The present invention relates to a novel and improved process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (I), to the compound of the formula (I) in crystalline form and to their use for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular, cardiopulmonary and cardiorenal disorders.

Methods of preparing a fenfluramine active pharmaceutical ingredient are provided. Aspects of the method include (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (c) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine composition. Also provided are compositions and pharmaceutical ingredients prepared according to the subject methods including a pharmaceutically acceptable salt of fenfluramine and having less than 0.2% by weight in total of trifluoromethyl regioisomers.

Methods of preparing a fenfluramine active pharmaceutical ingredient are provided. Aspects of the method include (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (c) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine composition. Also provided are compositions and pharmaceutical ingredients prepared according to the subject methods including a pharmaceutically acceptable salt of fenfluramine and having less than 0.2% by weight in total of trifluoromethyl regioisomers.

Disclosed are compounds and compositions that modulate cannabinoid receptors, methods of modulating cannabinoid receptors, and methods of treating various disorders related to the modulation of cannabinoid receptors. This disclosure is directed to methods of treating cannabinoid dependence, neuropathy, inflammation, glaucoma, a neurodegenerative disorder, a motor function disorder, a gastrointestinal disorder, hypothermia, emesis, loss of appetite, or anorexia associated with AIDS.

Disclosed are compounds and compositions that modulate cannabinoid receptors, methods of modulating cannabinoid receptors, and methods of treating various disorders related to the modulation of cannabinoid receptors. This disclosure is directed to methods of treating cannabinoid dependence, neuropathy, inflammation, glaucoma, a neurodegenerative disorder, a motor function disorder, a gastrointestinal disorder, hypothermia, emesis, loss of appetite, or anorexia associated with AIDS.

Described herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, or combinations thereof, as well as uses thereof. Such uses include promoting tissue self-repair or tissue regeneration of an organ, stimulating the generation of tissue growth, modulating (e.g., increasing) the level of a tissue-repair marker, treating physical injury in an organ, tissue or cell, promoting wound healing, as well as anti-aging applications. Corresponding compositions, methods, kits, and uses are also described. Formula I wherein A is C.sub.5 alkyl, C.sub.6 alkyl, C.sub.5 alkenyl, C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3 or 4; R.sub.1 is H, F of OH; R.sub.2 is H, F, OH, C.sub.5 alkyl, C.sub.6 alkyl, C.sub.5 alkenyl, C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3 or 4; R.sub.3 is H, F, OH, or CH.sub.2Ph; R.sub.4 is H, F or OH; Q is 1) (CH.sub.2), C(O)OH wherein m is 1 or 2 2) CH(CH.sub.3)C(O)OH, 3) C(CH.sub.3).sub.2C(O)OH, 4) CH(F)C(O)OH, 5) CF.sub.2C(O)OH or 6) C(O)C(O)OH.

Described herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, or combinations thereof, as well as uses thereof. Such uses include promoting tissue self-repair or tissue regeneration of an organ, stimulating the generation of tissue growth, modulating (e.g., increasing) the level of a tissue-repair marker, treating physical injury in an organ, tissue or cell, promoting wound healing, as well as anti-aging applications. Corresponding compositions, methods, kits, and uses are also described. Formula I wherein A is C.sub.5 alkyl, C.sub.6 alkyl, C.sub.5 alkenyl, C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3 or 4; R.sub.1 is H, F of OH; R.sub.2 is H, F, OH, C.sub.5 alkyl, C.sub.6 alkyl, C.sub.5 alkenyl, C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3 or 4; R.sub.3 is H, F, OH, or CH.sub.2Ph; R.sub.4 is H, F or OH; Q is 1) (CH.sub.2), C(O)OH wherein m is 1 or 2 2) CH(CH.sub.3)C(O)OH, 3) C(CH.sub.3).sub.2C(O)OH, 4) CH(F)C(O)OH, 5) CF.sub.2C(O)OH or 6) C(O)C(O)OH.

Object of the present invention is an efficient process for the preparation of the active pharmaceutical ingredient Sitagliptine and the 2,4,5-trifluorophenylacetic acid (TFAA) and salt thereof, which is a key intermediate for the synthesis of Sitagliptine.

##STR00001##

Object of the present invention is an efficient process for the preparation of the active pharmaceutical ingredient Sitagliptine and the 2,4,5-trifluorophenylacetic acid (TFAA) and salt thereof, which is a key intermediate for the synthesis of Sitagliptine.

##STR00001##

The present invention relates to a process for the manufacturing of 1-aryl-1-trifluoromethylcyclopropanes, which serve as intermediates for the manufacturing of calcium T channel blockers of the general formula (A) ##STR00001##
which are described in WO 2015/186056.