JP2006169154A - Method for producing quaternary ammonium salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a quaternary ammonium salt of formula(3)[ wherein, X is a group forming a counteranion as a result of being eliminated; Y is a (substituted) 1-2C alkylene group; and Z is a (substituted) methylene group or (substituted) imino group ] without discontinuing the reaction during the process and also slight in the fluctuation of reaction rate. <P>SOLUTION: The method for producing a quaternary ammonium salt of formula(3) comprises carrying out a reaction between a compound of formula(1) ( wherein, Z means the same as mentioned above ) and a compound of formula 2( wherein, X and Y each means the same as mentioned above ) in an organic solvent in the presence of potassium carbonate ≤200μm in average particle size(50%D). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a quaternary ammonium salt.

で示される化合物に代表される式（５）

（式中、Ａは置換されていてもよい炭素数２〜４のアルキレン基または置換されていてもよい炭素数２〜４のアルケニレン基を表わし、Ｄはカルボニル基またはスルホニル基を表わす。Ｙは置換されていてもよい炭素数１〜２のアルキレン基を表わし、Ｚは置換されていてもよいメチレン基または置換されていてもよいイミノ基を表わす。）
で示されるイミド化合物は、例えば統合失調症、老年性精神疾患、躁鬱病、神経症等の治療薬の中間体として有用であり、式（３）

（式中、Ｘ^-は対アニオンを表わし、ＹおよびＺは上記と同一の意味を表わす。）
で示される第四級アンモニウム塩が、かかる式（５）で示されるイミド化合物の重要な合成中間体であることが知られている（例えば特許文献１参照。）。 Formula (4)

Formula (5) represented by the compound represented by

(In the formula, A represents an optionally substituted alkylene group having 2 to 4 carbon atoms or an optionally substituted alkenylene group having 2 to 4 carbon atoms, D represents a carbonyl group or a sulfonyl group, Y represents Represents an optionally substituted alkylene group having 1 to 2 carbon atoms, and Z represents an optionally substituted methylene group or an optionally substituted imino group.)
The imide compound represented by the formula (3) is useful as an intermediate for therapeutic agents for schizophrenia, senile mental illness, manic depression, neurosis, etc.

(In the formula, X ⁻ represents a counter anion, and Y and Z have the same meaning as described above.)
It is known that the quaternary ammonium salt shown by these is an important synthetic intermediate of the imide compound shown by this Formula (5) (for example, refer patent document 1).

（式中、Ｚは上記と同一の意味を表わす。）
で示される化合物と式（２）

（式中、Ｘは脱離して対アニオンを形成する基を表わし、Ｙは上記と同一の意味を表わす。）
で示される化合物とを、炭酸カリウムの存在下に反応させる方法が知られている（例えば特許文献１および２参照。）が、反応速度に振れが見られ、反応が途中で停止してしまう場合もあった。 As a method for producing the quaternary ammonium salt represented by the formula (3), the formula (1) is used in an organic solvent.

(In the formula, Z represents the same meaning as described above.)
And a compound of formula (2)

(In the formula, X represents a group capable of leaving to form a counter anion, and Y represents the same meaning as described above.)
Is known in the presence of potassium carbonate (see, for example, Patent Documents 1 and 2), but the reaction rate fluctuates and the reaction stops midway. There was also.

Japanese Patent Laid-Open No. 5-17440 JP 2003-160583 A

  Under such circumstances, the present inventors have studied to develop a method for producing a quaternary ammonium salt represented by the formula (3), in which the reaction does not stop midway and the reaction rate fluctuation is small. However, the average particle size of the potassium carbonate to be used greatly affects the reaction rate. By using potassium carbonate having an average particle size (50% D) of 200 μm or less, the reaction proceeds at a stable reaction rate. Thus, the present inventors have found that the quaternary ammonium salt represented by the target formula (3) can be produced without stopping the reaction.

（式中、Ｚは置換されていてもよいメチレン基または置換されていてもよいイミノ基を表わす。）
で示される化合物と式（２）

（式中、Ｘは脱離して対アニオンを形成する基を表わし、Ｙは置換されていてもよい炭素数１〜２のアルキレン基を表わす。）
で示される化合物とを、平均粒子径（５０％Ｄ）が２００μｍ以下の炭酸カリウムの存在下に反応させることを特徴とする式（３）

（式中、Ｘ、ＹおよびＺは上記と同一の意味を表わす。）
で示される第四級アンモニウム塩の製造方法を提供するものである。 That is, the present invention provides a compound of formula (1) in an organic solvent.

(In the formula, Z represents an optionally substituted methylene group or an optionally substituted imino group.)
And a compound of formula (2)

(In the formula, X represents a group which is eliminated to form a counter anion, and Y represents an optionally substituted alkylene group having 1 to 2 carbon atoms.)
The compound represented by formula (3) is reacted in the presence of potassium carbonate having an average particle size (50% D) of 200 μm or less.

(In the formula, X, Y and Z have the same meaning as described above.)
The manufacturing method of the quaternary ammonium salt shown by these is provided.

  According to the present invention, the reaction proceeds at a stable reaction rate, and the quaternary ammonium salt can be produced without stopping the reaction on the way, which is industrially advantageous.

