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(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile

IP.com Disclosure Number: IPCOM000220659D
Publication Date: 2012-Aug-10
Document File: 3 page(s) / 46K

Publishing Venue

The IP.com Prior Art Database

Abstract

A straightforward synthesis of N-Boc-protected (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, an advanced and key intermediate for the synthesis of (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is described herein

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Preparation of an advanced intermediate for the synthesis of Saxagliptin

(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, having the following formula (0)

(0)

Saxagliptin

is a dipeptidyl peptidase IV (DPP4) inhibitor, used in the treatment of diabetes type 2.

A straightforward synthesis of N-Boc-protected Saxagliptin (5), an advanced and key intermediate for the synthesis of Saxagliptin (0), is described herein.

Synthetic scheme

Example 1.

5 g

of amide compound 1 was suspended with 25 ml EtOAc. The resulting mixture was stirred to homogenize and 8.2 ml of Ethyl nicotinate were then added. The mixture was then cooled to

-8ºC

and 4 ml of trifluoroacetic anhydride were added. The mixture was stirred for about 30 minutes and let to reach

0ºC

. Then 10ml of water were added and 4.5 ml of TMEDA were charged.  The pH was rectified to about 3 and the two layers were let to separate. The organic layer was washed with a mixture of 5 ml water and pH adjusted to about 2 with concentrated aqueous HCl.  The organic layer containing nitrile compound (2) was separated.

Example 2.

2 g

of amide compound 1 was suspended with 10 ml of EtOAc. The resulting mixture was stirred to homogenize and 0.58 ml of TMEDA was added. The mixture was cooled to

-8ºC

and 1.59 ml of trifluoroacetic anhydride added. The mixture was stirred for about 30 minutes and let to reach

0ºC

. 4 ml of water were added. The organic layer containing nitrile (2) compound was separated.

Example 3.

5 g

of amide compound 1 was suspended with 25 ml of EtOAc. The resulting mixture was stirred to homogenize and 5.5 ml of TEA and 5.51 ml of T3P 50 % in ethyl acetate solution were sequentially added. The mixture was stirred for 30 minutes and heated to

60ºC

for 30 minutes. After that, 6.57 ml T3P and 3.06 ml TEA were added and heated for an extra 30 minutes. Then, after cooling down to room temperature, 10 ml of water were added and the aqueous phase was washed with 3x10 ml of EtOAc. The volume of the organic layer containing nitrile compound (2) was reduced to about 25ml.

Example 4.

The organic layer as obtained in example 1 was treated with 5ml IPA and 10.2 ml of concentrated aqueous HCl. The mixture was stirred at room temperatu...