Method for isomerization of trans-form 2-methylspiro (1,3-oxathiolane-5,3') q

A method for isomerization of trans-form 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salts thereof, which comprises isomerizing said trans-form quinuclidine or acid addition salts thereof to cis-form 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salts thereof in the presence of at least one acid catalyst selected from the group consisting of an organic sulfuric acid, a halide functioning as a Lewis acid, and sulfuric acid.

The present invention relates to a method for isomerization of trans-form 
2-methylspiro(1,3-oxathiolane-5,3')quinuclidine (hereinafter referred to 
simply as T-MSOQ) or acid addition salts thereof. More particularly, it 
relates to a method for isomerizing T-MSOQ or acid addition salts thereof 
to cis-form 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine (hereinafter 
referred to simply as C-MSOQ) or acid addition salts thereof in the 
presence of a certain acid catalyst. C-MSOQ or acid addition salts thereof 
obtainable by this isomerization reaction are useful for the treatment of 
diseases of the central nervous system in mammals, particularly for the 
treatment of diseases due to disturbances of central cholinergic function. 
C-MSOQ or acid addition salts thereof referred to in this invention are 
disclosed in EP 205,247A. This publication also discloses a method wherein 
3-hydroxy-3-mercaptomethylquinuclidine and acetaldehyde are subjected to a 
cyclization reaction in the presence of borontrifluoride etherate to 
obtain 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine (hereinafter 
referred to simply as MSOQ) or acid addition salts thereof, followed by 
fractional crystallization to obtain C-MSOQ or acid addition salts 
thereof, but does not disclose or suggest the isomerization of T-MSOQ or 
acid addition salts thereof to obtain C-MSOQ or acid addition salts 
thereof. 
Noting that during the preparation of MSOQ or acid addition salts thereof, 
geometrical isomers i.e. T-MSOQ or acid addition salts thereof and C-MSOQ 
or acid addition salts thereof are formed, and among them C-MSOQ or acid 
addition salts thereof are effective for the treatment of diseases of the 
central nervous system in mammals, particularly for the treatment of 
diseases due to disturbances of central cholinergic functions, the present 
inventors have paid a particular attention to conversion of T-MSOQ or acid 
addition salts thereof to C-MSOQ or acid addition salts thereof. 
The present inventors have conducted extensive research by using various 
catalysts to convert T-MSOQ or acid addition salts thereof to C-MSOQ or 
acid addition salts thereof and as a result, have found that when a 
certain acid catalyst is used, isomerization of T-MSOQ or acid additions 
salts thereof to C-MSOQ or acid addition salts thereof can readily be 
accomplished. The present invention has been accomplished on the basis of 
this discovery. 
The present invention provides a method for isomerization of trans-form 
2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salts 
thereof, which comprises isomerizing said trans-form quinuclidine or acid 
addition salts thereof to cis-form 
2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salts 
thereof in the presence of at least one acid catalyst selected from the 
group consisting of an organic sulfonic acid, a halide functioning as a 
Lewis acid, and sulfuric acid. 
Now, the present invention will be described in detail with reference to 
the preferred embodiments. 
MSOQ is represented by the following formula: 
##STR1## 
This includes geometrical isomers i.e. T-MSOQ and C-MSOQ. In T-MSOQ, the 
methyl group at the 2-position on the 1,3-oxathiolane ring and the 
nitrogen atom at the 1'-position of the quinuclidine ring are located at 
the opposite sides of the plane of the 1,3-oxathiolane ring. Whereas, in 
C-MSOQ, the methyl group at the 2-position and the nitrogen atom at the 
1'-position are located on the same side of the plane of 1,3-oxathiolane 
ring. T-MSOQ and C-MSOQ have mirror-image isomers, respectively. 
For the purpose of the present invention, the acid addition salts may be 
inorganic or organic salts such as salts of sulfuric acid, phosphoric 
acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, 
methansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic 
acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, 
gluconic acid, ascorbic acid, benzoic acid and cinnamic acid. 
