CZ2011512A3 - Process for preparing (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl[2,3-bicyclo[2.2.1]heptanedicarboxamide hydrochloride - Google Patents

Abstract

Process for preparing polymorphic forms 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] heptanedicarboxamide hydrochloride of formula I by crystallization from polar organic solvents and mixing with water.

Description

Preparation of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl [1,2-a] 3-Bicyclo [2.2.1] heptanedicarboxamide hydrochloride

Technical field

The present invention relates to a novel process for the preparation and purification 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] heptanedicarboxamide hydrochloride of formula I,

BACKGROUND OF THE INVENTION

The synthesis of the compound of formula I is described by Japanese authors (EP 0464846). This application describes the preparation of a compound of formula I as a free base of formula II,

which must be chromatographically purified and then converted to the hydrochloride of formula I by treatment with isopropanolic hydrogen chloride. In addition, an expensive dibenzo-18-crown-6-ether phase transfer catalyst must be used. This process is completely unsuitable from an industrial point of view, since chromatographic purification allows only small amounts of the substance to be prepared. In addition, the product obtained having the melting point of 215-217 ° C described above is in polymorphic form III (Fig. 3), which is difficult to handle and, in addition, the product does not achieve sufficient purity. When reproducing

In this procedure, the XRPD spectrum of this material, shown in Figure 3, was measured as polymorphic form III.

SUMMARY OF THE INVENTION

The present invention provides the preparation 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] heptanedicarboxamide hydrochloride of formula I in a suitable crystallographic form and containing a maximum uniform impurity of less than 0,1%. The preparation of a compound of formula I in a certain polymorphic form is important in terms of its physico-mechanical properties. These properties of the solid affect, for example, the flowability of the material during grinding. The ease with which the material flows during transport and grinding is very important for industrial processing. Another factor influenced by the crystallographic structure of the substance is the affinity for electrostatic charging. Again, this has a great effect on the ease of handling of the material and can sometimes make it even practically impossible to grind the material. In some cases, an unsuitable polymorphic form can even cause a large bulk concentration of dissipating energy released during grinding, which causes local thermal degradation of the material and thus deterioration of the drug. Solubility in aqueous solutions or storage stability are affected. Therefore, there is a need to find suitable polymorphic forms.

These practical physical properties are determined by the conformation and orientation of the molecules in the crystal lattice, which defines a certain polymorphic form of the substance. The polymorphic form has a different thermal behavior from the amorphous material or other polymorphic form. Thermal behavior is measured by various laboratory techniques such as: melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (XRPD), infrared spectroscopy (IR).

The preparation process proposed by us allows the preparation of a compound of formula I in a suitable polymorphic form 1 (FIG. 1), which is very suitable for handling in terms of physico-mechanical properties. In addition, the process described provides a compound of formula I of high purity.

By appropriate pH adjustment to form the hydrochloride of formula I, polymorph form II was also obtained (FIG. 2).

The crystalline form I is characterized by the following data: XRPD diffractogram (Fig. 1) peaks around 9, 11.6, 13, 17.5, 19, 20.8, 23, 25, 29.3 ± 0.2 degrees 2 theta. DSC thermogram (Fig. 4) with an endothermic peak around 182 ° C or 175 ° C. Melting point about 172-177 ° C or 181-183 ° C.

The crystalline form II is characterized by the following data: XRPD diffractogram (Fig. 2) peaks around 9, 11.6, 13, 17.5, 20.8, 25, 29.3, 31.8 ± 0.2 degrees 2 theta. DSC thermogram (Fig. 5) with an endothermic peak around 183 ° C. Melting point about 181-183 ° C.

The crystalline form III is characterized by the following data: XRPD diffractogram (Fig. 3) peaks around 4.5, 9, 12, 14.5, 15.5, 17, 21, 24 ± 0.2 degrees 2 theta. DSC thermogram (Fig. 6) with endothermic peaks around 101.5, 216.7, 223.6 ° C. Melting point about 217-223 ° C.

The advantages of the method according to the invention are as follows:

• high crystallization yields and high purity of the substances;

• obtaining a suitable polymorphic form for easy material handling • simple isolation of substances

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1 - XRPD Diffractogram Form I

Giant. 2 - XRPD Form Diffractogram II

Giant. 3 - XRPD Form Diffractogram III

Giant. 4 - DSC Thermogram of Form I

Giant. 5 - DSC Thermogram Form II

Giant. 6 - DSC Thermogram of Form III

DETAILED DESCRIPTION OF THE INVENTION

The principles of the process according to the invention are illustrated in more detail in the following examples. These examples are illustrative only and in no way limit the scope of the invention.

