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IMPURITIES OF DARUNAVIR AND PROCESSES FOR THEIR PREPARATION

IP.com Disclosure Number: IPCOM000233987D
Publication Date: 2014-Jan-06
Document File: 8 page(s) / 99K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides compounds of Formula II, Formula III, Formula IV, and a compound detected by HPLC at relative retention time (RRT) 2.06 (M + H = 1095.6) and processes for their preparation. The present disclosure further provides use of the compounds of Formula II, or Formula III, or Formula IV, or the compound detected by HPLC at RRT 2.06 (M + H = 1095.6) in the analysis of darunavir.

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IMPURITIES OF DARUNAVIR AND PROCESSES FOR THEIR PREPARATION

Abstract

The present disclosure provides compounds of Formula II, Formula III, Formula IV, and a compound detected by HPLC at relative retention time (RRT) 2.06 (M + H = 1095.6) and processes for their preparation.  The present disclosure further provides use of the compounds of Formula II, or Formula III, or Formula IV, or the compound detected by HPLC at RRT 2.06 (M + H = 1095.6) in the analysis of darunavir.

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Darunavir is chemically known as the [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester of Formula I.

Formula I

Impurities, even in trace amounts, may influence the efficacy and safety of a pharmaceutical product.  Therefore, identification of impurities is necessary in the synthesis of active pharmaceutical ingredients and manufacture of dosage forms in order to meet regulatory standards.

Reported herein are compounds of Formula II,

Formula II

Formula III,

Formula III

Formula IV,

Formula IV

and the compound detected by HPLC at RRT 2.06 (M + H = 1095.6) as impurities (side products) in darunavir, for the development of analytical methods suitable for the analysis of darunavir destined for pharmaceutical purposes.

Also reported herein is a process for the preparation of a compound of Formula II

Formula II

wherein the process comprises treating darunavir with ethyl halide.

The starting material, darunavir, may be prepared by any method provided in the prior art, for example, U.S. Patent No. 7,700,645, PCT Publication No. WO 2011/048604, or PCT Publication No. WO 2011/051978.  Darunavir is treated with ethyl halide in a solvent optionally in the presence of a base.  The ethyl halide is selected from the group comprising ethyl iodide, ethyl bromide, or ethyl chloride.  The base is selected from the group comprising triethylamine or diethylamine.  The solvent is selected from the group comprising dichloromethane, dichloroethane, chloroform, or a mixture thereof.  The mixture is heated to the reflux temperature of the solvent.  The mixture is heated from about 5 hours to about 40 hours.  The product may be isolated from the mixture by methods including decantation, filtration, concentration, chromatography, distillation, evaporation, centrifugation, or a combination thereof.

Also reported herein is a process for the preparation of a compound of Formula III

                                              

Formula III

wherein the process comprises treating darunavir with acetaldehyde.

Darunavir is treated with acetaldehyde in a solvent, optionally in the presence of an acid.  Acetaldehyde may be added all at once or in parts to the reaction mixture.  The acid is hydrochloric acid.  The solvent is selected from the group comprising dichloromethane, d...