WO2017134984A1 - Method for producing 2-methylspiro (1,3-oxathiolane-5,3') quinuclidine sulfate - Google Patents
Method for producing 2-methylspiro (1,3-oxathiolane-5,3') quinuclidine sulfate Download PDFInfo
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- WO2017134984A1 WO2017134984A1 PCT/JP2017/000456 JP2017000456W WO2017134984A1 WO 2017134984 A1 WO2017134984 A1 WO 2017134984A1 JP 2017000456 W JP2017000456 W JP 2017000456W WO 2017134984 A1 WO2017134984 A1 WO 2017134984A1
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- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D497/20—Spiro-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- the present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans).
- 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc.
- Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline) (see, for example, Patent Document 1).
- Conventional methods for producing cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine include, for example, 3-hydroxy-3-mercapto Methylquinuclidine and boron trifluoride-ether complex were reacted to obtain an isomeric mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, which was separated by fractional crystallization.
- the cis form of the compound is separated from the isomer mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate or isomerized from the trans form to the cis form.
- 2-methylspiro (1,3-oxathiolane-) can be obtained at a high isomer ratio (cis / trans) without requiring isomer fractionation or isomerization.
- a method for obtaining quinuclidine sulfate has been demanded.
- An object of the present invention is to mix a metal halide and an acetaldehyde compound and then further mix and react 3-hydroxy-3-mercaptomethylquinuclidine (1) to produce free 2-methylspiro (1,3- Obtaining oxathiolane-5,3 ′) quinuclidine halogen (2);
- the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at ⁇ 5 to 45 ° C.
- the isomers of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate are the following four types, and the cis form is represented by the following formulas (3-C1) and (3-C2).
- the transformer type is represented by the following formula (3-T1) and formula (3-T2).
- the isomer ratio is the ratio of cis to trans, and is calculated as cis / trans.
- 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to form free 2-methylspiro (1, 3-oxathiolane-5,3 ′) quinuclidine (2), the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) and sulfuric acid at ⁇ 5 to 45 ° C.
- one embodiment of the present invention is a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, in the following order (Ia): Mixing a metal halide and an acetaldehyde compound in the absence of 3-hydroxy-3-mercaptomethylquinuclidine (1), (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) A step of further mixing and reacting with a mixture of a metal halide and an acetaldehyde compound to obtain free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2); and (II) the free 2 -Methylspiro (1,3-oxathiolane-5,3 ') quinuclidine (2) is contacted with sulfuric acid at -5 to 45 ° C.
- Rusupiro (1,3-oxathiolane-5,3 ') comprising the step of converting the quinuclidine sulfate (3), to provide a manufacturing method.
- Another aspect of the present invention is a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, comprising (Ia) 3-hydroxy-3-mercaptomethylquinuclide. Mixing the metal halide and the acetaldehyde compound in the absence of gin (1), further adding (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) to the mixture of the metal halide and the acetaldehyde compound.
- Aspect 8 The production method according to any one of Aspects 1 to 7, wherein the reaction temperature at the time of further mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine is 30 to 45 ° C.
- Aspect 9 The production method according to any one of Aspects 1 to 8, wherein the temperature at the time of mixing the metal halide and the acetaldehyde compound is 15 to 25 ° C.
- Aspect 10 The temperature according to any one of Aspects 1 to 9, wherein the temperature at the time of contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is 0 to 30 ° C. Production method.
- 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate is obtained from 3-hydroxy-3-mercaptomethylquinuclidine with a high isomer ratio (cis / trans) by a simple method. It is possible to provide a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate having an industrially suitable high isomer ratio (cis / trans).
- the production method of the present invention is a method for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate having a high isomer ratio (cis / trans) including the following two steps. First step; After mixing the metal halide and the acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A step of obtaining quinuclidine (2).
- 3-hydroxy-3-mercaptomethylquinuclidine (1) is compound (1) or QHT and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is compound (2) or MSOQ and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) are sometimes referred to as compound (3) or MSOQ sulfate.
- Compound (1) is a compound represented by the following formula (1).
- Compound (1) can be synthesized from quinuclidin-3-one by a known method and is usually used as an isomer mixture.
- the metal halide used in this step is, for example, metal fluorides such as antimony pentafluoride and antimony trifluoride; tin tetrachloride, silicon tetrachloride, titanium tetrachloride, antimony pentachloride, antimony trichloride, aluminum trichloride Metal chlorides and the like can be mentioned, but metal chlorides are preferred, and tin tetrachloride is more preferred. These metal halides may be used alone or in combination of two or more, and may be a hydrate or a solvate. In addition to the above metal halides, sulfates, nitrates, phosphates, carboxylates, sulfonates, and the like can also be used.
- the amount of the metal halide to be used is preferably 1 to 5 mol, more preferably 2 to 4 mol, per 1 mol of compound (1). By setting it as this range, a compound (2) can be obtained with a high isomer pair ratio and a high yield.
- acetaldehyde compound examples include (i) acetaldehyde (monomer); (ii) multimers of aldehydes such as paraaldehyde and metaaldehyde; and (iii) acetals such as dimethoxyethane and diethoxyethane. And acetaldehyde protected with amines such as bis (dimethylamino) ethane and bis (diethylamino) ethane, or thiols such as bis (thiomethoxy) ethane and bis (thioethoxy) ethane. In addition, these acetaldehyde compounds may be used individually or in mixture of 2 or more types, and can also be used as aqueous solution or an organic-solvent solution.
- the amount of the aldehyde compound to be used is preferably 1 to 10 mol, more preferably 1 to 6 mol, more preferably 2 to 4 mol, based on acetaldehyde, relative to 1 mol of compound (1). By setting it as this range, a compound (2) can be obtained with a sufficient yield.
- solvent In this step, the uniformity and stirring properties of the reaction solution can be improved by using a solvent.
- Solvents that can be used are not particularly limited as long as they do not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol; heterocyclic amines such as pyridine and quinoline; acetone , Ketones such as methyl ethyl ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; dimethyl sulfoxide Sulfones such as sulfolane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and di
- the amount of the solvent to be used is preferably 1 to 30 mL, more preferably 5 to 15 mL, per 1 g of compound (1). By setting it as this range, the uniformity and stirring property of a reaction liquid are ensured, and a compound (2) can be obtained with a high isomer ratio.
- reaction in this step is to obtain a free compound (2) after the post-treatment by further mixing and reacting the compound (1) after mixing a metal halide and an acetaldehyde compound and, if necessary, a solvent. Can do.
- mixing and reacting in this order mixing the metal halide and the acetaldehyde compound and then mixing the compound (1)
- the generation of solids is suppressed and the isomer ratio is reduced due to partial heating. Generation of reaction can be suppressed.
- the metal halide or the acetaldehyde compound can be further added and reacted after mixing the compound (1) to the extent that the effects of the present invention are not impaired.
- reaction temperature reaction temperature
- reaction pressure reaction temperature
- the reaction temperature in this step is preferably 10 to 60 ° C, more preferably 20 to 50 ° C, more preferably 30 to 45 ° C. By setting it as this range, a compound (2) can be obtained with a high isomer ratio and a high yield, maintaining the favorable stirring property of a reaction liquid.
- the pressure in this step is not particularly limited, and is usually performed under normal pressure.
- the compound (2) obtained in this step may be used in the next step (second step) without any particular isolation / purification, but may be neutralized, extracted, filtered, washed, re-used as necessary. It can also be used in the next step after undergoing treatment such as crystallization and crystallization. By performing these treatments, the complexity of the reaction in the next step can be suppressed. In order to make the post-treatment at the end of the reaction in this step easier, a hydrophilic medium such as alcohol may be added as appropriate.
- the compound (2) is considered to be complexed with the metal halide, but the free compound (2) can be obtained by, for example, post-treatment using water, base, or acid. it can.
- This step is carried out by bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (compound (2)) into contact with sulfuric acid at ⁇ 5 to 45 ° C.
- a post-treatment such as reacting a complex of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and a metal halide produced by the reaction with a base to give free cis-type 2-methylspiro (1 , 3-oxathiolane-5,3 ′) quinuclidine, and then contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine with sulfuric acid may be employed.
- sulfuric acid As the sulfuric acid used in this step, commercially available one can be used, and its concentration is not particularly limited.
- the amount of sulfuric acid used is not particularly limited as long as 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained sufficiently, but with respect to 1 mol of compound (2).
- the amount is preferably 0.5 to 10 mol, more preferably 0.6 to 5 mol, more preferably 0.8 to 2 mol.
- compound (3) can be obtained by a method such as bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine into contact with sulfuric acid, but preferably the liquid temperature is ⁇ 5. While maintaining at ⁇ 45 ° C., free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine is contacted with sulfuric acid and reacted at the same temperature to produce compound (3). By setting it within this range, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained (isolated) from the reaction solution with good yield.
- reaction temperature reaction temperature
- reaction pressure reaction temperature
- the contact temperature with free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is preferably ⁇ 5 to 45 ° C., more preferably 0 to 30 ° C.
- the pressure at that time is not particularly limited.
- the organic solvent is not particularly limited as long as it can dissolve free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine, and examples thereof include alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol.
- Aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; Halogenated aliphatic hydrocarbons such as methylene chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Chlorobenzene and dichlorobenzene Halogenated aromatic hydrocarbons; Esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and caprolactone; Ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and cyclohexanone; Diethyl ether , T-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane, anisole and the like, preferably ketones such as acetone,
- the amount of the organic solvent used is not particularly limited as long as it can dissolve 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine substantially completely, but with respect to 1 g of compound (2),
- the amount is preferably 1 to 50 mL, more preferably 2 to 30 mL.
- the compound (3) obtained in this step can be isolated and purified by a general method such as neutralization, extraction, filtration, washing, recrystallization, and crystallization.
- a small amount of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (2: 1) may be mixed in the compound (3).
- the 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate obtained through the first and second steps of the present invention has an isomer ratio (cis / trans) of 92/8 or more, preferably 94/6 or more.
- the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be further crystallized by dissolving in an appropriate solvent and recrystallizing.
- a suitable embodiment in that case is, for example, a method of dissolving crystals in a mixed solvent of water and ketones and further adding ketones to precipitate crystals.
- the amount and composition ratio of the mixed solvent can be appropriately adjusted according to the amount of the target product obtained and the purification efficiency.
- Example 1 Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate
- paraacetaldehyde (15.3 g) (346 mmol as acetaldehyde) and methylene chloride (100 mL)
- methylene chloride 100 mL
- 90.2 g (346 mmol) of tin (IV) chloride was added.
- Example 2 (Synthesis of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate) [First step] In the same manner as in Example 1, 35.7 g of an organic solvent solution containing 4.01 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained.
- Example 3 Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate [First step] After mixing 0.39 g of paraacetaldehyde (2.9 mmol as acetaldehyde) and 5 mL of ethyl acetate in a 20 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 20-30 ° C. While adding 2.23 g (8.7 mmol) of tin (IV) chloride.
- Example 4 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate) [First step] The reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to toluene in Example 3. As a result, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 84. % (Isomer ratio: 94.4 / 5.6).
- Example 5 Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate
- the reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to chloroform in Example 3.
- 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 68. % (Isomer ratio: 93.6 / 6.4).
- Example 6 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate) [First step] A reaction was conducted in the same manner as in Example 3 except that the amount of tin (IV) chloride used was changed to 1.51 g (5.78 mmol) in Example 3. 2-Methylspiro (1,3-oxathiolane) -5,3 ') Quinuclidine was produced in a yield of 88% (isomer ratio: 95.0 / 5.0).
- 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained in high yield and high isomer ratio even when the conditions are changed. Can do.
- Example 7 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate) 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (isomer ratio: 96.0 / 4.0) obtained through the first step and the second step in the same manner as in Example 1.
