JPH06220052A - Method for producing imide derivative - Google Patents

Abstract

(57) [Summary] [Purpose] Formula (1) having the antipsychotic effect [Chemical formula 1] The compound represented by is efficiently produced. [Configuration] Formula [Chemical Formula 2] The compound of formula (1) is converted to a quaternary ammonium salt, the R ¹ group is removed, and the hydroxyl group is sulfonylated to react with the imide compound to obtain the compound of formula (1).

Description

Detailed Description of the Invention

[0001]

The present invention relates to a compound having an antipsychotic effect (for example, JP-A-62-123179 and JP-A-58-110).
No. 576 publication).

[0002]

2. Description of the Related Art Japanese Patent Laid-Open No. 58-110576 discloses a formula

[Chemical 6] It is disclosed that a spiro quaternary salt represented by the following formula is reacted with an imide compound. However, the method described in this publication has a very long reaction time and the yield is not satisfactory. In addition, the present inventors

[Chemical 7] (In the formula, R ² and R ³ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogen atom or a lower alkoxy group.) When a compound represented by methanesulfonic acid chloride is reacted, the hydroxyl group is mesyl. It was confirmed that the converted compound was not obtained, and instantly changed to the spiro quaternary salt represented by the above formula. On the other hand, when protecting a tertiary amine, an example of using a methylammonium salt (Can.J.Che
m., 54 , 3310 (1976))) and benzyl ammonium salt (Chem. Rev., 70 , 439 (197
0))) is known, in the latter case the benzyl group is removed by reaction with potassium phthalimide.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to the production of a compound having an antipsychotic effect (for example, JP-A-62-123179) by the general formula (1)

[Chemical 8] (Wherein R ¹ represents a hydroxyl-protecting group, and R ² and R ³ have the same meanings as described above), and a method for obtaining the compound in high yield is provided.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors did not ammonium chloride in the molecule if the reaction was carried out by protecting the tertiary amine in the form of an ammonium salt. Therefore, it has been found that the imidization reaction proceeds extremely smoothly and the yield is improved.

That is, in the production method of the present invention, the 1,2-benzisothiazole derivative represented by the general formula (1) is represented by the general formula (2) R ⁴ —X (2) (wherein R ⁴ is A benzyl group, a substituted benzyl group, a naphthylmethyl group, an allyl group, a substituted allyl group or a methyl group,
X represents a chlorine atom, a bromine atom or an iodine atom. ) Is reacted with a compound represented by

[Chemical 9] (In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described above.) A quaternary ammonium compound represented by General formula

[Chemical 10] (In the formula, R ²⁰ is an organic sulfonic acid residue, and R ² , R ³ , R
⁴ and X have the same meanings as described above. ), A sulfonic acid ester represented by the general formula (3)

[Chemical 11] (In the formula, A represents a divalent hydrocarbon group which may be crosslinked with an oxygen atom.) The compound is reacted with a cyclic imide compound represented by the general formula (7).

[Chemical 12] (Wherein R ² , R ³ and A have the same meanings as described above).

In the above formula, the divalent hydrocarbon group which may be crosslinked by an oxygen atom represented by A is, for example, the general formula (4) described in JP-A-62-123179. )

[Chemical 13] (In formula, E represents a methylene group, an ethylene group, or an oxygen atom, -L- represents a single bond or a double bond.), General formula (5).

[Chemical 14] (In the formula, F represents a methylene group or an ethylene group, and -L
-Denotes the same meaning as described above. ) And general formula (6)

[Chemical 15] (In the formula, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ represent a hydrogen atom or a methyl group.).

The lower alkyl group includes, for example, a linear or branched alkyl group having 6 or less carbon atoms, specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like can be mentioned.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 6 or less carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy and 2-
Methyl propoxy, butoxy, pentoxy, hexoxy and the like can be mentioned.

The substituent of the substituted benzyl group is present on the benzene ring, and examples thereof include a lower alkyl group, a halogen atom and a lower alkoxy group. As the substituted benzyl group,
Specifically, 4-chlorobenzyl, 2-methylbenzyl,
2-fluorobenzyl, 3,4-dimethylbenzyl,
2,6-dichlorobenzyl, 4-methoxybenzyl and the like can be mentioned.

Examples of the substituent of the substituted allyl group include a lower alkyl group and an aryl group (for example, an aryl group having 6 or less carbon atoms such as phenyl and naphthyl). Specific examples of the substituted allyl group include a cinnamyl group, a crotyl group, and a 3-methylcrotyl group.