で示される化合物（以下、化合物（１）と略記する。）の式中、Ｚは置換されていてもよいメチレン基または置換されていてもよいイミノ基を表わす。置換されていてもよいメチレン基の置換基としては、例えば低級アルキル基、低級アルコキシ基、低級アルキルチオ基、低級アルキリデン基、シクロアルキル基、シクロアルキルオキシ基、シクロアルキルチオ基、シクロアルケニル基、シクロアルケニルオキシ基、シクロアルケニルチオ基、アリール基、アリールオキシ基、アリールチオ基、ヘテロアリール基、ヘテロアリールオキシ基、ヘテロアリールチオ基等が挙げられる。 Formula (1)

In the formula of the compound represented by (hereinafter abbreviated as compound (1)), Z represents an optionally substituted methylene group or an optionally substituted imino group. Examples of the substituent of the methylene group which may be substituted include a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylidene group, a cycloalkyl group, a cycloalkyloxy group, a cycloalkylthio group, a cycloalkenyl group, and a cycloalkenyl group. Examples thereof include an oxy group, a cycloalkenylthio group, an aryl group, an aryloxy group, an arylthio group, a heteroaryl group, a heteroaryloxy group, and a heteroarylthio group.

  Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, and a tert-pentyl group. A linear or branched alkyl group having 1 to 6 carbon atoms such as a group, neopentyl group, 1-methylbutyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, etc. It is done. Examples of the lower alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an isopentyloxy group. Tert-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 1-ethylpropoxy group, n-hexyloxy group, isohexyloxy group, 1-methylpentyloxy group, etc. Examples thereof include a linear or branched alkoxy group. Examples of the lower alkylthio group include groups in which the oxygen atom of the lower alkoxy group such as a methylthio group or an ethylthio group is replaced with a sulfur atom.

  Examples of the lower alkylidene group include a methylidene group, an ethylidene group, an isopropylidene group, a cyclohexylidene group, a benzylidene group, a 1-phenylbenzylidene group, and a di (4-fluorophenyl) methylidene group. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the cycloalkyloxy group include groups composed of the cycloalkyl group such as a cyclopentyloxy group and a cyclohexyloxy group and an oxygen atom. Examples of the cycloalkylthio group include groups in which the oxygen atom of the cycloalkyloxy group such as a cyclopentylthio group is replaced with a sulfur atom.

  Examples of the cycloalkenyl group include C3-C6 cycloalkenyl groups such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group. Examples of the cycloalkenyloxy group include a cyclopentenyloxy group. Examples include a group composed of the cycloalkenyl group and an oxygen atom. Examples of the cycloalkenylthio group include groups in which the oxygen atom of the cycloalkenyloxy group such as a cyclohexylthio group is replaced with a sulfur atom. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the aryloxy group include a group composed of the aryl group such as a phenoxy group and an oxygen atom. Examples of the arylthio group include a phenylthio group. In which the oxygen atom of the aryloxy group is replaced by a sulfur atom.

  Examples of the heteroaryl group include pyridyl group, pyrimidinyl group, thiazolyl group, oxazolyl group, isoxazolyl group, isothiazolyl group, furyl group, imidazolyl group, benzisothiazolyl group, benzisoxazolyl group, benzfuryl group, quinolyl group, Ring at least one hetero atom of nitrogen, oxygen and sulfur atoms such as isoquinolyl group, indolyl group, indazolyl group, benzimidazolyl group, benzoxazolyl group, naphthyridinyl group, thienofuranyl group, imidazolophenyl group Examples thereof include groups contained as constituent atoms. Examples of the heteroaryloxy group include a group composed of the heteroaryl group and an oxygen atom, and examples of the heteroarylthio group include a group composed of the heteroaryl group and a sulfur atom.

  Such cycloalkyl group, cycloalkyloxy group, cycloalkylthio group, cycloalkenyl group, cycloalkenyloxy group, cycloalkenylthio group, aryl group, heteroaryl group and the like are, for example, the lower alkyl group, the lower alkoxy group, the lower It may be substituted with an alkylthio group, for example, a halogen atom such as a fluorine atom or a chlorine atom.

  Examples of the substituent of the optionally substituted imino group include the lower alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, and the heteroaryl group.

  Examples of the compound (1) include 4-phenylpiperazine, 4- (2-methoxyphenyl) piperazine, 4-cyclohexylpiperazine, 4- (2-pyridinyl) piperazine, 4- (2-pyrimidinyl) piperazine, 4- ( 2-quinolyl) piperazine, 4- (4-quinolyl) piperazine, 4- (1,2-benzisothiazol-3-yl) piperazine, 4- (4-fluorophenyl) piperidine, 4-[(4-fluorophenyl) ) Thio] piperidine, 4- (3-chlorophenyl) piperazine, 4- (1,2-benzisoxazol-3-yl) piperidine, 4- (5-benzofuranyl) piperazine, 4- (1-naphthylpiperazine, 4- [Bis (4-fluorophenyl) methylene] piperidine, 4- (3-isoquinolyl) piperazine, - (8-quinolyl) piperazine, 4- (7-benzofuranyl) piperazine, 4- (5-fluoro-1,2-benzisoxazol-3-yl) piperidine, and the like.

  Such compound (1) is disclosed in, for example, JP-A-63-83085, J. Pat. Med. Chem. , 28, 761 (1985), J. et al. Med. Chem. , 32, 1024 (1989) and the like. Further, the compound (1) may be an acid addition salt such as hydrochloride or sulfate.

で示される化合物（以下、化合物（２）と略記する。）の式中、Ｘは脱離してアニオンを形成する基を表わし、Ｙは置換されていてもよい炭素数１〜２のアルキレン基を表わす。 Formula (2)

In the formula (hereinafter abbreviated as compound (2)), X represents a group capable of leaving to form an anion, and Y represents an optionally substituted alkylene group having 1 to 2 carbon atoms. Represent.