- 3 g (10.1 mmol) 6 mL of acetone and 0.66 mL of water were mixed, 24 mL of acetone was added at room temperature, and the precipitated solid was filtered to obtain 2-methylspiro (1,3-oxathiolane having a cis ratio of 98.5%.
- the present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans).
- 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc.
- Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline).
Abstract
The invention provides a method for obtaining 2-methylspiro (1,3-oxathiolane-5,3') quinuclidine sulfate at a high isomer ratio (cis/trans) from 3-hydroxy-3-mercaptomethylquinuclidine without requiring fractionation of isomers or an isomerization step. The invention relates to a method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine sulfate including a step in which a metal halide and an acetaldehyde compound are mixed and then 3-hydroxy-3-mercaptomethylquinuclidine is mixed and reacted to obtain free 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine, and a step in which the free 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine is brought into contact with sulfuric acid at –5–45°C and thereby converted into 2-methylspiro (1,3-oxathiolane-5,3') quinuclidine sulfate.
Description
本願は、特願２０１６－０１６８８１号（出願日：２０１６年２月１日）の優先権の利益を享受する出願であり、これらは引用することによりその全体が本明細書に取り込まれる。
This application is an application that enjoys the benefit of the priority of Japanese Patent Application No. 2016-016881 (filing date: February 1, 2016), which is incorporated herein by reference in its entirety.
本発明は、３－ヒドロキシ－３－メルカプトメチルキヌクリジンから２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を製造する方法に関し、特に高い異性体比率（シス／トランス）で２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を製造する方法に関する。
当該化合物は、哺乳類の中枢神経の病気、特にコリン作用機能障害による病気、シエーグレン症候群と称される自己免疫疾患などの治療に有用なシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン塩酸塩（セビメリン）の合成中間体として有用な化合物である（例えば、特許文献１参照）。 The present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans). To 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
The compound is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc. Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline) (see, for example, Patent Document 1).
当該化合物は、哺乳類の中枢神経の病気、特にコリン作用機能障害による病気、シエーグレン症候群と称される自己免疫疾患などの治療に有用なシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン塩酸塩（セビメリン）の合成中間体として有用な化合物である（例えば、特許文献１参照）。 The present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans). To 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
The compound is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc. Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline) (see, for example, Patent Document 1).
従来、３－ヒドロキシ－３－メルカプトメチルキヌクリジンからシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を製造する方法としては、例えば、３－ヒドロキシ－３－メルカプトメチルキヌクリジンと三フッ化ホウ素・エーテル錯体とを反応させて、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体混合物を得た後、これを分別結晶法により分離してシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を得る方法が開示されている（例えば、特許文献１～２参照）。
一方、トランス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩と、金属ハロゲン化物のルイス酸、硫酸または有機スルホン酸と接触させることにより、当該当該化合物のシス型に異性化する方法が開示されている（例えば、特許文献３～７参照）。 Conventional methods for producing cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine include, for example, 3-hydroxy-3-mercapto Methylquinuclidine and boron trifluoride-ether complex were reacted to obtain an isomeric mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, which was separated by fractional crystallization. Discloses a method for obtaining cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate by separation (see, for example, Patent Documents 1 and 2).
On the other hand, by contacting trans 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate with a metal halide Lewis acid, sulfuric acid or organic sulfonic acid, the cis form of the compound is isomerized. Has been disclosed (see, for example, Patent Documents 3 to 7).
一方、トランス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩と、金属ハロゲン化物のルイス酸、硫酸または有機スルホン酸と接触させることにより、当該当該化合物のシス型に異性化する方法が開示されている（例えば、特許文献３～７参照）。 Conventional methods for producing cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine include, for example, 3-hydroxy-3-mercapto Methylquinuclidine and boron trifluoride-ether complex were reacted to obtain an isomeric mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, which was separated by fractional crystallization. Discloses a method for obtaining cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate by separation (see, for example, Patent Documents 1 and 2).
On the other hand, by contacting trans 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate with a metal halide Lewis acid, sulfuric acid or organic sulfonic acid, the cis form of the compound is isomerized. Has been disclosed (see, for example, Patent Documents 3 to 7).
しかしながら、上記の方法では、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体混合物から、当該化合物のシス型を分離したり、トランス型からシス型に異性化させたりするなど、シス型を取得するために煩雑な操作が必要であった。
そのため、３－ヒドロキシ－３－メルカプトメチルキヌクリジンから、異性体の分別や異性化工程を必要とすることなく、高い異性体比率（シス／トランス）で２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を得る方法が求められていた。 However, in the above method, the cis form of the compound is separated from the isomer mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate or isomerized from the trans form to the cis form. In order to obtain a cis type, a complicated operation is required.
Therefore, from 3-hydroxy-3-mercaptomethylquinuclidine, 2-methylspiro (1,3-oxathiolane-) can be obtained at a high isomer ratio (cis / trans) without requiring isomer fractionation or isomerization. 5,3 ′) A method for obtaining quinuclidine sulfate has been demanded.
そのため、３－ヒドロキシ－３－メルカプトメチルキヌクリジンから、異性体の分別や異性化工程を必要とすることなく、高い異性体比率（シス／トランス）で２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を得る方法が求められていた。 However, in the above method, the cis form of the compound is separated from the isomer mixture of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate or isomerized from the trans form to the cis form. In order to obtain a cis type, a complicated operation is required.
Therefore, from 3-hydroxy-3-mercaptomethylquinuclidine, 2-methylspiro (1,3-oxathiolane-) can be obtained at a high isomer ratio (cis / trans) without requiring isomer fractionation or isomerization. 5,3 ′) A method for obtaining quinuclidine sulfate has been demanded.
本発明の課題は、金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンハロゲン（２）を得る工程と、
前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程とを含む、
２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法によって解決される。 An object of the present invention is to mix a metal halide and an acetaldehyde compound and then further mix and react 3-hydroxy-3-mercaptomethylquinuclidine (1) to produce free 2-methylspiro (1,3- Obtaining oxathiolane-5,3 ′) quinuclidine halogen (2);
The free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3 Converting to oxathiolane-5,3 ′) quinuclidine sulfate (3),
This is solved by a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程とを含む、
２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法によって解決される。 An object of the present invention is to mix a metal halide and an acetaldehyde compound and then further mix and react 3-hydroxy-3-mercaptomethylquinuclidine (1) to produce free 2-methylspiro (1,3- Obtaining oxathiolane-5,3 ′) quinuclidine halogen (2);
The free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3 Converting to oxathiolane-5,3 ′) quinuclidine sulfate (3),
This is solved by a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
なお、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体は下記の４種類であり、シス型は下記式（３－Ｃ１）及び式（３－Ｃ２）で示され、トランス型は下記式（３－Ｔ１）及び式（３－Ｔ２）で示される。
また、異性体比率とは、トランス型に対するシス型の比率であり、シス型／トランス型で算出される。 The isomers of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate are the following four types, and the cis form is represented by the following formulas (3-C1) and (3-C2). The transformer type is represented by the following formula (3-T1) and formula (3-T2).
The isomer ratio is the ratio of cis to trans, and is calculated as cis / trans.
また、異性体比率とは、トランス型に対するシス型の比率であり、シス型／トランス型で算出される。 The isomers of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate are the following four types, and the cis form is represented by the following formulas (3-C1) and (3-C2). The transformer type is represented by the following formula (3-T1) and formula (3-T2).
The isomer ratio is the ratio of cis to trans, and is calculated as cis / trans.
本発明の一つの態様は、金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程と、前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程とを含む、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法を提供する。
In one embodiment of the present invention, after mixing a metal halide and an acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to form free 2-methylspiro (1, 3-oxathiolane-5,3 ′) quinuclidine (2), the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) and sulfuric acid at −5 to 45 ° C. Converting to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) represented by the formula (3), and contacting with 2-methylspiro (1,3-oxathiolane- 5,3 ′) A method for producing quinuclidine sulfate is provided.
別の言い方をすれば、本発明の一つの態様は、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法であって、以下の順序で、（Ｉ－ａ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）の非存在下で金属ハロゲン化物及びアセトアルデヒド化合物を混合する工程、（Ｉ－ｂ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を金属ハロゲン化物及びアセトアルデヒド化合物の混合物に更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程、並びに（ＩＩ）前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程を含む、製造方法を提供する。また、本発明の一つの態様は、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法であって、（Ｉ－ａ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）の非存在下で金属ハロゲン化物及びアセトアルデヒド化合物を混合する工程、（Ｉ－ｂ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を金属ハロゲン化物及びアセトアルデヒド化合物の混合物に更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程、並びに（ＩＩ）遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程から成る群より選択される少なくとも１つの工程、好ましくは２以上の工程を含む、製造方法にも関する。これらの製造方法に関連する本発明の態様には、例えば以下が含まれる。
In other words, one embodiment of the present invention is a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, in the following order (Ia): Mixing a metal halide and an acetaldehyde compound in the absence of 3-hydroxy-3-mercaptomethylquinuclidine (1), (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) A step of further mixing and reacting with a mixture of a metal halide and an acetaldehyde compound to obtain free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2); and (II) the free 2 -Methylspiro (1,3-oxathiolane-5,3 ') quinuclidine (2) is contacted with sulfuric acid at -5 to 45 ° C. Rusupiro (1,3-oxathiolane-5,3 ') comprising the step of converting the quinuclidine sulfate (3), to provide a manufacturing method. Another aspect of the present invention is a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, comprising (Ia) 3-hydroxy-3-mercaptomethylquinuclide. Mixing the metal halide and the acetaldehyde compound in the absence of gin (1), further adding (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) to the mixture of the metal halide and the acetaldehyde compound. Mixing and reacting to give free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2), and (II) free 2-methylspiro (1,3-oxathiolane-5, 3 ′) Contacting quinuclidine (2) with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3-oxathiolane represented by the formula (3) 5,3 ') at least one step selected from the group consisting of the step of converting the quinuclidine sulfate (3), preferably two or more steps, also relates to a manufacturing method. The aspects of the present invention related to these production methods include, for example, the following.
［態様１］金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程と、前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程とを含む、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法。
［態様２］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法であって、以下の順序で、（Ｉ－ａ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）の非存在下で金属ハロゲン化物及びアセトアルデヒド化合物を混合する工程、（Ｉ－ｂ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を金属ハロゲン化物及びアセトアルデヒド化合物の混合物に更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程、並びに（ＩＩ）前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程を含む、製造方法。
［態様３］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法であって、（Ｉ－ａ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）の非存在下で金属ハロゲン化物及びアセトアルデヒド化合物を混合する工程、（Ｉ－ｂ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を金属ハロゲン化物及びアセトアルデヒド化合物の混合物に更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程、並びに（ＩＩ）遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程から成る群より選択される少なくとも１つの工程、好ましくは２以上の工程を含む、製造方法。
［態様４］金属ハロゲン化物が金属塩化物である、上記態様１～３のいずれかに記載の製造方法。
［態様５］金属塩化物が四塩化スズ、四塩化ケイ素、四塩化チタン、五塩化アンチモン、三塩化アンチモン、三塩化アルミニウム、およびそれらの混合物から成る群より選択される、上記態様１～４のいずれかに記載の製造方法。
［態様６］アセトアルデヒド化合物がパラアルデヒドである、上記態様１～５のいずれか１つに記載の製造方法。
［態様７］３－ヒドロキシ－３－メルカプトメチルキヌクリジンを更に混合して反応させる際の反応温度が１０～６０℃である、上記態様１～６のいずれか１つに記載の製造方法。
［態様８］３－ヒドロキシ－３－メルカプトメチルキヌクリジンを更に混合して反応させる際の反応温度が３０～４５℃である、上記態様１～７のいずれか１つに記載の製造方法。
［態様９］金属ハロゲン化物及びアセトアルデヒド化合物を混合する際の温度が１５～２５℃である、上記態様１～８のいずれか１つに記載の製造方法。
［態様１０］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させる際の温度が０～３０℃である、上記態様１～９のいずれか１つに記載の製造方法。
［態様１１］遊離２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させて２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩に変換することにより得られる２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率（シス／トランス）が９２／８以上、好適には９４／６以上である、上記態様１～１０のいずれか１つに記載の製造方法。
［態様１２］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を水とケトン類との混合溶媒に溶解させた後、ケトン類を更に添加して結晶を析出させる工程を更に含む、上記態様１～１１のいずれか１つに記載の製造方法。
［態様１３］前記ケトン類がアセトンである、上記態様１２に記載の製造方法。 [Aspect 1] After mixing a metal halide and an acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane- 5,3 ′) obtaining quinuclidine (2), contacting the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) with sulfuric acid at −5 to 45 ° C., Converting to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) represented by the formula (3), and 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A method for producing quinuclidine sulfate.
