JPH04108792A - Production of readily pulverizable cis-2-methylspiro (1,3-oxathiolane-5,3')quinuclidine hydrochloride 1/2 hydrate - Google Patents
Production of readily pulverizable cis-2-methylspiro (1,3-oxathiolane-5,3')quinuclidine hydrochloride 1/2 hydrateInfo
- Publication number
- JPH04108792A JPH04108792A JP2225558A JP22555890A JPH04108792A JP H04108792 A JPH04108792 A JP H04108792A JP 2225558 A JP2225558 A JP 2225558A JP 22555890 A JP22555890 A JP 22555890A JP H04108792 A JPH04108792 A JP H04108792A
- Authority
- JP
- Japan
- Prior art keywords
- oxathiolane
- organic solvent
- methylspiro
- cis
- hydrate
- 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.)
- Granted
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は、シス−２−メチルスピロ（１，３−オキサチ
オラン−５，３’ ）キヌクリジン塩酸塩１／２水和物
の製造方法に関する０本発明の方法によると、得られる
水和物が跪く、粉砕し易いものとなり、その結果、適度
な粒度をもち、しかも化学的に安定な結晶体であるので
、得られる水和物は医薬品として使用し易いものとなる
。Detailed Description of the Invention <Industrial Application Field> The present invention relates to a method for producing cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride hemihydrate. According to the method of the invention, the obtained hydrate is easy to crush and has a suitable particle size and is chemically stable crystalline, so that the obtained hydrate can be used as a medicine. It becomes easier to do.
〈従来の技術〉
シス−２−メチルスピロ（１，３−オキサチオラン５、
３’ ）キヌクリジン塩酸塩（以下ＡＦ １０２Ｂと称
する）は、アセチルコリンレセプターのアゴニストとし
て作用する物質で、痴呆症、例えばアルツハイマータイ
プの老人性痴呆症の治療に有用な物質である。<Prior art> Cis-2-methylspiro (1,3-oxathiolane 5,
3') Quinuclidine hydrochloride (hereinafter referred to as AF 102B) is a substance that acts as an agonist of acetylcholine receptors, and is a substance useful in the treatment of dementia, for example, senile dementia of the Alzheimer type.
ＡＦ １０２Ｂは下記の構造式（１）で表わされる。AF102B is represented by the following structural formula (1).
ＡＦ １０２Ｂは、特開昭６１−２８０４９７号公報に
その製造方法、物理化学的な性質が開示されている。Ａ
Ｆ１０２Ｂは、上記公報に開示された合成方法に従って
精製品を得た場合は、 （１）の構造式で示されるよう
な無水物の結晶として得られる。この無水物を常温、常
湿中に放置するか、もしくは、一定湿度に調節した恒温
槽に静置することにより、１分子当り１／２ｍｏｌｅの
結晶水を持った結晶体となり物理化学的に安定な形態を
とりうることが知られている〔式（■）〕
そして、この結晶水をもった物質については、Ｘ線解析
・カールフィシャー法による水分定量などにより、結晶
として安定な構造となっていることが確認されている。The manufacturing method and physicochemical properties of AF 102B are disclosed in JP-A-61-280497. A
When F102B is purified according to the synthesis method disclosed in the above publication, it is obtained as an anhydride crystal as shown by the structural formula (1). By leaving this anhydride at room temperature and humidity, or in a constant temperature bath with constant humidity, it becomes a crystalline substance with 1/2 mole of crystal water per molecule, which is physicochemically stable. It is known that substances with this water of crystallization can have a stable structure as a crystal by X-ray analysis and water determination using the Karl Fischer method. It has been confirmed that there are.