  Examples of the group capable of leaving to form an anion include halogen atoms such as chlorine atom, bromine atom and iodine atom, and sulfonyloxy groups such as methanesulfonyloxy group and p-toluenesulfonyloxy group. Examples of the optionally substituted alkylene group having 1 to 2 carbon atoms include an unsubstituted alkylene group having 1 to 2 carbon atoms such as a methylene group and an ethylene group, and these unsubstituted alkylene groups having 1 to 2 carbon atoms. May be substituted with a substituent such as the lower alkyl group, the lower alkoxy group, or a hydroxyl group, and these substituents together may be an alkylene chain or oxygen which may have an oxygen atom. You may form the alkenylene chain | strand which may have an atom. Examples of the alkylene group having 1 to 2 carbon atoms substituted with such a substituent include, for example, a hydroxymethylene group, a cyclohexane-1,2-diyl group, a cyclopentane-1,2-diyl group, and a bicyclo [2.2.1]. Examples include heptane-2,3-diyl group, 1-cyclohexene-4,5-diyl group, 7-oxabicyclo [2.2.1] -hept-5-ene-2,3-diyl group.

  Examples of the compound (2) include 1,4-dibromobutane, 1,4-dichlorobutane, 1,4-diiodobutane, 1,4-dimethanesulfonyloxybutane, 1,4-di (p-toluenesulfonyloxy). ) Butane, 2-hydroxy-1,3-dibromopropane, 2-hydroxy-1,3-dichloropropane, 2-hydroxy-1,3-dimethanesulfonyloxypropane, 1,2-bis (bromomethyl) cyclohexane, 1 , 2-bis (methanesulfonyloxymethyl) cyclohexane, 1,2-bis (bromomethyl) cyclopentane, 1,2-bis (methanesulfonyloxymethyl) cyclopentane, 2,3-bis (bromomethyl) -bicyclo [2. 2.1] Heptane, 2,3-bis (methanesulfonyloxymethyl) -bicyclo [2 2.1] Heptane, 4,5-bis (bromomethyl) -1-cyclohexene, 4,5-bis (methanesulfonyloxymethyl) -1-cyclohexene, 2,3-bis (bromomethyl) -7-oxabicyclo [2 2.1] -hept-5-ene and the like. As this compound (2), a commercially available product is usually used. Some of the compounds (2) have an asymmetric carbon atom in the molecule and an optical isomer exists. In the present invention, the optical isomer alone may be used. In addition, a mixture of optical isomers in an arbitrary ratio may be used.

  The usage-amount of a compound (2) is 1-2 mole times normally with respect to a compound (1).

（式中、Ｘ、ＹおよびＺは上記と同一の意味を表わす。）
で示される第四級アンモニウム塩（以下、第四級アンモニウム塩（３）と略記する。）を製造することができる。 In the present invention, the compound (1) and the compound (2) are reacted in the presence of potassium carbonate having an average particle size (50% D) of 200 μm, preferably potassium carbonate of 100 μm or less is used. . Although there is no particular lower limit of the average particle size (50% D), it is practically 5 μm or more. By using potassium carbonate having an average particle size (50% D) of 200 μm or less, the reaction proceeds at a stable reaction rate, and the reaction does not stop on the way.

(In the formula, X, Y and Z have the same meaning as described above.)
Can be produced (hereinafter abbreviated as quaternary ammonium salt (3)).

  The potassium carbonate having an average particle size (50% D) of 200 μm or less may be a commercially available fine powder potassium carbonate having an average particle size (50% D) of 200 μm or less, or the average particle size (50% D). A commercially available potassium carbonate having a mean particle size (50% D) of 200 μm or less may be used by pulverizing commercially available potassium carbonate having a particle size of greater than 200 μm by, for example, mortar grinding, airflow grinding, hammer grinding or the like. Moreover, it is also possible to prepare powder potassium carbonate by putting it in a sieve with a predetermined sieve and mixing the sieved powder potassium carbonate so that the average particle diameter (50% D) is 200 μm or less. it can. The average particle size (50% D) of the potassium carbonate is measured by a normal low tap sieve shaking method or a laser diffraction particle size distribution measuring method.

  The amount of potassium carbonate having an average particle size (50% D) of 200 μm or less is usually 0.8 mol times or more with respect to the compound (1), and there is no particular upper limit. Therefore, it is practically less than 2 mole times. In addition, when the acid addition salt is used as the compound (1), it is preferable to separately use an amount of a base sufficient to neutralize the acid addition salt, and potassium carbonate is usually used as the base. .

  The reaction is usually carried out by contacting and mixing compound (1), compound (2), and potassium carbonate having an average particle size (50% D) of 200 μm or less in a solvent, and the mixing order is not particularly limited. . Further, potassium carbonate having an average particle size (50% D) of 200 μm or less may be added all at once, but it is preferable to add it in two or more in terms of suppressing the formation of by-products.

  Examples of the solvent include alcohol solvents such as methanol and ethanol, aprotic polar solvents such as acetonitrile and N, N-dimethylformamide, and single or mixed solvents such as aromatic carbon solvents such as toluene and xylene. The amount used is not particularly limited.