[Aspect 2] A process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate in the following order: (Ia) 3-hydroxy-3-mercaptomethylquinuclidine Mixing the metal halide and acetaldehyde compound in the absence of (1), (Ib) further mixing 3-hydroxy-3-mercaptomethylquinuclidine (1) into the mixture of metal halide and acetaldehyde compound Reaction to give free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2), and (II) the free 2-methylspiro (1,3-oxathiolane-5, 3 ′) Contacting quinuclidine (2) with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3-oxathiolane-5 represented by the formula (3) 3 ') comprising the step of converting the quinuclidine sulfate (3) The production method.
[Aspect 3] A process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, wherein (Ia) 3-hydroxy-3-mercaptomethylquinuclidine (1) Mixing the metal halide and the acetaldehyde compound in the presence, (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted with the mixture of the metal halide and the acetaldehyde compound. Obtaining free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2), and (II) free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2 ) And sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine represented by the formula (3) A production method comprising at least one step selected from the group consisting of the step of converting to sulfate (3), preferably two or more steps.
[Aspect 4] The production method according to any one of Aspects 1 to 3, wherein the metal halide is a metal chloride.
[Aspect 5] The above aspect 1 to 4, wherein the metal chloride is selected from the group consisting of tin tetrachloride, silicon tetrachloride, titanium tetrachloride, antimony pentachloride, antimony trichloride, aluminum trichloride, and mixtures thereof. The manufacturing method in any one.
[Aspect 6] The production method according to any one of Aspects 1 to 5, wherein the acetaldehyde compound is paraaldehyde.
[Aspect 7] The production method according to any one of Aspects 1 to 6, wherein the reaction temperature at the time of further mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine is 10 to 60 ° C.
[Aspect 8] The production method according to any one of Aspects 1 to 7, wherein the reaction temperature at the time of further mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine is 30 to 45 ° C.
[Aspect 9] The production method according to any one of Aspects 1 to 8, wherein the temperature at the time of mixing the metal halide and the acetaldehyde compound is 15 to 25 ° C.
[Aspect 10] The temperature according to any one of Aspects 1 to 9, wherein the temperature at the time of contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is 0 to 30 ° C. Production method.
[Aspect 11] Contact with free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid to convert to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate The isomer ratio (cis / trans) of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate obtained by the above is 92/8 or more, preferably 94/6 or more. The manufacturing method according to any one of 10.
[Aspect 12] A step of dissolving 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate in a mixed solvent of water and ketones, and further adding ketones to precipitate crystals. The production method according to any one of the above aspects 1 to 11, further comprising:
[Aspect 13] The production method according to Aspect 12, wherein the ketone is acetone.
［態様３］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法であって、（Ｉ－ａ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）の非存在下で金属ハロゲン化物及びアセトアルデヒド化合物を混合する工程、（Ｉ－ｂ）３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を金属ハロゲン化物及びアセトアルデヒド化合物の混合物に更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程、並びに（ＩＩ）遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程から成る群より選択される少なくとも１つの工程、好ましくは２以上の工程を含む、製造方法。
［態様４］金属ハロゲン化物が金属塩化物である、上記態様１～３のいずれかに記載の製造方法。
［態様５］金属塩化物が四塩化スズ、四塩化ケイ素、四塩化チタン、五塩化アンチモン、三塩化アンチモン、三塩化アルミニウム、およびそれらの混合物から成る群より選択される、上記態様１～４のいずれかに記載の製造方法。
［態様６］アセトアルデヒド化合物がパラアルデヒドである、上記態様１～５のいずれか１つに記載の製造方法。
［態様７］３－ヒドロキシ－３－メルカプトメチルキヌクリジンを更に混合して反応させる際の反応温度が１０～６０℃である、上記態様１～６のいずれか１つに記載の製造方法。
［態様８］３－ヒドロキシ－３－メルカプトメチルキヌクリジンを更に混合して反応させる際の反応温度が３０～４５℃である、上記態様１～７のいずれか１つに記載の製造方法。
［態様９］金属ハロゲン化物及びアセトアルデヒド化合物を混合する際の温度が１５～２５℃である、上記態様１～８のいずれか１つに記載の製造方法。
［態様１０］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させる際の温度が０～３０℃である、上記態様１～９のいずれか１つに記載の製造方法。
［態様１１］遊離２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させて２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩に変換することにより得られる２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率（シス／トランス）が９２／８以上、好適には９４／６以上である、上記態様１～１０のいずれか１つに記載の製造方法。
［態様１２］２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を水とケトン類との混合溶媒に溶解させた後、ケトン類を更に添加して結晶を析出させる工程を更に含む、上記態様１～１１のいずれか１つに記載の製造方法。
［態様１３］前記ケトン類がアセトンである、上記態様１２に記載の製造方法。 [Aspect 1] After mixing a metal halide and an acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane- 5,3 ′) obtaining quinuclidine (2), contacting the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) with sulfuric acid at −5 to 45 ° C., Converting to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) represented by the formula (3), and 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A method for producing quinuclidine sulfate.
[Aspect 3] A process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate, wherein (Ia) 3-hydroxy-3-mercaptomethylquinuclidine (1) Mixing the metal halide and the acetaldehyde compound in the presence, (Ib) 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted with the mixture of the metal halide and the acetaldehyde compound. Obtaining free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2), and (II) free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2 ) And sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine represented by the formula (3) A production method comprising at least one step selected from the group consisting of the step of converting to sulfate (3), preferably two or more steps.
[Aspect 4] The production method according to any one of Aspects 1 to 3, wherein the metal halide is a metal chloride.
[Aspect 5] The above aspect 1 to 4, wherein the metal chloride is selected from the group consisting of tin tetrachloride, silicon tetrachloride, titanium tetrachloride, antimony pentachloride, antimony trichloride, aluminum trichloride, and mixtures thereof. The manufacturing method in any one.
[Aspect 6] The production method according to any one of Aspects 1 to 5, wherein the acetaldehyde compound is paraaldehyde.
[Aspect 7] The production method according to any one of Aspects 1 to 6, wherein the reaction temperature at the time of further mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine is 10 to 60 ° C.
[Aspect 8] The production method according to any one of Aspects 1 to 7, wherein the reaction temperature at the time of further mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine is 30 to 45 ° C.
[Aspect 9] The production method according to any one of Aspects 1 to 8, wherein the temperature at the time of mixing the metal halide and the acetaldehyde compound is 15 to 25 ° C.
[Aspect 10] The temperature according to any one of Aspects 1 to 9, wherein the temperature at the time of contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is 0 to 30 ° C. Production method.
[Aspect 11] Contact with free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid to convert to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate The isomer ratio (cis / trans) of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate obtained by the above is 92/8 or more, preferably 94/6 or more. The manufacturing method according to any one of 10.
[Aspect 12] A step of dissolving 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate in a mixed solvent of water and ketones, and further adding ketones to precipitate crystals. The production method according to any one of the above aspects 1 to 11, further comprising:
[Aspect 13] The production method according to Aspect 12, wherein the ketone is acetone.
本発明により、簡便な方法により、３－ヒドロキシ－３－メルカプトメチルキヌクリジンから、高い異性体比率（シス／トランス）で２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を得る、工業的に好適な高い異性体比率（シス／トランス）を有する２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法を提供することができる。
According to the present invention, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate is obtained from 3-hydroxy-3-mercaptomethylquinuclidine with a high isomer ratio (cis / trans) by a simple method. It is possible to provide a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate having an industrially suitable high isomer ratio (cis / trans).
本発明の製造方法は、下記のふたつの工程を含む高い異性体比率（シス／トランス）を有する２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法である。
第１工程；
金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程。
第２工程；
前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程。 The production method of the present invention is a method for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate having a high isomer ratio (cis / trans) including the following two steps.
First step;
After mixing the metal halide and the acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A step of obtaining quinuclidine (2).
Second step;
The free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3 -Oxathiolane-5,3 ') converting to quinuclidine sulfate (3).
第１工程；
金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程。
第２工程；
前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程。 The production method of the present invention is a method for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate having a high isomer ratio (cis / trans) including the following two steps.
First step;
After mixing the metal halide and the acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A step of obtaining quinuclidine (2).
Second step;
The free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3 -Oxathiolane-5,3 ') converting to quinuclidine sulfate (3).
以下、各工程を詳しく説明する。
なお、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を化合物（１）又はＱＨＴと、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を化合物（２）又はＭＳＯＱと、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）を化合物（３）又はＭＳＯＱ硫酸塩と称することもある。 Hereinafter, each process will be described in detail.
In addition, 3-hydroxy-3-mercaptomethylquinuclidine (1) is compound (1) or QHT and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is compound (2) or MSOQ and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) are sometimes referred to as compound (3) or MSOQ sulfate.
なお、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を化合物（１）又はＱＨＴと、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を化合物（２）又はＭＳＯＱと、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）を化合物（３）又はＭＳＯＱ硫酸塩と称することもある。 Hereinafter, each process will be described in detail.
In addition, 3-hydroxy-3-mercaptomethylquinuclidine (1) is compound (1) or QHT and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is compound (2) or MSOQ and 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) are sometimes referred to as compound (3) or MSOQ sulfate.
［第１工程］
本工程は、金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンハロゲン（２）を得る工程である。 [First step]
In this step, after mixing a metal halide and an acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane- 5,3 ′) A step of obtaining quinuclidine halogen (2).
本工程は、金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンハロゲン（２）を得る工程である。 [First step]
In this step, after mixing a metal halide and an acetaldehyde compound, 3-hydroxy-3-mercaptomethylquinuclidine (1) is further mixed and reacted to give free 2-methylspiro (1,3-oxathiolane- 5,3 ′) A step of obtaining quinuclidine halogen (2).
（３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１））
化合物（１）は、下記式（１）で示される化合物である。 (3-hydroxy-3-mercaptomethylquinuclidine (1))
Compound (1) is a compound represented by the following formula (1).
化合物（１）は、下記式（１）で示される化合物である。 (3-hydroxy-3-mercaptomethylquinuclidine (1))
Compound (1) is a compound represented by the following formula (1).
化合物（１）は、キヌクリジン－３－オンから公知の方法によって合成することができ、通常、異性体混合物として使用される。
Compound (1) can be synthesized from quinuclidin-3-one by a known method and is usually used as an isomer mixture.
（金属ハロゲン化物）
本工程で使用する金属ハロゲン化物は、例えば、五フッ化アンチモン、三フッ化アンチモン等の金属フッ化物；四塩化スズ、四塩化ケイ素、四塩化チタン、五塩化アンチモン、三塩化アンチモン、三塩化アルミニウム等の金属塩化物などが挙げられるが、好ましくは金属塩化物、更に好ましくは四塩化スズが用いられる。
なお、これらの金属ハロゲン化物は、単独又は二種以上を混合して使用しても良く、水和物や溶媒和物であっても良い。
上記金属ハロゲン化物以外にも、硫酸塩、硝酸塩、リン酸塩、カルボン酸塩、スルホン酸塩なども使用することができる。 (Metal halide)
The metal halide used in this step is, for example, metal fluorides such as antimony pentafluoride and antimony trifluoride; tin tetrachloride, silicon tetrachloride, titanium tetrachloride, antimony pentachloride, antimony trichloride, aluminum trichloride Metal chlorides and the like can be mentioned, but metal chlorides are preferred, and tin tetrachloride is more preferred.
