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WO2017134984A1 - Procédé de production de sulfate de 2-méthylspiro (1,3-oxathiolane-5,3') quinuclidine - Google Patents

Procédé de production de sulfate de 2-méthylspiro (1,3-oxathiolane-5,3') quinuclidine Download PDF

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Publication number
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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Prior art keywords
oxathiolane
methylspiro
quinuclidine
sulfate
compound
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English (en)
Japanese (ja)
Inventor
秀好 島
洋治 小俣
康仁 山本
昭 高間
米田　康洋
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Ube Corp
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Ube Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • 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).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé d'obtention de sulfate de 2-méthylspiro (1,3-oxathiolane-5,3') quinuclidine selon un rapport élevé d'isomères (cis/trans), à partir de 3-hydroxy-3-mercaptométhylquinuclidine, ledit procédé ne nécessitant pas de fractionnement des isomères ni d'étape d'isomérisation. L'invention concerne un procédé de production sulfate de 2-méthylspiro (1,3-oxathiolane-5,3 ') quinuclidine comprenant une étape dans laquelle un halogénure métallique et un composé d'acétaldéhyde sont mélangés, puis le 3-hydroxy-3-mercaptométhylquinuclidine est mélangé et mis à réagir afin d'obtenir de la 2-méthylspiro (1,3-oxathiolane-5,3 ') quinuclidine libre; et une étape dans laquelle la 2-méthylspiro (1,3-oxathiolane-5,3') quinuclidine libre est amenée en contact avec de l'acide sulfurique à une température comprise entre –5 et –45 °C, et convertie ainsi en sulfate de 2-méthylspiro (1,3-oxathiolane -5,3') quinuclidine.
PCT/JP2017/000456 2016-02-01 2017-01-10 Procédé de production de sulfate de 2-méthylspiro (1,3-oxathiolane-5,3') quinuclidine Ceased WO2017134984A1 (fr)

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JP2016-016881 2016-02-01
JP2016016881A JP2019052093A (ja) 2016-02-01 2016-02-01 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

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61280497A (ja) * 1985-05-10 1986-12-11 イスラエル国 キヌクリジン誘導体
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 (ja) * 1994-05-19 1996-12-03 Ishihara Sangyo Kaisha Ltd ２−メチルスピロ（１，３−オキサチオラン−５，３’）キヌクリジンの製造方法
JP2011088857A (ja) * 2009-10-23 2011-05-06 Daiichi Fine Chemical Co Ltd キヌクリジン類の製造法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61280497A (ja) * 1985-05-10 1986-12-11 イスラエル国 キヌクリジン誘導体
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 (ja) * 1994-05-19 1996-12-03 Ishihara Sangyo Kaisha Ltd ２−メチルスピロ（１，３−オキサチオラン−５，３’）キヌクリジンの製造方法
JP2011088857A (ja) * 2009-10-23 2011-05-06 Daiichi Fine Chemical Co Ltd キヌクリジン類の製造法

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