CLIAMS:1. A crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt of formula-II,

Formula II
has purity more than 99 % when measured by HPLC.

2. The crystalline solid form of claim 2, 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 9.39, 14.03, 18.80, 20.43, 21.40, 23.01 and 28.34 ± 0.2o.
iii. a Differential scanning calorimetric (DSC) thermogram substantially in accordance with FIG. 2,
iv. a Thermogavimetric Analysis (TGA) substantially in accordance with FIG. 3.

3. A process for the preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, an intermediate of Saxagliptin, has purity more than 99 %, the process comprising;
a) reacting (1S, 3S, 5S)-tert-butyl 3-cyano-2-aza-bicyclo [3.1.0] hexane-2-carboxylate of formula III with methane sulfonic acid in alcoholic solvent,

Formula III
b) heating the reaction mixture at suitable temperature ,
c) isolating crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt.

4. The process of claim 3, wherein the alcoholic solvent is selected from the group comprising one or more of methanol, ethanol, ethylene glycol, 1-propanol, isopropyl alcohol, 2 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, diethylene glycol and mixtures thereof

5. The process of claim 4, wherein the alcoholic solvent is isopropanol.

6. The process of claim 3, wherein suitable temperature is about 40oC to 65oC.

7. The process of claim 3, wherein compound of formula-III subsequently converted to Saxagliptin or a pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

The present invention relates to a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt. In particular, the present invention relates to the process of preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, which is used as an intermediate for the preparation of Saxagliptin and the conversion of the intermediate to Saxagliptin or pharmaceutically acceptable salts thereof.

Background of the invention

Saxagliptin is an orally-active DPP4 inhibitor used in the treatment of type 2 diabetes. It has chemical name (lS,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and has the structural formula I,

Formula I
Saxagliptin hydrochloride is marketed under the trade name Onglyza by Bristol-Myers Squibb for the treatment of type 2 diabetes. Saxagliptin or a pharmaceutically acceptable salt described in U.S. Patent No. 6,395,767 with its process for the preparation. The process for the preparation also described in several patents, e.g. US patent Nos. 7,420,079, 8,278,462, 7,705,033, 7,214,702, 7,186,846; US application No US2008300251 A1 the PCT application nos. WO2014118612, WO2014000629 and WO2013111158.

Various other prior art references, for example, Tran et al., in Journal of labeled compounds and radiopharmaceuticals, 2014, Volume 57, Page No. 136-140; Cao et al., in Journal of labeled compounds and radiopharmaceuticals, 2007, Volume 50, Page No. 1224-1229 and IP.com journal, 2012, Volume 12, Page No. 25 disclose processes for preparing Saxagliptin or a pharmaceutically acceptable salt.

The object of present invention relates to a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt. In further aspect, the present invention relates to the process of preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, which is used as an intermediate for the preparation of Saxagliptin the conversion of the intermediate to Saxagliptin or pharmaceutically acceptable salts thereof.

Summary of the Invention

The present invention provides a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt of formula-II,

Formula II
has purity more than 99 % when measured by HPLC.

The present invention provides a process for the preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, an intermediate of Saxagliptin, has purity more than 99 %, the process includes the steps of,
a) reacting (1S, 3S, 5S)-tert-butyl 3-cyano-2-aza-bicyclo [3.1.0] hexane-2-carboxylate with methane sulfonic acid in alcoholic solvent,
b) heating the reaction mixture at suitable temperature,
c) isolating 1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt
A further aspect of the present invention relates to conversion of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt to Saxagliptin or its pharmaceutical acceptable salts thereof.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of crystalline solid form (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt.

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt.

Figure 3 shows an illustrative example of thermo gravimetric analysis curve of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate 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.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

In an aspect, the present invention provides a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt of formula-II,

Formula II
has purity more than 99 % when measured by HPLC

In another aspect, the present invention provides a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2 and thermo gravimetric analysis curve as shown in Figure 3.

In one another aspect, the present invention provides a crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate 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 9.39, 14.03,18.80, 20.43, 21.40, 23.01 and 28.34  0.2.

The XRPD characteristic peaks of the crystalline solid form of 3(1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, has purity more than 99 %, further defined from the Table 1:

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
8.04 10.98 0.95
9.39 9.41 100.00
14.03 6.31 7.42
17.54 5.05 1.03
18.13 4.89 0.95
18.80 4.71 43.94
20.43 4.34 19.60
21.40 4.15 7.24
23.01 3.86 16.02
24.00 3.70 2.18
25.68 3.46 2.50
26.21 3.39 3.75
27.92 3.19 0.81
28.34 3.14 10.42
29.39 3.03 2.33
29.86 2.99 2.66
30.26 2.95 2.74
31.66 2.82 1.77
32.04 2.79 1.98
32.95 2.71 1.45
33.84 2.64 3.54
34.80 2.57 0.74
36.34 2.47 0.25
36.96 2.43 0.38
38.09 2.36 3.59
39.56 2.27 1.22

The crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt 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 an another aspect, the present invention provides a process for the preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, an intermediate of Saxagliptin, has purity more than 99 %, the process includes the steps of;
a) reacting (1S, 3S, 5S)-tert-butyl 3-cyano-2-aza-bicyclo [3.1.0] hexane-2-carboxylate of formula III

Formula III
with methane sulfonic acid in alcoholic solvent,
b) heating the reaction mixture at suitable temperature,
c) isolating crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt.

In the present invention process for the preparation of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt involves reacting (1S, 3S, 5S)-tert-butyl 3-cyano-2-aza-bicyclo [3.1.0] hexane-2-carboxylate with methane sulfonic acid in alcoholic solvent and heating the reaction mixture at suitable temperature for a period of 3 hours, wherein the suitable temperature is between the range of 40oC to 65oC. The reaction mixture is cooled at temperature between of 5oC to10oC for a period of 1 hour after the completion of the reaction. The solid obtained is filtered and washed with chilled alcoholic solvent. The wet cake obtained is dried in vacuum at temperature between of 50oC to 55oC for a period of 5 hours to 7 hours to get crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt.

The alcoholic solvent is selected from the group comprising one or more of methanol, ethanol, 2-nitroethanol, ethylene glycol, 1-propanol, isopropyl alcohol, 2 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, diethylene glycol and mixtures thereof.

In one another aspect, the present invention relates to conversion of crystalline solid form of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt, to Saxagliptin or its pharmaceutical acceptable salts thereof.

The (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate salt can be converted into Saxagliptin or its pharmaceutical acceptable salt thereof according to known methods in the literature for example given in PCT application number WO2014118612.

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.

Example

Example-1: - Preparation of (1S, 3S, 5S) 3-cyano-2-aza-bicyclo [3.1.0] hexane methane sulfonate

Charged (1S, 3S, 5S)-tert-butyl 3-cyano-2-aza-bicyclo [3.1.0] hexane-2-carboxylate (1 gm) in isopropanol (5 mL) followed by methane sulfonic acid (0.6 gm) was added. The reaction mixture was heated to temperature 50oC to 55oC for a period of 3 hours. After completion of the reaction, the reaction mixture was cooled to temperature 5oC to10oC for a period of 1 hour. The solid obtained was filtered and washed with chilled isopropanol (2mL). The wet cake obtained was dried in vacuum at temperature 50oC to 55oC for a period of 6 hours to get crystalline solid form titled compound.

Yield: 0.85 gm (83%)
Mass: [109.1] M+1
HPLC Purity: 99.2%