These metal halides may be used alone or in combination of two or more, and may be a hydrate or a solvate.
In addition to the above metal halides, sulfates, nitrates, phosphates, carboxylates, sulfonates, and the like can also be used.
本工程で使用する金属ハロゲン化物は、例えば、五フッ化アンチモン、三フッ化アンチモン等の金属フッ化物；四塩化スズ、四塩化ケイ素、四塩化チタン、五塩化アンチモン、三塩化アンチモン、三塩化アルミニウム等の金属塩化物などが挙げられるが、好ましくは金属塩化物、更に好ましくは四塩化スズが用いられる。
なお、これらの金属ハロゲン化物は、単独又は二種以上を混合して使用しても良く、水和物や溶媒和物であっても良い。
上記金属ハロゲン化物以外にも、硫酸塩、硝酸塩、リン酸塩、カルボン酸塩、スルホン酸塩なども使用することができる。 (Metal halide)
The metal halide used in this step is, for example, metal fluorides such as antimony pentafluoride and antimony trifluoride; tin tetrachloride, silicon tetrachloride, titanium tetrachloride, antimony pentachloride, antimony trichloride, aluminum trichloride Metal chlorides and the like can be mentioned, but metal chlorides are preferred, and tin tetrachloride is more preferred.
These metal halides may be used alone or in combination of two or more, and may be a hydrate or a solvate.
In addition to the above metal halides, sulfates, nitrates, phosphates, carboxylates, sulfonates, and the like can also be used.
前記金属ハロゲン化物の使用量は、化合物（１）１モルに対して、好ましくは１～５モル、更に好ましくは２～４モルである。
この範囲とすることで、高い異性対比率、及び高い収率で化合物（２）を得ることができる。 The amount of the metal halide to be used is preferably 1 to 5 mol, more preferably 2 to 4 mol, per 1 mol of compound (1).
By setting it as this range, a compound (2) can be obtained with a high isomer pair ratio and a high yield.
この範囲とすることで、高い異性対比率、及び高い収率で化合物（２）を得ることができる。 The amount of the metal halide to be used is preferably 1 to 5 mol, more preferably 2 to 4 mol, per 1 mol of compound (1).
By setting it as this range, a compound (2) can be obtained with a high isomer pair ratio and a high yield.
（アセトアルデヒド化合物）
本工程で使用するアセトアルデヒド化合物とは、例えば、（ｉ）アセトアルデヒド（単量体）；（ｉｉ）パラアルデヒド、メタアルデヒドなどのアルデヒドの多量体；（ｉｉｉ）ジメトキシエタンおよびジエトキシエタンなどのアセタール類、ビス（ジメチルアミノ）エタンおよびビス（ジエチルアミノ）エタンなどのアミン類、またはビス（チオメトキシ）エタンおよびビス（チオエトキシ）エタンなどのチオール類で保護されたアセトアルデヒドが挙げられる。
なお、これらのアセトアルデヒド化合物は、単独又は二種以上を混合して使用しても良く、水溶液や有機溶媒溶液としても使用できる。 (Acetaldehyde compound)
Examples of the acetaldehyde compound used in this step include (i) acetaldehyde (monomer); (ii) multimers of aldehydes such as paraaldehyde and metaaldehyde; and (iii) acetals such as dimethoxyethane and diethoxyethane. And acetaldehyde protected with amines such as bis (dimethylamino) ethane and bis (diethylamino) ethane, or thiols such as bis (thiomethoxy) ethane and bis (thioethoxy) ethane.
In addition, these acetaldehyde compounds may be used individually or in mixture of 2 or more types, and can also be used as aqueous solution or an organic-solvent solution.
本工程で使用するアセトアルデヒド化合物とは、例えば、（ｉ）アセトアルデヒド（単量体）；（ｉｉ）パラアルデヒド、メタアルデヒドなどのアルデヒドの多量体；（ｉｉｉ）ジメトキシエタンおよびジエトキシエタンなどのアセタール類、ビス（ジメチルアミノ）エタンおよびビス（ジエチルアミノ）エタンなどのアミン類、またはビス（チオメトキシ）エタンおよびビス（チオエトキシ）エタンなどのチオール類で保護されたアセトアルデヒドが挙げられる。
なお、これらのアセトアルデヒド化合物は、単独又は二種以上を混合して使用しても良く、水溶液や有機溶媒溶液としても使用できる。 (Acetaldehyde compound)
Examples of the acetaldehyde compound used in this step include (i) acetaldehyde (monomer); (ii) multimers of aldehydes such as paraaldehyde and metaaldehyde; and (iii) acetals such as dimethoxyethane and diethoxyethane. And acetaldehyde protected with amines such as bis (dimethylamino) ethane and bis (diethylamino) ethane, or thiols such as bis (thiomethoxy) ethane and bis (thioethoxy) ethane.
In addition, these acetaldehyde compounds may be used individually or in mixture of 2 or more types, and can also be used as aqueous solution or an organic-solvent solution.
前記アルデヒド化合物の使用量は、化合物（１）１モルに対して、アセトアルデヒド基準で、好ましくは１～１０モル、更に好ましくは１～６モル、より好ましくは２～４モルである。
この範囲とすることで、化合物（２）を収率良く得ることが出来る。 The amount of the aldehyde compound to be used is preferably 1 to 10 mol, more preferably 1 to 6 mol, more preferably 2 to 4 mol, based on acetaldehyde, relative to 1 mol of compound (1).
By setting it as this range, a compound (2) can be obtained with a sufficient yield.
この範囲とすることで、化合物（２）を収率良く得ることが出来る。 The amount of the aldehyde compound to be used is preferably 1 to 10 mol, more preferably 1 to 6 mol, more preferably 2 to 4 mol, based on acetaldehyde, relative to 1 mol of compound (1).
By setting it as this range, a compound (2) can be obtained with a sufficient yield.
（溶媒）
本工程では、溶媒を使用することによって、反応液の均一性や攪拌性を向上させることができる。使用できる溶媒としては、反応を阻害しないものならば特に限定されず、例えば、水；メタノール、エタノール、イソプロピルアルコール、ｔ－ブチルアルコールなどのアルコール類；ピリジン、キノリンなどの複素環式アミン類；アセトン、メチルエチルケトン、メチルイソブチルケトンなどのケトン類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドンなどのアミド類；Ｎ，Ｎ’－ジメチルイミダゾリジノンなどの尿素類；ジメチルスルホキシドなどのスルホキシド類；スルホランなどのスルホン類；アセトニトリル、プロピオニトリルなどのニトリル類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル類；ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；酢酸メチル、酢酸エチル、酢酸ブチルなどのエステル類；ジクロロメタン、クロロホルム、ジクロロエタンなどのハロゲン化炭化水素類が挙げられるが、好ましくは芳香族炭化水素類、エステル類、ハロゲン化炭化水素類、更に好ましくはトルエン、酢酸エチル、ジクロロメタン、クロロホルムが使用される。
なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。 (solvent)
In this step, the uniformity and stirring properties of the reaction solution can be improved by using a solvent. Solvents that can be used are not particularly limited as long as they do not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol; heterocyclic amines such as pyridine and quinoline; acetone , Ketones such as methyl ethyl ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; dimethyl sulfoxide Sulfones such as sulfolane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aroma such as benzene, toluene and xylene Aromatic hydrocarbons; esters such as methyl acetate, ethyl acetate, and butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like, preferably aromatic hydrocarbons, esters, and halogenated hydrocarbons More preferably, toluene, ethyl acetate, dichloromethane, chloroform are used.
In addition, you may use these solvents individually or in mixture of 2 or more types.
本工程では、溶媒を使用することによって、反応液の均一性や攪拌性を向上させることができる。使用できる溶媒としては、反応を阻害しないものならば特に限定されず、例えば、水；メタノール、エタノール、イソプロピルアルコール、ｔ－ブチルアルコールなどのアルコール類；ピリジン、キノリンなどの複素環式アミン類；アセトン、メチルエチルケトン、メチルイソブチルケトンなどのケトン類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドンなどのアミド類；Ｎ，Ｎ’－ジメチルイミダゾリジノンなどの尿素類；ジメチルスルホキシドなどのスルホキシド類；スルホランなどのスルホン類；アセトニトリル、プロピオニトリルなどのニトリル類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル類；ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；酢酸メチル、酢酸エチル、酢酸ブチルなどのエステル類；ジクロロメタン、クロロホルム、ジクロロエタンなどのハロゲン化炭化水素類が挙げられるが、好ましくは芳香族炭化水素類、エステル類、ハロゲン化炭化水素類、更に好ましくはトルエン、酢酸エチル、ジクロロメタン、クロロホルムが使用される。
なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。 (solvent)
In this step, the uniformity and stirring properties of the reaction solution can be improved by using a solvent. Solvents that can be used are not particularly limited as long as they do not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol; heterocyclic amines such as pyridine and quinoline; acetone , Ketones such as methyl ethyl ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; dimethyl sulfoxide Sulfones such as sulfolane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aroma such as benzene, toluene and xylene Aromatic hydrocarbons; esters such as methyl acetate, ethyl acetate, and butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like, preferably aromatic hydrocarbons, esters, and halogenated hydrocarbons More preferably, toluene, ethyl acetate, dichloromethane, chloroform are used.
In addition, you may use these solvents individually or in mixture of 2 or more types.
前記溶媒の使用量は、化合物（１）１ｇに対して、好ましくは１～３０ｍＬ、更に好ましく５～１５ｍＬである。
この範囲とすることで、反応液の均一性や攪拌性を担保し、高い異性体比率で化合物（２）を得ることができる。 The amount of the solvent to be used is preferably 1 to 30 mL, more preferably 5 to 15 mL, per 1 g of compound (1).
By setting it as this range, the uniformity and stirring property of a reaction liquid are ensured, and a compound (2) can be obtained with a high isomer ratio.
この範囲とすることで、反応液の均一性や攪拌性を担保し、高い異性体比率で化合物（２）を得ることができる。 The amount of the solvent to be used is preferably 1 to 30 mL, more preferably 5 to 15 mL, per 1 g of compound (1).
By setting it as this range, the uniformity and stirring property of a reaction liquid are ensured, and a compound (2) can be obtained with a high isomer ratio.
（本工程の反応）
本工程の反応は、金属ハロゲン化物及びアセトアルデヒド化合物、必要に応じて溶媒を混合した後に、化合物（１）を更に混合して反応させることで、後処理後、遊離の化合物（２）を得ることができる。
この順序（金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に化合物（１）を混合）で混合して反応させることで、固形物の発生を抑制して部分的な加熱による異性体比率の低下や、副反応の発生を抑止することができる。
なお、本発明の効果を損なわない程度において、金属ハロゲン化物やアセトアルデヒド化合物を、化合物（１）を混合した後に、更に加えて反応させることもできる。 (Reaction in this process)
The reaction in this step is to obtain a free compound (2) after the post-treatment by further mixing and reacting the compound (1) after mixing a metal halide and an acetaldehyde compound and, if necessary, a solvent. Can do.
By mixing and reacting in this order (mixing the metal halide and the acetaldehyde compound and then mixing the compound (1)), the generation of solids is suppressed and the isomer ratio is reduced due to partial heating. Generation of reaction can be suppressed.
In addition, the metal halide or the acetaldehyde compound can be further added and reacted after mixing the compound (1) to the extent that the effects of the present invention are not impaired.