  In addition, the reaction may be carried out in the presence of a phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, and the like. When the phase transfer catalyst is used, the amount used is usually 0.01 to 0.5 mol times relative to compound (1). The phase transfer catalyst is preferably added after the reaction between the compound (1) and the compound (2) has progressed to some extent.

  The reaction temperature is usually 60 to 180 ° C, preferably 90 to 150 ° C.

  After completion of the reaction, the quaternary ammonium salt (3) can be taken out, for example, by subjecting the reaction solution as it is or after partially concentrating, followed by filtration. Moreover, you may use for reaction mentioned later, without taking out quaternary ammonium salt (3) from the reaction liquid containing quaternary ammonium salt (3).

  Examples of the quaternary ammonium salt (3) thus obtained include, for example, 7-cyclohexyl-2-hydroxy-7-aza-4-azoniaspiro [3.5] nonane, 8-phenyl-8-aza-5-azoniaspiro [4]. .5] decane, 8- (2-methoxyphenyl) -8-aza-5-azoniaspiro [4.5] decane, 8- (2-pyridinyl) -8-aza-5-azoniaspiro [4.5] decane, 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane, 8- (2-quinolinyl) -8-aza-5-azoniaspiro [4.5] decane, 8- (4-quinolinyl) ) -8-aza-5-azoniaspiro [4.5] decane, 8- (1,2-benzisothiazol-3-yl) -8-aza-5-azoniaspiro [4.5] decane, 4 ′-( 1, 2 Benzisothiazol-3-yl) octahydro-spiro [2H-isoindole-2,1′-piperazinium], 4 ′-[(4-fluorophenyl) thio] octahydro-spiro [2H-isoindole-2,1 ′ -Piperidinium], 4 '-(2-pyrimidinyl) octahydro-spiro [2H-isoindole-2,1'-piperazinium], 4'-(4-fluorophenoxy) octahydro-spiro [2H-isoindole-2,1 '-Piperidinium], 4'-(1,2-benzisoxazol-3-yl) octahydro-spiro [2H-isoindole-2,1'-piperidinium], 4 '-(6-fluoro-1 , 2-Benzisoxazol-3-yl) -octahydro-spiro [2H-isoindole-2,1′-pipera Nium], 4 '-(2-pyridinyl) octahydro-spiro [2H-isoindole-2,1'-piperazinium], 4'-(3-chlorophenyl) octahydro-spiro [2H-isoindole-2,1'- Piperazinium], 4 '-(5-benzofuranyl) octahydro-spiro [2H-isoindole-2,1'-piperazinium], 4'-(1-naphthyl) octahydro-spiro [2H-isoindole-2,1'- Piperazinium], 4 ′-[bis (4-fluorophenyl) methylene] octahydro-spiro [2H-isoindole-2,1′-piperidinium], 4 ′-(2-methoxyphenyl) octahydro-spiro [2H-isoindole -2,1'-piperazinium], 4 '-(3-isoquinolinyl) octahydro-spir B [2H-isoindole-2,1′-piperazinium], 4 ′-(8-quinolinyl) octahydro-spiro [2H-isoindole-2,1′-piperazinium], 4 ′-(1,2-benziso Thiazol-3-yl) tetrahydro-spiro [cyclopenta [c] pyrrole-2 (1H), 1′-piperazinium], 4 ′-(1,2-benzisothiazol-3-yl) octahydro-spiro [4 , 7-methano-2H-isoindole-2,1′-piperazinium], 4 ′-(1,2-benzisothiazol-3-yl) -1,3,3a, 4,7,7a-hexahydro-spiro [2H-isoindole-2,1′-piperazinium], 4 ′-(1,2-benzisothiazol-3-yl) -1,3,3a, 4,7,7a-hexahydro-spir [4,7-epoxy-2H-isoindole-2,1′-piperazinium], chlorides and bromides such as 4 ′-(7-benzofuranyl) octahydro-spiro [2H-isoindole-2,1′-piperazinium] , Iodide, hydroxide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, methanesulfonate, p-toluenesulfonate, and the like.

（式中、Ａは置換されていてもよい炭素数２〜４のアルキレン基または置換されていてもよい炭素数２〜４のアルケニレン基を表わし、Ｄはカルボニル基またはスルホニル基を表わす。）
で示される化合物（以下、化合物（６）と略記する。）とを、固体無機塩基の存在下に反応させることにより、式（５）

（式中、Ａ、Ｄ、ＹおよびＺは上記と同一の意味を表わす。）
で示されるイミド化合物（以下、イミド化合物（５）と略記する。）を製造することができる。 The resulting quaternary ammonium salt (3) and formula (6)

(In the formula, A represents an optionally substituted alkylene group having 2 to 4 carbon atoms or an optionally substituted alkenylene group having 2 to 4 carbon atoms, and D represents a carbonyl group or a sulfonyl group.)
Is reacted with a compound represented by formula (hereinafter abbreviated as compound (6)) in the presence of a solid inorganic base to give a compound of formula (5)

(In the formula, A, D, Y and Z have the same meaning as described above.)
Can be produced (hereinafter abbreviated as imide compound (5)).

  Examples of the alkylene group having 2 to 4 carbon atoms include an ethylene group, a trimethylene group, a tetramethylene group, and the like. The alkylene group having 2 to 4 carbon atoms may have a substituent. Examples include the lower alkyl group, the lower alkoxy group, the lower alkenyl group, a lower alkyl group substituted with a lower alkoxy group, a lower alkenyl group substituted with a lower alkoxy group, and the like. Such substituents may together form an alkylene chain which may have an oxygen atom or an alkenylene chain which may have an oxygen atom.