The organic acid as an acid catalyst used in the method of the present 
invention, may be a sulfonic acid of the formula R-SO.sub.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, the alkenyl group and 
the alkynyl group for R may be straight chained or branched with from 1 to 
20 carbon atoms, and a part or whole of their hydrogen atoms may be 
substituted by halogen atoms such as fluorine. The aryl group for R 
includes a phenyl group or a naphthyl group, which may be substituted by 
substituents selected from the group consisting of an alkyl group, a 
trifluoromethyl group, a halogen atom, a nitro grop and a cyano group. The 
organic sulfonic acid of the above formula includes, for example, methane 
sulfonic acid, ethane sulfonic acid, vinyl sulfonic acid, acetylene 
sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, 
benzene sulfonic acid, p-toluene sulfonic acid, p-chlorobenzene sulfonic 
acid, dodecylbenzene sulfonic acid and naphthalene sulfonic acid. The 
polymeric organic sulfonic acid includes, for example, a fluorine resin 
such as a polytetrafluoroethylene resin having sulfonic acid groups. 
Specifically, NAFION (NAFION NR-50, tradename, manufactured by Du Pont 
Company) may be mentioned. Among them, an organic sulfonic acid of the 
above formula wherein R is an aryl group is preferred from the industrial 
point of view. 
The halide functioning as a Lewis acid as the acid catalyst includes, for 
example, halides of e.g. boron, aluminum, titanium, iron, zinc and 
antimony. Specifically, boron trifluoride, boron trichloride, boron 
tribromide, aluminum chloride, aluminum bromide, titanium tetrachloride, 
ferric chloride, zinc chloride, or antimony pentachloride may be 
mentioned. Among them, boron trifluoride, aluminum chloride and ferric 
chloride are preferred from the industrial point of view. 
The sulfuric acid as the acid catalyst usually has a concentration of from 
5 to 90%, preferably from 20 to 80%. 
The acid catalyst is used usually in an amount of from 0.1 to 10 moles, 
preferably from 0.2 to 5 moles, per mole of T-MSOQ or acid addition salts 
thereof. However, in a case where the acid catalyst used forms a salt with 
T-MSOQ, it will be necessary to use an additional amount necessary for the 
formation of the salt. 
To conduct the method for isomerization of the present invention, it is 
usual that T-MSOQ or acid addition salts thereof and the acid catalyst are 
mixed, and if necessary, a solvent is added thereto. 
As such a solvent, any solvent may be used so long as it does not adversely 
affect the isomerization reaction of the present invention. 
When the organic sulfonic acid is used as the acid catalyst, the solvent 
may be water, a hydrophilic organic solvent or a hydrophobic organic 
solvent. Specifically, it includes water; ketones such as methyl ethyl 
ketone and methyl isobutyl ketone; aliphatic hydrocarbons such as hexane 
and cyclohexane; halogenated hydrocarbons such as methylene chloride, 
chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene 
and toluene; ethers such as diethyl ether, tetrahydrofuran and dioxane; 
esters such as methyl acetate and ethyl acetate; and aprotic polar 
solvents such as dimethylformamide and dimethylsulfoxide. They may be used 
alone or in combination as a mixture. Among them, a hydrophobic organic 
solvent such as an aliphatic hydrocarbon or aromatic hydrocarbon is 
preferred. 
When the halide functioning as the Lewis acid is used as the acid catalyst, 
a hydrophobic organic solvent may be employed. Specifically, the 
above-mentioned aliphatic hydrocarbons, halogenated hydrocarbons and 
aromatic hydrocarbons may be employed. Among them, halogenated 
hydrocarbons are preferred. 
When sulfuric acid is used as the acid catalyst, water is employed as the 
solvent. 
The isomerization reaction is conducted usually within a temperature range 
of from 0.degree. to 150.degree. C., preferably from 40.degree. to 
130.degree. C. for from 0.2 to 48 hours. The isomerization reaction is 
followed by usual work up. 
According to the method of the present invention, about 20% or more of 
T-MSOQ or acid addition salts thereof can be isomerized to C-MSOQ or acid 
addition salts thereof. Further, by properly adjusting the reaction 
conditions, the isomerization ratio can be improved. 
The reaction product after completion of the isomerization may be withdrawn 
as an oily substance of MSOQ, or may be converted to an acid addtion salt 
of MSOQ in order to obtain stable crystal. For example, in the case of 
conversion to the hydrogen chloride salt, MSOQ as the reaction product is 
dissolved in a suitable solvent, to which hydrogen chloride is introduced, 
or an isopropyl alcohol solution of hydrogen chloride is added, whereby 
the disired hydrogen chloride salt will be obtained. 
MSOQ or acid addition salts thereof in the reaction product after 
completion of the isomerization, is withdrawn as described above, and then 
C-MSOQ or acid addition salts thereof can readily be isolated by an 
operation for separation such as fractional crystallization. 