本工程の反応は、金属ハロゲン化物及びアセトアルデヒド化合物、必要に応じて溶媒を混合した後に、化合物（１）を更に混合して反応させることで、後処理後、遊離の化合物（２）を得ることができる。
この順序（金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に化合物（１）を混合）で混合して反応させることで、固形物の発生を抑制して部分的な加熱による異性体比率の低下や、副反応の発生を抑止することができる。
なお、本発明の効果を損なわない程度において、金属ハロゲン化物やアセトアルデヒド化合物を、化合物（１）を混合した後に、更に加えて反応させることもできる。 (Reaction in this process)
The reaction in this step is to obtain a free compound (2) after the post-treatment by further mixing and reacting the compound (1) after mixing a metal halide and an acetaldehyde compound and, if necessary, a solvent. Can do.
By mixing and reacting in this order (mixing the metal halide and the acetaldehyde compound and then mixing the compound (1)), the generation of solids is suppressed and the isomer ratio is reduced due to partial heating. Generation of reaction can be suppressed.
In addition, the metal halide or the acetaldehyde compound can be further added and reacted after mixing the compound (1) to the extent that the effects of the present invention are not impaired.
（反応温度、反応圧力）
本工程の反応温度は、好ましくは１０～６０℃、更に好ましくは２０～５０℃、より好ましくは３０～４５℃である。
この範囲とすることで、反応液の良好な攪拌性を維持しつつ、高い異性体比率で、収率良く化合物（２）を得ることができる。
本工程の圧力は特に制限されず、通常、常圧下で行われる。 (Reaction temperature, reaction pressure)
The reaction temperature in this step is preferably 10 to 60 ° C, more preferably 20 to 50 ° C, more preferably 30 to 45 ° C.
By setting it as this range, a compound (2) can be obtained with a high isomer ratio and a high yield, maintaining the favorable stirring property of a reaction liquid.
The pressure in this step is not particularly limited, and is usually performed under normal pressure.
本工程の反応温度は、好ましくは１０～６０℃、更に好ましくは２０～５０℃、より好ましくは３０～４５℃である。
この範囲とすることで、反応液の良好な攪拌性を維持しつつ、高い異性体比率で、収率良く化合物（２）を得ることができる。
本工程の圧力は特に制限されず、通常、常圧下で行われる。 (Reaction temperature, reaction pressure)
The reaction temperature in this step is preferably 10 to 60 ° C, more preferably 20 to 50 ° C, more preferably 30 to 45 ° C.
By setting it as this range, a compound (2) can be obtained with a high isomer ratio and a high yield, maintaining the favorable stirring property of a reaction liquid.
The pressure in this step is not particularly limited, and is usually performed under normal pressure.
本工程で得られた化合物（２）は、特に単離・精製することなく次の工程（第２工程）で使用しても良いが、必要に応じて中和、抽出、濾過、洗浄、再結晶、晶析などの処理を経た後に次の工程に使用することもできる。
これらの処理をすることで、次の工程の反応の煩雑さを抑制することができる。
なお、本工程における反応終了時の後処理をより簡便とするために、適宜、アルコールなどの親水性媒体を添加しても良い。 The compound (2) obtained in this step may be used in the next step (second step) without any particular isolation / purification, but may be neutralized, extracted, filtered, washed, re-used as necessary. It can also be used in the next step after undergoing treatment such as crystallization and crystallization.
By performing these treatments, the complexity of the reaction in the next step can be suppressed.
In order to make the post-treatment at the end of the reaction in this step easier, a hydrophilic medium such as alcohol may be added as appropriate.
これらの処理をすることで、次の工程の反応の煩雑さを抑制することができる。
なお、本工程における反応終了時の後処理をより簡便とするために、適宜、アルコールなどの親水性媒体を添加しても良い。 The compound (2) obtained in this step may be used in the next step (second step) without any particular isolation / purification, but may be neutralized, extracted, filtered, washed, re-used as necessary. It can also be used in the next step after undergoing treatment such as crystallization and crystallization.
By performing these treatments, the complexity of the reaction in the next step can be suppressed.
In order to make the post-treatment at the end of the reaction in this step easier, a hydrophilic medium such as alcohol may be added as appropriate.
なお、このとき化合物（２）は金属ハロゲン化物と錯形成していると考えられるが、例えば、水、塩基、酸を用いた後処理を行うことにより、遊離の化合物（２）を得ることができる。
At this time, the compound (2) is considered to be complexed with the metal halide, but the free compound (2) can be obtained by, for example, post-treatment using water, base, or acid. it can.
［第２工程］
本発明の第２工程は、第１工程で得られた前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程である。 [Second step]
In the second step of the present invention, the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) obtained in the first step is contacted with sulfuric acid at −5 to 45 ° C. This is a step of converting to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) represented by the formula (3).
本発明の第２工程は、第１工程で得られた前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程である。 [Second step]
In the second step of the present invention, the free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) obtained in the first step is contacted with sulfuric acid at −5 to 45 ° C. This is a step of converting to 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (3) represented by the formula (3).
本工程では、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（化合物（２））と硫酸とを－５～４５℃で接触させることによって行われる。
なお、反応で生成する２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと金属ハロゲン化物との錯体を塩基と反応させるなどの後処理を行い、遊離のシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンを得た後に、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させる方法を採用することもできる。 This step is carried out by bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (compound (2)) into contact with sulfuric acid at −5 to 45 ° C.
A post-treatment such as reacting a complex of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and a metal halide produced by the reaction with a base to give free cis-type 2-methylspiro (1 , 3-oxathiolane-5,3 ′) quinuclidine, and then contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine with sulfuric acid may be employed.
なお、反応で生成する２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと金属ハロゲン化物との錯体を塩基と反応させるなどの後処理を行い、遊離のシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンを得た後に、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させる方法を採用することもできる。 This step is carried out by bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (compound (2)) into contact with sulfuric acid at −5 to 45 ° C.
A post-treatment such as reacting a complex of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and a metal halide produced by the reaction with a base to give free cis-type 2-methylspiro (1 , 3-oxathiolane-5,3 ′) quinuclidine, and then contacting 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine with sulfuric acid may be employed.
（硫酸）
本工程で使用する硫酸は一般的に市販されるものを使用することができ、その濃度は特に制限されない。
硫酸の使用量は、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を十分に得ることができる量であれば、特に制限されないが、化合物（２）１モルに対して、好ましくは０．５～１０モル、更に好ましくは０．６～５モル、より好ましくは０．８～２モルである。
この範囲とすることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンから２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩をほぼ定量的に得ることができる。 (Sulfuric acid)
As the sulfuric acid used in this step, commercially available one can be used, and its concentration is not particularly limited.
The amount of sulfuric acid used is not particularly limited as long as 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained sufficiently, but with respect to 1 mol of compound (2). The amount is preferably 0.5 to 10 mol, more preferably 0.6 to 5 mol, more preferably 0.8 to 2 mol.
By setting this range, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained almost quantitatively from 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine. it can.
本工程で使用する硫酸は一般的に市販されるものを使用することができ、その濃度は特に制限されない。
硫酸の使用量は、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を十分に得ることができる量であれば、特に制限されないが、化合物（２）１モルに対して、好ましくは０．５～１０モル、更に好ましくは０．６～５モル、より好ましくは０．８～２モルである。
この範囲とすることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンから２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩をほぼ定量的に得ることができる。 (Sulfuric acid)
As the sulfuric acid used in this step, commercially available one can be used, and its concentration is not particularly limited.
The amount of sulfuric acid used is not particularly limited as long as 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained sufficiently, but with respect to 1 mol of compound (2). The amount is preferably 0.5 to 10 mol, more preferably 0.6 to 5 mol, more preferably 0.8 to 2 mol.
By setting this range, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained almost quantitatively from 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine. it can.
（本工程の反応）
本工程は、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させるなどの方法によって化合物（３）を得ることができるが、好ましくは液温を－５～４５℃に維持しながら遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させて、同温度で反応させて化合物（３）を生成させる。
この範囲とすることで、収率良く２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を反応液から取得（単離）することができる。 (Reaction in this process)
In this step, compound (3) can be obtained by a method such as bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine into contact with sulfuric acid, but preferably the liquid temperature is −5. While maintaining at ˜45 ° C., free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine is contacted with sulfuric acid and reacted at the same temperature to produce compound (3).
By setting it within this range, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained (isolated) from the reaction solution with good yield.
本工程は、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させるなどの方法によって化合物（３）を得ることができるが、好ましくは液温を－５～４５℃に維持しながら遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンと硫酸とを接触させて、同温度で反応させて化合物（３）を生成させる。
この範囲とすることで、収率良く２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を反応液から取得（単離）することができる。 (Reaction in this process)
In this step, compound (3) can be obtained by a method such as bringing free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine into contact with sulfuric acid, but preferably the liquid temperature is −5. While maintaining at ˜45 ° C., free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine is contacted with sulfuric acid and reacted at the same temperature to produce compound (3).
By setting it within this range, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained (isolated) from the reaction solution with good yield.
（反応温度、反応圧力）
遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン及び硫酸との接触温度は、好ましくは－５～４５℃であり、より好ましくは０～３０℃である。その際の圧力は特に制限されない。 (Reaction temperature, reaction pressure)
The contact temperature with free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is preferably −5 to 45 ° C., more preferably 0 to 30 ° C. The pressure at that time is not particularly limited.
遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン及び硫酸との接触温度は、好ましくは－５～４５℃であり、より好ましくは０～３０℃である。その際の圧力は特に制限されない。 (Reaction temperature, reaction pressure)
The contact temperature with free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine and sulfuric acid is preferably −5 to 45 ° C., more preferably 0 to 30 ° C. The pressure at that time is not particularly limited.
有機溶媒は、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンを溶解できるものであれば特に限定されず、例えば、メタノール、エタノール、イソプロピルアルコール、ｔ－ブチルアルコールなどのアルコール類；ペンタン、ヘキサン、ヘプタン、シクロヘキサンなどの脂肪族炭化水素類；塩化メチレン、クロロホルムなどのハロゲン化脂肪族炭化水素類；ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；クロロベンゼン、ジクロロベンゼンなどのハロゲン化芳香族炭化水素類；酢酸メチル、酢酸エチル、酢酸イソプロピル、酢酸ブチル、カプロラクトンなどのエステル類；アセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン、シクロヘキサノンなどのケトン類；ジエチルエーテル、ｔ－ブチルメチルエーテル、シクロペンチルメチルエーテル、ジメトキシエタン、テトラヒドロフラン、ジオキサン、アニソールなどのエーテル類が挙げられるが、好ましくはアセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン、シクロヘキサノンなどのケトン類；更に好ましくはアセトンが使用される。
なお、これらの有機溶媒は、単独又は二種以上を混合して用いても良い。 The organic solvent is not particularly limited as long as it can dissolve free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine, and examples thereof include alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol. Aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; Halogenated aliphatic hydrocarbons such as methylene chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Chlorobenzene and dichlorobenzene Halogenated aromatic hydrocarbons; Esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and caprolactone; Ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and cyclohexanone; Diethyl ether , T-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane, anisole and the like, preferably ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, cyclohexanone; more preferably Acetone is used.
In addition, you may use these organic solvents individually or in mixture of 2 or more types.
なお、これらの有機溶媒は、単独又は二種以上を混合して用いても良い。 The organic solvent is not particularly limited as long as it can dissolve free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine, and examples thereof include alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol. Aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; Halogenated aliphatic hydrocarbons such as methylene chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Chlorobenzene and dichlorobenzene Halogenated aromatic hydrocarbons; Esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and caprolactone; Ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and cyclohexanone; Diethyl ether , T-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane, anisole and the like, preferably ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, cyclohexanone; more preferably Acetone is used.
In addition, you may use these organic solvents individually or in mixture of 2 or more types.