  Examples of the lower alkenyl group include a vinyl group, 1-propenyl group, 2-propenyl group, 1-methylvinyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-butadienyl group, 1- 2-6 carbon atoms such as pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, etc. An alkenyl group is mentioned. Examples of the lower alkyl group substituted with a lower alkoxy group include a lower alkyl group substituted with the lower alkoxy group such as a methoxymethyl group and a 2-methoxyethyl group, and a lower alkenyl group substituted with a lower alkoxy group. Examples thereof include a lower alkenyl group substituted with the lower alkoxy group such as a 2-methoxyvinyl group.

  Examples of the alkenylene group having 2 to 4 carbon atoms include ethenylene group, propenylene group, 1-butenylene group, 2-butenylene group, butadienylene group and the like. The alkenylene group having 2 to 4 carbon atoms has a substituent. The substituent may be, for example, the lower alkyl group, the lower alkoxy group, the lower alkenyl group, a lower alkyl group substituted with the lower alkoxy group, or a lower alkenyl group substituted with the lower alkoxy group. Etc. Such substituents may together form an alkylene chain which may have an oxygen atom or an alkenylene chain which may have an oxygen atom.

  Examples of the compound (6) include succinimide, 2,6-piperidinedione, 4,4-dimethyl-2,6-piperidinedione, 8-azaspiro [4.5] decane-7,9-dione, perhydroazepine- 2,7-dione, maleimide, phthalimide, tetrahydrophthalimide, cis-1,2-cyclohexanedicarboximide, trans-1,2-cyclohexanedicarboximide, cis-1,2-cyclohex-4-enedicarboximide, trans -1,2-cyclohex-4-enedicarboximide, cis-4-methyl-1,2-cyclohexanedicarboximide, trans-4-methyl-1,2-cyclohexanedicarboximide, cis-1,2-dimethyl -1,2-cyclohexanedicarboximide, trans- , 2-dimethyl-1,2-cyclohexanedicarboximide, cis-4,5-dimethyl-1,2-cyclohexanedicarboximide, trans-4,5-dimethyl-1,2-cyclohexanedicarboximide, cis- 3,6-dimethyl-1,2-cyclohexanedicarboximide, trans-3,6-dimethyl-1,2-cyclohexanedicarboximide, bicyclo [2.2.1] heptane-2,3-di-exo- Carboximide, bicyclo [2.2.1] heptane-2,3-di-endo-carboximide, bicyclo [2.2.1] hept-5-ene-2,3-di-exo-carboximide, bicyclo [2.2.1] Hepta-5-ene-2,3-di-endo-carboximide, bicyclo [2.2.2] octane-2,3 Di-exo-carboximide, bicyclo [2.2.2] octane-2,3-di-endo-carboximide, bicyclo [2.2.2] oct-5-ene-2,3-di-exo- Carboximide, bicyclo [2.2.2] oct-5-ene-2,3-di-endo-carboximide, bicyclo [2.2.2] oct-7-ene-2,3-di-exo- Carboximide, bicyclo [2.2.2] oct-7-ene-2,3-di-endo-carboximide, hexahydro-4,7-methano-1,2-benzisothiazol 3 (2H) -one 1,1-dioxide, 3,6-epoxy-1,2-cyclohexanedicarboximide, spiro [bicyclo [2.2.2] octane-2,3′-pyrrolidine] -2 ′, 5′-dione, etc. Can be mentioned.

  Some of the compounds (6) have optical isomers, and any one optical isomer or a mixture of optical isomers may be used in the present invention. .

  Such a compound (6) can be produced, for example, by reacting the corresponding carboxylic anhydride with ammonia (for example, JP-A-1-1999967).

  Examples of the solid inorganic base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkaline earth metal salts such as calcium carbonate and magnesium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Among them, alkali metal carbonates are preferable, and potassium carbonate is particularly preferable. Such solid inorganic bases may be used alone or in admixture of two or more. The solid inorganic base may be an anhydride or a hydrate.

  The amount of the solid inorganic base used is usually 0.7 mol times or more, preferably 0.9 mol times or more with respect to the quaternary ammonium salt (3), and there is no particular upper limit. Since it tends to be economically disadvantageous, it is practically 3 mol times or less, preferably 2.7 mol times or less, relative to the quaternary ammonium salt (3).

  The amount of the compound (6) used is usually 0.7 mol times or more with respect to the quaternary ammonium salt (3), and there is no particular upper limit, but if it is too much, it tends to be economically disadvantageous. Practically, it is 2.5 mol times or less with respect to the quaternary ammonium salt (3).

  The reaction is usually carried out in the presence of a solvent, and examples of the solvent include aromatic hydrocarbon solvents such as toluene, xylene, mesitylene, chlorobenzene and dichlorobenzene. The amount of the solvent used is usually 3 times by weight or more, preferably 5 times by weight or more with respect to the quaternary ammonium salt (3), and there is no particular upper limit, but if it is too much, the volume efficiency is deteriorated. Therefore, it is 20 weight times or less with respect to a quaternary ammonium salt (3) practically.

  This reaction is preferably carried out in the presence of water, and usually 0.05 to 3 mol times, preferably 0.1 to 1.5 mol times of water is reacted with respect to the quaternary ammonium salt (3). It is preferred to carry out the reaction by adding such an amount of water into the reaction system so that it is present in the system. In addition, when a hydrate is used as the solid inorganic base, the amount of water used may be determined in consideration of the water in the hydrate. Such water may be present in the reaction system at the start of the reaction, or may be present in the reaction system during the reaction, for example, by adding a predetermined amount of water. Further, water may be added in advance to the compound (6) and / or the quaternary ammonium salt (3).