Examples of the organic sulfonic acid halide include lower alkyl sulfonic acid chloride, aryl sulfonic acid chloride, lower alkyl aryl sulfonic acid chloride, and the like. Specifically, methane sulfonic acid chloride, ethane sulfonic acid chloride, benzene sulfonic acid. Examples thereof include chloride and 4-toluenesulfonic acid chloride.

Examples of the hydroxyl-protecting group include ether type, ester type and silyl ether type protecting groups. The ether-type protecting group includes a cyclic-type protecting group (eg, tetrahydropyranyl, tetrahydrofurfuryl, etc.), 1,1-dimethyl lower alkyl group (eg, 1,1-dimethylethyl, 1,1-dimethylpropyl, etc.) and Examples thereof include alkoxyalkyl groups (eg, methoxymethyl, 1-ethoxyethyl, etc.). Examples of the ester-type protecting group include an alkanoyl group having 6 or less carbon atoms (eg, formyl, acetyl, pivaloyl, etc.) and an aroyl group having 11 or less carbon atoms (eg, benzoyl). Examples of the silyl ether type protecting group include a trialkylsilyl group (eg, trimethylsilyl, triethylsilyl, (1,1-dimethylethyl) dimethylsilyl, etc.) and the like. Among these, preferable protecting groups include, for example, tetrahydropyranyl, 1,1-dimethylethyl, acetyl, trimethylsilyl and the like.

The 1,2-benzisothiazole derivative represented by the general formula (1) can be synthesized by any of the following three synthetic methods.

[Chemical 16]

[Chemical 17]

[Chemical 18] (Wherein, R ¹¹ is a protecting group of the ether type of hydroxyl, R ^1,
R ² , R ³ and X have the same meanings as described above. )

First, the method will be described. After reacting the amine (10) with an organolithium compound or an organomagnesium compound, the compound (12) is reacted, and then an oxidant is allowed to act. Furthermore, in the case of producing a compound in which the protective group for the hydroxyl group is an ester type or a silyl ether type, a 1,2-benzisothiazole derivative of the above formula (1) can be obtained by performing a conversion reaction of the protective group. .

Examples of the organic lithium compound include lower alkyl lithium, aryl lithium and the like, and specific examples include methyl lithium, butyl lithium, phenyl lithium and the like. Examples of the organomagnesium compound include lower alkyl magnesium halides, lower alkenyl magnesium halides, aryl magnesium halides and the like, and specifically, methyl magnesium chloride, ethyl magnesium iodide, propyl magnesium bromide, allyl magnesium chloride, phenyl magnesium bromide and the like. Is mentioned. Examples of the oxidizer include divalent copper salts and iodine, and examples of the divalent copper salts include cupric chloride, cupric bromide, cupric sulfate and the like.

Introduction and deprotection of a protective group for a hydroxyl group may be carried out according to a general method, for example, Protective Groups in Organic Synthesis (Protecti
ve Groups in Organic Synthesis, John Wiley & Sons, I
nc., New York, 1981) 10 to 86. That is, for example, the introduction of tetrahydropyranyl or 1,1-dimethylethyl can be carried out by reacting dihydropyran or isobutene in the presence of an acid catalyst such as sulfuric acid, methanesulfonic acid, or paratoluenesulfonic acid. Deprotection of tetrahydropyranyl or 1,1-dimethylethyl can be carried out by treatment with an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid. Further, for example, the introduction of acetyl can be carried out by reacting acetyl chloride or acetic anhydride in the presence of a base such as pyridine or triethylamine. Deprotection of acetyl can be carried out, for example, by acting potassium carbonate, ammonia or sodium methoxide in methanol, or by acting an aqueous sodium hydroxide solution. For example, trimethylsilyl can be introduced by reacting chlorotrimethylsilane in the presence of a base such as triethylamine. Deprotection of trimethylsilyl can be carried out by treating with an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid.

The amine (10) is, for example, a halide (1
4) and piperazine for organic synthesis (Org.Sy
nth., Coll. Vol. V., 88 (1973)) or by reacting according to this method for synthesis. Also,
The halide (14) can be synthesized by protecting the hydroxyl group of the corresponding hydroxy halide.

The 2,2'-dithiodibenzonitrile derivative (12) can be obtained from Journal of Organic Chemistry (J.Org.Chem.Vol.43,1604 (1978)) or Justus Liebigs Anneren der Chemie. (Just
us Liebigs Ann. Chem. Vol. 748, 201 (1971)) or according to these methods. It can also be synthesized by amidating a 2,2′-dithiodibenzoic acid derivative and dehydrating it.

