DESC:Field of the Invention:
The present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile. Anagliptin is used for the treatment of diabetes.
Background of the Invention:
Glucagon-like peptide-1 (GLP-1), a thirty-amino acid peptide hormone, is secreted by intestinal L-cells in response to food ingestion and stimulates insulin secretion from b-cells in a glucose-dependent manner. GLP-1 is also known to have multiple actions such as suppression of glucagon secretion, inhibition of gastric emptying and induction of satiety. Based on these findings, GLP-1 has been considered to be an attractive target for the therapy of type 2 diabetes mellitus (T2DM). However, GLP-1 is rapidly degraded into inactive GLP-1 by a serine protease, dipeptidyl peptidase IV (DPP-IV), which fueled the development of biologically stable GLP-1 analogs. Therefore, inhibitors of DPP-IV capable of increasing the circulating concentration of active GLP-1 have now emerged as promising treatments for T2DM. In addition, it was demonstrated in a clinical study of diabetic patients receiving active GLP-1 infusion that a 24-h infusion of active GLP-1 resulted in a more marked improvement in glycemic control than a 16-h infusion, and based on accumulating clinical studies, greater than 2-fold enhancement of circulating levels of active GLP-1 is known to result from inhibition of 80% or more of the plasma DPP-IV activity. Consequently, optimal glycemic control requires continuous high-level exposure to DPP-IV inhibitors.
US Patent 7,345,180 B2 relates to one such DPP-IV inhibitor, Anagliptin Hydrochloride (Formula I). US Patent ‘180 also discloses process and intermediates for preparation of Anagliptin Hydrochloride.

I

Object of the invention
The object of the present invention is to provide a novel salt of methane sulfonic acid (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
Another object of the present invention is to provide a process for preparation of novel salt (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
Further object of the present invention is use of novel salt of methane sulfonic acid (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
Summary of Invention:
In an embodiment of the present invention is disclosed a novel salt of methane sulfonic acid (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
In another embodiment of the present invention is disclosed a process for preparation of novel salt (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
In a further embodiment of the present invention is disclosed use of novel salt of methane sulfonic acid (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
Brief Description Of The Accompanying Drawings
Fig.1 XRD of polymorph L of ((2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
Fig.2 DSC of polymorph L of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
Detail Description of the Invention:
According to present invention, there is provided a novel salt (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II).

II IIa
US Patent 7,345,180 B2 patent discloses dihydrochloride salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II) and its conversion to Anagliptin free base.
The present invention involves synthesis of methane sulfonic acid salt (IIa) of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II) and its use for the preparation of anagliptin free base or its hydrochloride salt.
Anagliptin free base generated by this process has improved quality and overall yield as compared with prior art process. Also, content of total impurity is decreased.
Anagliptin free base generated by the process of said invention has less than 1% of total impurities and purity of 98.92% by HPLC.
(2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate is prepared by reacting t-butyl (S)-{2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methyl-1-propyl} carbamate hydrochloride (compound 3) with methane sulfonic acid.

3
The present invention also provides novel polymorph L of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
(2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate is reacted with 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid to get Anagliptin free base. This condensation can be carried out using various condensation reagent (for example, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or its hydrochloride, N,N'-carbonyldiimidazole or the like) as in the literature either alone or in combination with an additive (N-hydroxysuccinimide, hydroxybenzotriazole or the like) in the presence or absence of a base (for example, triethylamine, 4-dimethylaminopyridine or the like) in a suitable solvent (for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide or the like).
The above reaction can be carried out in polar and non-polar solvents. These solvents include, but are not limited to, Pentane, Cyclopentane, Hexane, Cyclohexane, Benzene,Toluene,1,4-Dioxane, Chloroform,Diethyl ether Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate, Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Propylene carbonate, Formic acid, n-Butanol, Isopropanol (IPA), n-Propanol, Ethanol, Methanol, Acetic acid, Nitromethane and Water.
Anagliptin free base can be converted to its hydrochloride salt by the processes as disclosed in the literature.
(2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt was characterized by XRD, DSC and HPLC.
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.
Differential scanning calorimetry (DSC) was done using Diamond DSC Perkin Elmer instrument. The scans were recorded between 50 and 300 °C at a constant heating rate of 10°C/min.
The starting material for (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt is t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl-1-propyl} carbamate hydrochloride which could be prepared by prior art process.
Example 1
(2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt
Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl-1-propyl} carbamate (25.0g) to acetonitrile (150 ml) followed by drop-wise addition of methane sulfonic acid (10 g). The reaction mass was heated to 50-55°C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5°C and stirred for 1 hour at same temperature. Obtained solid was filtered and washed with chilled acetonitrile (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt . Wet-cake was dried under vacuum till a constant weight was obtained (22.6g, yield 91.58% purity 99.93%).
Example 2 (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt
Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl-1-propyl}carb-amate (10g, 0.0277) to Toluene (60ml, 6 volumes) at 25-30°C, followed by drop-wise addition of methane sulfonic acid (4.0g, 0.0416 moles) at 25-30°C. The reaction mass was heated to50-55°C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5°C and stirred for 1 hour at same temperature. The obtained solid was filtered and washed with chilled toluene (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt. The Wet-cake was dried under vacuum till a constant weight.
Example 3 Anagliptin free base
2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid was coupled with (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt in presence of EDC.HCl, HOBT, TEA. The reaction was carried out in DCM (yield 69.3%, purity 99.73%).
Anagliptin free base could be converted to Anagliptin hydrochloride by processes as disclosed in the literature.
,CLAIMS:1. Methane sulfonic acid salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula IIa).

Formula IIa
2. Process for preparation of methane sulfonic acid salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula IIa) comprising reacting a compound of compound 3 with methane sulfonic acid.

compound 3
3. Process for preparation of Anagliptin comprising reacting (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt with 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid.

4. Use of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt for preparing Anagliptin or its hydrochloride salt.
4. Anagliptin free base having a purity of greater than 98.92%, in particular greater than 99.3%.
5. Anagliptin free base having content of total impurity less than 1.5%.

6. Form L of Methane sulfonate salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula IIa).

Formula IIa
7. Form L as claimed in claim 6 having XRD as per Fig.1.
8. Form L as claimed in claim 6 having DSC as per Fig.2.