MXPA06001128A - Process for producing imide compound - Google Patents

Abstract

A process for producing an imide compound hydrochloride. It is an excellent industrial process. The process, which is for producing either the imide compound hydrochloride represented by the formula (2):or enantiomers thereof, is characterized by treating either the compound represented by the formula (1):or enantiomers thereof with an aqueous hydrochloric acid solution in a hydrophilic medium and crystallizing the resultant hydrochloride.

Description

PROCEDURE TO PRODUCE AN IMIDA COMPOUND TECHNICAL FIELD The present invention relates to a process for producing an imide compound of the formula (2) or an enantiomer thereof, which is useful as a psychotropic substance.

BACKGROUND OF THE INVENTION It has been reported that the hydrochloride of the imide compound of the above formula (2) can be produced by treating an imide compound in free form of the formula (1): with a solution of 2-propanol hydrogen chloride in acetone, and crystallizing the resultant. However, said method is not sufficient for an industrial process in the aspect of the availability and handling of the reagents that are used therein (cf., JP-A-5-17440).

DETAILED DESCRIPTION PE THE INVENTION An object of the present invention is to provide an excellent industrial process for producing the above hydrochloride of the imide compound. The present inventors studied intensively to solve the aforementioned problems, and found that the hydrochloride of the measured compound of the above formula (2) can be obtained in a high amount and a high yield under mild and simple reaction conditions, by the treatment of the compound of the above formula (1) with an aqueous solution of hydrochloric acid in a hydrophilic solvent, and crystallizing the resultant, and the present invention was achieved. That is, the present invention relates to the following: [1] A process for producing a hydrochloride of the imide compound of the formula (2): (2) or an enantiomer thereof, which comprises treating a compound of the formula (1): or an enantiomer thereof with an aqueous solution of hydrochloric acid in a hydrophilic solvent, and crystallizing the resulting one. [2] The process for producing the hydrochloride of the imide compound according to [1] above, wherein the hydrophilic solvent is a ketone solvent. [3] The process for producing the hydrochloride of the imide compound according to the above [1] wherein the hydrophilic solvent is acetone. [4] The process for producing the hydrochloride of the imide compound according to any of the above [1], [2] and [3], wherein the aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid at 1.8 - 14.4 %. [5] The process for producing the hydrochloride of the imide compound according to any of the above [1], [2] and [3], wherein the aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid at 3.0 - 5.0 %.

The hydrochloride of the imide compound of the above formula (2) or an enantiomer thereof (hereinafter, referred to simply as the hydrochloride of the imide compound of the formula (2) or the hydrochloride of the imide compound (2) ) can be produced with the treatment of a solution of the compound of the above formula (1) or an enantiomer thereof (hereinafter, occasionally referred to simply as the compound of the formula (1) or the compound ( 1)) in a hydrophilic solvent with an aqueous solution of hydrochloric acid, and crystallizing the resulting one. The compound of the formula (1) can be produced according to the method described in JP-A-5-17440. The hydrophilic solvent includes, for example, ketone solvents, ether solvents, and alcohol solvents, and ketone solvents are preferable. The ketone solvent includes, for example, dialkyl ketones having no more than 6 carbon atoms such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc. The preferable ones are acetone, methyl ethyl ketone, and the most preferable one is acetone. The ether solvent includes, for example, cyclic ethers having no more than 6 carbon atoms, such as tetrahydrofuran, dioxane, etc., and acyclic dialkyl ethers having no more than 6 carbon atoms, such as dimethyl ether, diethyl ether, etc. The most preferred is tetrahydrofuran. The alcohol solvent includes, for example, alcohols having no more than 6 carbon atoms such as 2-propanol, ethanol, methanol, ethylene glycol, and the preferred one is 2-propanol. The hydrophilic solvent is normally used in a quantity of 3 to 100 times (by weight) of the amount of the compound (1), preferably in an amount of 5 to 30 times (by weight) of the amount of the compound (1), and more preferably in an amount of 7 to 15 times (by weight) of the amount of the compound (1). The temperature for dissolving the compound (1) in the hydrophilic solvent is usually in the range of 0 ° C to a reflux temperature, preferably in the range of 25 ° C to a reflux temperature. For solvents other than ether solvents, the temperature is preferably in the range of 45 ° C to a reflux temperature. The concentration of the hydrogen chloride in the aqueous solution of hydrochloric acid is not necessarily necessarily. For example, an aqueous solution of hydrochloric acid in a concentration of 0.3-36% can be exemplified. The concentration of the hydrogen chloride in the aqueous hydrochloric acid solution is preferably an aqueous hydrochloric acid solution at 1.8 to 14.4%, more preferably an aqueous solution of hydrochloric acid at 3.0 to 5.0%, from the point of view of (i) ) the amount of the hydrophilic solvent that is contained in the crystals of the hydrochloride of the imide compound, (ii) the amount of impurities contained in the crystals of the hydrochloride of the measured compound, and (iii) the yield (see Table 1).

