JP2529576B2 - Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ▲ ′ ▼) quinuclidine - Google Patents
Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ▲ ′ ▼) quinuclidineInfo
- Publication number
- JP2529576B2 JP2529576B2 JP62172451A JP17245187A JP2529576B2 JP 2529576 B2 JP2529576 B2 JP 2529576B2 JP 62172451 A JP62172451 A JP 62172451A JP 17245187 A JP17245187 A JP 17245187A JP 2529576 B2 JP2529576 B2 JP 2529576B2
- Authority
- JP
- Japan
- Prior art keywords
- msoq
- oxathiolane
- quinuclidine
- methylspiro
- type
- 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
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、トランス型２−メチルスピロ（1,3−オキ
サチオラン−5,3′）キヌクリジン（以下T-MSOQと略
す）を、特定の金属ハロゲン化物の存在下にシス型２−
メチルスピロ（1,3−オキサチオラン−5,3′）キヌクリ
ジン（以下C-MSOQと略す）に異性化する方法であり、こ
の異性化反応によって得られるC-MSOQは、哺乳類の中枢
神経系の病気、特にコリン作用性機能亢進による病気の
治療に有効である。DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to trans 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (hereinafter abbreviated as T-MSOQ) as a specific metal halogen. Cis type in the presence of compound 2-
Methylspiro (1,3-oxathiolane-5,3 ') quinuclidine (hereinafter abbreviated as C-MSOQ) is a method of isomerization, C-MSOQ obtained by this isomerization reaction is a disease of the central nervous system of mammals, It is especially effective for treating diseases caused by hypercholinergic function.
（従来の技術） 本発明でいうC-MSOQは特開昭61−280497号公報に記載
されており、またこの公報には３−ヒドロキシ−３−メ
ルカプトメチルキヌクリジンとアセトアルデヒドとを三
弗化ホウ素エーテル錯化合物の存在下で環化反応をさせ
て、２−メチルスピロ（1,3−オキサチオラン−5,3′）
キヌクリジン（以下MSOQと略す）を得、次いで分別結晶
法によりC-MSOQを得る方法について記載されているが、
T-MSOQをC-MSOQに異性化することについての記載はな
く、また示唆もない。(Prior Art) The C-MSOQ referred to in the present invention is described in JP-A-61-280497, and in this publication, 3-hydroxy-3-mercaptomethylquinuclidine and acetaldehyde are trifluorinated. The cyclization reaction was carried out in the presence of a boron ether complex compound to give 2-methylspiro (1,3-oxathiolane-5,3 ').
A method for obtaining quinuclidine (hereinafter abbreviated as MSOQ) and then obtaining C-MSOQ by a fractional crystallization method is described.
There is no description or suggestion of isomerizing T-MSOQ to C-MSOQ.
（発明が解決しようとする課題） 本発明者等は、MSOQを製造する際には幾何異性体であ
るT-MSOQ及びC-MSOQが生成し、これらのうちC-MSOQが哺
乳類の中枢神経系の病気、特にコリン作用性機能亢進に
よる病気の治療により有効であることから、T-MSOQに変
換することに着目した。(Problems to be Solved by the Invention) The present inventors have found that when producing MSOQ, geometric isomers T-MSOQ and C-MSOQ are produced, and among these, C-MSOQ is the mammalian central nervous system. Since it is more effective in the treatment of other diseases, especially diseases caused by hypercholinergic functioning, we focused on conversion to T-MSOQ.
（課題を解決するための手段） 本発明者等は、T-MSOQをC-MSOQに変換するため、種々
の触媒を用いて検討を重ねた結果、特定の金属ハロゲン
化物を使用した場合にT-MSOQからC-MSOQへの異性化が容
易に実現するとの知見を得、本発明を完成するに至っ
た。(Means for Solving the Problem) The inventors of the present invention conducted a study using various catalysts in order to convert T-MSOQ into C-MSOQ, and as a result, when a specific metal halide was used, T Based on the finding that isomerization of -MSOQ to C-MSOQ is easily realized, the present invention has been completed.
即ち本発明は、T-MSOQを金属ハロゲン化物からなるル
イス酸の存在下に異性化してC-MSOQを得る方法である。That is, the present invention is a method for obtaining C-MSOQ by isomerizing T-MSOQ in the presence of a Lewis acid composed of a metal halide.