結晶水を持たない形で結晶化されたＡＦ １０２Ｂを安
定形であるＡＦ１０２Ｂ・１／２ｎｚｏとする場合には
、上述したようなゆるやかな条件下で１７２結晶水を含
ませる方法が採用されているが、このような工程では結
晶が融合し、巨大塊となり、医薬品として使用するため
には、不適当であった。また、この塊は非常に堅く、粉
砕するためには多大の労力が必要であった。さらに粉砕
の過程で発生する熱により、結晶水が離脱し、医薬品と
しての成分のばらつきとなるなどの問題を有していた。When converting AF 102B crystallized without water of crystallization into the stable form AF102B・1/2nzo, the method of impregnating 172 water of crystallization under mild conditions as described above is adopted. However, in such a process, the crystals fuse and form a huge mass, making it unsuitable for use as a pharmaceutical. In addition, this lump was very hard and required a lot of effort to crush. Furthermore, the heat generated during the pulverization process causes water of crystallization to separate, resulting in variations in the composition of pharmaceutical products.
〈発明が解決しようとする課題〉
本発明者らは、ＡＦ １０２Ｂの水和物を研究する過程
において、精製、再結晶工程と水和とを同時に行うと、
粉砕が容易となり医薬品として適した粒度のＡＦ １０
２Ｂ・１／２水和物が得られることを見出し、本発明を
完成するに至った。<Problems to be Solved by the Invention> In the process of researching the hydrate of AF 102B, the present inventors discovered that if the purification, recrystallization process and hydration were performed simultaneously,
AF 10 has a particle size that is easy to crush and suitable for pharmaceutical use.
It was discovered that 2B 1/2 hydrate could be obtained, and the present invention was completed.
従って本発明は医薬品として粉砕が容易なＡＦ１０２Ｂ
・１／２水和物を製造する新規な方法を提供することを
課題とする。Therefore, the present invention provides AF102B, which is easy to crush as a pharmaceutical product.
- Our objective is to provide a new method for producing hemihydrate.
〈課題を解決するだめの手段〉
本発明は従来、目的とするＡＦ １０２Ｂ・１／２水和
物を得る際に、再結晶し無水物を得る工程、１／２水和
物に変換する工程の２段階工程を経ていたものを、同一
工程で行うようにした点に特徴を有する。<Means for Solving the Problems> The present invention conventionally involves a step of recrystallizing to obtain an anhydride and a step of converting it into a hemihydrate when obtaining the target AF 102B 1/2 hydrate. It is unique in that it is now done in the same process instead of the two-step process.
ＡＦ １０２Ｂをえる方法としては、特開昭６１−２８
０４９７号公報に開示されたキヌクリジン−３−オンよ
り合成し、ＡＦ １０２８ Ｎ製物を得る方法が採用し
得る。As a method to obtain AF 102B, please refer to JP-A-61-28
The method of synthesizing from quinuclidin-3-one and obtaining an AF 1028 N product as disclosed in Japanese Patent No. 0497 can be adopted.
この方法の工程の概要を下記に示す。A summary of the steps of this method is provided below.
ＡＦ １０２Ｂ
またこの方法以外の合成経路を経て得た合成ＡＦ１０２
Ｂテあッテも本方法によりＡＦ １０２Ｂ −１／２水
和物として調製することができる。AF 102B Synthetic AF102 obtained through a synthetic route other than this method
Bteatte can also be prepared by this method as AF 102B-1/2 hydrate.
本発明では、このようにして得られたＡＦ １０２Ｂを
出発物質として用いる。ＡＦ １０２Ｂは、前記方法に
よって得られた粗製品であってもあるいは精製品であっ
てもよい。また、ＡＦ １０２Ｂが粗大な硬い結晶とな
っているＡＦ １０２Ｂ・１／２Ｈ，Ｏも使用できる。In the present invention, AF 102B thus obtained is used as a starting material. AF 102B may be a crude product obtained by the above method or a purified product. Furthermore, AF 102B.1/2H,O, in which AF 102B is coarse and hard crystals, can also be used.
まず、ＡＦ１０２Ｂを水含有極性有機溶媒に溶解させる
。極性有機溶媒としては、従来極性有機溶媒として知ら
れているものであれば、特に制限されることなく使用で
きる。しかし、メチルアルコールエチルアルコール、ブ
チルアルコール、プロピルアルコール、イソブチルアル
コール、イソプロピルアルコール、アセトン、酢酸エチ
ル、ジメチルホルムアミドあるいはクロロホルム等が使
用される。これらは単独で用いてもあるいは２種以上を
併用して混合溶媒として用いてもよい。また、含水量は
、０．１〜２０％が適当である。特に、有機溶媒として
はイソプロパツールが好ましく、その場合の含水量は、
０．１〜１０％程度が好ましい。この溶液にＡＦ １０
２Ｂ ５〜２０ｇを加温下、例えば３０〜７０°Ｃ１好
適には約５０“Ｃに加温して溶解させる。First, AF102B is dissolved in a water-containing polar organic solvent. As the polar organic solvent, any conventionally known polar organic solvent can be used without particular limitation. However, methyl alcohol, ethyl alcohol, butyl alcohol, propyl alcohol, isobutyl alcohol, isopropyl alcohol, acetone, ethyl acetate, dimethylformamide or chloroform are used. These may be used alone or in combination of two or more as a mixed solvent. Moreover, the water content is suitably 0.1 to 20%. In particular, isopropanol is preferred as the organic solvent, and the water content in that case is
It is preferably about 0.1 to 10%. AF 10 in this solution
5 to 20 g of 2B are dissolved under heating, for example 30 to 70°C, preferably about 50"C.
次に、この溶液に、非極性有機溶媒を加える。Next, a non-polar organic solvent is added to this solution.
非極性有機溶媒としては、通常の非極性有機溶媒として
使用されているものであれば、特に限定されることなく
使用できる。しかし、ｎ−へキサン、シクロヘキサン、
ベンゼン、エチルエーテルあるいは石油エーテル等が使
用される。これらは単独で用いてもあるいは２種以上併
用して混合溶媒として用いてもよい。The non-polar organic solvent is not particularly limited and can be used as long as it is commonly used as a non-polar organic solvent. However, n-hexane, cyclohexane,
Benzene, ethyl ether or petroleum ether are used. These may be used alone or in combination of two or more as a mixed solvent.
非極性有機溶媒の使用量は、水含有極性有機溶媒１容量
当り５〜２０容量、好ましくは１０容量程度が用いられ
る。得られる水和物の純度、性質あるいは経済性からみ
て特に好ましい非極性有機溶媒はｎ−へキサンであり、
前記水含有極性有機溶媒１００１ｄ当たりｎ−ヘキサン
５００〜２０００ｊｄ、好ましくは１０００＋ｄを用い
ることが好ましい。The amount of non-polar organic solvent used is 5 to 20 volumes, preferably about 10 volumes per volume of water-containing polar organic solvent. A particularly preferred non-polar organic solvent in terms of the purity, properties, or economic efficiency of the resulting hydrate is n-hexane,
It is preferable to use 500 to 2000 jd, preferably 1000+d of n-hexane per 1001 d of the water-containing polar organic solvent.
このようにして非極性有機溶媒を加えた後、この溶液を
冷却下で静置して結晶を生成させ、沈澱させる。これは
結晶の大きさ等からみて溶液を１〜１０℃に冷却し１〜
８時間静置して結晶を生成させ、沈澱させることが好ま
しい。次いで結晶を吸引濾過し、結晶を回収する。結晶
中に残存する有機溶媒を１時間以上吸引を続けることに
より、蒸発させ、さらに結晶に含まれる該溶媒を３０°
Ｃの恒温槽に１時間以上放置し、蒸発させる。After adding the non-polar organic solvent in this manner, the solution is allowed to stand under cooling to form crystals and precipitate. This is done by cooling the solution to 1 to 10℃, considering the size of the crystals, etc.
It is preferable to allow the mixture to stand for 8 hours to generate crystals and precipitate them. The crystals are then collected by suction filtration. The organic solvent remaining in the crystals is evaporated by continuing suction for 1 hour or more, and the solvent contained in the crystals is heated at 30°C.
Leave it in a constant temperature bath at C for at least 1 hour to evaporate.
以下に実施例を示し、さらに本発明の詳細な説明する。Examples will be shown below to further explain the present invention in detail.
実施例
特開昭６１−２８０４９７号公報に開示された方法に従
い、ＡＦ １０２Ｂを合成し、精製した。二〇ＡＦ １
０２Ｂを４０’Ｃ相対温度２２．７％の恒温、恒湿槽内
に４８時間放置し、ＡＦ １０２Ｂ・１／２水和物を調
製した。この結晶は、粗大な固い結晶であった。Example AF 102B was synthesized and purified according to the method disclosed in JP-A-61-280497. 20AF 1
02B was left in a constant temperature and humidity chamber at a relative temperature of 40'C and 22.7% for 48 hours to prepare AF 102B 1/2 hydrate. This crystal was a coarse, hard crystal.
この結晶４ｇを１％水含有イソプロパツール１００ｄを
加えて溶解し、濾過した。濾液にｎ−ヘキサン１．０Ｏ
Ｏｄを加え、５℃の冷蔵庫中に１．５時間静置した。次
いで析出した結晶をブフナーロートを用いて吸引濾過し
、さらに１時間室温で吸引をつづけｎ−ヘキサンを蒸発
させた。得られた結晶は濾紙上に均一に拡げ、３０°Ｃ
の恒温槽中で２４時間乾燥した。4 g of this crystal was dissolved by adding 100 d of isopropanol containing 1% water and filtered. Add 1.0O of n-hexane to the filtrate.
Od was added, and the mixture was left standing in a refrigerator at 5°C for 1.5 hours. The precipitated crystals were then suction filtered using a Buchner funnel, and suction was continued for an additional hour at room temperature to evaporate n-hexane. The obtained crystals were spread uniformly on a filter paper and heated at 30°C.
It was dried in a constant temperature bath for 24 hours.
３．６ｇの結晶を得た（収率９０％）。3.6 g of crystals were obtained (yield 90%).
この結晶は下記の物理化学的な性質を有する、跪い粗結
晶であって、容易に粉砕可能で粉砕することによって医
薬品に適した適度な粒度を得ることができた。これらの
結果、特に水分定量、Ｘ線回折の結果から、得られた結
晶がＡＦ １０２Ｂ・１／２水和物であることが確認さ
れた。This crystal is a coarse crystal with the following physicochemical properties, and can be easily crushed to obtain a suitable particle size for pharmaceuticals. From these results, particularly from the results of water content determination and X-ray diffraction, it was confirmed that the obtained crystals were AF 102B 1/2 hydrate.
このようにして得られたＡＦ １０２Ｂ・１／２水和物
は下記の物理化学的な性質を有する。The AF 102B hemihydrate thus obtained has the following physicochemical properties.
（１）水分 カールフィッシャー法により ３．６８％
（２）元素分析
理論値Ｃ４９，０６７、Ｈ７，８２４，Ｎ ５．７２２
． Ｓ １３．０９９測定値０４合、７３３． Ｈ８，
１４６，Ｎ ５．６７２． Ｓ １２．９４５（３）融
点 約２０３°Ｃ（分解）
（４）残留溶媒 ｎ−ヘキサン ０．１５％以下
イソプロパツール ０２０５％以下
（５）赤外吸収スペクトル
再結晶前後の変化なし
く６） χ線回折 再結晶前後の変化なしく７）結晶
状態 脆い粗結晶状を呈し、簡単に砕粋され粒度３０メ
ツシユ以下となる。(1) Moisture 3.68% by Karl Fischer method
(2) Elemental analysis theoretical values C49,067, H7,824, N 5.722
．． S 13.099 Measured value 04 go, 733. H8,
146, N 5.672. S 12.945 (3) Melting point approximately 203°C (decomposed) (4) Residual solvent n-hexane 0.15% or less Isopropanol 0.205% or less (5) Infrared absorption spectrum No change before and after recrystallization 6) Chi-ray diffraction: No change before and after recrystallization 7) Crystalline state: Appears as a brittle coarse crystal and is easily crushed to a particle size of 30 mesh or less.
〈発明の効果〉
本発明の方法によるとＡＦ １０２Ｂ・１／２水和物が
詭い粗結晶の形で得られ、これは容易に粉砕できるので
医薬品に適した粒度のＡＦ １０２Ｂ・１／２水和物を
得ることができる。<Effects of the Invention> According to the method of the present invention, AF 102B 1/2 hydrate is obtained in the form of coarse crystals, which can be easily crushed to produce AF 102B 1/2 with a particle size suitable for pharmaceuticals. Hydrates can be obtained.
Claims (3)
ン−５，３′）キヌクリジン塩酸塩またはその１／２水
和物を水含有極性有機溶媒に溶解し、次いでこの溶解液
に非極性有機溶媒を添加することにより再結晶させ、水
和物を得、この結晶に含有される有機溶媒を蒸発させる
ことにより、適度な粒子のシス−２−メチルスピロ（１
，３−オキサチオラン−５，３′）キヌクリジン塩酸塩
の１／２水和物をえることを特徴とする粉砕容易なシス
−２−メチルスピロ（１，３−オキサチオラン−５，３
′）キヌクリジン塩酸塩１／２水和物の製造方法。(1) Dissolve cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride or its hemihydrate in a water-containing polar organic solvent, and then add a non-polar organic solvent to this solution. By recrystallizing the hydrate by adding
, 3-oxathiolane-5,3') cis-2-methylspiro(1,3-oxathiolane-5,3') which is easy to grind and is characterized by obtaining a hemihydrate of quinuclidine hydrochloride.
') Method for producing quinuclidine hydrochloride hemihydrate.
ール、ブチルアルコール、プロピルアルコール、イソブ
チルアルコール、イソプロピルアルコール、アセトン、
酢酸エチル、ジメチルホルムアミド及びクロロホルムか
らなる群から選択される１種又は２種以上の混合溶媒で
あることを特徴とする請求項（１）記載の粉砕容易なシ
ス−２−メチルスピロ（１，３−オキサチオラン−５，
３′）キヌクリジン塩酸塩１／２水和物の製造方法。(2) The polar organic solvent is methyl alcohol, ethyl alcohol, butyl alcohol, propyl alcohol, isobutyl alcohol, isopropyl alcohol, acetone,
The easily pulverizable cis-2-methylspiro(1,3- Oxathiolane-5,
3') Method for producing quinuclidine hydrochloride hemihydrate.
、ベンゼン、エチルエーテル、及び石油エーテルからな
る群から選択される１種又は２種以上の混合溶媒である
ことを特徴とする請求項（１）記載の粉砕容易なシス−
２−メチルスピロ（１，３−オキサチオラン−５，３′
）キヌクリジン塩酸塩１／２水和物の製造法。(3) Claim (1) characterized in that the nonpolar organic solvent is one or a mixed solvent of two or more selected from the group consisting of n-hexane, cyclohexane, benzene, ethyl ether, and petroleum ether. Easy-to-mill cis-
2-methylspiro(1,3-oxathiolane-5,3'
) A method for producing quinuclidine hydrochloride hemihydrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2225558A JP2761973B2 (en) | 1990-08-28 | 1990-08-28 | Process for producing easily crushable cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride hemihydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2225558A JP2761973B2 (en) | 1990-08-28 | 1990-08-28 | Process for producing easily crushable cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride hemihydrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04108792A true JPH04108792A (en) | 1992-04-09 |
| JP2761973B2 JP2761973B2 (en) | 1998-06-04 |
Family
ID=16831180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2225558A Expired - Lifetime JP2761973B2 (en) | 1990-08-28 | 1990-08-28 | Process for producing easily crushable cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride hemihydrate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2761973B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61280497A (en) * | 1985-05-10 | 1986-12-11 | イスラエル国 | Kynucredine derivative |
-
1990
- 1990-08-28 JP JP2225558A patent/JP2761973B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61280497A (en) * | 1985-05-10 | 1986-12-11 | イスラエル国 | Kynucredine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2761973B2 (en) | 1998-06-04 |
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