An Efficient Scale-Up Process for the Preparation of the APD334 Precursor 4-Chloromethyl-1-cyclopentyl-2-(trifluoromethyl)benzene
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- 作者：Dipanjan Sengupta ; Tawfik Gharbaoui ; Ashwin Krishnan ; Daniel J. Buzard ; Robert M. Jones ; You-An Ma ; Robert Burda ; Antonio Garrido Montalban ; Graeme Semple
- 刊名：Organic Process Research & Development
- 出版年：2015
- 出版时间：June 19, 2015
- 年：2015
- 卷：19
- 期：6
- 页码：618-623
- 全文大小：265K
- ISSN：1520-586X
文摘
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鈥揳lkyl 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.