The equivalents of the hydrochloric acid which is normally used are in the range of 0.9 to 3 equivalents, preferably in the range of 1.0 to 2.0 equivalents, more preferably in the scale of 1.0 to 1.3 equivalent, to one equivalent of the compound (1). The temperature for treating the compound (1) with an aqueous solution of hydrochloric acid in a hydrophilic solvent and crystallizing the resulting one, is not necessarily specific, and these procedures can be carried out either under cooling or under heating. The reaction temperature is usually in the range of 0 ° C to a reflux temperature, preferably in the range of 25 ° C to a reflux temperature, and more preferably in the scale of 50 ° C to a reflux temperature. The method for mixing a solution of the compound (1) in a hydrophilic solvent and an aqueous solution of hydrochloric acid is not necessarily specific. For example, a method for adding an aqueous solution of hydrochloric acid in a solution of the compound (1) in a hydrophilic solvent, a method for adding a solution of the compound (1) in a hydrophilic solvent in an aqueous solution of acid can be used. hydrochloric, a method for simultaneously adding both a solution of the compound (1) in a hydrophilic solvent, and an aqueous solution of hydrochloric acid in the reactor vessel, a method for adding a mixture of an aqueous solution of hydrochloric acid and a hydrophilic solvent in a solution of the compound (1), in a hydrophilic solvent, a method for adding a solution of the compound (1) to a hydrophilic, in a mixture of an aqueous solution of hydrochloric acid and a hydrophilic solvent, etc. The time needed to mix a solution of the compound (1) in a hydrophilic solvent and an aqueous solution of hydrochloric acid is not necessarily specified, for example, a method is exemplified for mixing both solutions at the same time, a method for mixing by adding one of them in the other during an extended period of time. Usually a method is used to mix adding one of them in the other occupying an extended period of time. In this case, the time that will be needed is on the scale, for example, from one minute to 6 hours, preferably on the scale of 3 minutes to 3 hours. The crystals of the hydrochloride of the imide compound precipitated by the hydrochloric acid treatment are separated by a conventional method, for example, by filtration, to produce the hydrochloride of the imide compound of the formula (2) above. The temperature of the reaction suspension before filtration is not necessarily specified, and normally the filtration is carried out after the reaction suspension has sufficiently crystallized by cooling or heating. The temperature for maintaining the reaction suspension is usually in the range of -20 ° C to 60 ° C, preferably in the range of -10 ° C to 25 ° C, more preferably in the range of 0 to 10 ° C. The hydrochloride of the imide compound (2) separated in this manner can be obtained in the solvent free form by drying it. The drying method is not necessarily specified, for example, drying under reduced pressure, drying under atmospheric pressure, drying with aeraseon of inert gas, such as nitrogen or air flow. The drying temperature is not necessarily specified, and the drying is carried out either by cooling or by heating, preferably at a temperature of 0 to 50 ° C. It is known that the hydrochloride of the imide compound represented by the above formula (2) is useful as an agent for the treatment of schizophrenia, etc. (Cf. JP-A-5-17440). By using an aqueous solution of hydrochloric acid, which is easily obtained and is excellent for its safety and operability, without the need to produce it from a gas of hydrochloric acid and a solvent by mixing them as hydrochloric acid / solvent system, it becomes possible the industrially advantageous production of the hydrochloride of the imide compound. The present invention is illustrated in more detail by the examples, but the present invention should not be limited by them.

