JPH0816111B2 - Method for isomerizing trans-type 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine or an acid addition salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides trans-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (hereinafter abbreviated as T-MSOQ) or an acid addition salt thereof. Is isomerized to cis 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine (hereinafter abbreviated as C-MSOQ) or an acid addition salt thereof in the presence of a specific organic sulfonic acid. , C-MSOQ or an acid addition salt thereof obtained by this isomerization reaction is effective for treating diseases of the central nervous system of mammals, particularly diseases caused by deficiency in cholinergic system.

(Prior Art) C-MSOQ or an acid addition salt thereof as used in the present invention is disclosed in JP-A-61
-280497 publication, and in this publication, 3
-Hydroxy-3-mercaptomethylquinuclidine and acetaldehyde are cyclized in the presence of a boron trifluoride ether complex compound to give 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine (hereinafter Abbreviated as MSOQ) or an acid addition salt thereof, and then a method for obtaining C-MSOQ or an acid addition salt thereof by a fractional crystallization method is described, but T-MSOQ or an acid addition salt of C-MSOQ is described.
Alternatively, there is no description or suggestion of isomerization into these acid addition salts.

(Problems to be Solved by the Invention) When the present inventors produce MSOQ or acid addition salts thereof, geometric isomers of T-MSOQ or acid addition salts thereof and C-MSOQ or acids thereof are used. Since T-MSOQ or these acid addition salts are effective for treating diseases of the central nervous system of mammals, especially diseases due to deficiency in cholinergic system, T-MSOQ or these Attention was paid to the conversion of the acid addition salt of C-MSOQ or these acid addition salts.

(Means for Solving the Problems) The present inventors have used T-MSOQ or an acid addition salt thereof as C-MS.
As a result of repeated investigations using various catalysts for conversion into OQ or acid addition salts thereof, when specific organic sulfonic acid was used, T-MSOQ or acid addition salts thereof were converted into C-MSOQ or these acid addition salts. The present inventors have found that isomerization to an acid addition salt is easily realized, and completed the present invention.

That is, the present invention is a method of isomerizing T-MSOQ or an acid addition salt thereof in the presence of an organic sulfonic acid to obtain C-MSOQ or an acid addition salt thereof.

MSOQ is the following formula: , Which is a geometric isomer of T-MSOQ and C-
Including MSOQ. T-MSOQ is a 2 on the 1,3-oxathiolane ring.
The methyl group at the -position 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. The group and the 1'-position nitrogen atom are located on the same side with respect to the plane of the 1,3-oxathiolane ring, and T-MSOQ and C-MSOQ each have enantiomers.

Examples of the acid addition salt in the present invention include salts of inorganic or organic acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid,
Sulfamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, succinic acid,
Examples include salts of maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid and the like.

The organic sulfonic acid used in the method of the present invention has the formula R-
Examples thereof include SO ₃ H (wherein R is an alkyl group, an alkenyl group, an alkynyl group, or an aryl group) or a polymeric organic sulfonic acid. The alkyl group, alkenyl group or alkynyl group represented by R in the above formula is a linear or branched group having 1 to 20 carbon atoms, and some or all of the hydrogen atoms thereof are substituted with halogen atoms. May be. Examples of the aryl group represented by R include a phenyl group and a naphthyl group, which are substituted with 1 to 3 identical or different alkyl groups, trifluoromethyl groups, halogen atoms, nitro groups or cyano groups. May be. Examples of the organic sulfonic acid represented by the above formula include methanesulfonic acid, ethanesulfonic acid,
Examples thereof include vinyl sulfonic acid, acetylene sulfonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, p-chlorobenzene sulfonic acid, dodecyl benzene sulfonic acid and naphthalene sulfonic acid, and also polymeric organic sulfonic acids. For example, a fluorine resin such as a polytetrafluoroethylene resin having a sulfonic acid group, specifically NAFION N
R-50: trade name manufactured by DuPont).

The amount of the organic sulfonic acid used is usually 0.1 to 10 mol, preferably 0.2 to 5 mol, per 1 mol of T-MSOQ or an acid addition salt thereof. However, when the organic sulfonic acid used forms a salt with T-MSOQ, it is necessary to additionally add the amount necessary for salt formation.

When carrying out the isomerization method of the present invention, T-MSOQ or an acid addition salt thereof is generally mixed with an organic sulfonic acid, and a solvent is further added if necessary.

As the solvent, any solvent which does not inhibit the isomerization reaction according to the present invention can be used, for example, water; methyl alcohol,
Alcohols such as ethyl alcohol; ketones such as methyl ethyl ketone and methyl isobutyl ketone; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane; benzene, Aromatic hydrocarbons such as toluene; ethers such as diethyl ether, tetrahydrofuran, dioxane; esters such as methyl acetate and ethyl acetate; aprotic polar ones such as dimethylformamide and dimethyl sulfoxide, or the like. And water, an aliphatic hydrocarbon, and an aromatic hydrocarbon are preferable.

