separated and washed with ethyl acetate-heptane (1: 8, 63 ml) at about 40 ° C. It was dried to obtain 35.08 g (yield: 99.2%) of the title compound.
[0184]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0185]
The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, sulfones, sulfides and other related substances did not exist as related substances in the crystals. The enantiomeric excess of (S) -lansoprazole in the crystals was 100% ee.
[0186]
The melting start temperature of the crystals was 127.0 ° C.
[0187]
Reference Example 6
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (1.5 g, 4.06 mmol ) Was dissolved in ethyl acetate (30 mL) and then concentrated under reduced pressure to 6 mL at an external temperature of about 25 ° C. Heptane (24 mL) was added dropwise at about −5 ° C. over about 30 minutes. After stirring for about 2.5 hours, the precipitated crystals were separated and dried to give the title compound (1.46 g, yield: 97.3%).
[0188]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0189]
The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, sulfones, sulfides and other related substances did not exist as related substances in the crystals. The enantiomeric excess of (R) -lansoprazole in the crystals was 100% ee.
[0190]
The melting start temperature of the crystals was 130.0 ° C.
[0191]
Reference Example 7
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (1.5 g, 4.06 mmol ) Was dissolved in ethyl acetate (30 mL) and then concentrated under reduced pressure to 20 mL at an external temperature of about 25 ° C. Heptane (90 mL) was added dropwise at about 25 ° C. over about 30 minutes. After stirring for about 2.5 hours, the precipitated crystals were separated and dried to give the title compound (1.40 g, yield: 93.3%).
[0192]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0193]
The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, sulfones, sulfides and other related substances did not exist as related substances in the crystals. The enantiomeric excess of (R) -lansoprazole in the crystals was 100% ee. The melting start temperature of the crystals was 128.5 ° C.
[0194]
Example 1
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole high-melting-point crystal production method
[0195]
The wet crystals obtained by the method of Reference Example 2 were dissolved in ethyl acetate (50 L) and then separated. The organic layer was concentrated under reduced pressure until the liquid volume was about 25 L. Ethyl acetate (30 L) was added to the residue, and the mixture was concentrated under reduced pressure until the liquid volume became about 15 L. To the residue was added ethyl acetate (30 L) and activated carbon (150 g). The activated carbon was removed and washed with ethyl acetate (1.5 L). The concentration of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole is about 0.28 g / mL. The filtrate was concentrated under reduced pressure until 12.5 L. The mixture was stirred under a nitrogen stream at about 25 ° C. for about 2 hours. After confirming the precipitation of crystals, heptane (25 L) was added dropwise over about 1.5 hours, and then stirred for about 1.5 hours. The precipitated crystals were separated, washed with ethyl acetate-heptane (ethyl acetate: heptane = 1: 5) (6 L), dried and dried to give the title compound (3.66 kg, 2-[[[3-methyl-4- (2 , 2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole yield: 70%).
[0196]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0197]
The crystals were analyzed by high performance liquid chromatography (conditions (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)- The enantiomeric excess of 2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole was 100% ee.
[0198]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), 0.01% sulfone was present as the related substance in the crystal, and the sulfide and other related substances were not present. . The melting start temperature of the crystals was 134.0 ° C.
[0199]
Example 2
Crystals of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (3 g, 8.12 mmol) were obtained. After dissolving in ethyl acetate (12 mL) at about 50 ° C., the mixture was stirred at about 25 ° C. for about 6 hours. The precipitated crystals were separated, washed with ethyl acetate-heptane (ethyl acetate: heptane = 1: 5) (3 mL) and dried to give the title compound (1.55 g, yield: 52%).
[0200]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0201]
The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, sulfones, sulfides and other related substances did not exist as related substances in the crystals. The enantiomeric excess of (R) -lansoprazole in the crystals was 100% ee.
[0202]
The melting start temperature of the crystals was 135.0 ° C.
[0203]
Example 3
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (1.5 g, 4.06 mmol ) Was dissolved in n-propyl acetate (30 mL), and then concentrated under reduced pressure to 6 mL at an external temperature of about 25 ° C. After stirring for about 2.5 hours, the precipitated crystals were separated and dried to give the title compound (0.94 g, yield: 63%). The melting start temperature of the crystals was 134.5 ° C.
[0204]
Example 4
Crystals of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (3.0 g, 8.12 mmol ) Was dissolved in ethyl acetate (12 mL) at about 50 ° C. and then stirred at about 25 ° C. for about 2.5 hours. After confirming the precipitation of crystals, heptane (60 mL) was added dropwise thereto over about 15 minutes, and then the precipitated crystals were separated, washed with ethyl acetate-heptane (ethyl acetate: heptane = 1: 5) (3 mL), Drying gave the title compound (2.84 g, yield: 95%).
[0205]
The melting start temperature of the crystal was 133.5 ° C.
[0206]
Example 5
