JP3726291B2 - Benzoxazine compound having stable crystal structure and process for producing the same - Google Patents
Benzoxazine compound having stable crystal structure and process for producing the same Download PDFInfo
- Publication number
- JP3726291B2 JP3726291B2 JP15328394A JP15328394A JP3726291B2 JP 3726291 B2 JP3726291 B2 JP 3726291B2 JP 15328394 A JP15328394 A JP 15328394A JP 15328394 A JP15328394 A JP 15328394A JP 3726291 B2 JP3726291 B2 JP 3726291B2
- Authority
- JP
- Japan
- Prior art keywords
- crystal
- benzoxazine
- type
- dihydro
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Images
Description
【０００１】
【産業上の利用分野】
本発明は、優れたセロトニン−３受容体拮抗作用を有し、シスプラチン等の抗悪性腫瘍剤投与による嘔吐等を抑制する制吐剤または慢性胃炎や過敏性腸炎症候群等の消化器系疾患の治療剤として有用な（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩の安定な結晶およびその製造法に関する。
【０００２】
【従来の技術】
特開平２−２８１８２号公報には、優れたセロトニン−３受容体拮抗作用を有し、シスプラチン等の抗悪性腫瘍剤投与による嘔吐等を抑制する制吐剤または過敏性腸炎症候群等の消化器系疾患の治療剤として有用な（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩（以下、化合物Ａと称することもある）が記載されている。同公報によると、化合物Ａは、（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−２Ｈ−１，４−ベンゾオキサジン−８−カルボン酸クロリドおよび３−アミノキヌクリジンとをＮ−メチルモルホリンの存在下反応させ、反応生成物をエタノール−イソプロピルエーテルから再結晶し、エーテル性塩酸で処理することにより製造され、その融点は２８１℃（分解）である旨開示されている。
【０００３】
【発明が解決しようとする課題】
ところで、化合物Ａのその後の工業化合成研究により化合物Ａは温度や湿度により結晶形が変化すること、すなわち化合物Ａには結晶多形が存在することが明らかとなり、医薬品として開発する場合、とりわけ製剤製造上より安定な結晶構造を有する化合物Ａの提供が望まれていた。
【０００４】
【課題を解決するための手段】
そこで、本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、特定方法により晶出することにより、温度や湿度等に対し、安定で、かつ大量合成に適した新規結晶構造を有する化合物Ａが得られることを見いだし、本発明を完成させるに至った。
【０００５】
すなわち、本発明は、（１）Ｃｕ−Ｋα線を用いたＸ線回折により２θ＝１５．７６゜、１６．４６４゜および２０．６３９゜に特徴的なピークを示す安定な結晶構造を有する（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩（以下、Ｉ型結晶と称することもある）、（２）（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミドの含水エタノール懸濁液に塩酸を加え、得られた溶解液のｐＨを希塩酸または希アルカリにより３．８〜４．２とし、ついで４０〜５０℃または種晶を用いる場合には３０〜４０℃でエタノールから結晶を析出させることを特徴とするＣｕ−Ｋα線を用いたＸ線回折により２θ＝１５．７６゜、１６．４６４゜および２０．６３９゜に特徴的なピークを示す安定な結晶構造を有する（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩の製造法、および（３）（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩の含水エタノール溶解液のｐＨを希塩酸または希アルカリにより３．８〜４．２とし、ついで４０〜５０℃または種晶を用いる場合には３０〜４０℃でエタノールから結晶を析出させることを特徴とするＣｕ−Ｋα線を用いたＸ線回折により２θ＝１５．７６゜、１６．４６４゜および２０．６３９゜に特徴的なピークを示す安定な結晶構造を有する（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩の製造法に関する。