MSOQは次式： で表わされるが、これは幾何異性体であるT-MSOQとC-MS
OQを含む。T-MSOQは１、３−オキサチオラン環上の２−
位のメチル基とキヌクリジン環の１′−位の窒素原子と
が、1,3−オキサチオラン環の面に対して反対の側に位
置するものであり、一方C-MSOQは２−位のメチル基と
１′−位の窒素原子とが、1,3−オキサチオラン環の面
に対して同じ側に位置するものであり、またT-MSOQ及び
C-MSOQは各々鏡像異性体を有する。MSOQ is the following formula: , Which is a geometrical isomer of T-MSOQ and C-MS.
Including OQ. T-MSOQ is 2-on the 1,3-oxathiolane ring.
The methyl group at the 1-position of the quinuclidine ring and the nitrogen atom at the 1'-position of the quinuclidine ring are on the opposite side of the plane of the 1,3-oxathiolane ring, while C-MSOQ is the methyl group at the 2-position And the nitrogen atom at the 1'-position are on the same side with respect to the plane of the 1,3-oxathiolane ring, and the T-MSOQ and
Each C-MSOQ has an enantiomer.
本発明方法で用いられる金属ハロゲン化物からなるル
イス酸としては、例えばホウ素、アルミニウム、チタニ
ウム、鉄、亜鉛、アンチモンなどの金属のハロゲン化物
が挙げられ、具体的には三弗化ホウ素、三塩化ホウ素、
三臭化ホウ素、塩化アルミニウム、臭化アルミニウム、
四塩化チタニウム、塩化第二鉄、塩化亜鉛、五塩化アン
チモンなどが挙げられるが、中でも工業的には三弗化ホ
ウ素、塩化アルミニウム及び塩化第二鉄が望ましい。該
ハロゲン化物の使用量は、T-MSOQ1モルに対して通常1.1
−５モルであり、望ましくは1.2−２モルである。Examples of the Lewis acid composed of a metal halide used in the method of the present invention include metal halides such as boron, aluminum, titanium, iron, zinc and antimony. Specific examples thereof include boron trifluoride and boron trichloride. ,
Boron tribromide, aluminum chloride, aluminum bromide,
Examples thereof include titanium tetrachloride, ferric chloride, zinc chloride, antimony pentachloride, and the like. Among them, boron trifluoride, aluminum chloride, and ferric chloride are industrially preferable. The amount of the halide used is usually 1.1 with respect to 1 mol of T-MSOQ.
-5 mol, preferably 1.2-2 mol.
本発明異性化方法の実施に際しては、通常T-MSOQと前
記特定の金属ハロゲン化物とを混合し、さらに必要に応
じ溶媒を加える。In carrying out the isomerization method of the present invention, T-MSOQ is usually mixed with the specific metal halide, and a solvent is added if necessary.
溶媒としては、本発明に係る異性化反応を阻害しない
ものであれば使用でき、例えばヘキサン、シクロヘキサ
ンのような脂肪族炭化水素；塩化メチレン、クロロホル
ム、1,2−ジクロロエタンのようなハロゲン化炭化水
素；ベンゼン、トルエンのような芳香族炭化水素；ジエ
チルエーテル、テトラヒドロフラン、ジオキサンのよう
なエーテル類；酢酸メチル、酢酸エチルのようなエステ
ル類；ジメチルホルムアミド、ジメチルスルホキシドの
ような非プロトン性極性のものなど、あるいはこれらの
混合物が挙げられ、中でもハロゲン化炭化水素が望まし
い。As the solvent, any solvent which does not inhibit the isomerization reaction according to the present invention can be used. For example, aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane. ; Aromatic hydrocarbons such as benzene, toluene; ethers such as diethyl ether, tetrahydrofuran, dioxane; esters such as methyl acetate, ethyl acetate; aprotic polar ones such as dimethylformamide, dimethyl sulfoxide, etc. , Or a mixture thereof, among which halogenated hydrocarbon is preferable.
異性化反応は、通常０℃から120℃の範囲、望ましく
は室温から50℃の範囲で、通常反応時間0.2−12時間で
おこなわれる。異性化反応終了後は通常の後処理をおこ
なう。The isomerization reaction is usually carried out in the range of 0 ° C to 120 ° C, preferably room temperature to 50 ° C, and the reaction time is usually 0.2-12 hours. After completion of the isomerization reaction, usual post-treatment is performed.
本発明方法によれば、T-MSOQのほぼ30％以上をC-MSOQ
に異性化することができ、さらに反応条件を変えること
により、異性化率を向上させることができる。According to the method of the present invention, almost 30% or more of T-MSOQ is C-MSOQ.
The isomerization rate can be improved by changing the reaction conditions.