Crystals of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (3.0 g, 8.12 mmol ) Was dissolved in ethyl acetate (12 mL) at about 50 ° C. and then stirred at about 25 ° C. for about 2 hours. After confirming the precipitation of crystals, hexane (24 mL) was added dropwise thereto over about 20 minutes, and then the precipitated crystals were separated and washed with ethyl acetate-hexane (ethyl acetate: hexane = 1: 5) (3 mL), Drying gave the title compound.
[0207]
The melting start temperature of the crystal was 133.5 ° C.
[0208]
Example 6
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (2.0 g, 5.41 mmol ) Was dissolved in n-propyl acetate (30 mL) at about 30 ° C., and then concentrated under reduced pressure to 8 mL at an external temperature of about 25 ° C. After stirring for about 1.5 hours, precipitation of crystals was confirmed, and then heptane (16 mL) was added dropwise over about 20 minutes. The precipitated crystals were separated, washed twice with n-propyl acetate-heptane (n-propyl acetate: heptane = 1: 5) (6 mL) and dried to give the title compound (1.86 g, yield: 93%). Obtained.
[0209]
The melting start temperature of the crystals was 134.0 ° C.
[0210]
Example 7
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (2.0 g, 5.41 mmol ) Was dissolved in i-propyl acetate (40 mL) at about 35 ° C. and then concentrated under reduced pressure to 8 mL at an external temperature of about 35 ° C. After stirring for about 1.5 hours, precipitation of crystals was confirmed, and then heptane (16 mL) was added dropwise over about 20 minutes. The precipitated crystals were separated, washed twice with i-propyl acetate-heptane (i-propyl acetate: heptane = 1: 5) (6 mL) and dried to give the title compound (1.89 g, yield: 95%). Obtained. The melting start temperature of the crystals was 133.0 ° C.
[0211]
Example 8
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (2.0 g, 5.41 mmol ) Was dissolved in n-butyl acetate (40 mL) at about 35 ° C. and then concentrated under reduced pressure to 8 mL at an external temperature of about 35 ° C. After stirring for about 1 hour, precipitation of crystals was confirmed, and then heptane (16 mL) was added dropwise over about 20 minutes. The precipitated crystals were separated, washed twice with n-butyl acetate-heptane (n-butyl acetate: heptane = 1: 5) (6 mL) and dried to give the title compound (1.87 g, yield: 93%). Obtained. The melting start temperature of the crystals was 133.0 ° C.
[0212]
Example 9
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (2.0 g, 5.41 mmol ) Was dissolved in methyl acetate (15 mL) and then concentrated under reduced pressure to 8 mL at an external temperature of about 25 ° C. After stirring for about 1.5 hours, precipitation of crystals was confirmed, and then heptane (16 mL) was added dropwise over about 20 minutes. The precipitated crystals were separated, washed twice with methyl acetate-heptane (methyl acetate: heptane = 1: 5) (6 mL) and dried to give the title compound (1.71 g, yield: 86%). The melting start temperature of the crystals was 134.0 ° C.
[0213]
Example 10
The wet crystals obtained by the method of Reference Example 4 were dissolved in ethyl acetate (50 L) and then separated. The organic layer was concentrated under reduced pressure until the liquid volume was about 27 L. Ethyl acetate (30 L) was added to the residue, and the mixture was concentrated under reduced pressure until the liquid volume was about 16 L. To the residue was added ethyl acetate (30 L) and activated carbon (150 g). The activated carbon was removed and washed with ethyl acetate (1.5 L). The concentration of (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole is about 0.27 g / mL. The filtrate was concentrated under reduced pressure until 12.5 L. After stirring under a nitrogen stream at about 25 ° C. for about 2 hours, the precipitation of crystals was confirmed, then heptane (25 L) was added dropwise over about 1.5 hours, and then stirred for about 1.5 hours. The precipitated crystals were separated, washed with ethyl acetate-heptane (ethyl acetate: heptane = 1: 5) (6 L), dried and dried to give the title compound (3.76 kg, 2-[[[3-methyl-4- (2 , 2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole yield (72%).
[0214]
As a result of analyzing the crystal by powder X-ray diffraction, the crystal had a lattice spacing (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.43. It showed a powder X-ray diffraction pattern in which peaks characteristic of 09, 3.94, 3.89, 3.69, 3.41, 3.11 angstrom appear.
[0215]
The crystals were analyzed by high performance liquid chromatography (conditions (A)). As a result, (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)- The enantiomeric excess of 2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole was 100% ee.
[0216]
As a result of analyzing the crystal by high performance liquid chromatography (condition (B)), as a related substance in the crystal, a sulfone form, a sulfide form and other related substances did not exist.
[0217]
The melting start temperature of the crystal was 133.5 ° C.
[0218]
Example 11
(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole crystals (1.5 g, 4.06 mmol ) Was dissolved in ethyl acetate (30 mL) and then concentrated under reduced pressure to 6 mL at an external temperature of about 25 ° C. After stirring at the same temperature for about 2 hours, the precipitation of crystals was confirmed, and then heptane (24 mL) was added dropwise over about 30 minutes. After stirring for about 2.5 hours, the precipitated crystals were separated and dried to give the title compound (1.46 g, yield: 97.3%). The melting start temperature of the crystal was 133.5 ° C.
[0219]
Test example Stability test (Relationship between melting start temperature and stability)
Table 1 below shows an example of the results of a stability test performed at 60 ° C. for one month on the various (R) -lansoprazole crystals obtained in the above Reference Examples and Examples.
[0220]
[Table 1]