  In addition, for example, the reaction may be carried out in the presence of a phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, etc. The usage-amount is 0.01-0.5 mol times normally with respect to a quaternary ammonium salt (3).

  The reaction temperature is usually 80 to 180 ° C, preferably 95 to 150 ° C.

The reaction between the quaternary ammonium salt (3) and the compound (6) is usually carried out by contacting and mixing the quaternary ammonium salt (3), the compound (6) and a solid inorganic base, and the mixing order thereof. Is not particularly limited. The solid inorganic base may be added all at once, or may be added in portions, and preferably added in portions.

  After completion of the reaction, a reaction solution containing the imide compound (5) can be obtained. For example, water is added to the reaction solution, followed by stirring and standing, followed by liquid separation treatment, and the resulting organic layer is treated with activated carbon as necessary. Thereafter, the imide compound (5) can be taken out by concentration treatment. Further, the imide compound (5) is converted into crystals by, for example, a method of cooling the organic layer as it is or partially concentrating, and a method of adding an organic solvent that is relatively difficult to dissolve the imide compound (5) to the organic layer. It can also be taken out. Examples of the organic solvent in which the imide compound (5) is relatively difficult to dissolve include aliphatic hydrocarbon solvents such as pentane, hexane, and heptane, and alcohol solvents such as methanol, ethanol, and isopropanol.

  Moreover, the imide compound (5) can also be taken out from the reaction solution containing the obtained imide compound (5) by filtering off the insoluble matter as necessary, followed by concentration treatment. Further, after the reaction solution is directly or partially concentrated, the imide compound (5) is converted into crystals by, for example, a method of cooling or a method of adding an organic solvent that is relatively difficult to dissolve the imide compound (5) to the organic layer. It can also be taken out.

  The imide compound (5) taken out may be further purified by ordinary purification means such as recrystallization and column chromatography. The imide compound (5) is an acid addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, for example, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid. It can also be taken out as an acid addition salt with an organic acid such as

  Examples of the imide compound (5) thus obtained include 2- [4- (4-phenyl-1-piperazinyl) butyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2- [4- ( 4-phenyl-1-piperazinyl) butyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2- [4- [4- (2-methoxyphenyl) -1-piperazinyl ] Butyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2- [4- [4- (2-methoxyphenyl) -1-piperazinyl] butyl] hexahydro-4,7-methano-1H- Isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl Methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl) -1- Piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide, 2-[[2-[[4- (1, 2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (2- Pyrimidinyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1, -Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -3a, 4,7,7a-tetrahydro-1H-isoindole-1,3 (2H) -dione, 8-[[2 -[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -8-azaspiro [4,5] decane-7,9-dione, 1-[[ 2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -4,4-dimethyl-2,6-piperidinedione, 2-[[2- [[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-epoxy-1H-isoindole-1,3 (2H) -dione, 1 ′-[[2-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -spiro [bicyclo [2.2. 2] Octane-2,3′-pyrrolidine] -2 ′, 5′-dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] Cyclohexyl] methyl] hexahydro-3a, 7a-dimethyl-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl)- 1-piperazinyl] methyl] cyclohexyl] methyl] -3a, 4,7,7a-tetrahydro-4,7-ethano-1H-isoindole-1,3 (2H) -dione,

2-[[2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-ethano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -1H-isoindole-1,3 ( 2H) -dione, 2-[[2-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] -4,5,6,7-tetrahydro- 1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4-[(4-fluorophenyl) thio] -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-4, -Methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4-[(4-fluorophenyl) thio] -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-1H -Isoindole-1,3 (2H) -dione, 2-[[2-[[4- (4-fluorophenoxy) -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H- Isoindole-1,3 (2H) -dione, 2-[[2-[[4- (4-fluorophenoxy) -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 ( 2H) -dione, 2-[[2-[[4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] methyl] cyclohexyl] methyl Hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1,2-benzisoxazol-3-yl) -1-piperidinyl ] Methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (6-fluoro-1,2-benzisoxazol-3-yl] ) -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (6-fluoro-1 , 2-Benzisoxazol-3-yl) -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- ( 2 -Pyridinyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (2-pyridinyl) ) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (2-pyrimidinyl) -1-piperazinyl] methyl] Cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (2-pyrimidinyl) -1-piperazinyl] methyl] cyclohexyl] Methyl] hexahydro-1H-isoindole-1,3 (2H) -dione,

2-[[2-[[4- (3-Chlorophenyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2- [[2-[[4- (3-Chlorophenyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (5-benzofuranyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (5 -Benzofuranyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4 (1-naphthyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (1 -Naphthyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- [bis (4-fluorophenyl] ) Methylene] -1-piperidinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2- [4- (2-Methoxyphenyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[ 4- (2-methoxyphenyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (3-isoquinolinyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (3-isoquinolinyl) -1 -Piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (8-ki Norinyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione,

2-[[2-[[4- (8-quinolinyl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[ 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclopentyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2- [[2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclopentyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2- [[3-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] bicyclo [2.2.1] hept-2-yl] methyl] hexahydro- , 7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[3-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] bicyclo [2.2.1] Hept-2-yl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (7-benzofuranyl) -1-piperazinyl ] Methyl] cyclohexyl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[2-[[4- (7-benzofuranyl) -1-piperazinyl] methyl ] Cyclohexyl] methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[3-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methy L] -7-oxabicyclo [2.2.1] hept-5-en-2-yl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2- [[3-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] -7-oxabicyclo [2.2.1] hept-5-en-2-yl] Methyl] hexahydro-1H-isoindole-1,3 (2H) -dione, 2-[[6-[[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] -3 -Cyclohexen-1-yl] methyl] hexahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione, 2-[[6-[[4- (1,2-benzisothiazole- 3-yl) -1-piperazinyl] methyl] 3-cyclohexen-1-yl] methyl] hexahydro--1H- isoindole-1,3 (2H) - dione, and the like.