Example 1

2.6 g 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] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. Then 0.9 ml of 20% hydrochloric acid was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. Then it is filtered,

the product on the filter was washed with 2 x 5 ml acetone and dried at 65-70 ° C in a hot air oven.

2.25 g (85%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. B.T = 183 DEG C., DSC-FIG. Impurity content 0.17%.

Example 2

2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are added to 23 ml of acetone with stirring. -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride (containing 0.1-0.3% impurity), 3.6 mL of water and heated to reflux until complete dissolution. Subsequently, 0.041 g of activated carbon was added to the resulting solution and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of acetone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred at 0-5 ° C for 1 hour and then filtered. The product on the filter is washed with 2 x 5 ml acetone and dried at 65-70 ° C in a hot air oven. 1.75 g (76% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1) as a white crystalline powder. Mp: 181-182 ° C, DSC-Fig. 4. Impurity content 0.04%.

Example 3

2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are added to 23 ml of diethyl ketone with stirring. -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride (0.1-0.3% impurity content), 3.6 ml water and heated to reflux. 0.041 g of charcoal is then added and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of diethyl ketone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred at 0-5 ° C for 1 hour and then filtered. The product on the filter was washed with 2 x 5 ml diethyl ketone and dried at 65-70 ° C in a hot air oven. 1.6 g (69% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are obtained. 1-Cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride Form I (Figure 1), as a white crystalline powder. B. T = 175-178 ° C, DSC-Fig. 4. Impurity content 0.07%.

Example 4 ·················

To 23 ml of 2-butanone was added 2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-] with stirring. piperazinylmethyl] -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride (containing 0.1-0.3% impurity), 3.6 mL of water and heated to reflux. 0.041 g of charcoal is then added and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of 2-butanone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred for 1 h at 0-5 C, ^Q, and then filtered. The product on the filter was washed with 2 x 5 ml 2-butanone and dried at 65-70 ° C in a hot-air oven. 1.55 g (67% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-] were obtained. piperazinylmethyl] -1 cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1), as a white crystalline powder. BT = 175-178 ° C, DSC-Fig.4. Impurity content 0.08%.

Example 5

0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] is added to 1 ml of methanol with stirring. -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride, 2.1 ml of water and heated to reflux until complete dissolution. Then the resulting solution is cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for a further 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. There was obtained 0.182 g (73% crystallization) 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] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. M.p. 81-118 ° C, DSC-Fig. 4.

Example 6

To 1 ml of ethanol was added 0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] while stirring. -1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, 2.1 mL of water was added and cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for a further 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.2 g (80% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. 1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1), as a white crystalline powder. Mp: 176-177 ° C, DSC-Fig. 4.

£ 4 4 * 4 4 4 4 · 4 ⁱⁿ ··· ·· ·· 4 * ··· ···

Example 7

To 1 ml of n-propanol was added with stirring 0.25 g 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] heptanedicarboxamide hydrochloride and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, 2.1 mL of water was added and cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for a further 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.21 g (84% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1] was obtained. -piperazinylmethyl-1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1), as a white crystalline powder. Bt = 174-177 ° C, DSC-Fig. 4.

Example 8

To 1 ml of 2-propanol was added with stirring 0.25 g 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] heptanedicarboxamide hydrochloride and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, 2.1 mL of water was added and cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for a further 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.21 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl is obtained. [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride Form I (Figure 1) as a white crystalline powder. B.TM 74-177 ° C, DSC-Fig.4.

Example 9

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. 0.8 ml of 20% hydrochloric acid is then added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.28 g (86%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. B.T = 181-183 ° C, DSC-fig 4. Impurity content 0.22%

Example 10

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. Then, 1.5 ml of 20% hydrochloric acid was added to the resulting solution, and it was refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.18 g (82%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1), as a white crystalline powder. B.T = 172-174 ° C, DSC-Fig. 4. Impurity content 0.18%.

Example 11

To 1 ml of acetic acid was added with stirring 0.25 g 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] heptanedicarboxamide hydrochloride was heated to reflux with stirring. To the resulting solution was added 10 mL of water and cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for a further 5 minutes and then filtered. The product on the filter was washed with 2 ml of water and dried at 65-70 ^C C air oven. 0.165 g (66% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] - was obtained. 1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. BT = 173-174 ° C, DSC-Fig. 4.