[0221]
Crystals obtained by the method of the present invention showed a residual rate of 99% or more in a stability test at 60 ° C. for one month, but crystals obtained by the conventional method were found to decrease to a residual rate of about 90 to 94%.
[0222]
In addition, Table 2 shows an example of the results of a stability test conducted at 40 ° C. for one month on the crystals of (R) -lansoprazole.
[0223]
[Table 2]

[0224]
In the method of the present invention, no decomposition was observed in the stability test at 40 ° C. for one month, but it was found that the conventional method deteriorated the appearance, decreased the content, and increased the amount of related substances.
[0225]
FIG. 1 shows that before the stability test of a crystal having a melting start temperature of about 134 ° C. (Example 1) and a crystal having a melting start temperature of about 130 ° C. (Reference Example 6), 40 ° C., 2 weeks, 50 ° C. -Appearance after stability test for 2 weeks and 60 ° C for 2 weeks. It was found that the appearance of the crystal having the melting start temperature of about 134 ° C. did not change, but the appearance of the crystal having the melting start temperature of about 130 ° C. was clearly deteriorated.
[0226]
From the above results, in the case of (R) -lansoprazole and (S) -lansoprazole crystals, there is a clear relationship between the melting start temperature and the stability, and crystals with a melting start temperature of about 131 ° C. or more are stable. However, it was found that crystals having a melting start temperature of less than about 131 ° C. are unstable.
[0227]
Formulation Example 1
Manufacture of capsules
15 mg capsules were obtained according to the method shown below with the following charge amount-1 in [Table 3] ([Table 4] shows the prescription amount per capsule).
[0228]
(1) (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole obtained in Example 1 And the components (3) to (6) were mixed well to obtain a spray. In the centrifugal fluid type coating granulator, (2) non-parrel was put, and (7) the above-mentioned spraying agent was coated while spraying an aqueous solution in which hydroxypropylcellulose was dissolved in purified water. The spherical granules were vacuum-dried at 40 ° C. for 16 to 20 hours and passed through a sieve (600 μm, 1180 μm) to obtain main drug granules. The main drug particles were put into a rolling fluid type coating machine, and a suspension obtained by suspending (8) methacrylic acid copolymer LD to (12) polysorbate 80 in purified water was coated. The coated particles were sieved with a sieve (710 μm, 1400 μm) and vacuum dried at 40 ° C. for 16-20 hours to obtain enteric particles. (13) Talc and (14) light anhydrous silicic acid were added to the enteric grains, and the mixture grains were prepared using a tumbler mixer. The mixed particles were filled into (17) HPMC capsule No. 2 by a capsule filling machine to obtain 15 mg capsules.
[0229]
Furthermore, 20 mg and 10 mg capsules were prepared by adjusting the filling amount of the above mixed grains.
[0230]
[Table 3]

[0231]
[Table 4]