異性化終了後の反応生成物は油状物として取り出す
か、あるいはさらに安定な結晶を得るために塩に変換し
て取り出す。なお塩への変換は異性化反応終了後の後処
理の段階でおこなうか、あるいは後処理終了後におこな
う。The reaction product after completion of the isomerization is taken out as an oily substance, or converted to a salt and taken out in order to obtain more stable crystals. The salt is converted at the stage of post-treatment after completion of the isomerization reaction or after completion of post-treatment.
変換する塩としては例えば塩酸塩が挙げられるが、こ
の場合反応生成物を一旦適当な溶媒に溶解し、これに例
えば塩化水素を通じるか、あるいは塩化水素のイソプロ
ピルアルコール溶液を加える等すれば目的の塩が得られ
る。Examples of salts to be converted include hydrochlorides. In this case, the reaction product is once dissolved in a suitable solvent, and hydrogen chloride is passed through this, for example, or an isopropyl alcohol solution of hydrogen chloride is added to obtain the desired product. A salt is obtained.
異性化終了後の反応生成物は、上記の如く取り出した
後、通常の分別結晶法によって処理し、これによって異
性化されたC-MSOQを容易に単離することができる。The reaction product after completion of the isomerization can be taken out as described above and then treated by a conventional fractional crystallization method to easily isolate the isomerized C-MSOQ.
（実施例） 本発明方法に係る実施例の数例を以下に示すが、本発
明はこれら実施例のみに限定されるものではない。(Examples) Some examples of the method according to the present invention are shown below, but the present invention is not limited to these examples.
実施例１ 窒素気流下で、トランス型２−メチルスピロ（1,3−
オキサチオラン−5,3′）キヌクリジン1gを溶解させた
クロロホルム溶液20ml中に、塩化第二鉄1.06gを加え、
室温で3.5時間撹拌下に反応させた。Example 1 Under a nitrogen stream, trans-type 2-methylspiro (1,3-
Oxathiolane-5,3 ′) quinuclidine (1 g) was dissolved in chloroform solution (20 ml), and ferric chloride (1.06 g) was added.
The reaction was carried out at room temperature for 3.5 hours with stirring.
反応終了後、10％水酸化ナトリウム水溶液10mlを加
え、分液し、得られた水層をクロロホルム10mlで２回抽
出した。クロロホルム層をあわせ、これを水10mlで洗浄
後、無水硫酸ナトリウム1gを加えて乾燥した。乾燥後ク
ロロホルムを減圧留去し、２−メチルスピロ（1,3−オ
キサチオラン−5,3′）キヌクリジン0.54gを得た。After completion of the reaction, 10 ml of 10% aqueous sodium hydroxide solution was added, the layers were separated, and the obtained aqueous layer was extracted twice with 10 ml of chloroform. The chloroform layers were combined, washed with water (10 ml), and dried with anhydrous sodium sulfate (1 g). After drying, chloroform was distilled off under reduced pressure to obtain 0.54 g of 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine.
これを高速液体クロマトグラフィーによって分析した
ところ、シス型２−メチルスピロ（1,3−オキサチオラ
ン−5,3′）キヌクリジンのモル分率は52％（異性化
率）であった。When analyzed by high performance liquid chromatography, the molar fraction of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine was 52% (isomerization rate).
実施例１で得られた２−メチルスピロ（1,3−オキサ
チオラン−5,3′）キヌクリジン0.54gをヘキサン30mlに
溶解した後、5N−塩化水素イソプロピルアルコールを溶
液をpHが３になるまで加え、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結晶0.4
6gを得た。After dissolving 0.54 g of 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine obtained in Example 1 in 30 ml of hexane, 5N-isopropyl hydrogen chloride alcohol was added to the solution until the pH reached 3, and 2-methylspiro (1,3-
Crystals of oxathiolane-5,3 ') quinuclidine hydrochloride 0.4
6g was obtained.
実施例２及び３ 実施例１に準じておこなった実施例を下表に示す。Examples 2 and 3 Examples performed according to Example 1 are shown in the table below.
なお、金属ハロゲン化物として塩化亜鉛、五塩化アン
チモンを各々使用して、実施例１〜３に準じた異性化反
応をおこなった場合、上記結果とほぼ同程度の結果を得
る。 When zinc chloride and antimony pentachloride are used as the metal halides and the isomerization reaction according to Examples 1 to 3 is performed, the results are almost the same as the above results.
