ANHYDROUS AND DIHYDRATE FORMS OF 2-([(2S)-2-([(3R,4R)-4-(3-HYDROXYPHENYL)-3,4-DIMETHYLPIPERIDIN-1-YL]METHYL)-3-PHENYLPROPANOYL]AMINO)ACETIC ACID
Publication Date: 2011-Mar-22
The IP.com Prior Art Database
ANHYDROUS AND DIHYDRATE FORMS OF 2-([(2S)-2-([(3R,4R)-4-(3-HYDROXYPHENYL)-3,4-DIMETHYLPIPERIDIN-1-YL]METHYL)-3-PHENYLPROPANOYL]AMINO)ACETIC ACID AND PROCESSES FOR THEIR PREPARATION
Alvimopan (compound (I)) is the international commonly accepted name for 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl)-3-phenylpropanoyl]amino)acetic acid. Alvimopan has an empirical formula of C25H32N2O4 and a molecular weight of 424.53 g/mol.
Alvimopan has been approved in the
United Statesfor accelerating the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. Alvimopan dihydrate is marketed in the
United Statesunder the trade name of EnteregTM in form of capsules for oral administration containing 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol.
The existence of both dihydrate and anhydrous forms of alvimopan is described in J. Org. Chem. 1996, 61, 587-
597. Inthe experimental section of this article it is described the synthesis of alvimopan dihydrate by hydrolysis of the 2-methylpropyl ester of 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl)-3-phenylpropanoyl]amino)acetic acid with 3.0 molar equivalents of sodium hydroxide in a mixture of ethanol and water at
25 ºC. It is described that a precipitate is formed after neutralization to pH 6.0 with concentrated hydrochloric acid and seeding, and that the filtered cake is washed with water and dried overnight (
25 ºC, 33% relative humidity) by pulling air through the product in the filter funnel under slight suction to give alvimopan dihydrate, as confirmed by Karl Fischer analysis. The anhydrate of alvimopan is described to be obtained by block drying at
120 ºCof the dihydrate form.
Alvimopan dihydrate has been prepared according to the process depicted in Scheme 1,
wherein R is selected from the group comprising alkyl, cycloalkyl, aralkyl or heteroaralkyl, which groups may optionally be mono- or polysubstituted. Preferably, R is C1 to C6 alkyl, more preferably R is 2-methylpropyl, ethyl or methyl.
The process depicted in Scheme 1 comprises hydrolysis of compound (II) under alkaline conditions in a suitable solvent or mixture of solvents at about room temperature to about reflux temperature followed by neutralization of the reaction mixture once the hydrolysis has been completed to allow precipitation of alvimopan dihydrate.
Preferably, alkaline conditions are established by using alkali metal hydroxides such as sodium hydroxide or potassium hydroxide and preferred solvents are selected from alcohols, such as ethanol and methanol, and mixtures of alcohols and water, such as ethanol and water.
Preferably, neutralization is accomplished by adding an inorganic acid such as hydrochloric acid until pH of about 5.0 to about 7.0, more preferably until pH of about 6.0. Optionally, after neutralization the reaction mixture can be seeded to accelerate the pr...