[0232]
Formulation Example 2
Manufacture of capsules
15 mg capsules were obtained according to the following method with the charge amount-2 shown in [Table 5] below ([Table 6] shows the prescription amount per capsule). (1) Compound A and components (3) to (6) were mixed well to obtain a main agent spray. The components (7) to (9) were mixed well to obtain a top spraying agent. In the centrifugal flow type coating granulator, (2) Non-parrel was put, and (10) The above main agent spray agent and top spray agent were coated in that order while spraying an aqueous solution in which hydroxypropylcellulose was dissolved in purified water. . The spherical granules were vacuum-dried at 40 ° C. for 16 to 20 hours and passed through a sieve (600 μm, 1180 μm) to obtain main drug granules. The main drug particles were put into a rolling fluid type coating machine, and a suspension obtained by suspending (11) methacrylic acid copolymer LD to (15) polysorbate 80 in purified water was coated. The coated particles were sieved with a sieve (710 μm, 1400 μm) and vacuum dried at 40 ° C. for 16-20 hours to obtain enteric particles. (16) Talc and (17) light anhydrous silicic acid were added to the enteric granules, and the mixture grains were prepared using a tumbler mixer. The mixed particles were filled into (18) HPMC capsule No. 2 by a capsule filling machine to obtain 15 mg capsules.
[0233]
[Table 5]

[0234]
[Table 6]

[0235]
【The invention's effect】
According to the production method of the present invention, (R) -lansoprazole or (S) -lansoprazole crystals excellent in storage stability can be efficiently produced on an industrial large scale.
[0236]
[Brief description of the drawings]
FIG. 1 shows a crystal having a melting start temperature of about 134 ° C. (Example 1) and a crystal having a melting start temperature of about 130 ° C. (Reference Example 6) before the stability test (initial), 40 ° C., 2 weeks, 50 Appearances after stability test at ℃ · 2 weeks and 60 ℃ · 2 weeks are shown.

Claims (17)

(R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[ 3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole 0 . 1 g / ml to 0 . And characterized in that out at a temperature of acetic acid C _1-4 alkyl ester solution or et 0 ° C. to 3 5 ° C. crystals in a concentration of 5g / ml (R) -2 - [[[3- methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoro) A method for producing crystals of ethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole. (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[ 3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole 0 . 1 g / ml to 0 . 5 g / ml concentration crystallized out with acetic acid C _1-4 alkyl ester solution or et 0 ° C. to 3 5 ° C. temperature containing in the then seven times less acetic acid C _1-4 alkyl ester solution volume at the same temperature characterized by dropping the C _5-8 hydrocarbon (R) -2 - [[[ 3- methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] Preparation of crystals of -1H-benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole Law. The production method according to claim 1 or 2, wherein the crystallization temperature is 20 ° C to 30 ° C. The process according to claim 1 or 2, wherein the crystallization time is from 30 minutes to 4 hours. The process according to claim 1 or 2, wherein the acetic acid C _1-4 alkyl ester is ethyl acetate or propyl acetate. The method according to claim 2, wherein C _5-8 hydrocarbon having an amount of 5 times or less the amount of acetic acid C _1-4 alkyl ester solution is dropped. The process according to claim 2, wherein the C _5-8 hydrocarbon is heptane or hexane. The method according to claim 2, wherein the dropping time of the C _5-8 hydrocarbon is 15 minutes to 4 hours.   (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H produced by the production method according to claim 1 or 2. -Crystals of benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole.   (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H produced by the production method according to claim 1 or 2. -Crystals of benzimidazole. Melting onset temperature of 1 31 ° C. or more (R) -2 - [[[ 3- methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl]-1H-benzimidazole Or (S) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole. The crystal according to claim 11, wherein the melting start temperature is 135 ° C.   A pharmaceutical composition comprising the crystal according to claim 9 or 11.   Peptic ulcer; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MALT lymphoma; upper gastrointestinal bleeding; ulcers caused by non-steroidal anti-inflammatory agents; The pharmaceutical composition according to claim 13, which is a prophylactic / therapeutic agent for diseases caused by Helicobacter pylori. Containing crystals of claim 9 or 11 wherein, peptic ulcer; due to non-steroidal anti-inflammatory agent; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MALT lymphoma; upper gastrointestinal bleeding An agent for the prevention or treatment of ulcers; gastric hyperacidity and ulcers caused by postoperative stress; or diseases caused by Helicobacter pylori.   Peptic ulcer; gastritis; reflux esophagitis; NUD (Non Ulcer Dyspepsia); gastric cancer; gastric MALT lymphoma; upper gastrointestinal bleeding; ulcers caused by non-steroidal anti-inflammatory agents; Use of the crystal according to claim 9 or 11 for producing a pharmaceutical composition for prevention / treatment of diseases caused by Helicobacter pylori. (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[ 3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole 0 . 1 g / ml to 0 . And characterized in that out at a temperature of acetic acid C _1-4 alkyl ester solution or et 0 ° C. to 3 5 ° C. crystals in a concentration of 5g / ml (R) -2 - [[[3- methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or (S) -2-[[[3-methyl-4- (2,2,2-trifluoro) Method for stabilizing crystals of ethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole.

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