前記有機溶媒の使用量は、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンを実質的に完全に溶解できる量であれば特に制限されないが、化合物（２）１ｇに対して、好ましくは１～５０ｍＬ、更に好ましくは２～３０ｍＬである。
The amount of the organic solvent used is not particularly limited as long as it can dissolve 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine substantially completely, but with respect to 1 g of compound (2), The amount is preferably 1 to 50 mL, more preferably 2 to 30 mL.
本工程で得られる化合物（３）は、例えば、中和、抽出、濾過、洗浄、再結晶、晶析などの一般的な方法により単離・精製することができる。
なお、化合物（３）中に少量の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（２：１）が混入していても構わない。 The compound (3) obtained in this step can be isolated and purified by a general method such as neutralization, extraction, filtration, washing, recrystallization, and crystallization.
A small amount of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (2: 1) may be mixed in the compound (3).
なお、化合物（３）中に少量の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（２：１）が混入していても構わない。 The compound (3) obtained in this step can be isolated and purified by a general method such as neutralization, extraction, filtration, washing, recrystallization, and crystallization.
A small amount of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (2: 1) may be mixed in the compound (3).
本発明の第１工程及び第２工程を通じて得られる２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩は、異性体比率（シス／トランス）が９２／８以上、好適には９４／６以上である。
The 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate obtained through the first and second steps of the present invention has an isomer ratio (cis / trans) of 92/8 or more, preferably 94/6 or more.
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩は、適当な溶媒に溶解させて再結晶することで、更に異性体比率を向上させることができる。
その際の好適な実施態様は、例えば、水とケトン類との混合溶媒に溶解させた後、ケトン類を更に添加して結晶を析出させる方法である。
なお、当該混合溶媒の量や組成比は、目的物の取得量や精製効率に応じて、適宜調整することができる。 The obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be further crystallized by dissolving in an appropriate solvent and recrystallizing.
A suitable embodiment in that case is, for example, a method of dissolving crystals in a mixed solvent of water and ketones and further adding ketones to precipitate crystals.
The amount and composition ratio of the mixed solvent can be appropriately adjusted according to the amount of the target product obtained and the purification efficiency.
その際の好適な実施態様は、例えば、水とケトン類との混合溶媒に溶解させた後、ケトン類を更に添加して結晶を析出させる方法である。
なお、当該混合溶媒の量や組成比は、目的物の取得量や精製効率に応じて、適宜調整することができる。 The obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be further crystallized by dissolving in an appropriate solvent and recrystallizing.
A suitable embodiment in that case is, for example, a method of dissolving crystals in a mixed solvent of water and ketones and further adding ketones to precipitate crystals.
The amount and composition ratio of the mixed solvent can be appropriately adjusted according to the amount of the target product obtained and the purification efficiency.
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
実施例１（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、パラアセトアルデヒド１５．３ｇ（アセトアルデヒドとして３４６ｍｍｏｌ）及び塩化メチレン１００ｍＬとを混合した後、混合液を１５～２５℃に維持しながら塩化スズ（ＩＶ）９０．２ｇ（３４６ｍｍｏｌ）を加えた。
次いで、液温を３０～４０℃に保ちながら、３－ヒドロキシ－３－メルカプトメチルキヌクリジン２０ｇ（１１５ｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３時間反応させた。更に、反応液に４ｍｏｌ／Ｌ塩酸２８．９ｍＬ（１１５ｍｍｏｌ）及びトルエン１００ｍＬを加え、攪拌しながら同温度で１５時間反応させた。
反応終了後、反応液を濃縮した後、濃縮物に水１００ｍＬを加えた後、水酸化ナトリウム３９５ｇ（３．２ｍｏｌ）及びトルエン１００ｍＬと混合した。この混合液から有機層を取り出し、塩化ナトリウム水溶液で洗浄した後に有機層を濃縮した。得られた濃縮物をアセトン２００ｍＬに溶解させて、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン２１．６ｇを含有する有機溶媒溶液１７７．２９ｇを得た。 Example 1 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
After mixing paraacetaldehyde (15.3 g) (346 mmol as acetaldehyde) and methylene chloride (100 mL) in a 200 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 15 to 25 ° C. 90.2 g (346 mmol) of tin (IV) chloride was added.
Next, 20 g (115 mol) of 3-hydroxy-3-mercaptomethylquinuclidine was slowly added while maintaining the liquid temperature at 30 to 40 ° C., and the mixture was reacted at the same temperature for 3 hours while stirring. Furthermore, 28.9 mL (115 mmol) of 4 mol / L hydrochloric acid and 100 mL of toluene were added to the reaction solution, and reacted at the same temperature for 15 hours while stirring.
After completion of the reaction, the reaction mixture was concentrated, 100 mL of water was added to the concentrate, and then mixed with 395 g (3.2 mol) of sodium hydroxide and 100 mL of toluene. The organic layer was taken out from the mixed solution, washed with an aqueous sodium chloride solution, and then concentrated. The obtained concentrate was dissolved in 200 mL of acetone to obtain 177.29 g of an organic solvent solution containing 21.6 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine.
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、パラアセトアルデヒド１５．３ｇ（アセトアルデヒドとして３４６ｍｍｏｌ）及び塩化メチレン１００ｍＬとを混合した後、混合液を１５～２５℃に維持しながら塩化スズ（ＩＶ）９０．２ｇ（３４６ｍｍｏｌ）を加えた。
次いで、液温を３０～４０℃に保ちながら、３－ヒドロキシ－３－メルカプトメチルキヌクリジン２０ｇ（１１５ｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３時間反応させた。更に、反応液に４ｍｏｌ／Ｌ塩酸２８．９ｍＬ（１１５ｍｍｏｌ）及びトルエン１００ｍＬを加え、攪拌しながら同温度で１５時間反応させた。
反応終了後、反応液を濃縮した後、濃縮物に水１００ｍＬを加えた後、水酸化ナトリウム３９５ｇ（３．２ｍｏｌ）及びトルエン１００ｍＬと混合した。この混合液から有機層を取り出し、塩化ナトリウム水溶液で洗浄した後に有機層を濃縮した。得られた濃縮物をアセトン２００ｍＬに溶解させて、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン２１．６ｇを含有する有機溶媒溶液１７７．２９ｇを得た。 Example 1 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
After mixing paraacetaldehyde (15.3 g) (346 mmol as acetaldehyde) and methylene chloride (100 mL) in a 200 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 15 to 25 ° C. 90.2 g (346 mmol) of tin (IV) chloride was added.
Next, 20 g (115 mol) of 3-hydroxy-3-mercaptomethylquinuclidine was slowly added while maintaining the liquid temperature at 30 to 40 ° C., and the mixture was reacted at the same temperature for 3 hours while stirring. Furthermore, 28.9 mL (115 mmol) of 4 mol / L hydrochloric acid and 100 mL of toluene were added to the reaction solution, and reacted at the same temperature for 15 hours while stirring.
After completion of the reaction, the reaction mixture was concentrated, 100 mL of water was added to the concentrate, and then mixed with 395 g (3.2 mol) of sodium hydroxide and 100 mL of toluene. The organic layer was taken out from the mixed solution, washed with an aqueous sodium chloride solution, and then concentrated. The obtained concentrate was dissolved in 200 mL of acetone to obtain 177.29 g of an organic solvent solution containing 21.6 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine.
［第２工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、前記工程で得られた有機溶媒溶液８８．７ｇ（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４６ｍｍｏｌ含有）を加え、液温を０℃付近に維持しながら、９７％硫酸４．７ｇ（４６ｍｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩１２．６ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；７３％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、９６．８／３．２であった。 [Second step]
The organic solvent solution 88.7 g (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was 46 mmol in a 200 mL internal volume container equipped with a stirrer, a thermometer and a reflux condenser. While maintaining the liquid temperature at around 0 ° C., 4.7 g (46 mmol) of 97% sulfuric acid was slowly added and reacted at the same temperature for 30 minutes while stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 12.6 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 73%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 96.8 / 3.2.
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、前記工程で得られた有機溶媒溶液８８．７ｇ（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４６ｍｍｏｌ含有）を加え、液温を０℃付近に維持しながら、９７％硫酸４．７ｇ（４６ｍｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩１２．６ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；７３％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、９６．８／３．２であった。 [Second step]
The organic solvent solution 88.7 g (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was 46 mmol in a 200 mL internal volume container equipped with a stirrer, a thermometer and a reflux condenser. While maintaining the liquid temperature at around 0 ° C., 4.7 g (46 mmol) of 97% sulfuric acid was slowly added and reacted at the same temperature for 30 minutes while stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 12.6 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 73%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 96.8 / 3.2.
得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の物性値は下記の通りであった。
１Ｈ－ＮＭＲ（Ｄ２Ｏ，δ（ｐｐｍ））：１．５７～１．５８（ｍ，３Ｈ）、１．８３～２．２０（ｍ，４Ｈ）、２．４７～２．４８（ｍ，１Ｈ）、３．０５～３．０８（ｍ，１Ｈ）、３．２６～３．５４（ｍ，７Ｈ）、５．２５～５．３０（ｍ，１Ｈ）
元素分析（％）：炭素４０．３７％（理論値４０．３９％）、水素６．２５％（理論値６．４４％）、窒素４．６８％（理論値４．７１％）、酸素２７．２０％（理論値２６．９０％） The physical properties of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate were as follows.
1 H-NMR (D 2 O, δ (ppm)): 1.57 to 1.58 (m, 3H), 1.83 to 2.20 (m, 4H), 2.47 to 2.48 (m , 1H), 3.05 to 3.08 (m, 1H), 3.26 to 3.54 (m, 7H), 5.25 to 5.30 (m, 1H)
Elemental analysis (%): carbon 40.37% (theoretical value 40.39%), hydrogen 6.25% (theoretical value 6.44%), nitrogen 4.68% (theoretical value 4.71%), oxygen 27 20% (theoretical value 26.90%)
１Ｈ－ＮＭＲ（Ｄ２Ｏ，δ（ｐｐｍ））：１．５７～１．５８（ｍ，３Ｈ）、１．８３～２．２０（ｍ，４Ｈ）、２．４７～２．４８（ｍ，１Ｈ）、３．０５～３．０８（ｍ，１Ｈ）、３．２６～３．５４（ｍ，７Ｈ）、５．２５～５．３０（ｍ，１Ｈ）
元素分析（％）：炭素４０．３７％（理論値４０．３９％）、水素６．２５％（理論値６．４４％）、窒素４．６８％（理論値４．７１％）、酸素２７．２０％（理論値２６．９０％） The physical properties of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate were as follows.
1 H-NMR (D 2 O, δ (ppm)): 1.57 to 1.58 (m, 3H), 1.83 to 2.20 (m, 4H), 2.47 to 2.48 (m , 1H), 3.05 to 3.08 (m, 1H), 3.26 to 3.54 (m, 7H), 5.25 to 5.30 (m, 1H)
Elemental analysis (%): carbon 40.37% (theoretical value 40.39%), hydrogen 6.25% (theoretical value 6.44%), nitrogen 4.68% (theoretical value 4.71%), oxygen 27 20% (theoretical value 26.90%)
比較例１（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの合成）
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、塩化スズ（ＩＶ）２２．５ｇ（８６．４ｍｍｏｌ）及び塩化メチレン２５ｍＬを混合した後、混合液を１５～２５℃に維持しながら３－ヒドロキシ－３－メルカプトメチルキヌクリジン５ｇ（２８．９ｍｍｏｌ）を加えた。
次いで、液温を３０～４０℃に保ちながら、パラアセトアルデヒド３．８１ｇ（アセトアルデヒドとして２８．８ｍｍｏｌ）をゆるやかに加えたところ、混合液の粘性が高くなり攪拌が困難になるとともに、大量の固形物が発生し、続く反応を行うことができなかった。 Comparative Example 1 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine)
[First step]
After mixing 22.5 g (86.4 mmol) of tin (IV) chloride and 25 mL of methylene chloride in a 100 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 15 to 25 ° C. Then, 5 g (28.9 mmol) of 3-hydroxy-3-mercaptomethylquinuclidine was added.