【０００６】
本発明の化合物ＡのＩ型結晶を製造する際に用いられる含水エタノールとしては、その濃度が約１〜約７０％でよく、これを約１．５〜約３倍量使用して（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミドを懸濁するか、またはその塩酸塩である化合物Ａを溶解させることができる。上記懸濁液中の（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミドは塩酸を用いて塩酸塩化する必要があり、使用される塩酸としては一塩酸塩である目的とする化合物Ａを生成させうる量の濃塩酸でよい。これらベンゾオキサジン化合物は、前記特開平２−２８１８２号公報に記載の方法により製造することができる。
【０００７】
このようにして得られた化合物Ａの含水エタノール溶解液を希塩酸または希アルカリによりそのｐＨを約３．８〜約４．２に調整するが、使用される希塩酸としては０．１〜０．３規定のものがよく、また希アルカリとしては前記溶解液のｐＨを約３．８〜約４．２に調整できるものがよく、希水酸化ナトリウム、希水酸化カリウム、希炭酸ナトリウム、希炭酸カリウム、希水酸化アンモニウム等が例示される。
【０００８】
晶出は、溶媒としてメタノール、イソプロピルアルコールでもよいが、エタノールを用いることが好ましい。晶出温度としては、たとえば４０〜５０℃または種晶を用いる場合には３０〜４０℃がよい。なお、化合物Ａを１０℃以下という比較的低温で晶出すると、前記特開平２−２８１８２号公報の実施例１５記載の融点が２８１℃（分解）である結晶（以下、ＩＩ型結晶という）が得られ、このＩＩ型結晶はＣｕ−Ｋα線を用いたＸ線回折により２θ＝１１．４９４゜に特徴的なピークを示す。ＩＩ型結晶は加温、加湿によりＩ型結晶に変換するが、得られた結晶は純品ではなく、溶媒であるエタノールも残存していて、その除去にさらに工程を要し、工業的ではない。また、化合物Ａをエタノール性塩酸から５０〜６０℃という比較的高温で晶出させると、Ｉ型結晶が生成するが、この結晶は減圧乾燥、加温、加湿等の通常手段では除去できない程の４〜５％のエタノールを含有するという問題を有している。一方、室温程度で化合物Ａをエタノール性塩酸から晶出させると、融点３０５〜３０７℃（分解）を示す結晶（以下、ＩＩＩ型結晶という）が生成する。このＩＩＩ型結晶はＣｕ−Ｋα線を用いたＸ線回折により２θ＝７．３０３゜に特徴的なピークを示す。ＩＩＩ型結晶も、加温、加湿等によりＩ型結晶に変換するが、その選択性、再現性が乏しいという問題点があり、残存溶媒の処理等が必要であるという点で、工業的ではない。
【０００９】
このようにして晶出された本発明の化合物ＡのＩ型結晶は、冷却、濾取、乾燥等通常の簡易な手段により、または適宜組み合わせることにより容易に単離取得することができる。
【００１０】
本発明により得られるＩ型結晶は、融点が３０７℃（分解）を示し、また赤外線スペクトルおよび粉末Ｘ線回折パターンはそれぞれ図１、２に示した通りである。Ｉ型結晶の粉末Ｘ線回折パターンからの回折角と相対強度は表１に示す。
【００１１】
一方、ＩＩ型結晶およびＩＩＩ型結晶の融点は、それぞれ２８１℃（分解）および３０５〜３０７℃（分解）であり、また赤外線吸収スペクトルおよび粉末Ｘ線回折パターンを図３〜６に、粉末Ｘ線回折パターンからの回折角と相対強度を表２、３に示す。
【００１３】
【実施例】
以下、実施例、参考例および試験例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。
【００１６】
実施例１ （±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド８８６ｇを５０％含水エタノール１７８０ｍｌに懸濁し、濃塩酸２５３ｇを加え溶解させる。この溶解液に０．１規定塩酸を加えて、ｐＨを約４に調整後、エタノール８９００ｍｌを加えて４０〜５０℃で結晶を析出させ、冷却、濾取、乾燥することにより、融点３０７℃（分解）の（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩のＩ型結晶が得られる。
【００１７】