Now, the present invention will be described with reference to some 
Examples. However, it should be understood that the present invention is 
by no means restricted to such specific Examples.

EXAMPLE 1 
Into a 10 ml round-bottom flask equipped with a reflux condenser, 1.18 g of 
T-MSOQ hydrochloride, 1.9 g of p-toluene sulfonic acid monohydrate and 1.9 
g of water were charged and stirred by a stirrer at room temperature. The 
mixture was then gradually heated in an oil bath and then reacted at 
80.degree. C. for two hours. After completion of the reaction, the 
reaction product was analysed by high performance liquid chromatography, 
whereby the molar fraction of C-MSOQ was 51.9% (isomerization ratio). 
EXAMPLE 2 
Into a 20 ml round-bottom flask equipped with a reflux condenser, 3.0 g of 
T-MSOQ, 5.72 g of p-toluene sulfonic acid monohydrate and 5.72 g of water 
were charged and stirred by a stirrer at room temperature. The mixture was 
gradually heated in an oil bath and then reacted at 80.degree. C. for 6 
hours. After completion of the reaction, this reaction product was 
analysed by high performance liquid chromatography, whereby the molar 
fraction of C-MSOQ was 26.3% (isomerization ratio). 
EXAMPLE 3 
Into a 50 ml round-bottom flask equipped with a Dean-Stark trap, a reflux 
condenser and a calcium chloride tube, 603 mg of trifluoromethane sulfonic 
acid and 20 ml of benzene were added, refluxed for 20 minutes and then 
left to cool for 5 minutes. To this mixture, 400 mg of T-MSOQ was added, 
and the mixture was reacted at a reflux temperature for 20 minutes. After 
completion of the reaction, the reaction product was analysed by high 
performance liquid chromatography, whereby the molar fraction of C-MSOQ 
was 50% (isomerization ratio). 
EXAMPLE 4 
Into a 50 ml round-bottom flask equipped with a Dean-Stark trap, a reflux 
condenser and a calcium chloride tube, 0.77 g of methanesulfonic acid and 
40 ml of benzene were added, refluxed for 20 minutes and then left to cool 
for 5 minutes. To this mixture, 0.8 g of T-MSOQ was added, and the mixture 
was reacted at a reflux temperature for two hours. After completion of the 
reaction, this reaction product was analysed by high performance liquid 
chromatography, whereby the molar fraction of C-MSOQ was 25% 
(isomerization ratio). 
EXAMPLE 5 
Into a 50 ml round-bottom flask equipped with a Dean-Stark trap, a reflux 
condenser and a calcium chloride tube, 1.53 g of p-toluene sulfonic acid 
monohydrate, 40 ml of benzene and 0.8 g of T-MSOQ were charged and reacted 
for one hour while azeotropically dehydrating at a reflux temperature. 
After completion of the reaction, this reaction product was analysed by 
high performance liquid chromatography, whereby the molar fraction of 
C-MSOQ was 19.2% (isomerization ratio). 
EXAMPLES 6 to 9 
The reactions were conducted in the same manner as in Example 5 under the 
reaction conditions as indentified in Table 1. The results are shown in 
Table 1. 
TABLE 1 
__________________________________________________________________________ 
Molar fraction 
(%) of C-MSOQ in 
Type and amount 
Type and reaction product 
Example 
Amount (g) 
(g) of acid 
amount (ml) 
Reaction 
Reaction 
(isomerization 
No. of T-MSOQ 
catalyst of solvent 
temperature 
time (hr) 
ratio) 
__________________________________________________________________________ 
p-Toluene 
Toluene 
Reflux 
6 10 sulfonic acid 
50 temperature 
3 48 
monohydrate 
19.1 
" Hexane Reflux 
7 10 19.1 40 temperature 
10 50 
" Chloroform 
Reflux 
8 1 1.9 50 temperature 
24 22.3 
As HCl salt 
" Toluene 
Reflux 
9 11.8 19.1 50 temperature 
3 48 
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EXAMPLE 10 
Into a 20 ml round-bottom flask equipped with a reflux condenser, 3.0 g of 
T-MSOQ hydrogen chloride and 9 ml of a 50% sulfuric acid aqueous solution 
comprising equal weight amounts of conc-sulfuric acid and water were 
charged and stirred by a stirrer at room temperature. The mixture was 
gradually heated in a warm water bath and then reacted at a temperature of 
from 50.degree. to 60.degree. C. for 30 minutes. 