The isomerization reaction is usually performed in the range of 40 ° C to 150 ° C, preferably in the range of 60 ° C to 120 ° C, and usually for a reaction time of 1 to 48 hours. After completion of the isomerization reaction, usual post-treatment is performed.

According to the method of the present invention, approximately 20% or more of T-MSOQ or these acid addition salts can be isomerized to C-MSOQ or these acid addition salts, and the isomerization rate can be changed by changing the reaction conditions. Can be improved.

The reaction product after completion of the isomerization is taken out as an oily product of MSOQ, or converted to an acid addition salt of MSOQ 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.

Examples of salts to be converted include salts of inorganic or organic acids as described above.For example, when converting to a hydrochloride, MSOQ of the reaction product is dissolved in a suitable solvent, and hydrogen chloride is passed through this, for example. Alternatively, the desired salt can be obtained by adding hydrogen chloride in isopropyl alcohol.

To easily isolate C-MSOQ or these acid addition salts by separation operation such as fractional crystallization method after taking out MSOQ or these acid addition salts in the reaction product after completion of isomerization as described above. You can

(Examples) Some examples of the method according to the present invention are shown below, but the present invention is not limited to these examples.

Example 1 1.18 g of hydrochloride of T-MSOQ, 1.9 g of p-toluenesulfonic acid hydrate and water in a 10 ml eggplant-shaped flask equipped with a reflux condenser.
1.9 g was added, and the mixture was stirred on a stirrer at room temperature. This was gradually heated in an oil bath and then reacted at 80 ° C. for 2 hours. When this reaction product was analyzed by high performance liquid chromatography, the molar fraction (isomerization rate) of C-MSOQ was 51.9%.

Example 2 T-MSOQ3.0 in a 20 ml eggplant-shaped flask equipped with a reflux condenser.
g, 5.72 g of p-toluenesulfonic acid hydrate and 5.72 g of water were added, and the mixture was stirred on a stirrer at room temperature. This was gradually heated in an oil bath and then reacted at 80 ° C. for 6 hours. When this reaction product was analyzed by high performance liquid chromatography, the mole fraction (isomerization rate) of C-MSOQ was 26.3%.

Example 3 603 mg of trifluoromethanesulfonic acid and 20 ml of benzene were added to a 50 ml eggplant-shaped flask equipped with a Dean-Stark azeotropic dehydrator, a reflux condenser and a calcium chloride tube, and the mixture was refluxed for 20 minutes and then allowed to cool for 5 minutes. T-MSOQ
400 mg was added, and the mixture was reacted at reflux temperature for 20 minutes. When the reaction product was analyzed by high performance liquid chromatography, the molar fraction (isomerization rate) of C-MSOQ was 50%.

Example 4 0.77 g of methanesulfonic acid and 40 ml of benzene were added to a 50 ml eggplant-shaped flask equipped with a Dean-Stark azeotropic dehydrator, a reflux condenser and a calcium chloride tube, and the mixture was refluxed for 20 minutes and then allowed to cool for 5 minutes. T-MSOQ 0.8g was added to this, and it was made to react at reflux temperature for 2 hours. When this reaction product was analyzed by high performance liquid chromatography, the molar fraction (isomerization rate) of C-MSOQ was 25%.

Example 5 1.53 g of p-toluenesulfonic acid hydrate, 40 ml of benzene and T-MSO were placed in a 50 ml eggplant-shaped flask equipped with a Dean-Stark azeotropic dehydrator, a reflux condenser and a calcium chloride tube.
Q0.8 g was added, and the reaction was carried out for 1 hour while azeotropically dehydrating at the reflux temperature. When this reaction product was analyzed by high performance liquid chromatography, the molar fraction (isomerization rate) of C-MSOQ was 19.2%.

Examples 6 to 9 The results of carrying out the reaction under the reaction conditions shown in Table 1 below in accordance with Example 5 are shown in the same table.

(Effects of the invention) The present invention provides trans-type 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine or an acid addition salt thereof with cis-type 2-methylspiro (in the presence of a specific organic sulfonic acid). 1,3-oxathiolane-5,3 ') quinuclidine or an acid addition salt thereof, which is an industrially advantageous method for isomerizing, and the cis-isomer obtained by this method is a central nervous system disease of mammals, especially choline. It is effective in treating diseases caused by deficiency in the action system.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masaru Maeda 2-3-1, Nishi-Shibukawa, Kusatsu-shi, Shiga Ishihara Sangyo Co., Ltd. Central Research Laboratory Kazuyuki Yoshizumi

Claims (1)

[Claims] 1. A trans-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine or an acid addition salt thereof is treated with cis-type 2-methylspiro (40-150 ° C.) in the presence of an organic sulfonic acid. 1,3-Oxathiolane-5,3 ') quinuclidine or an acid addition salt thereof, which is isomerized to trans 2-methylspiro (1,3-oxathiolane-5,3') quinuclidine or an acid thereof. Method for isomerizing addition salts.