EXAMPLE 1 (2) It was dissolved (1 R, 2S, 3R, 4S) -N - [(1 R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide (8.25 g) in acetone (102 g) with heating, under reflux to produce an acetone solution thereof. To this solution was added dropwise an aqueous solution of 3.6% hydrochloric acid (18.5 g, 1.1 equivalent) over a period of about 15 minutes while maintaining the solution at about 55 ° C. After the addition was complete the reaction mixture was stirred at about 60 ° C for 1 hour. The reaction mixture was cooled to 0 ° C, and stirred at the same temperature for one hour. The mixture was filtered, and the resulting solid was dried at room temperature under reduced pressure to produce (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1) hydrochloride , 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide (7.5 g, yield: 85%).

EXAMPLE 2 It was dissolved (1 R, 2S> 3RI4S) -N - [(1R, 2R) -2- [4- (1, 2-benzothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1 jheptanedicarboxyimide (8.25 g) in acetone (102 g) with heating under reflux to produce an acetone solution thereof. To this acetone solution was added dropwise a 3.6% aqueous hydrochloric acid solution (18.5 g, 1.1 equivalent) at about 55 ° C over a period of about 15 minutes. After the mixture was stirred at about 60 ° C for one hour, the reaction mixture was cooled to 0 ° C, and stirred at the same temperature for one hour, the mixture was filtered, and the resulting solid was dried at room temperature under reduced pressure to produce (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] hydrochloride - 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide (7.5, yield: 85%).

EXAMPLE 3 In the procedure of Example 2, 3.6% (1.1 equivalent) hydrochloric acid aqueous solution (1.1 equivalent) was added dropwise over a period of one hour. (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] hydrochloride was obtained -2.3- bicyclo [2.2.1] heptanedicarboxyimide in the same manner as in Example 2 except for the addition time.

EXAMPLE 4 It was dissolved (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl3 -2,3-bicyclo [2.2.1] heptanedicarboxyimide (3.5 g) in acetone (43 g) with heating under reflux to produce an acetone solution. To this acetone solution was added dropwise an aqueous 1.8% hydrochloric acid solution (1.1 equivalent) at about 55 ° C over a period of about 5 minutes. The mixture was then stirred at about 60 ° C for one hour. The reaction mixture was cooled to 0 ° C and stirred at the same temperature for one hour. The mixture was filtered, and the resulting solid was dried at room temperature under a reduced pressure to produce hydrochloride of (IR ^ S.SR ^ SJ-N-IR ^ R ^ -yl ^ -benzisothiazol-Si-1-piperacinylmethyl- l-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide.

EXAMPLE 5 Hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperacillimethyl] ] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as in Example 4 except that an aqueous solution of 3.0% hydrochloric acid (1.1 equivalent) was used instead of the aqueous solution of 1.8% hydrochloric acid (1.1 equivalent) of Example 4.

EXAMPLE 6 Hydrochloride of (IR ^ S.SR ^ S ^ N-KIR ^ R ^ - -II ^ -bencisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1 ] heptanedicarboxyimide in the same manner as in Example 4, except that an aqueous 3.6% hydrochloric acid solution (1.1 equivalent) was used instead of the 1.8% aqueous hydrochloric acid solution (1.1 equivalent) of Example 4.

EXAMPLE 7 Hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl was obtained ] -2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as in Example 4, except that an aqueous solution of 4.2% hydrochloric acid (1.1 equivalent) was used instead of the aqueous solution of hydrochloric acid at 1.8% (1.1 equivalent) of Example 4.

EXAMPLE 8 Hydrochloride of (1R, 2S, 3RI4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl-2 was obtained , 3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as in Example 4, except that an aqueous 5.0% hydrochloric acid solution (1.1 equivalent) was used instead of the 1.8% hydrochloric acid aqueous solution ( 1.1 equivalent) of example 4.

EXAMPLE 9 (1R, 2S, 3RI4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2 hydrochloride was obtained , 3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as in Example 1, except that an aqueous 5.0% hydrochloric acid solution (1.1 equivalent) was used instead of the 3.6% hydrochloric acid aqueous solution ( 1.1 equivalent) of example 1.

EXAMPLE 10 An aqueous solution of 5.0% hydrochloric acid (1.1 equivalent) was added over a period of one hour instead of the 3.6% hydrochloric acid (1.1 equivalent) aqueous solution of example 2. Hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2-? 4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl-2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as example 2, except for the addition time and the concentration of the aqueous hydrochloric acid solution.