Next, the method will be described. Amine (1
When an organolithium compound or an organomagnesium compound is reacted with 0) and then chloride (13) is reacted to produce a compound whose hydroxyl protecting group is an ester type or a silyl ether type, further conversion of the protecting group is carried out. By carrying out the reaction, the compound of the above formula (1) can be obtained.

Conventionally, the reaction of a primary or secondary amine with chloride (13) has been carried out without the presence of a base. In that case, a compound in which the 1,2-benzisothiazole ring is opened is a by-product. However, the yield was slightly poor (JP-A-58-110).
576, West German patent specification 1,174,783, Justus Liebigs (Justus Liebigs)
Ann. Chem., Vol. 729, 146 (1969)). However, by converting the amine into lithium amide or magnesium amide and then reacting with chloride (13), compound (1) can be obtained in high yield with almost no generation of by-products.

Chloride (13) is Chemiste Berchte (Chem. Ber., 99 , 2566 (1966)) or JP-A-61-11206.
It can be synthesized by the method described in JP-A-3. Next, the method will be described. When the halide (14) is reacted with the amine (15) in the same manner as in the synthesis of the amine (10) to produce a compound having a hydroxyl protecting group of an ester type or a silyl ether type, a conversion reaction of the protecting group is further performed. By carrying out, the compound of the formula (1) can be obtained. The amine (15) can be synthesized according to the method described in JP-A-58-110576. The imide (3) can be synthesized by the method described in JP-A-62-123179.

The production method of the present invention can be carried out by continuously performing the following four operations. Operation 1: Operation of reacting compound (1) with halide (2) to form ammonium salt. Operation 2: Operation for deprotecting the protective group for the hydroxyl group. Operation 3: Operation for reacting with organic sulfonic acid halide. Operation 4: Operation of reacting with imide (3). In the following description, the molar ratio of compounds, the amount of solvent, and the like are based on the compound (1) that is the main raw material.

First, the operation 1 will be described. Preferred examples of the halide (2) include, for example, benzyl bromide, benzyl chloride, 4-chlorobenzyl chloride, 2-methylbenzyl bromide, 1- (chloromethyl) naphthalene, allyl bromide, crotyl chloride, cinnamil chloride, iodide. Examples thereof include methyl, and particularly preferable examples include benzyl bromide and cinnamil chloride. The halide (2) can be used in an amount of 1 to 5 times, preferably 1 to 2 times the mol of the compound (1). Examples of the reaction solvent include ketone solvents such as acetone, 2-butanone, and 3-methyl-2-butanone; amide solvents such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile;
Examples thereof include esters such as ethyl acetate and butyl acetate, ethers such as tetrahydrofuran, dimethoxyethane and diglyme, and mixtures thereof. Preferred solvents include ketone solvents and amide solvents. The amount of solvent is usually 1 to 50 times by weight, preferably 2 to 20 times by weight, based on the compound (1). The reaction temperature is in the range of room temperature to the boiling point of the reaction solvent, and the preferable reaction temperature is in the range of 50 to 100 ° C. In this reaction, it is also possible to carry out the reaction in the presence of an alkali metal carbonate such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate. After completion of the reaction, the following operation may be carried out as it is, or treatment with ammonia or amine may be carried out before the next operation, or washing with water may be carried out. Preferably, it is treated with ammonia or amine before the next operation. The temperature of the treatment with ammonia or amine may be in the range of 0 ° C. to the boiling point of the solvent. Examples of ammonia include ammonia gas and aqueous ammonia, and examples of amine include primary amines such as methylamine, ethylamine and propylamine, and secondary amines such as dimethylamine and diethylamine.
Ammonia or amine is preferably used in an amount of 1 time mol or more with respect to the halide (2). Washing with water can be carried out by adding an ester such as ethyl acetate or a halogenated hydrocarbon such as methylene chloride or chloroform and then washing with water.

