WO 2016012927, ANAGLIPTIN HYDROCHLORIDE , NEW PATENT, LUPIN

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WO 2016012927,  ANAGLIPTIN HYDROCHLORIDE , NEW PATENT, LUPIN

A PROCESS FOR PREPARATION OF ANAGLIPTIN HYDROCHLORIDE 



ANSARI, Shahid, Akhtar; (IN).
YADAV, Ashok, Keshavlal; (IN).
PATIL, Tushar, Yashwant; (IN).
PATHAK, Dharmendrakumar, Shripati; (IN).
BARIA, Reenaben, Ratansing; (IN).
PATIL, Shashikant, Prabhakar; (IN)


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 (formula IIa). Anagliptin is used for the treatment of diabetes.

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)-l-{ [(l-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.

Object of the invention

The object of the present invention is to provide a novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-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 (Ila) of (2S)-l-{ [(l-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 (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.

Example 1

(2S)-l-{[(l-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-l-yl)-2-oxoethylamino]-2-methyl-l -propyl} carbamate (25. Og) 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)-l-{[(l-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-l-yl)-2-oxoethylamino]-2-methyl-l -propyl} carb-amate (lOg, 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.HC1, 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