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1-CHLOROACETYL-2-(L)-CYANOPYRROLIDINE, AND PROCESSES FOR PREPARATION THEREOF

IP.com Disclosure Number: IPCOM000176760D
Publication Date: 2008-Nov-24
Document File: 7 page(s) / 95K

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1-CHLOROACETYL-2-(L)-CYANOPYRROLIDINE, AND PROCESSES FOR PREPARATION THEREOF

[001] The hypoglycemic agent, (2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl} pyrrolidine-2-carbonitrile is a dipeptidyl peptidase IV inhibitor having the following scheme:

HN

O

N

C

C

N

HO

C17H25N3O2.

[002] (2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile can be obtained by a condensation of two key intermediates: 1-chloroacetyl-2-(L)- cyanopyrrolidine of the following formula:

Cl

O

N

C

C

N ,

and 1-aminoadamantane-3-ol of the following formula:

1

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NH2

HO .

[003] US 2006/0199854 describes the synthesis of (2S)-1-{2-[(3-hydroxy-1- adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile via 1-chloroacetyl-2-(L)- cyanopyrrolidine in a one-pot process, using chloroacetyl chloride, dimethylformamide and vilsmeier reagent.

[004] In the provided below procedures, 1-chloroacetyl-2-(L)-cyanopyrrolidine is prepared by providing a mixture of chloroacetyl chloride, L-prolinamide, and dimethylformamide. The reaction mixture can be obtained by adding chloroacetyl chloride to a mixture of L-prolinamide and the solvent ("normal addition") or by adding a solution of L-prolinamide in a solvent to choloacetyl chloride ("reversed addition"). Preferably, the reaction mixture is obtained in a reversed addition manner.

[005] The 1-chloroacetyl-2-(L)-cyanopyrrolidine obtained by the process described in the provided below procedures has high optical purity and contains less than about 5% of its D-enantiomer. Preferably less than about 2%, more preferably less than about 0.1% of its D-enantiomer.

[006] The procedures below also provide a process for further purifying 1- chloroacetyl-2-(L)-cyanopyrrolidine obtained according to the process described above, allowing even higher optical purity, by crystallizing or re-slurrying the above obtained 1-chloroacetyl-2-(L)-cyanopyrrolidine from a C4-C12 aliphatic ether.

[007] The optically pure 1-chloroacetyl-2-(L)-cyanopyrrolidine obtained by the provided examples may be further converted to (2S)-1-{2-[(3-hydroxy-1- adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile and thus allowing preparation of optically pure (2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2- carbonitrile.

2

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HPLC method for measuring optical purity:

Column: Diacel Chiracel, OD-H, 150*4.6 mm *5µ

Eluent: 30% IPA : 70% Hexane

Flow: 0.8mL/min

Detection: 220 nm

Sample conc: 10mg/mL

Sample vol: 5μL

Column temp: 25ºC

Detection limit: 0.1%

Example 1: Preparation of 1-chloroacetyl-2-(L)-cyanopyrrolidine (reversed addition):
[001] 93.9 gr of chloroacetyl chloride was charged into reaction flask under room temperature. A solution of 20.0 gr of L-prolinamide in 64.0 gr of DMF was added to the flask during 2 hours by keeping the temperature at 30-35oC. The reaction was completed at 25-35oC during additional 22 hours and then concentrated under reduced pressure and heating below 50oC to a...