実施例２ （±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩（エタノール含有Ｉ型結晶、ＩＩ型結晶もしくはＩＩＩ型結晶、またはそれらの混合物のいずれでもよい）１１６０ｇを５０％含水エタノール２０００ｍｌに溶解させ、この溶解液に０．１規定塩酸を加えて、ｐＨを約４に調整後、エタノール１０００００ｍｌを加えて４０〜５０℃で結晶を析出させ、冷却、濾取、乾燥することにより、融点３０７℃（分解）の（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩のＩ型結晶が得られる。
【００１８】
参考例１ （±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド１６００ｇをエタノール６６００ｍｌに加熱溶解させる。５０℃にて２１％エタノール性塩酸１０６６ｇを加えると、内温が５７℃に上昇する。２時間撹拌後、氷冷し、析出する結晶を濾取し、乾燥すると、４％のエタノールを含有した（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩のＩ型結晶が得られる。この残存溶媒は加温、加湿により除去することはできなかった。
【００１９】
参考例２ （±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド１２５１ｇをエタノール５０００ｍｌに加熱溶解させる。２５℃まで冷却し、２１％エタノール性塩酸８０４ｇを加えると、内温が４４℃に上昇する。２時間撹拌後、氷冷し、析出する結晶を濾取し、乾燥すると、（±）−６−クロロ−３，４−ジヒドロ−４−メチル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−１，４−ベンゾオキサジン−８−カルボキサミド塩酸塩のＩＩＩ型結晶が得られる。このＩＩＩ結晶は加温、加湿によりＩ型結晶に変化する。このようにして得られたＩ型結晶は、エタノールを残存溶媒として含有していた。
【００２０】
結晶学的安定性に関する試験例 Ｉ型結晶を４０℃、７５％相対湿度下に６ヶ月保存した試料、ＩＩ型結晶を３５℃、７５％相対湿度下１日保存した試料およびＩＩＩ型結晶を３５℃、７５％相対湿度下３日保存した試料についてそれぞれ粉末Ｘ線回折を測定した。その結果を図７〜９に示す。Ｉ型結晶は、図７に示すように、保存前後で粉末Ｘ線回折パターンはまったく変化せず、安定な結晶であることが確認された。一方、ＩＩ型結晶およびＩＩＩ型結晶は、それぞれ図８および図９に示すように、保存によりＩ型結晶への変化が認められ、これら結晶は容易にＩ型結晶へ転移することが確認された。
【００２１】
【発明の効果】
本発明の化合物ＡのＩ型結晶は、従来得られていたＩＩ型結晶とは異なり新規であり、また、ＩＩ型結晶およびＩＩＩ型結晶に比し、温度や湿度に対し、安定性が良好で、かつ大量に製造できる。したがって、制吐剤または慢性胃炎等の治療剤の原薬としての均質性が確立される。
【図面の簡単な説明】
【図１】 本発明により得られるＩ型結晶の赤外線スペクトルである。
【図２】 本発明により得られるＩ型結晶の粉末Ｘ線回折パターンである。
【図３】 化合物ＡのＩＩ型結晶の赤外線スペクトルである。
【図４】 化合物ＡのＩＩ型結晶の粉末Ｘ線回折パターンである。
【図５】 化合物ＡのＩＩＩ型結晶の赤外線スペクトルである。
【図６】 化合物ＡのＩＩＩ型結晶の粉末Ｘ線回折パターンである。
【図７】 Ｉ型結晶を４０℃、７５％相対湿度下に６ケ月保存した試料についての粉末Ｘ線回折測定結果を示す。
【図８】 ＩＩ型結晶を３５℃、７５％相対湿度下１日保存した試料についての粉末Ｘ線回折測定結果を示す。
【図９】 ＩＩＩ型結晶を３５℃、７５％相対湿度下３日保存した試料についての粉末Ｘ線回折測定結果を示す。[0001]
[Industrial application fields]
The present invention relates to an antiemetic agent having an excellent serotonin-3 receptor antagonistic action and suppressing vomiting or the like caused by administration of an antineoplastic agent such as cisplatin or a therapeutic agent for digestive system diseases such as chronic gastritis and irritable enteritis syndrome Of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride useful as The present invention relates to a crystal and a production method thereof.