After completion of the reaction, the reaction product was changed to 
alkaline by an addition of 40 ml of a 20% sodium hydroxide aqueous 
solution while cooling with ice water and then extracted four times with 
n-hexane. The extracted layer thus obtained was dried by an addition of 5 
g of anhydrous sodium sulfate to obtain 40 ml of a n-hexane solution 
containing 2.0 g of MSOQ. 
This solution was analysed by high performance liquid chromatography, 
whereby the molar fraction of C-MSOQ was 52.7% (isomerization ratio). 
REFERENCE EXAMPLE 1 
40 ml of n-hexane solution containing 2.0 g of MSOQ obtained in the same 
manner as in Example 10 was adjusted to pH 4 by an addition of 3.5 ml of a 
4N hydrogen chloride isopropyl alcohol solution. Crystals thereby formed 
were collected by filtration and vacuum-dried at 40.degree. C. over a 
period of 8 hours to obtain 2.2 g of MSOQ hydrogen chloride. 
EXAMPLES 11 to 15 and REFERENCE EXAMPLES 2 to 6 
The reactions were conducted in the same manner as in Examples 10 and 
Reference Example 1 under the reaction conditions as identified in Table 
2. The results are shown in Table 2. 
TABLE 2 
__________________________________________________________________________ 
Amount 
Amount (g) Molar fraction (g) of 
of T-MSOQ 
Type and amount 
Reaction (%) of C-MSOQ 
Reference 
obtained 
Example 
hydrogen 
(g) of acid 
temperature 
Reaction 
(isomerization 
Example 
MSOQ hydro- 
No. chloride 
catalyst (.degree.C.) 
time (hr) 
ratio) No. gen chloride 
__________________________________________________________________________ 
20% 
11 5.0 sulfuric acid 
100 1.25 51.2 2 2.37 
57.6 
40% 
12 5.0 sulfuric acid 
50-60 1 53.4 3 3.61 
27.4 
80% 
13 5.0 sulfuric acid 
20-25 1 53.7 4 3.01 
8.21 
40% 
14 5.0 sulfuric acid 
50-60 7 48.2 5 2.70 
5.47 
40% 
15 5.0 sulfuric acid 
40-50 3 44.5 6 2.86 
50.7 
__________________________________________________________________________ 
EXAMPLE 16 
1.06 g of ferric chloride was added to 20 ml of a chloroform solution 
containing 1 g of T-MSOQ under a nitrogen stream, and the mixture was 
reacted at room temperature (30.degree. C.) for 3.5 hours under stirring. 
After completion of the reaction, 10 ml of a 10% sodium hydroxide aqueous 
solution was added thereto, followed by liquid separation. The aqueous 
layer thus obtained was extracted twice with 10 ml of chloroform. The 
chloroform layers were put together, washed with 10 ml of water and dried 
by an addition of 1 g of anhydrous sodium sulfate. After drying, 
chloroform was distilled off under reduced pressure to obtain 0.54 g of 
MSOQ. 
This product was analysed by high pressure liquid chromatography, whereby 
the molar fraction of C-MSOQ was 52% (isomerization ratio). 
REFERENCE EXAMPLE 7 
0.54 g of MSOQ obtained in Example 16 was dissolved in 30 ml of hexane, and 
a 5N hydrogen chloride isopropyl alcohol solution was added thereto until 
the pH became 3, whereby 0.46 g of crystals of MSOQ hydrogen chloride were 
obtained. 
EXAMPLES 17 and 18 
The reactions were conducted in the same manner as in Example 16 under the 
reaction conditions as identified in Table 3. The results are shown in 
Table 3. 
TABLE 3 
__________________________________________________________________________ 
Molar fraction 
Amount (g) of C-MSOQ in 
of T-MSOQ 
Type and amount 
Type and 
Reaction reaction product 
Example 
hydrogen 
(g) of acid 
amount (g) 
temperature 
Reaction 
(isomerization 
No. chloride 
catalyst of solvent 
(.degree.C.) 
time (hr) 
ratio) 
__________________________________________________________________________ 
17 2.36 AlCl.sub.3 
Chloroform 
40 1.5 51.7 
2 20 
18 2.00 BF.sub.3 Chloroform/ 
25 26 51.5 
Dimethyl- 
sulfoxide 
2.9 (20/1) 
42 
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