CLIAMS:1. A crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II

Formula-II

2. A crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, has purity more than 99 % as measured by HPLC

3. The compound crystalline solid form of claim 1, characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a powder X-ray diffraction pattern having peaks at about 10.71, 12.94, 16.54, 20.85, 21.02 and 24.56  0.2
iii. a Differential scanning calorimetric (DSC) thermogram substantially in accordance with FIG. 2,
iv. a Thermogavimetric Analysis (TGA) substantially in accordance with FIG. 3.

4. A process for the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II,

Formula-II
the process comprises the steps of;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine in a ketone solvent with D(+) camphor sulphonic acid in a ketone solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
b) optionally purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

5. The process of claim 3, wherein solvent is selected from the group comprising one or more of acetone, methyl isopropyl ketone, methyl isobutyl ketone, 2-hexanone, ethyl isopropyl ketone, butanone and mixture thereof.

6. The process of claim 4, wherein solvent is acetone.

7. A process for the preparation of Lorcaserin Hydrochloride, compound of formula-I,

Formula-I
the process comprises of ;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine in a ketone solvent with D(+) camphor sulphonic acid in a ketone solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
b) optionally purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
d) converting (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt to Lorcaserin Hydrochloride.

,TagSPECI:Field of Invention

The present invention relates to crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, which is used as an intermediate for the preparation of Lorcaserin Hydrochloride. A further aspect of the present invention relates to a process for the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt or salt thereof and its conversion to Lorcaserin Hydrochloride.
Background of the invention

Lorcaserin hydrochloride is a serotonin 2C receptor agonist for oral administration used for chronic weight management. It has the chemical name ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate and has the structural formula I,

Formula I

Lorcaserin hydrochloride is marketed under the trade name BelviqTM in the United States. Lorcaserin or a pharmaceutically acceptable salt was first described in U.S. Patent No. 6,953,787 with its process for the preparation. The process for the preparation also described in several patents, e.g. US patent Nos. US 8,546,379, US 7,977,329, US 8,367,657, US 8,168,624 US 8,697,686 and US application no 20130310369.

Summary of the Invention

The present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II

Formula-II

The present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, has purity more than 99 % when measured by HPLC.

The present invention provides a process for the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II,

Formula-II
the process includes the steps of ;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine with D(+) camphor sulphonic acid in a solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
b) optionally purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

A further aspect of the present invention relates to conversion of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt to Lorcaserin Hydrochloride.
A further aspect of the present invention provides a process for the preparation of Lorcaserin Hydrochloride, compound of formula-I,

Formula-I
the process includes the steps of ;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine with D(+) camphor sulphonic acid in a solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
b) optionally purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
d) converting (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt to Lorcaserin Hydrochloride.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of crystalline solid form (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of crystalline solid form of 3 (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

Figure 3 shows an illustrative example of Thermo gravimetric analysis curve of crystalline solid form of 3 (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

In an aspect the present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt of formula-II

Formula-II

In an another aspect, the present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, has purity more than 99 % when measured by HPLC.

In another aspect, the present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2 and thermogavimetric analysis curve as shown in Figure 3.

In another aspect, the present invention provides a crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, having an X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 10.71, 12.94, 16.54, 20.85, 21.02 and 24.56  0.2.

The XRPD characteristic peaks of the crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, has purity more than 99 %, further defined from the Table 1:

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
10.25 8.62 2.88
10.71 8.25 100.00
11.60 7.62 2.18
12.94 6.83 12.27
13.43 6.59 4.61
14.62 6.05 11.74
15.40 5.75 4.68
16.10 5.50 7.81
16.21 5.46 8.81
16.40 5.40 6.22
16.54 5.35 12.69
17.95 4.94 3.88
18.60 4.76 11.39
19.20 4.62 6.45
19.81 4.48 1.14
20.85 4.25 48.28
21.02 4.22 93.02
22.42 3.96 3.09
23.29 3.81 10.68
24.56 3.62 12.73
24.87 3.57 4.95
25.07 3.55 4.51
25.54 3.48 5.28
25.78 3.45 1.60
26.03 3.42 3.02
27.23 3.27 0.91
28.41 3.14 0.94
28.93 3.08 1.22
29.46 3.03 1.20
30.40 2.93 0.75
31.62 2.82 1.30
31.93 2.80 5.83
32.48 2.75 3.67
33.21 2.69 6.70
33.96 2.63 1.29
34.88 2.57 2.99
35.56 2.52 6.61
36.47 2.46 3.44
37.86 2.37 1.81

The crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt obtained as per Example 1 to the present invention was stored at 25°C for a period of 3 months and no conversion in the polymorphic form was observed.

In one another embodiment, the present invention provides a process for the preparation of crystalline solid form of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II,

Formula-II
the process includes the steps of ;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine with D(+) camphor sulphonic acid in a solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine(1S)-(+)-10-camsylate salt,
b) optionally, purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

The step a) of the present invention involves the reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine in a solvent with D (+) camphor sulphonic acid in a solvent at temperature between the range of 25oC to 35oC. The reaction mass is refluxed for a period of 3 hours and cooled to temperature 25oC to 35oC, followed by stirring for a period of 24 hours at temperature between the range of 25oC to 35oC. After completion of reaction, the precipitated mass is filtered and washed with acetone to obtain wet cake of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt.

The step b) of present invention involves purification of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt obtained in step (a). The purification involves the refluxing of the precipitated mass in solvent for a period of 3 hours and further cooled to temperature 25oC to 35oC. The reaction mass is further stirred at temperature between the range of 25oC to 35oC for a period of 20 to 30 hours.

The solvent is selected from the group comprising one or more of acetone, methyl isopropyl ketone, methyl isobutyl ketone, 2-hexanone, ethyl isopropyl ketone, butanone and mixture thereof.

The step c) of the present invention involves the isolation of the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt. Isolation involves filtration of precipitated mass and subsequently washing with solvent and drying at temperature 45oC to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt as crystalline solid.

In one another aspect, the present invention relates to conversion of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt, compound of formula-II to Lorcaserin Hydrochloride.

In one another aspect, the present invention provides a process for the preparation of Lorcaserin Hydrochloride, compound of formula-I,

Formula-I
the process includes the steps of ;
a) reacting racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine in a ketone solvent with D(+) camphor sulphonic acid in a ketone solvent to obtain (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
b) optionally purifying the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
c) isolating the (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt,
d) converting (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt to Lorcaserin Hydrochloride.

The step d) of present invention involves conversion of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt to Lorcaserin Hydrochloride.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt

Charge D (+) camphor sulphonic acid (71.8 gm) in acetone (290 mL) to racemic 8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (110 gm) in acetone (440 mL) at temperature 25°C to 35°C. The reaction mass is refluxed for a period of 3 hours and further cooled to temperature 25°C to 35°C. The reaction mass was again stirred for a period of 24 hours at temperature 25°C to 35°C to obtain wet cake of (R)-8-chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt. The wet cake is heated to temperature 70oC to 80oC in acetone for a period of 3 hours and cooled to temperature 25°C to35°C. The reaction mass was further stirred for a period of 24 hours at temperature 25°C to 35°C. The precipitated mass was filtered and washed with acetone (220 ml) and dried at 45 °C to obtain the titled compound.

Yield: 69.0 gm
HPLC Purity: 99.92%
Enantiomeric excess purity: 99.19%
(S) enantiomer: 0.77%