（発明の効果） 本発明は、トランス型２−メチルスピロ（1,3−オキ
サチオラン−5,3′）キヌクリジンを、特定の金属ハロ
ゲン化物の存在下にシス型２−メチルスピロ（1,3−オ
キサチオラン−5,3′）キヌクリジンに異性化する工業
的有利な方法であり、この方法によって得られるシス型
異性体は哺乳類の中枢神経系の病気、特にコリン作用性
機能亢進による病気の治療に有効である。(Effects of the Invention) The present invention provides trans 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine in the presence of a specific metal halide as cis 2-methylspiro (1,3-oxathiolane- 5,3 ') It is an industrially advantageous method of isomerizing to quinuclidine, and the cis-isomer obtained by this method is effective for treating diseases of the central nervous system of mammals, particularly diseases caused by hypercholinergic functioning. .
───────────────────────────────────────────────────── フロントページの続き (72)発明者 前田 勝 滋賀県草津市西渋川２丁目３番１号 石 原産業株式会社中央研究所内 審査官 吉住 和之 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masaru Maeda 2-3-1, Nishi-Shibukawa, Kusatsu-shi, Shiga Ishihara Industry Co., Ltd. Central Research Laboratory Examiner Kazuyuki Yoshizumi
Claims (1)
サチオラン−5,3′）キヌクリジンを、金属ハロゲン化
物からなるルイス酸の存在下でシス型２−メチルスピロ
（1,3−オキサチオラン−5,3′）キヌクリジンに異性化
することを特徴とする、トランス型２−メチルスピロ
（1,3−オキサチオラン−5,3′）キヌクリジンの異性化
方法。1. Trans-type 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine is added to cis-type 2-methylspiro (1,3-oxathiolane-5,3) in the presence of a Lewis acid consisting of a metal halide. 3 ′) Isomerization to quinuclidine, a method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62172451A JP2529576B2 (en) | 1987-07-10 | 1987-07-10 | Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ▲ ′ ▼) quinuclidine |
| US07/215,532 US4861886A (en) | 1987-07-10 | 1988-07-06 | Method for isomerization of trans-form 2-methylspiro (1,3-oxathiolane-5,3')q |
| EP88110895A EP0298491B1 (en) | 1987-07-10 | 1988-07-07 | Method for isomerization of trans-form 2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine or acid addition salts thereof |
| DE88110895T DE3880566T2 (en) | 1987-07-10 | 1988-07-07 | Process for the isomerization of trans-2-methylspiro- (1,3-oxathiolane-5,3 ') quinuclidine or acid addition salts thereof. |
| ES88110895T ES2054739T3 (en) | 1987-07-10 | 1988-07-07 | A METHOD FOR THE ISOMERIZATION OF 2-METHYLSPIRE (1,3-OXATIOLAN-5,3 ') QUINUCLIDINE IN TRANS FORM OR ITS ADDITIONAL SALTS OF ACID. |
| AT88110895T ATE88709T1 (en) | 1987-07-10 | 1988-07-07 | PROCESS FOR THE ISOMERIZATION OF TRANS-2METHYLSPIRO-(1,3-OXATHIOLANE-5,3')QUINCLIDINE OR ACID ADDITIONAL SALTS THEREOF. |
| CA000571612A CA1331183C (en) | 1987-07-10 | 1988-07-08 | Method for isomerization of trans-form 2-methylspiro- (1,3-oxathiolane-5,3')quinuclidine or acid addition salts thereof |
| RO13482388A RO102034B1 (en) | 1987-07-10 | 1988-08-08 | Synergetic herbicidal composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62172451A JP2529576B2 (en) | 1987-07-10 | 1987-07-10 | Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ▲ ′ ▼) quinuclidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6416787A JPS6416787A (en) | 1989-01-20 |
| JP2529576B2 true JP2529576B2 (en) | 1996-08-28 |
Family
ID=15942230
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62172451A Expired - Lifetime JP2529576B2 (en) | 1987-07-10 | 1987-07-10 | Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ▲ ′ ▼) quinuclidine |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP2529576B2 (en) |
| RO (1) | RO102034B1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL87234A (en) * | 1987-08-13 | 1992-02-16 | Israel Inst Biolog Res | Optical isomers of 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine,their preparation and pharmaceutical compositions containing them |
| US5571918A (en) | 1994-05-19 | 1996-11-05 | Ishihara Sangyo Kaisha Ltd. | Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine |
| JP5452165B2 (en) * | 2009-10-23 | 2014-03-26 | 第一ファインケミカル株式会社 | Process for producing quinuclidine |
-
1987
- 1987-07-10 JP JP62172451A patent/JP2529576B2/en not_active Expired - Lifetime
-
1988
- 1988-08-08 RO RO13482388A patent/RO102034B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RO102034B1 (en) | 1993-01-10 |
| JPS6416787A (en) | 1989-01-20 |
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