  When the optically active compound (6) and / or the optically active quaternary ammonium salt (3) is used, the optically active imide compound (5) is obtained.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples. The analysis was performed by a high performance liquid chromatography (LC) method.

Example 1
While stirring, 16.4 g of (1R, 2R) -1,2-bis (methanesulfonyloxymethyl) cyclohexane, 10 g of 4- (1,2-benzisothiazol-3-yl) piperazine and 162 g of toluene were stirred. In addition, potassium carbonate having an average particle size (50% D) of 11 μm (Asahi Glass Co., Ltd. product; average particle size (50% D) is a laser diffraction particle size distribution meter method (wet method using isopropanol, SALD-2100 manufactured by Shimadzu Corporation). Measured according to use) 3.8 g was added. After distilling off 22 g of toluene, the mixture was stirred and reacted for 6 hours under reflux conditions. When the reaction solution was analyzed by LC, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine (calculated according to the following formula (7)) was 17%.

  After cooling to an internal temperature of about 60 ° C., 1.9 g of potassium carbonate (same as above) having an average particle size (50% D) of 11 μm and 0.62 g of tetra-n-butylammonium hydrogen sulfate were added, and the mixture was refluxed. The mixture was further stirred for 9 hours and reacted, and 4 ′-(1,2-benzoisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-isoindole-2,1′-piperidinium] methanesulfone A reaction solution containing an acid salt was obtained.

Example 2
4 ′-(1,2-Benzisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-isoindole-2,1′-piperidinium] methanesulfonic acid obtained in Example 1 above To the reaction solution containing salt, 11.3 g of hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione, 7.6 g of potassium carbonate and 22 g of toluene Was added. Thereafter, 22 g of toluene was distilled off, 0.4 g of water was added, and the mixture was reacted for 2 hours under reflux conditions. After completion of the reaction, the reaction mixture was cooled to room temperature, and 200 g of water was added for liquid separation, and the obtained toluene layer was washed with 175 g of 2.3 wt% saline. Further, 0.9 g of activated carbon was added, and the mixture was stirred for 1 hour, and then the activated carbon was separated by filtration, and 2-[[(1R, 2R) -2-[[4- (1,2-benzisothiazol-3-yl)- 278.8 g of a toluene solution containing 1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione It was. 2-[[(1R, 2R) -2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR ) -4,7-methano-1H-isoindole-1,3 (2H) -dione content: 7.6% by weight (calculated by LC absolute calibration curve method). Yield: 93.9%.

Example 3
In Example 1, instead of 3.8 g of potassium carbonate having an average particle diameter (50% D) of 11 μm, potassium carbonate having an average particle diameter (50% D) of 26 μm (Asahi Glass Co., Ltd. product; average particle diameter) (50% D) is a 6-hour reaction in the same manner as in Example 1 except that 3.8 g was used (measured by a laser diffraction particle size distribution analyzer method (wet method using isopropanol, SALD-2100 manufactured by Shimadzu Corporation)). I let you. When the reaction solution was analyzed by LC, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine (calculated according to the above formula (7)) was 17%.

  After cooling to an internal temperature of about 60 ° C., 1.9 g of potassium carbonate (same as above) having an average particle size (50% D) of 26 μm and 0.62 g of tetra-n-butylammonium hydrogen sulfate were added, And stirred for an additional 16 hours, 4 '-(1,2-benzisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-isoindole-2,1'-piperidinium] methanesulfone A reaction solution containing an acid salt was obtained.

  Reaction liquid containing 4 ′-(1,2-benzisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-isoindole-2,1′-piperidinium] methanesulfonate obtained Was added 11.3 g of hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione, 7.6 g of potassium carbonate and 22 g of toluene. Thereafter, 23 g of toluene was distilled off, 0.4 g of water was added, and the mixture was reacted for 2 hours under reflux conditions. After completion of the reaction, the reaction mixture was cooled to room temperature, and 200 g of water was added for liquid separation, and the obtained toluene layer was washed with 175 g of 2.3 wt% saline. Further, 0.9 g of activated carbon was added, and the mixture was stirred for 1 hour, and then the activated carbon was separated by filtration, and 2-[[(1R, 2R) -2-[[4- (1,2-benzisothiazol-3-yl)- 1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione was obtained 288.7 g of toluene solution. It was. 2-[[(1R, 2R) -2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR ) -4,7-methano-1H-isoindole-1,3 (2H) -dione content: 6.9% by weight (calculated by LC absolute calibration curve method). Yield: 89.5%.