Next, 3.81 g (28.8 mmol as acetaldehyde) of paraacetaldehyde was slowly added while maintaining the liquid temperature at 30 to 40 ° C., and the viscosity of the liquid mixture became high and stirring became difficult. Occurred and the subsequent reaction could not be performed.
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、塩化スズ（ＩＶ）２２．５ｇ（８６．４ｍｍｏｌ）及び塩化メチレン２５ｍＬを混合した後、混合液を１５～２５℃に維持しながら３－ヒドロキシ－３－メルカプトメチルキヌクリジン５ｇ（２８．９ｍｍｏｌ）を加えた。
次いで、液温を３０～４０℃に保ちながら、パラアセトアルデヒド３．８１ｇ（アセトアルデヒドとして２８．８ｍｍｏｌ）をゆるやかに加えたところ、混合液の粘性が高くなり攪拌が困難になるとともに、大量の固形物が発生し、続く反応を行うことができなかった。 Comparative Example 1 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine)
[First step]
After mixing 22.5 g (86.4 mmol) of tin (IV) chloride and 25 mL of methylene chloride in a 100 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 15 to 25 ° C. Then, 5 g (28.9 mmol) of 3-hydroxy-3-mercaptomethylquinuclidine was added.
Next, 3.81 g (28.8 mmol as acetaldehyde) of paraacetaldehyde was slowly added while maintaining the liquid temperature at 30 to 40 ° C., and the viscosity of the liquid mixture became high and stirring became difficult. Occurred and the subsequent reaction could not be performed.
比較例２（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン４ｇ（２３．１ｍｍｏｌ）、パラアルデヒド３．１１ｇ（アセトアルデヒドとして２３．２ｍｍｏｌ）及び塩化メチレン２０ｍＬを混合した。
次いで、液温を３０～４０℃に保ちながら、塩化スズ（ＩＶ）１７．８ｇ（６８．４ｍｍｏｌ）をゆるやかに加えたところ、混合液の粘性が高くなり攪拌が困難になるとともに、大量の固形物が発生し、続く反応を行うことができなかった。 Comparative Example 2 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
In a container having a volume of 100 mL equipped with a stirrer, a thermometer and a reflux condenser, 4-g (23.1 mmol) 3-hydroxy-3-mercaptomethylquinuclidine, 3.11 g paraaldehyde (23.2 mmol as acetaldehyde) and 20 mL of methylene chloride was mixed.
Next, when 17.8 g (68.4 mmol) of tin (IV) chloride was slowly added while maintaining the liquid temperature at 30 to 40 ° C., the viscosity of the mixed liquid became high and stirring became difficult, and a large amount of solids A product was generated and the subsequent reaction could not be performed.
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン４ｇ（２３．１ｍｍｏｌ）、パラアルデヒド３．１１ｇ（アセトアルデヒドとして２３．２ｍｍｏｌ）及び塩化メチレン２０ｍＬを混合した。
次いで、液温を３０～４０℃に保ちながら、塩化スズ（ＩＶ）１７．８ｇ（６８．４ｍｍｏｌ）をゆるやかに加えたところ、混合液の粘性が高くなり攪拌が困難になるとともに、大量の固形物が発生し、続く反応を行うことができなかった。 Comparative Example 2 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
In a container having a volume of 100 mL equipped with a stirrer, a thermometer and a reflux condenser, 4-g (23.1 mmol) 3-hydroxy-3-mercaptomethylquinuclidine, 3.11 g paraaldehyde (23.2 mmol as acetaldehyde) and 20 mL of methylene chloride was mixed.
Next, when 17.8 g (68.4 mmol) of tin (IV) chloride was slowly added while maintaining the liquid temperature at 30 to 40 ° C., the viscosity of the mixed liquid became high and stirring became difficult, and a large amount of solids A product was generated and the subsequent reaction could not be performed.
実施例２（シス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
実施例１と同様な方法により、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン４．０１ｇを含有する有機溶媒溶液３５．７ｇを得た。 Example 2 (Synthesis of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
In the same manner as in Example 1, 35.7 g of an organic solvent solution containing 4.01 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained.
［第１工程］
実施例１と同様な方法により、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン４．０１ｇを含有する有機溶媒溶液３５．７ｇを得た。 Example 2 (Synthesis of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
In the same manner as in Example 1, 35.7 g of an organic solvent solution containing 4.01 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained.
［第２工程］
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、前記工程で得られた有機溶媒溶液３５．７ｇ（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２０．１ｍｍｏｌ含有）を加え、液温を２０～３０℃に維持しながら、９７％硫酸１．９７ｇ（１９．５ｍｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩４．１２ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；６０％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、９８．２／１．８であった。 [Second step]
In a container having a volume of 100 mL equipped with a stirrer, a thermometer and a reflux condenser, 35.7 g (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was charged with 205.7 g of the organic solvent solution. While maintaining the liquid temperature at 20 to 30 ° C., 1.97 g (19.5 mmol) of 97% sulfuric acid was slowly added and reacted at the same temperature for 30 minutes while stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 4.12 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 60%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 98.2 / 1.8.
攪拌装置、温度計及び還流冷却器を備えた内容積１００ｍＬの容器に、前記工程で得られた有機溶媒溶液３５．７ｇ（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２０．１ｍｍｏｌ含有）を加え、液温を２０～３０℃に維持しながら、９７％硫酸１．９７ｇ（１９．５ｍｍｏｌ）をゆるやかに加え、攪拌しながら同温度で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩４．１２ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；６０％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、９８．２／１．８であった。 [Second step]
In a container having a volume of 100 mL equipped with a stirrer, a thermometer and a reflux condenser, 35.7 g (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was charged with 205.7 g of the organic solvent solution. While maintaining the liquid temperature at 20 to 30 ° C., 1.97 g (19.5 mmol) of 97% sulfuric acid was slowly added and reacted at the same temperature for 30 minutes while stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 4.12 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 60%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 98.2 / 1.8.
比較例３（シス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクジン硫酸塩の合成）
［第１工程］
実施例１と同様な方法により、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン４．６１ｇを含有する有機溶媒溶液３０ｇを得た。
［第２工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、前記工程で得られた有機溶媒溶液３０ｇ（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１５．３ｍｍｏｌ含有）を加え、液温を０～５℃に維持しながら、９７％硫酸１．９７ｇ（１９．５ｍｍｏｌ）をゆるやかに加え、攪拌しながら５０～６０℃で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩１．４１ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；１７％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、８７．３／１２．７であった。 Comparative Example 3 (Synthesis of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinucidine sulfate)
[First step]
In the same manner as in Example 1, 30 g of an organic solvent solution containing 4.61 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained.
[Second step]
In a container with an internal volume of 200 mL equipped with a stirrer, a thermometer, and a reflux condenser, 15.3 mmol of 30 g of the organic solvent solution (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was added. While maintaining the liquid temperature at 0 to 5 ° C., 1.97 g (19.5 mmol) of 97% sulfuric acid was slowly added, and the mixture was reacted at 50 to 60 ° C. for 30 minutes with stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 1.41 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 17%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 87.3 / 12.7.
［第１工程］
実施例１と同様な方法により、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン４．６１ｇを含有する有機溶媒溶液３０ｇを得た。
［第２工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２００ｍＬの容器に、前記工程で得られた有機溶媒溶液３０ｇ（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１５．３ｍｍｏｌ含有）を加え、液温を０～５℃に維持しながら、９７％硫酸１．９７ｇ（１９．５ｍｍｏｌ）をゆるやかに加え、攪拌しながら５０～６０℃で３０分間反応させた。
反応終了後、析出した固体を濾過後、濾物を乾燥させて、白色固体として２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩１．４１ｇを得た（３－ヒドロキシ－３－メルカプトメチルキヌクリジン基準の単離収率；１７％）。
なお、得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性体比率は、８７．３／１２．７であった。 Comparative Example 3 (Synthesis of cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′) quinucidine sulfate)
[First step]
In the same manner as in Example 1, 30 g of an organic solvent solution containing 4.61 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained.
[Second step]
In a container with an internal volume of 200 mL equipped with a stirrer, a thermometer, and a reflux condenser, 15.3 mmol of 30 g of the organic solvent solution (2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the above step was added. While maintaining the liquid temperature at 0 to 5 ° C., 1.97 g (19.5 mmol) of 97% sulfuric acid was slowly added, and the mixture was reacted at 50 to 60 ° C. for 30 minutes with stirring.
After completion of the reaction, the precipitated solid was filtered, and the filtrate was dried to obtain 1.41 g of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate as a white solid (3-hydroxy- Isolated yield based on 3-mercaptomethylquinuclidine; 17%).
The isomer ratio of the obtained 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 87.3 / 12.7.
以上、実施例１及び２と、比較例１及び２との対比から、混合して反応させる順序により合成に大きな差が出ること、即ち、本発明の第１工程以外では化合物（２）が得られにくいことが分かった。
また、実施例１及び２と、比較例３との対比から、化合物（２）と硫酸とを接触させて化合物（３）を得る際に、本発明の第２工程以外では化合物（３）が収率良く得られないことが分かった。また、この場合には異性体比率も低かった。
従って、本発明の第１工程及び第２工程を経ることにより、目的とする化合物が収率良く、高い異性対比率で得られることが判明した。 As described above, from the comparison between Examples 1 and 2 and Comparative Examples 1 and 2, there is a large difference in synthesis depending on the order of mixing and reaction, that is, compound (2) is obtained except in the first step of the present invention. I found it difficult to do.
Further, from the comparison between Examples 1 and 2 and Comparative Example 3, when compound (2) and sulfuric acid are brought into contact with each other to obtain compound (3), compound (3) is produced except in the second step of the present invention. It was found that the yield was not good. In this case, the isomer ratio was also low.
Therefore, it has been found that the target compound can be obtained with a high yield and a high ratio of isomers through the first step and the second step of the present invention.
また、実施例１及び２と、比較例３との対比から、化合物（２）と硫酸とを接触させて化合物（３）を得る際に、本発明の第２工程以外では化合物（３）が収率良く得られないことが分かった。また、この場合には異性体比率も低かった。
従って、本発明の第１工程及び第２工程を経ることにより、目的とする化合物が収率良く、高い異性対比率で得られることが判明した。 As described above, from the comparison between Examples 1 and 2 and Comparative Examples 1 and 2, there is a large difference in synthesis depending on the order of mixing and reaction, that is, compound (2) is obtained except in the first step of the present invention. I found it difficult to do.
Further, from the comparison between Examples 1 and 2 and Comparative Example 3, when compound (2) and sulfuric acid are brought into contact with each other to obtain compound (3), compound (3) is produced except in the second step of the present invention. It was found that the yield was not good. In this case, the isomer ratio was also low.
Therefore, it has been found that the target compound can be obtained with a high yield and a high ratio of isomers through the first step and the second step of the present invention.
実施例３（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２０ｍＬの容器に、パラアセトアルデヒド０．３９ｇ（アセトアルデヒドとして２．９ｍｍｏｌ）及び酢酸エチル５ｍＬとを混合した後、混合液を２０～３０℃に維持しながら塩化スズ（ＩＶ）２．２３ｇ（８．７ｍｍｏｌ）を加えた。
次いで、３－ヒドロキシ－３－メルカプトメチルキヌクリジン０．５ｇ（２．８９ｍｏｌ）をゆるやかに加え、攪拌しながら同温度で１５時間反応させた。
反応終了後、反応液を分析したところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８３％で生成していた（異性体比率；９４．８／５．２）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 3 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
After mixing 0.39 g of paraacetaldehyde (2.9 mmol as acetaldehyde) and 5 mL of ethyl acetate in a 20 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 20-30 ° C. While adding 2.23 g (8.7 mmol) of tin (IV) chloride.