[0002]
[Prior art]
JP-A-2-28182 discloses an antiemetic which has an excellent serotonin-3 receptor antagonistic action and suppresses vomiting or the like caused by administration of an antineoplastic agent such as cisplatin or digestive system diseases such as irritable enteritis syndrome +/- 6-6-Chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride useful as a therapeutic agent for (Hereinafter also referred to as Compound A). According to the publication, compound A comprises (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride and 3-aminoquinu. It is disclosed that it is produced by reacting klysine in the presence of N-methylmorpholine, recrystallizing the reaction product from ethanol-isopropyl ether and treating with ethereal hydrochloric acid, and its melting point is 281 ° C. (decomposition). Has been.
[0003]
[Problems to be solved by the invention]
By the way, subsequent industrialization synthesis research of Compound A reveals that Compound A changes its crystal form depending on temperature and humidity, that is, Compound A has a crystalline polymorph. It has been desired to provide Compound A having a more stable crystal structure.
[0004]
[Means for Solving the Problems]
Therefore, as a result of intensive studies to solve the above problems, the present inventors have developed a new crystal structure that is stable with respect to temperature, humidity, etc. and suitable for mass synthesis by crystallization by a specific method. It has been found that a compound A having the following can be obtained, and the present invention has been completed.
[0005]
That is, the present invention has (1) a stable crystal structure showing characteristic peaks at 2θ = 15.76 °, 16.464 ° and 20.0.639 ° by X-ray diffraction using Cu—Kα ray ( ±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride (hereinafter referred to as Form I crystals) (2) (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8- hydrochloric acid was added to the aqueous ethanol suspension carboxamide, Ri by the pH of the resulting solution into dilute hydrochloric acid or dilute alkali 3. 8-4 . 2 and then, when using a seed crystal, the crystal is precipitated from ethanol at 30 to 40 ° C., 2θ = 15.76 ° by X-ray diffraction using Cu—Kα ray, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) having a stable crystal structure with characteristic peaks at 16.464 ° and 20.39 ° ) -2H-1,4-benzoxazine-8-carboxamide hydrochloride, and (3) (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3) - quinuclidinyl) Ri by the pH of the aqueous ethanol solution of-2H-1,4-benzoxazine-8-carboxamide hydrochloride into dilute hydrochloric acid or dilute alkali 3. 8-4 . 2 and then, when using a seed crystal, the crystal is precipitated from ethanol at 30 to 40 ° C., 2θ = 15.76 ° by X-ray diffraction using Cu—Kα ray, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) having a stable crystal structure with characteristic peaks at 16.464 ° and 20.39 ° ) -2H-1,4-benzoxazine-8-carboxamide hydrochloride.
[0006]
The water-containing ethanol used in the production of the type I crystal of the compound A of the present invention may have a concentration of about 1 to about 70%, which is used in an amount of about 1.5 to about 3 times (±). Suspend -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide or with its hydrochloride A certain compound A can be dissolved. The (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide in the above suspension is hydrochloric acid. Hydrochloric acid must be converted to hydrochloric acid, and the hydrochloric acid used may be concentrated hydrochloric acid in an amount capable of producing the target compound A which is a monohydrochloride. These benzoxazine compounds can be produced by the method described in JP-A-2-28182.
[0007]
The pH of the aqueous ethanol solution of Compound A thus obtained is adjusted to about 3.8 to about 4.2 with dilute hydrochloric acid or dilute alkali. The dilute hydrochloric acid used is 0.1 to 0.3. The specified one is good, and as the dilute alkali, it is good to adjust the pH of the solution to about 3.8 to about 4.2, dilute sodium hydroxide, dilute potassium hydroxide, dilute sodium carbonate, dilute potassium carbonate Examples thereof include dilute ammonium hydroxide.