Next, the operation 2 will be described. Deprotection of the hydroxyl-protecting group is carried out in the same manner as described above. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, acetone, 2-butanone,
Examples thereof include ketone solvents such as 3-methyl-2-butanone, amide solvents such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, ethers such as tetrahydrofuran, dimethoxyethane and diglyme, water and a mixture thereof. Preferred solvents include alcohol solvents, mixed solvents of alcohol solvents and the above solvents, or mixed solvents of water and the above solvents. When a solvent different from the solvent used in operation 1 is used, the solvent is distilled off and a new solvent is added. Also,
The reaction can be performed by further adding an alcohol solvent or water to the solvent used in the operation 1. The amount of the solvent used is usually in the range of 2 to 50 times by weight that of the compound (1), but is preferably in the range of 3 to 20 times by weight. The reaction temperature is
It depends on the type of protecting group and the reagent used for deprotection. For example, the protecting group tetrahydropyranyl, 1,
1-dimethyl ethyl or trimethyl silyl is hydrochloric acid,
When removing with an aqueous solution of a mineral acid such as sulfuric acid, the reaction temperature is preferably in the range of room temperature to 70 ° C. Moreover, for example, when deprotecting acetyl which is a protecting group using sodium methoxide, the reaction temperature is preferably in the range of 10 to 40 ° C. After completion of the reaction, the reaction solvent is exchanged or washed with water. The reaction solvent is exchanged by distilling off the solvent of the reaction solution, and then adding pyridines such as pyridine, picoline and lutidine, or methylene chloride, halogenated hydrocarbons such as chloroform and distilling the solvent again. It can be carried out once to several times. Washing with water can be carried out by adding halogenated hydrocarbons such as methylene chloride and chloroform, and then washing with a basic aqueous solution such as aqueous ammonia once to plural times.

Next, the operation 3 will be described. Operation 3
Then, the compound obtained in operation 2 is reacted with an organic sulfonic acid halide in the presence of a base to synthesize a sulfonic acid ester. Examples of the base include tertiary amines such as triethylamine and tripropylamine, pyridines such as pyridine, picoline and lutidine, and N, N-dimethylaminopyridine. The preferred base is
Examples include triethylamine and pyridine.
The base is used in an amount of 1 equivalent or more relative to the compound (1), and for example,
A large excess can be used as a reaction solvent. The organic sulfonic acid halide is preferably used in 1 to 3 times the molar amount of the compound (1). Particularly preferably, it is in the range of 1 to 2 times by mole. As the reaction solvent, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran, dimethoxyethane and diglyme, tertiary amines such as triethylamine and tripropylamine, pyridines such as pyridine, picoline and lutidine, or These mixed solvents are mentioned. Preferred solvents include halogenated hydrocarbons and pyridines. The amount of the solvent is usually 2 to 50 times by weight, preferably 3 to 20 times by weight, relative to the compound (1). The reaction temperature is 0 ° C to the boiling point of the reaction solvent, preferably 0-40 ° C. After completion of the reaction, a basic solvent such as aqueous ammonia may be added and extraction may be performed with a halogenated hydrocarbon such as methylene chloride or chloroform, or the reaction solvent may be distilled off and the following operation may be carried out as it is.

Next, the operation 4 will be described. Operation 4
Then, the sulfonic acid ester obtained in operation 3 is reacted with 2 equivalents of imide (3) in the presence of a base to imidize and deprotect the ammonium salt to synthesize an imide derivative (7). Examples of the base include carbonates of alkali metals, specifically potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and the like. The base is preferably used in a 1- to 10-fold molar quantity versus compound (1). Particularly preferably, it is in the range of 2 to 4 times by mole. The imide (3) is 2 with respect to the compound (1)
It is preferable to use a 10-fold molar amount. Particularly preferably 2
A range of up to 4 times the molar amount is included. Examples of the reaction solvent include ketone solvents such as acetone, 2-butanone and 3-methyl-2-butanone, amide solvents such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, ethers such as tetrahydrofuran, dimethoxyethane and diglyme. , Dimethyl sulfoxide, or a mixture thereof. Preferred solvents include amide solvents. The amount of the solvent is appropriately in the range of 3 to 50 times by weight with respect to the compound (1), but preferably 5 to 5.
A range of 20 times by weight is included. Since this reaction has two reaction points, the reaction proceeds in two stages. Therefore,
The reaction temperature can be changed in two steps to carry out the reaction sequentially, or the reaction temperature can be raised from the beginning to react at once. When raising the reaction temperature in two steps, the first step reaction is carried out, for example, in the range of 50 to 100 ° C., preferably 70 to 90 ° C., and the second step reaction is carried out, for example, in the range of 100 to 140 ° C. Range, preferably 110-13
It is carried out in the range of 0 ° C. When raising the reaction temperature from the beginning, the reaction temperature is the same as the reaction temperature in the above-mentioned second step.
Since the reaction proceeds in two stages as described above, the amount of the imide (3) used can be reduced by carrying out the second stage deprotection reaction of the ammonium salt using another imide. Examples of other imides include phthalimide and succinimide. After completion of the reaction, the imide derivative (7) is isolated by adding an extraction solvent and washing with water, distilling off the solvent and crystallizing as it is or in the form of a salt, or by purifying by column chromatography. be able to. As the extraction solvent, aromatic hydrocarbons such as toluene and xylene, methylene chloride, chloroform, 1,2-
Examples thereof include halogenated hydrocarbons such as dichloroethane, esters such as ethyl acetate, or a mixture thereof. Aromatic hydrocarbons are mentioned as a preferable extraction solvent.