Next, 0.5 g (2.89 mol) of 3-hydroxy-3-mercaptomethylquinuclidine was slowly added, and the mixture was reacted at the same temperature for 15 hours while stirring.
When the reaction solution was analyzed after completion of the reaction, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was produced in a yield of 83% (isomer ratio: 94.8 / 5.2). .
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
［第１工程］
攪拌装置、温度計及び還流冷却器を備えた内容積２０ｍＬの容器に、パラアセトアルデヒド０．３９ｇ（アセトアルデヒドとして２．９ｍｍｏｌ）及び酢酸エチル５ｍＬとを混合した後、混合液を２０～３０℃に維持しながら塩化スズ（ＩＶ）２．２３ｇ（８．７ｍｍｏｌ）を加えた。
次いで、３－ヒドロキシ－３－メルカプトメチルキヌクリジン０．５ｇ（２．８９ｍｏｌ）をゆるやかに加え、攪拌しながら同温度で１５時間反応させた。
反応終了後、反応液を分析したところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８３％で生成していた（異性体比率；９４．８／５．２）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 3 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
After mixing 0.39 g of paraacetaldehyde (2.9 mmol as acetaldehyde) and 5 mL of ethyl acetate in a 20 mL container equipped with a stirrer, thermometer and reflux condenser, the mixture was maintained at 20-30 ° C. While adding 2.23 g (8.7 mmol) of tin (IV) chloride.
Next, 0.5 g (2.89 mol) of 3-hydroxy-3-mercaptomethylquinuclidine was slowly added, and the mixture was reacted at the same temperature for 15 hours while stirring.
When the reaction solution was analyzed after completion of the reaction, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was produced in a yield of 83% (isomer ratio: 94.8 / 5.2). .
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
実施例４（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
実施例３において、溶媒を酢酸エチルからトルエンに変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８４％で生成していた（異性体比率；９４．４／５．６）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 4 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
The reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to toluene in Example 3. As a result, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 84. % (Isomer ratio: 94.4 / 5.6).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
［第１工程］
実施例３において、溶媒を酢酸エチルからトルエンに変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８４％で生成していた（異性体比率；９４．４／５．６）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 4 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
The reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to toluene in Example 3. As a result, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 84. % (Isomer ratio: 94.4 / 5.6).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
実施例５（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
実施例３において、溶媒を酢酸エチルからクロロホルムに変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率６８％で生成していた（異性体比率；９３．６／６．４）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 5 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
The reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to chloroform in Example 3. As a result, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 68. % (Isomer ratio: 93.6 / 6.4).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
［第１工程］
実施例３において、溶媒を酢酸エチルからクロロホルムに変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率６８％で生成していた（異性体比率；９３．６／６．４）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 5 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
The reaction was conducted in the same manner as in Example 3 except that the solvent was changed from ethyl acetate to chloroform in Example 3. As a result, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine was obtained in a yield of 68. % (Isomer ratio: 93.6 / 6.4).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
実施例６（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
［第１工程］
実施例３において、塩化スズ（ＩＶ）の使用量を１．５１ｇ（５．７８ｍｍｏｌ）に変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８８％で生成していた（異性体比率；９５．０／５．０）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 6 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
A reaction was conducted in the same manner as in Example 3 except that the amount of tin (IV) chloride used was changed to 1.51 g (5.78 mmol) in Example 3. 2-Methylspiro (1,3-oxathiolane) -5,3 ') Quinuclidine was produced in a yield of 88% (isomer ratio: 95.0 / 5.0).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
［第１工程］
実施例３において、塩化スズ（ＩＶ）の使用量を１．５１ｇ（５．７８ｍｍｏｌ）に変えたこと以外は、実施例３と同様に反応を行ったところ、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンが収率８８％で生成していた（異性体比率；９５．０／５．０）。
［第２工程］
第１工程で得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジンの有機溶媒溶液を、－５～４５℃で硫酸と接触させることで、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を高い異性体比率で得ることができる。 Example 6 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
[First step]
A reaction was conducted in the same manner as in Example 3 except that the amount of tin (IV) chloride used was changed to 1.51 g (5.78 mmol) in Example 3. 2-Methylspiro (1,3-oxathiolane) -5,3 ') Quinuclidine was produced in a yield of 88% (isomer ratio: 95.0 / 5.0).
[Second step]
By contacting the organic solvent solution of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine obtained in the first step with sulfuric acid at −5 to 45 ° C., 2-methylspiro (1,3- Oxathiolane-5,3 ′) quinuclidine sulfate can be obtained with a high isomer ratio.
以上、実施例３～６で示した通り、条件を変更した場合でも、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を、高い収率、高い異性体比率で得ることができる。
As described above, as shown in Examples 3 to 6, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate can be obtained in high yield and high isomer ratio even when the conditions are changed. Can do.
実施例７（２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の合成）
実施例１と同様にして第１工程及び第２工程を経て得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（異性体比率；９６．０／４．０）３ｇ（１０．１ｍｍｏｌ）、アセトン６ｍＬ及び水０．６６ｍＬを混合し、室温でアセトン２４ｍＬを加えて析出した固体を濾過することで、シス比９８．５％の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩２．５ｇを得た。
なお、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性対比率は９８．５／１．５であった。
この操作を更に２回繰り返すことで、異性体比率は９９．７／０．３まで向上した。 Example 7 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (isomer ratio: 96.0 / 4.0) obtained through the first step and the second step in the same manner as in Example 1. 3 g (10.1 mmol), 6 mL of acetone and 0.66 mL of water were mixed, 24 mL of acetone was added at room temperature, and the precipitated solid was filtered to obtain 2-methylspiro (1,3-oxathiolane having a cis ratio of 98.5%. -5,3 ') 2.5 g of quinuclidine sulfate was obtained.
The isomer ratio of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 98.5 / 1.5.
By repeating this operation twice more, the isomer ratio was increased to 99.7 / 0.3.
実施例１と同様にして第１工程及び第２工程を経て得られた２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（異性体比率；９６．０／４．０）３ｇ（１０．１ｍｍｏｌ）、アセトン６ｍＬ及び水０．６６ｍＬを混合し、室温でアセトン２４ｍＬを加えて析出した固体を濾過することで、シス比９８．５％の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩２．５ｇを得た。
なお、２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の異性対比率は９８．５／１．５であった。
この操作を更に２回繰り返すことで、異性体比率は９９．７／０．３まで向上した。 Example 7 (Synthesis of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate)
2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate (isomer ratio: 96.0 / 4.0) obtained through the first step and the second step in the same manner as in Example 1. 3 g (10.1 mmol), 6 mL of acetone and 0.66 mL of water were mixed, 24 mL of acetone was added at room temperature, and the precipitated solid was filtered to obtain 2-methylspiro (1,3-oxathiolane having a cis ratio of 98.5%. -5,3 ') 2.5 g of quinuclidine sulfate was obtained.
The isomer ratio of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate was 98.5 / 1.5.
By repeating this operation twice more, the isomer ratio was increased to 99.7 / 0.3.
本明細書に記載の実施例および態様は例示を目的としたものに過ぎず、当業者には、それらに照らし種々の修正や変更が示唆され、本願の趣旨および範囲ならびに添付の特許請求の範囲の中に含まれるものと理解される。本明細書において引用される全ての刊行物、特許および特許出願は、その全体が参照により本明細書に組み入れられる。
The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes will be suggested to those skilled in the art in light of the spirit and scope of the present application and the appended claims. Is understood to be included in All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.
本発明は、３－ヒドロキシ－３－メルカプトメチルキヌクリジンから２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を製造する方法に関し、特に高い異性体比率（シス／トランス）で２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩を製造する方法に関する。
当該化合物は、哺乳類の中枢神経の病気、特にコリン作用機能障害による病気、シエーグレン症候群と称される自己免疫疾患などの治療に有用なシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン塩酸塩（セビメリン）の合成中間体として有用な化合物である。 The present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans). To 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
The compound is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc. Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline).
当該化合物は、哺乳類の中枢神経の病気、特にコリン作用機能障害による病気、シエーグレン症候群と称される自己免疫疾患などの治療に有用なシス型２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン塩酸塩（セビメリン）の合成中間体として有用な化合物である。 The present invention relates to a process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate from 3-hydroxy-3-mercaptomethylquinuclidine, and particularly high isomer ratio (cis / trans). To 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
The compound is useful for the treatment of diseases of the central nervous system of mammals, particularly diseases caused by cholinergic dysfunction, autoimmune diseases called Siegren's syndrome, etc. Cis-type 2-methylspiro (1,3-oxathiolane-5,3 ′ ) A compound useful as an intermediate for the synthesis of quinuclidine hydrochloride (cevimeline).
Claims (4)
- 金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させて、遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）を得る工程と、
前記遊離の２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン（２）と硫酸とを－５～４５℃で接触させて、式（３）で示される２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩（３）に変換する工程とを含む、
２－メチルスピロ（１，３－オキサチオラン－５，３’）キヌクリジン硫酸塩の製造方法。
The free 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (2) is contacted with sulfuric acid at −5 to 45 ° C. to give 2-methylspiro (1,3 Converting to oxathiolane-5,3 ′) quinuclidine sulfate (3),
A process for producing 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine sulfate.
- 金属ハロゲン化物が金属塩化物である、請求項１記載の製造方法。 The production method according to claim 1, wherein the metal halide is a metal chloride.
- アセトアルデヒド化合物がパラアルデヒドである、請求項１～２のいずれか１項に記載の製造方法。 The production method according to claim 1, wherein the acetaldehyde compound is paraaldehyde.
- 金属ハロゲン化物及びアセトアルデヒド化合物を混合した後に、３－ヒドロキシ－３－メルカプトメチルキヌクリジン（１）を更に混合して反応させる際の反応温度が１０～６０℃である、請求項１～３のいずれか１項に記載の製造方法。 The reaction temperature when mixing and reacting 3-hydroxy-3-mercaptomethylquinuclidine (1) after mixing the metal halide and the acetaldehyde compound is 10 to 60 ° C. The manufacturing method of any one of Claims.
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| JP2016016881A JP2019052093A (en) | 2016-02-01 | 2016-02-01 | Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine sulfate |
| JP2016-016881 | 2016-02-01 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61280497A (en) * | 1985-05-10 | 1986-12-11 | イスラエル国 | Kynucredine derivative |
| JPS6445387A (en) * | 1987-08-13 | 1989-02-17 | Ishihara Mining & Chemical Co | Method for isomerizing trans-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salt thereof |
| JPH08319287A (en) * | 1994-05-19 | 1996-12-03 | Ishihara Sangyo Kaisha Ltd | Production of 2-methylspiro(1,3-oxathiolan-5,3')quinuclidine |
| JP2011088857A (en) * | 2009-10-23 | 2011-05-06 | Daiichi Fine Chemical Co Ltd | Process for producing quinuclidines |
-
2016
- 2016-02-01 JP JP2016016881A patent/JP2019052093A/en active Pending
-
2017
- 2017-01-10 WO PCT/JP2017/000456 patent/WO2017134984A1/en active Application Filing
- 2017-01-24 TW TW106102536A patent/TW201730194A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61280497A (en) * | 1985-05-10 | 1986-12-11 | イスラエル国 | Kynucredine derivative |
| JPS6445387A (en) * | 1987-08-13 | 1989-02-17 | Ishihara Mining & Chemical Co | Method for isomerizing trans-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine or acid addition salt thereof |
| JPH08319287A (en) * | 1994-05-19 | 1996-12-03 | Ishihara Sangyo Kaisha Ltd | Production of 2-methylspiro(1,3-oxathiolan-5,3')quinuclidine |
| JP2011088857A (en) * | 2009-10-23 | 2011-05-06 | Daiichi Fine Chemical Co Ltd | Process for producing quinuclidines |
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| JP2019052093A (en) | 2019-04-04 |
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