Example 12

0.53 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2, 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 6.6 ml of 2-butanone and the mixture is heated to reflux until complete dissolution. 1 ml of 20% hydrochloric acid is then added to the solution and refluxed for 20 minutes. The resulting emulsion was cooled to 0-5 ° C with stirring and stirred at 0-5 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 1 ml of 2-butanone and dried at 65-70 ° C in a hot-air oven. 0.2 g (32%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. 1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. B.T = 173.5-179 ° C, DSC-Fig. 4. Impurity content 0.02%.

♦ ··

Example 13

0.85 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide was added with stirring 15 ml of toluene and 1 ml of a solution of hydrogen chloride in 2-propanol was added at 20-25 ° C. The resulting mixture was heated to 65-70 ° C and stirred at this temperature for 10 minutes. The resulting suspension was cooled to 20-25 ° C with stirring and stirred at 20-25 ° C for 1 hour. It is then filtered, the product on the filter is washed twice with 1 ml of toluene and dried at 65-70 ° C in a hot-air oven. 0.71 g (77%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form III (Figure 3), as a white crystalline powder. B.T = 217-223 ° C, DSC-Fig.6.

Example 14

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 10 ml of ethanol and the mixture is heated to reflux until complete dissolution with stirring. Then 0.5 ml of 36% hydrochloric acid was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 30-40 ° C with stirring and a total of 25 mL of water was added slowly. The resulting suspension was cooled to 20-25 ° C, 10 mL of water was added and stirred at 20-25 ° C for 30 minutes. Then it is filtered, the product on the filter is washed twice with 10 ml of water and dried at 65-70 ° C in a hot-air oven. 2.33 g (88%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 were obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Fig. 1), as a white crystalline powder. Bt = 174-177 ° C, DSC-Fig. 4. Impurity content 0.38%.

Example 15

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. Thereafter, 0.8 ml of 20% hydrochloric acid was added to the resulting solution to obtain a pH of 1-2. The reaction mixture was neutralized with 10% aqueous sodium hydroxide to pH 6-7 and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 1.92 g (73%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- was obtained. cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide • 4 994 · 444 * 444 * 44

Form II hydrochloride (Figure 2), as a white crystalline powder. Mp: 181-183 ° C, DSC-Fig. 5. Impurity content 0,12%

Example 16

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. Then 0.9 ml of an 8-14% aqueous hydrochloric acid solution was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.25 g (85%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1) as a white crystalline powder. Impurity content 0.15%.

Example 17

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl [-2] 3-Bicyclo [2.2.1] heptanedicarboxamide is added with 20 ml of acetone and the mixture is heated under reflux until complete dissolution. Thereafter, 0.9 ml of a 15-35% aqueous hydrochloric acid solution was added to the resulting solution and refluxed for a further 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.29 g (87%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride form I (Figure 1) as a white crystalline powder. Impurity content 0.25%.

Claims (12)

PATENT CLAIMS A method for preparing pure (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl [-2] 3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride of formula I, having a maximum uniform impurity content of less than 0,1%, () characterized in that it is carried out by crystallizing the crude hydrochloride of the formula I from polar organic solvents in a mixture with water. Process according to claim 1, characterized in that C3-C5 aliphatic ketones are used as the polar solvent, The process according to claim 2, characterized in that acetone, diethyl ketone, or 2-butanone are used as the C3-C5 aliphatic ketones. Process according to claim 3, characterized in that acetone is preferably used. Process according to Claim 1, characterized in that C1-C3 aliphatic alcohols are used as the polar solvent. Process according to claim 5, characterized in that methanol, ethanol, n-propanol or 2-propanol are used as C1-C3 aliphatic alcohols. Method according to claim 6, characterized in that methanol is preferably used. 8. Process according to claim 6, characterized in that ethanol is preferably used. Process according to claim 1, characterized in that acetic acid is used as the polar solvent. A process for preparing pure (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl [-2] 3-bicyclo [2.2.1] heptanedicarboxamide hydrochloride of formula I, () characterized in that it is carried out by treating a toluene solution of the crude base (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-) with a solution of hydrogen chloride in 2-propanol. Benzisothiazol-3-yl) -1-piperazinylmethyl-1-cyclohexylmethyl [-2,3-bicyclo [2.2.1] heptanedicarboxamide of formula II. Polymorphic Form I of the crystalline hydrochloride of Formula I, characterized by selected data: XRPD peak diffraction pattern of about 9, 11.6, 13, 17.5, 19, 20.8, 23, 25, 29.3 ± 0.2 degrees 2 theta. 12. Polymorph form II of crystalline hydrochloride of formula I, characterized by selected data: XRPD peak diffraction pattern around 9, 11.6, 13, 17.5, 20.8, 25, 29.3, 31.8 ± 0.2 degrees 2 theta.