[0008]
For crystallization, methanol or isopropyl alcohol may be used as a solvent, but ethanol is preferably used. The crystallization temperature is preferably 40 to 50 ° C. or 30 to 40 ° C. when a seed crystal is used, for example. When compound A is crystallized at a relatively low temperature of 10 ° C. or less, a crystal having a melting point of 281 ° C. (decomposition) described in Example 15 of the above-mentioned JP-A-2-28182 (hereinafter referred to as type II crystal) is obtained. The obtained type II crystal shows a characteristic peak at 2θ = 11.494 ° by X-ray diffraction using Cu—Kα ray. Type II crystals are converted to type I crystals by heating and humidification, but the obtained crystals are not pure products, and ethanol as a solvent remains, which requires a further process for removal and is not industrial. . Further, when Compound A is crystallized from ethanolic hydrochloric acid at a relatively high temperature of 50 to 60 ° C., a type I crystal is formed, but this crystal cannot be removed by usual means such as drying under reduced pressure, heating, and humidification. It has the problem of containing 4-5% ethanol. On the other hand, when Compound A is crystallized from ethanolic hydrochloric acid at about room temperature, crystals having a melting point of 305 to 307 ° C. (decomposition) (hereinafter referred to as type III crystals) are formed. This type III crystal shows a characteristic peak at 2θ = 7.303 ° by X-ray diffraction using Cu—Kα rays. Type III crystals are also converted to type I crystals by heating, humidification, etc., but there is a problem in that the selectivity and reproducibility are poor, and it is not industrial in that treatment of the remaining solvent is necessary. .
[0009]
The thus-crystallized type I crystal of the compound A of the present invention can be easily isolated and obtained by ordinary simple means such as cooling, filtration, drying, or a suitable combination.
[0010]
The type I crystal obtained by the present invention has a melting point of 307 ° C. (decomposition), and the infrared spectrum and the powder X-ray diffraction pattern are as shown in FIGS. Table 1 shows the diffraction angle and relative intensity from the powder X-ray diffraction pattern of the type I crystal.
[0011]
On the other hand, the melting points of the type II crystal and the type III crystal are 281 ° C. (decomposition) and 305 to 307 ° C. (decomposition), respectively, and the infrared absorption spectrum and the powder X-ray diffraction pattern are shown in FIGS. Tables 2 and 3 show diffraction angles and relative intensities from the diffraction pattern.
[0013]
【Example】
EXAMPLES Hereinafter, although an Example, a reference example, and a test example demonstrate this invention in detail, this invention is not limited to these.
[0016]
Example 1 50% water containing 886 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide Suspend in 1780 ml of ethanol and add 253 g of concentrated hydrochloric acid to dissolve. 0.1N hydrochloric acid was added to this solution to adjust the pH to about 4, and then 8900 ml of ethanol was added to precipitate crystals at 40-50 ° C., followed by cooling, filtration and drying to obtain a melting point of 307 ° C. ( Type I) of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride Crystals are obtained.
[0017]
Example 2 (±) -6-Chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride (with ethanol) 1160 g (which may be any of type I crystal, type II crystal or type III crystal, or a mixture thereof) is dissolved in 2000 ml of 50% water-containing ethanol, 0.1N hydrochloric acid is added to this solution, and the pH is adjusted to about 4. After the adjustment, 100000 ml of ethanol was added to precipitate crystals at 40 to 50 ° C., cooled, filtered and dried to obtain (±) -6-chloro-3,4-dihydro-4 having a melting point of 307 ° C. (decomposition). Form I crystals of -methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride are obtained.
[0018]
Reference Example 1 1600 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide was added to 6600 ml of ethanol. Dissolve by heating. When 1066 g of 21% ethanolic hydrochloric acid is added at 50 ° C., the internal temperature rises to 57 ° C. After stirring for 2 hours, the mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N containing 4% ethanol was obtained. A type I crystal of-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride is obtained. This residual solvent could not be removed by heating or humidification.