EXAMPLE 11 (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] hydrochloride was obtained 2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as Example 4, except that an aqueous solution of 7.2% hydrochloric acid (1.1 equivalent) was used instead of the 1.8% aqueous hydrochloric acid solution ( 1.1 equivalent) of example 4.

EXAMPLE 12 Hydrochloride of (R, 2S, 3R, 4S) -N - [(1 R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- was obtained cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as Example 4, except that an aqueous solution of hydrochloric acid at 14.4% (1.1 equivalent) was used instead of the aqueous solution of hydrochloric acid at room temperature. 1.8% (1.1 equivalent) of Example 4.

EXAMPLE 13 Hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl-3- was obtained 2,3-bicyclo [2.2.13heptanedicarboxyimide in the same manner as example 4, except that an aqueous solution of 36% hydrochloric acid (1.1 equivalent) was used instead of the 1.8% aqueous hydrochloric acid solution (1.1 equivalent) ) of example 4.

EXAMPLE 14 In the procedure of Example 1, a solution of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazole-3-) was added dropwise. il) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide (8.25 g) in acetone, to an aqueous 3.6% hydrochloric acid solution (1.1 equivalent) over a period of one hour. Hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl was obtained -2,3-bicyclo [2.2.1] heptanedicarboxyimide in the same manner as Example 1, except for the addition method. The hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] was analyzed. -2,3-bicyclo [2.2.1] heptanedicarboxyimide obtained in examples 1 to 14, and the results thereof are shown in table 1.

TABLE 1 The amount of acetone in the crystals was determined by gas chromatography using a capillary column and an FID detector, and the amounts of impurities were determined by liquid chromatography using a reverse phase ODS column and a UV detector.

EXAMPLE 15 It was dissolved (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2, 3-bicyclo [2.2.1] heptanedicarboxyimide (1.5 g) in tetrahydrofuran (5.5 g) with heating under reflux to provide a solution of tetrahydrofuran. To this solution was added 3.6% hydrochloric acid (6.18 g) under reflux, and the reaction mixture was cooled to 20 ° C, filtered, and the resulting solid was dried under reduced pressure to produce hydrochloride of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1 jheptanedicarboxyimide (1.34 g yield: 83%).

EXAMPLE 16 It was dissolved (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2, 3-bicyclo [2.2.1] heptanedicarboxyimide (2.0 g) in methyl ethyl ketone (22 g) with heating at about 60 ° C to produce a methyl ethyl ketone solution. To this solution was added 3.6% hydrochloric acid (4.52 g) at about 60 ° C, and the reaction mixture was cooled to 0 ° C. The reaction mixture was filtered, and the resulting solid was dried under reduced pressure at room temperature to provide (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1 , 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxyimide (0.84 g yield: 39%).

EXAMPLE 17 It was dissolved (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2 , 3-bicyclo [2.2.1] heptanedicarboxyimide (2.0 g) in (200 g) with heating at about 80 ° C to provide a solution of 2-propanol. To this solution was added 14.4% hydrochloric acid (1.54 g) at about 80 ° C, and the reaction mixture was cooled to 0 ° C. The reaction mixture was filtered, and the resulting solid was dried under a reduced pressure at room temperature to provide hydrochloride of (1 R, 2S, 3R, 4S) -N - [(1 R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl-2,3-bicyclo [2.2.13heptanedicarboxyimide (2.05 g yield: 95%).

APPLICATION IN THE INDUSTRY . In accordance with the present invention, it is possible to provide an industrially advantageous process for producing the hydrochloride of the imide compound of the above formula (2).

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1- A process for producing a hydrochloride of the imide compound of the formula (2): or an enantiomer thereof, which comprises treating a compound of the formula (1): or an enantiomer thereof with an aqueous solution of hydrochloric acid in a hydrophilic solvent, followed by crystallization of the resulting compound. 2. The process for producing the hydrochloride of the imide compound according to claim 1, further characterized in that the hydrophilic solvent is a ketone solvent. 3. The process for producing the hydrochloride of the imide compound according to claim 1, further characterized in that the hydrophilic solvent is acetone. 4. The process for producing the hydrochloride of the imide compound according to any of claims 1, 2 and 3, further characterized in that the aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid at 1.8-14.4%. 5. The process for producing the hydrochloride of the imide compound according to any of claims 1, 2 and 3, further characterized in that the aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid at 3.0-5.0%.