Examples of the salt of the imide derivative (7) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide and sulfate, and acetate, oxalate, citrate and malic acid. Organic salts such as salts, tartrates, fumarates and maleates can be mentioned. As the solvent for crystallization, hexane, hydrocarbons such as heptane, toluene, aromatic hydrocarbons such as xylene, methylene chloride, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane, esters such as ethyl acetate, methanol, ethanol, 2
-Alcoholic solvents such as propanol, water, or a mixture thereof. An alcohol solvent is mentioned as a preferable solvent.

[0029]

EFFECTS OF THE INVENTION According to the method of the present invention, the imide derivative (7) can be industrially produced in a short reaction time and in a high yield.

[0030]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Reference Example 1 Synthesis of 2,2′-dithiodibenzonitrile 2,2′-dithiodibenzoic acid 91.8 g (300 mmo
l), toluene 390 g, dimethylformamide 0.3
g mixture was heated to 73-77 ° C and thionyl chloride 8 was added.
2.2 g (691 mmol) was added dropwise. After the dropping, the mixture was kept at the same temperature for 3 hours, concentrated under reduced pressure, 180 g of toluene was added, and 126 g (2.07 mo of 28% ammonia water under ice cooling was added.
l) was added dropwise. After dropping, the mixture was reacted at 20 to 25 ° C. for 3 hours, and then 480 g of water and 48% sodium hydroxide aqueous solution 129
g (1.55 mol) was added, and the mixture was stirred at 40 to 45 ° C. for 3 hours. The reaction solution was separated, the aqueous layer was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration to give 2,2′-dithiodibenzoic acid amide 8
7.8 g (96% yield) was obtained. Melting point 250-253 [deg.] C. Then, the above 2,2'-dithiodibenzoic acid amide 11.4
g (37.5 mmol) to phosphorus oxychloride 37.5 g
It was mixed with (245 mmol) and heated at 90 to 95 ° C. for 1 hour. The reaction solution was cooled, concentrated to about 1/2, poured into ice water, and extracted with toluene. The toluene layer was washed with a 5% aqueous sodium hydroxide solution and washed with water. The toluene layer was dried and the solvent was distilled off. The crystalline residue was collected by filtration to give the title compound 2,
6.0 g of 2'-dithiodibenzonitrile (yield 60%)
Got Melting point 98-101 ° C ¹ H-NMR (CDCl ₃ ) δ: 7.33-7.45
(2H, m), 7.53-7.65 (2H, m), 7.
66 (2H, d, J = 7.6Hz), 7.78 (2H,
d, J = 7.8 Hz)

Reference Example 2 Synthesis of 1- (4- (2-tetrahydropyranyloxy) butyl) piperazine 15.4 g (183 mmol) of dihydropyran was dissolved in 260 ml of methylene chloride to give 1.9 g of p-toluenesulfonic acid pyridinium salt. 7.6 mmol) was added thereto, and 15.4 g (14
2 mmol) was added dropwise. After the dropping, the mixture was stirred at room temperature for 3 hours, washed with water and dried. After distilling off the solvent, the residual oily substance was distilled under reduced pressure, and 21.9 g of 4- (2-tetrahydropyranyloxy) butyl-1-chloride (yield 8
0.0%) was obtained. Boiling point 109 ° C./10 mmHg Next, 19.3 g (100 mmol) of this oily substance was dissolved in 800 ml of acetonitrile, and 43 g of piperazine (500
mmol), 43 g of potassium iodide (259 mm
ol) and 43 g (311 mmol) of potassium carbonate were sequentially added, and the mixture was heated under reflux for 4 hours. The reaction solution was cooled, acetonitrile was distilled off under reduced pressure, ice water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water, dried and the solvent was distilled off. The residual oil was distilled under reduced pressure to give the title compound 1- (4- (2-tetrahydropyranyloxy) butyl) piperazine 18.
8 g (yield 77.6%) was obtained. Boiling point 137 ° C / 1 mmHg ¹ H-NMR (CDCl ₃ ) δ: 1.4-1.9 (10
H, m), 2.3-2.5 (6H, m), 2.85-
2.95 (4H, m), 3.30-3.55 (2H,
m), 3.70-3.90 (2H, m), 4.55 (1
H, s)