Comparative Example 1
In Example 1, in place of 3.8 g of potassium carbonate having an average particle diameter (50% D) of 11 μm, potassium carbonate having an average particle diameter (50% D) of 480 μm (Asahi Glass Co., Ltd. product: average particle diameter) (50% D) was measured by a low-tap sieve shaking method) The reaction was carried out for 6 hours in the same manner as in Example 1 except that 3.8 g was used. When the reaction solution was analyzed by LC, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine (calculated according to the above formula (7)) was 63%.

  Furthermore, although the reaction was continued at the same temperature, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine when about 10 hours passed from the start of the reaction was about 45%. Thereafter, the reaction was continued, but it was found that there was no significant change in the residual rate, the reaction hardly proceeded, and was stopped midway. In addition, the residual rate of 4- (1,2-benzisothiazol-3-yl) piperazine at the time point after 16 hours from the start of the reaction was 43%.

Comparative Example 2
In Example 1, in place of 3.8 g of potassium carbonate having an average particle diameter (50% D) of 11 μm, potassium carbonate having an average particle diameter (50% D) of 290 μm (Asahi Glass Co., Ltd. product; average particle diameter) (50% D) was measured by a low-tap sieve shaking method) The reaction was carried out for 6 hours in the same manner as in Example 1 except that 3.8 g was used. When the reaction solution was analyzed by LC, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine (calculated according to the above formula (7)) was 61%.

  Furthermore, although the reaction was continued at the same temperature, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine when about 10 hours passed from the start of the reaction was about 40%. Thereafter, the reaction was continued, but it was found that there was no significant change in the residual rate, the reaction hardly proceeded, and was stopped midway. In addition, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine at the time point after 17 hours from the start of the reaction was 35%.

Example 4
In Example 1, in place of 3.8 g of potassium carbonate having an average particle diameter (50% D) of 11 μm, potassium carbonate having an average particle diameter (50% D) of 55 μm (Asahi Glass Co., Ltd. product; average particle diameter) (50% D) is a 6-hour reaction in the same manner as in Example 1 except that 3.8 g was used (measured by a laser diffraction particle size distribution analyzer method (wet method using isopropanol, SALD-2100 manufactured by Shimadzu Corporation)). I let you. When the reaction solution was analyzed by LC, the residual ratio of 4- (1,2-benzisothiazol-3-yl) piperazine (calculated according to the above formula (7)) was 20%.

  Furthermore, after reacting at the same temperature for 1 hour, the internal temperature was once cooled to about 60 ° C., 1.9 g of potassium carbonate (same as above) having an average particle diameter (50% D) of 55 μm, and tetra-n-butyl hydrogen sulfate. 0.62 g of ammonium was added, and the mixture was further stirred and reacted under reflux conditions for 8 hours. 4 ′-(1,2-Benzisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-iso A reaction liquid containing indole-2,1′-piperidinium] methanesulfonate was obtained.

Reaction liquid containing 4 ′-(1,2-benzisothiazol-3-yl)-(3aR, 7aR) -octahydro-spiro [2H-isoindole-2,1′-piperidinium] methanesulfonate obtained Was added 11.3 g of hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione, 7.6 g of potassium carbonate and 22 g of toluene. Thereafter, 22 g of toluene was distilled off, 0.4 g of water was added, and the mixture was reacted for 3 hours under reflux conditions. After completion of the reaction, the reaction solution was cooled to room temperature, and 200 g of water was added to carry out a liquid separation treatment, and the obtained toluene layer was washed with 175 g of 2.3 wt% saline. Further, 0.9 g of activated carbon was added, and the mixture was stirred for 1 hour, and then the activated carbon was separated by filtration, and 2-[[(1R, 2R) -2-[[4- (1,2-benzoisothiazol-3-yl)- 1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR) -4,7-methano-1H-isoindole-1,3 (2H) -dione 350.7 g of toluene solution is obtained. It was. 2-[[(1R, 2R) -2-[[4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclohexyl] methyl] hexahydro- (3aS, 4R, 7S, 7aR ) -4,7-methano-1H-isoindole-1,3 (2H) -dione content: 5.7% by weight (calculated by LC absolute calibration curve method). Yield: 89.2%.

Claims (6)

Formula (1) in organic solvent

(In the formula, Z represents an optionally substituted methylene group or an optionally substituted imino group.)
And a compound of formula (2)

(In the formula, X represents a group which is eliminated to form a counter anion, and Y represents an optionally substituted alkylene group having 1 to 2 carbon atoms.)
The compound represented by formula (3) is reacted in the presence of potassium carbonate having an average particle size (50% D) of 200 μm or less.

(In the formula, X, Y and Z have the same meaning as described above.)
The manufacturing method of the quaternary ammonium salt shown by these. The method for producing a quaternary ammonium salt according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst. The manufacturing method of the quaternary ammonium salt of Claim 1 using the potassium carbonate whose average particle diameter (50% D) is 5-200 micrometers. The manufacturing method of the quaternary ammonium salt of Claim 1 using the potassium carbonate whose average particle diameter (50% D) is 5-100 micrometers. A quaternary ammonium salt represented by the formula (3) obtained by any one of claims 1 to 4 and the formula (6)

(In the formula, A represents an optionally substituted alkylene group having 2 to 4 carbon atoms or an optionally substituted alkenylene group having 2 to 4 carbon atoms, and D represents a carbonyl group or a sulfonyl group.)
A compound represented by formula (5) is reacted in the presence of a solid inorganic base:

(In the formula, A, D, Y and Z have the same meaning as described above.)
The manufacturing method of the imide compound shown by these. The method for producing an imide compound according to claim 5, wherein the reaction is carried out in the presence of water.