[0019]
Reference Example 2 1251 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide was added to 5000 ml of ethanol. Dissolve by heating. When it is cooled to 25 ° C. and 804 g of 21% ethanolic hydrochloric acid is added, the internal temperature rises to 44 ° C. After stirring for 2 hours, the mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried to give (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl)- Type III crystals of 2H-1,4-benzoxazine-8-carboxamide hydrochloride are obtained. These III crystals change to I-type crystals by heating and humidification. The type I crystal thus obtained contained ethanol as a residual solvent.
[0020]
Example of Crystallographic Stability Samples of type I crystals stored at 40 ° C. and 75% relative humidity for 6 months, type II crystals stored at 35 ° C. and 75% relative humidity for 1 day, and type III crystals of 35 Powder X-ray diffraction was measured for each sample stored for 3 days at 75 ° C. and 75% relative humidity. The results are shown in FIGS. As shown in FIG. 7, the powder X-ray diffraction pattern did not change at all before and after storage, and it was confirmed that the type I crystal was a stable crystal. On the other hand, as shown in FIGS. 8 and 9, respectively, the II type crystal and the III type crystal were changed to the I type crystal upon storage, and it was confirmed that these crystals easily transferred to the I type crystal. .
[0021]
【The invention's effect】
The type I crystal of the compound A of the present invention is novel, unlike the type II crystal obtained heretofore, and is more stable with respect to temperature and humidity than the type II crystal and type III crystal. And can be manufactured in large quantities. Therefore, homogeneity as an active ingredient of an antiemetic or a therapeutic agent such as chronic gastritis is established.
[Brief description of the drawings]
FIG. 1 is an infrared spectrum of a type I crystal obtained by the present invention.
FIG. 2 is a powder X-ray diffraction pattern of a type I crystal obtained by the present invention.
FIG. 3 is an infrared spectrum of a type II crystal of compound A.
4 is a powder X-ray diffraction pattern of a type II crystal of compound A. FIG.
FIG. 5 is an infrared spectrum of a type III crystal of compound A.
FIG. 6 is a powder X-ray diffraction pattern of a type III crystal of compound A.
FIG. 7 shows the results of powder X-ray diffraction measurement of a sample obtained by storing type I crystals at 40 ° C. and 75% relative humidity for 6 months.
FIG. 8 shows the result of powder X-ray diffraction measurement of a sample obtained by storing type II crystals at 35 ° C. and 75% relative humidity for 1 day.
FIG. 9 shows the result of powder X-ray diffraction measurement of a sample obtained by storing type III crystals for 3 days at 35 ° C. and 75% relative humidity.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15328394A JP3726291B2 (en) | 1993-07-05 | 1994-07-05 | Benzoxazine compound having stable crystal structure and process for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19175093 | 1993-07-05 | ||
| JP5-191750 | 1993-07-05 | ||
| JP15328394A JP3726291B2 (en) | 1993-07-05 | 1994-07-05 | Benzoxazine compound having stable crystal structure and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0770120A JPH0770120A (en) | 1995-03-14 |
| JP3726291B2 true JP3726291B2 (en) | 2005-12-14 |
Family
ID=26481953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15328394A Expired - Lifetime JP3726291B2 (en) | 1993-07-05 | 1994-07-05 | Benzoxazine compound having stable crystal structure and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3726291B2 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19958460A1 (en) * | 1999-12-03 | 2001-06-07 | Boehringer Ingelheim Pharma | Process for the preparation of epinastine hydrochloride in high-melting crystal modification |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| DE102004054054A1 (en) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
| DE102005035891A1 (en) * | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals |
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| MX2008014024A (en) | 2006-05-04 | 2008-11-14 | Boehringer Ingelheim Int | Polymorphs. |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| JP2008007418A (en) * | 2006-06-27 | 2008-01-17 | Tokuyama Corp | Method for producing benzoxazine compound having stable crystal structure |
| JP5188757B2 (en) * | 2006-07-18 | 2013-04-24 | 株式会社トクヤマ | Benzoxazine compound having crystal structure and method for producing the same |
| PE20091730A1 (en) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | FORMULATIONS INVOLVING A DPP4 INHIBITOR |
