An Efficient Scale-Up Process for the Preparation of the APD334 Precursor 4-Chloromethyl-1-cyclopentyl-2-(trifluoromethyl)benzene

Synthetic studies of the APD334 precursor 4-chloromethyl-1-cyclopentyl-2-(trifluoromethyl)benzene (6) are described. A two-step scalable process was developed starting from commercially available and inexpensive starting materials. An iron(III) chloride-catalyzed aryl–alkyl cross-coupling reaction provided the intermediate 1-cyclopentyl-2-(trifluoromethyl)benzene (9), which was converted to the target building block 6 by a direct regioselective chloromethylation reaction with trioxane/thionyl chloride or chlorosulfonic acid in sulfuric acid. The process was transferred to pilot-plant scale to produce >100 kg of 6 with >98 area % HPLC purity.

[1]  Y. Kubota,et al.  The chloromethylation of biphenyls catalyzed by group 3 and 4 metal triflates , 2006 .

[2]  T. Gunnlaugsson,et al.  Fluorescent sensing of pyrophosphate and bis-carboxylates with charge neutral PET chemosensors. , 2002, Organic letters.

[3]  B. Narayanan,et al.  Formation of 2-Trifluoromethylphenyl Grignard Reagent via Magnesium−Halogen Exchange: Process Safety Evaluation and Concentration Effect , 2009 .

[4]  D. Cárdenas,et al.  Nickel-catalysed Negishi cross-coupling reactions: scope and mechanisms. , 2009, Chemical Society reviews.

[5]  A. Blackburn,et al.  Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. , 2014, ACS medicinal chemistry letters.

[6]  Donald C. Bachert,et al.  An improved preparation of 3,5-bis(trifluoromethyl)acetophenone and safety considerations in the preparation of 3,5-bis(trifluoromethyl)phenyl Grignard reagent. , 2003, The Journal of organic chemistry.

[7]  Alois Fürstner,et al.  The promise and challenge of iron-catalyzed cross coupling. , 2008, Accounts of chemical research.

[8]  G. Mignani,et al.  Selected patented cross-coupling reaction technologies. , 2006, Chemical reviews.

[9]  L. Zani,et al.  Iron-catalyzed reactions in organic synthesis. , 2004, Chemical reviews.

[10]  Yingwu Yin,et al.  An efficient synthesis of diarylmethanes via InCl3·4H2O-catalyzed dehydration of electron-rich arenes with trioxane , 2006 .

[11]  A. Jacobi von Wangelin,et al.  Domino iron catalysis: direct aryl-alkyl cross-coupling. , 2009, Angewandte Chemie.