Reference Example 3 Synthesis of 1- (4- (1,1-dimethylethoxy) butyl) piperazine 4-chloro-1-butanol 21.7 g (0.20 mo)
l) was dissolved in 60 ml of 1,4-dioxane, 19.2 g (0.20 mol) of methanesulfonic acid was added, and the mixture was stirred at room temperature for 1 hour and a half while bubbling isobutene.
A dioxane solution of -chloro-1- (1,1-dimethylethoxy) butane was obtained. Under a nitrogen atmosphere, 86.1 g (1.00 mol) of anhydrous piperazine and 16.0 g (0.40 mol) of sodium hydroxide were added to 200 ml of water,
While refluxing, the dioxane solution of 4-chloro-1- (1,1-dimethylethoxy) butane was added dropwise.
Refluxed for 5 hours. The reaction solution is cooled and 200 ml of toluene
2 times, dried over magnesium sulfate, distilled off the toluene, and added 1- (4- (1,1-dimethylethoxy) butyl) piperazine and 1,4-bis (4- (1,1-dimethylethoxy) ) Butyl) piperazine, 82: 18 ^* ) was obtained as a mixture of 35.2 g (66% yield from 4-chloro-1-butanol). This product can be used in the next step as it is, but it can be further purified by vacuum distillation. The physical property data of the purified product are as follows. ( ^*)
Analysis by gas chromatography) Boiling point 142-144 ° C 10 mmHg ¹ H-NMR (CDCl ₃ ) δ: 1.18 (9H,
s), 1.45 to 1.65 (4H, m), 2.33 (2
H, t, J = 7.4 Hz), 2.41 (4H, br
s), 2.85-2.95 (4H, m), 3.35 (2
H, t, J = 5.6Hz)

Reference Example 4 4- (1,2-benzisothiazol-3-yl) -1
-(4- (2-tetrahydropyranyloxy) butyl)
Synthesis of piperazine 203 mg (8.3 mmol) of magnesium and 75 of 1-bromoproban in 5 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere.
9 μl (8.4 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A solution of 1- (4- (2-tetrahydropyranyloxy) butyl) piperazine (2.02 g, 8.3 mmol) in anhydrous tetrahydrofuran (16 ml) was added under reflux, and the mixture was refluxed for 20 minutes. Further, under reflux, 671 mg (2.5%) of 2,2'-dithiodibenzonitrile
Anhydrous tetrahydrofuran (5 ml) solution of (mmol) was added dropwise, and the mixture was refluxed for 1.5 hours. After cooling to room temperature, iodine 6
35 mg (2.5 mmol) was added and stirred for 1 hour. 20 ml of water was added, extracted twice with 40 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off, followed by purification by silica gel column chromatography (5% methanol / chloroform (volume ratio)). 1.84 g of-(1,2-benzisothiazol-3-yl) -1- (4- (2-tetrahydropyranyloxy) butyl) piperazine (yield 98.
2%). ¹ H-NMR (CDCl ₃ ) δ: 1.40 to 1.90 (10H,
m), 2.47 (2H, br.s), 2.60-2.75 (4H,
m), 3.35-3.67 (2H, m), 3.50-3.65 (4H,
m), 3.73-3.96 (2H, m), 4.60 (1H.s), 7.
30-7.42 (1H, m), 7.42-7.55 (1H, m), 7.81
(1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 8.3
Hz)

Reference Example 5 4- (1,2-benzisothiazol-3-yl) -1
Synthesis of-(4-acetoxybutyl) piperazine Under a nitrogen atmosphere, anhydrous tetrahydrofuran 45 ml, magnesium 790 ml (32.5 mmol) and 1-bromopropane 2.
95 ml (32.5 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. N- (4- (1,1-dimethylethoxy) butyl) under reflux
6.60 g (30.1 mmol) of piperazine was added dropwise and the mixture was refluxed for 10 minutes. Further, under reflux, 2,2'-dithiodibenzonitrile 3.36 g (12.5 mmol) anhydrous tetrahydrofuran (12 m
l) The solution was added dropwise and refluxed for 2 hours. After cooling to room temperature, cupric chloride, 4.27 g (25.0 mmol) of dihydrate in water (50
ml) solution was added and stirred at room temperature for 1 hour. 50 ml of concentrated hydrochloric acid
Was added, the mixture was refluxed for 30 minutes, cooled to room temperature, and washed with 100 ml of methylene chloride. The mixture was made alkaline with 100 ml of 29% aqueous ammonia, extracted once with 150 ml of toluene, dried over anhydrous magnesium sulfate, and concentrated to a liquid volume of 60 ml. Triethylamine 5.22 under nitrogen atmosphere
ml (37.5 mmol) and acetic anhydride 4.72 ml (50.0 mmol) were added,
The mixture was stirred at 60 ° C for 2 hours. The reaction solution was cooled, added with 5 ml of methanol at room temperature, stirred for 10 minutes, washed with 53 ml of 5% sodium carbonate aqueous solution and 50 ml of water, and dried over anhydrous magnesium sulfate. By distilling off the solvent, 4-
(1,2-Benzisothiazol-3-yl) -1-
7.53-g (4-acetoxybutyl) piperazine (yield 90.3
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.80 (4H,
m), 2.06 (3H, s), 2.46 (2H, t, J = 7.3H
z), 2.60-2.75 (4H, m), 3.50-3.65 (4H,
m), 4.11 (2H, t, J = 6.3 Hz), 7.30-7.42 (1
H, m), 7.42-7.53 (1H, m), 7.81 (1H, d,
J = 7.9 Hz), 7.91 (1H, d, J = 7.9 Hz)

Reference Example 6 4- (1,2-benzisothiazol-3-yl) -1
Synthesis of-(4- (1,1-dimethylethoxy) butyl) piperazine In the same manner as in Reference Example 4 and Reference Example 4, 4- (1,2-
Benzisothiazol-3-yl) -1- (4- (1,
1-Dimethylethoxy) butyl) piperazine yield 97.5
Earned in%. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (9H, s), 1.5
0-1.75 (4H, m), 2.45 (2H, t, J = 7.4Hz)
, 2.60-2.75 (4H, m), 3.38 (2H, t, J = 6.1
Hz), 3.50-3.65 (4H, m), 7.31-7.42 (1H,
m), 7.42-7.53 (1H, m), 7.81 (1H, d, J =
7.31Hz), 7.91 (1H, d, J = 7.1 Hz)

Reference Example 7 4- (1,2-benzisothiazol-3-yl) -1
-(4- (2-tetrahydropyranyloxy) butyl)
Synthesis of piperazine 1.45 g (6.0 mmol) of 1- (4- (2-tetrahydropyranyloxy) butyl) piperazine was dissolved in 6 ml of tetrahydrofuran under a nitrogen atmosphere, and 3.75 ml of a 1.6N, n-butyllithium hexane solution was added at 5 ° C. (6.0 mmol) was added dropwise and 20
Stir for minutes. 3-chloro-1,2-benzisothiazole 849 mg (5.0 mmol) tetrahydrofuran (1 ml)
The solution was added dropwise at 30 ° C. and stirred for 2 hours. 10 ml of water was added, the mixture was extracted twice with 10 ml of ethyl acetate and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (5% methanol / chloroform (volume ratio)) to give 4- (1,2-benzisothiazol-3-yl) -1- (4- (. 2-tetrahydropyranyloxy) butyl) piperazine 1.83 g (yield 97.5
%) Was obtained. ^It was in agreement with the compound obtained in Reference Example 4 in ¹ H-NMR.

Example 1 Synthesis of cis-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) cyclohexane-1,2-dicarboximide Under nitrogen atmosphere , 4- (1,2-benzisothiazole-
3-yl) -1- (4-acetoxybutyl) piperazine
1.00 g (3.0 mmol) was dissolved in 5 ml of acetone, 714 μl (6.0 mmol) of benzyl bromide was added, and the mixture was refluxed for 2 hours. Two
10 ml of 9% aqueous ammonia, 3 ml of methanol and 120 mg (3.0 mmol) of sodium hydroxide were added, and the mixture was stirred at room temperature for 12 hours. It was extracted once with 20 ml of chloroform and three times with 10 ml, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was dissolved in 10 ml of methylene chloride and triethylamine was added.
1.26 ml (9.0 mmol) was added, methanesulfonic acid chloride 464 μl (6.0 mmol) was added at room temperature, and the mixture was stirred for 1 hour. Two
10 ml of 9% aqueous ammonia was added, the mixture was extracted twice with 10 ml of methylene chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dissolved in 10 ml of N, N-dimethylformamide, 1.24 g (9.0 mmol) of potassium carbonate and 1.38 g (9.0 mmol) of cis-cyclohexane-1,2-dicarboximide were added, and the mixture was kept at 90 ° C. for 45 minutes. The mixture was stirred at 130 ° C for 4 hours.
30 ml of toluene was added, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (ethyl acetate) to give cis-N-.
(4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) cyclohexane-
1.16 g (yield 91%) of 1,2-dicarboximide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 to 1.95 (12H,
m), 2.45 (2H, t, J = 7.1 Hz), 2.60-2.75 (4
H, m), 2.85 (2H, t, J = 4.5 Hz), 3.47-3.65
(6H, m), 7.30-7.42 (1H, m), 7.42-7.53
(1H, m), 7.81 (1H, d, J = 8.2 Hz), 7.90
(1H, d, J = 8.2 Hz)

Example 2 Synthesis of cis-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) cyclohexane-1,2-dicarboximide Under nitrogen atmosphere , 4- (1,2-benzisothiazole-
3-yl) -1- (4- (1,1-dimethylethoxy)
Butyl) piperazine 304mg (0.87mmol) in acetone 1.5m
It was dissolved in 1 liter, 178 μl (1.5 mmol) of benzyl bromide was added, and the mixture was heated under reflux for 1.5 hours. 2 ml of methanol and concentrated hydrochloric acid
0.8 ml was added and the mixture was refluxed for 30 minutes, and the solvent was distilled off. The procedure of adding 2 ml of pyridine and distilling off the solvent was repeated twice, then 2 ml of methylene chloride and 1 ml of pyridine were added, 233 μl (3.0 mmol) of methanesulfonic acid chloride was added at room temperature, and the mixture was stirred for 30 minutes. 29% ammonia water 3 in the reaction solution
ml and methylene chloride (15 ml) were added, and the mixture was stirred and then separated, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was dissolved in 5 ml of dimethylformamide, and 552 mg (4.0 mmol) of potassium carbonate and cis-cyclohexane-1,
612 mg (4.0 mmol) of 2-dicarboximide was added, and 9
The mixture was stirred at 0 ° C for 20 minutes and then at 130 ° C for 20 minutes. Toluene (20 ml) was added, washed with water (20 ml) twice and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate) to give cis-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl. ) Cyclohexane-1,2-dicarboximide 33
7 mg (yield 90%) was obtained. ^It was in agreement with the compound obtained in Example 1 in ¹ H-NMR.

Example 3 Synthesis of cis-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) cyclohexane-1,2-dicarboximide Under nitrogen atmosphere , 4- (1,2-benzisothiazole-
3-yl) -1- (4- (2-tetrahydropyranyloxy) butyl) piperazine (458 mg, 1.22 mmol) was dissolved in dimethylformamide (1 ml), and benzyl chloride 28
8 μl (2.94 mmol) and 188 mg of sodium iodide (1.2
5 mmol) was added and the mixture was stirred at 50 ° C. for 2.5 hours. Water (1 ml) was added, the mixture was extracted 3 times with ethyl acetate (1 ml), dried over magnesium sulfate, and the solvent was evaporated. The resulting oily substance was dissolved in 10 ml of methanol under a nitrogen atmosphere, and 0.25 ml of concentrated hydrochloric acid (~ 3 m) was added.
mol) was added and the mixture was stirred at 40 ° C. for 30 minutes. The solvent was distilled off, 10 ml of methylene chloride was added, the solvent was distilled off again, and then 10 ml of methylene chloride and 0.5 ml of pyridine (6.
2 mmol) was added, and methanesulfonic acid chloride 23 was added.
2 μl (3.0 mmol) was added and stirred for 1.5 hours. After the reaction was completed, methylene chloride was distilled off, and 5 ml of dimethylformamide was added.
Was added and potassium carbonate 1.38 g (10 mmol) and cis-cyclohexane-1,2-dicarboximide 1.53 g (10
mmol) and added at 100 ° C for 20 minutes, then 140 ° C.
And stirred for 20 minutes. Add 20 ml of water and add 20 ml of toluene.
It was extracted twice with and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate) to give cis-N- (4- (4-
405 mg (yield 78%) of (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) cyclohexane-1,2-dicarboximide was obtained. ¹ H-N
It was identical with the compound obtained in Example 1 in MR.

Claims (1)

[Claims] 1. A general formula: (In the formula, R ¹ represents a hydroxyl-protecting group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogen atom or a lower alkoxy group.) A compound represented by the general formula R ⁴ -X (In the formula, R ⁴ represents a benzyl group, a substituted benzyl group, a naphthylmethyl group, an allyl group, a substituted allyl group or a methyl group,
X represents a chlorine atom, a bromine atom or an iodine atom. ) By reacting with a compound represented by the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described above.) A quaternary ammonium compound represented by By reacting with the general formula: (In the formula, R ²⁰ is an organic sulfonic acid residue, and R ² , R ³ , R
⁴ and X have the same meanings as described above. ) And a sulfonic acid ester represented by the general formula: (Wherein A represents a divalent hydrocarbon group which may be crosslinked with an oxygen atom), and is reacted with a cyclic imide compound represented by the following general formula: (In the formula, R ² , R ³ and A have the same meanings as described above.) A method for producing an imide derivative.