| BRPI0916997A2 (en) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | DPP-4 INHIBITOR AND ITS USE |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| EP3646859A1 (en) | 2009-11-27 | 2020-05-06 | Boehringer Ingelheim International GmbH | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
| AU2011249722B2 (en) | 2010-05-05 | 2015-09-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
| US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
| EP3685839A1 (en) | 2012-05-14 | 2020-07-29 | Boehringer Ingelheim International GmbH | Linagliptin for use in the treatment of albuminuria and kidney related diseases |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| BR112018072401A2 (en) | 2016-06-10 | 2019-02-19 | Boehringer Ingelheim International Gmbh | combinations of linagliptin and metformin |
-
1994
- 1994-07-05 JP JP15328394A patent/JP3726291B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0770120A (en) | 1995-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3726291B2 (en) | Benzoxazine compound having stable crystal structure and process for producing the same | |
| EP0780390A1 (en) | Crystalline modification of CDCH, process for its preparation and pharmaceutical compositions containing it | |
| EP3205653A1 (en) | Crystal form of bisulfate of jak inhibitor and preparation method therefor | |
| KR102522895B1 (en) | Crystal Form of JAK Kinase inhibitor Bisulfate and a preparation method therefor | |
| CN102321019A (en) | The crystalline form of quinoline compound and working method thereof | |
| KR102090912B1 (en) | The edoxaban a novel crystalline form and the manufacturing method thereof | |
| JP4015954B2 (en) | Suplatast tosilate crystal | |
| JP3317649B2 (en) | Carbapenem compounds in crystalline form | |
| SK283188B6 (en) | Preparation method for crystalline form of 3/2 hydrate 7-[(7- (S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1- [(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid | |
| JP2017530107A (en) | Sodium-glucose cotransporter 2 inhibitor L-proline compound, and monohydrate and crystal of L-proline compound | |
| MXPA01012328A (en) | Polymorphs of crystalline (2-benzhydryl-1-azabicyclo[2.2. 2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate as nk-1 receptor antagonists. | |
| JP2707012B2 (en) | Crystal polymorph of N-tert-butyl-1-methyl-3,3-diphenylpropylamine hydrochloride and method for producing the same | |
| TW201908320A (en) | Crystalline form of btk kinase inhibitor and a preparation method thereof | |
| JP2914324B2 (en) | Crystal of piperidine derivative, intermediate for producing the same, and production method | |
| US20040038985A1 (en) | Crystal forms of 1- [6-chloro-5-(trifluoromethly) -2-pyridinyl] piperazine hydrochloride | |
| JP2621392B2 (en) | Crystalline nohydrate of sodium salt of N- (1H-tetrazol-5-ylno-1-phenoxy-4H-quinolizin-4-one-3-carboxamide | |
| HU210879A9 (en) | Pharmaceutical agents | |
| RU2178789C2 (en) | Novel polymorphous forms of lesopitron dihydrochloride and hydrate forms thereof, preparation methods, and compositions based on them | |
| CN110950910A (en) | Stable minodronic acid compound | |
| JPH0753490A (en) | New stable crystal form of bezafibrate | |
| JPS62234094A (en) | Novel crystal of nalpha-(((s)-4-oxo-2-azetidinyl)carbonyl)-l-histidyl-l-prolinamide and production thereof | |
| JPH07252213A (en) | Tosyl acid suplatast having excellent absorbability and its production | |
| EP1768961A1 (en) | Novel form of celecoxib | |
| JPH0971575A (en) | New crystalline sulfonamide compound | |
| WO1997001563A1 (en) | Stable bicozamycin benzoate crystals |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20050301 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050317 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20050906 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20050919 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313111 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081007 Year of fee payment: 3 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091007 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101007 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101007 Year of fee payment: 5 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101007 Year of fee payment: 5 |
|
| R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101007 Year of fee payment: 5 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111007 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111007 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121007 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121007 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131007 Year of fee payment: 8 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |