New chemo-enzymatic synthesis of (R)-1-chloro-3-(piperidin-1-yl) propan-2-ol Linga Banoth a , Thete Karuna Narayan a , Brahmam Pujala b , Asit K. Chakraborti b , Uttam Chand Banerjee a,⇑ a Biocatalysis Laboratory, Department of Pharmaceutical Technology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India b Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India article info Article history: Received 12 September 2012 Accepted 16 October 2012 abstract The present study deals with the efficient chemo-enzymatic synthesis of enantiopure (R)-1-chloro-3- (piperidin-1-yl) propan-2-ol 3, as an intermediate for (R)-arimoclomol. This intermediate was synthe- sized from racemic alcohol (RS)-3 using lipases with vinylacetate as the acyl donor in three different ionic liquids (1-butyl-3-methyl imidazolium tetrafluoroborate [BMIM][BF 4 ], 1-butyl-3-methyl imidazolium hexafluorophosphate [BMIM][PF 6 ] ,and 1-ethyl-3-methyl imidazolium tetrafluoroborate [EMIM][BF 4 ]) in combination with an organic solvent (toluene). Various reaction parameters, such as temperature, time, substrate and enzyme concentration, and reaction medium (organic solvent and ionic liquid) were optimized using Pseudomonas aeruginosa MTCC 5113 lipases (PAL). It was observed that 30 mM of (RS)-3 and 30 mg/mL of PAL in 4 mL of solvent (toluene:[BMIM][BF 4 ]::70:30) using vinyl acetate as the acyl donor at 30 °C gave good conversion (C = 50.02%) and enantiomeric excess (ee P = 98.91% and ee S = 99%) in 18 h. The (S)-1-chloro-3-(piperidin-1-yl) propan-2-yl acetate 4 and (R)-3 were separated by flash chro- matography. Compound (R)-3 is a key intermediate for the synthesis of enantiopure arimoclomol and bimoclomol. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Lou Gehrig’s disease, an amyotrophic lateral sclerosis (ALS), is a fatal, neurodegenerative disease characterized by the deterioration of neurons in the motor cortex, brainstem, and the spinal cord. 1 ALS is an orphan disease that affects 350,000 people worldwide and results in death within 3–5 years. This makes developing riluz- ole important for the management of ALS, as survival is modestly prolonged with this drug. 2 The CytRx Corporation, a biopharma- ceutical company based in Los Angeles, developed the drug arimo- clomol in 2006. 3 This oral drug, approved by the FDA, is used to treat ALS. Arimoclomol delays the process of motor neuron death by co-inducing heat shock proteins, thereby prolonging survival. 4 Arimoclomol engenders the phosphorylation of a heat shock protein-inducing factor (HSF-1) and upregulates the expression of heat shock proteins, HSP-70 and HSP-90. 5 The produced HSPs and their cochaperones, are effective in controlling other neurode- generative diseases, such as, Parkinson’s, Creutzfeldt–Jakob, Alzheimer’s, Huntington’s, 6 ischemia, reperfusion injuries, 7 cardiovascular injuries, 8 and diabetic neuropathies. 9 The synthesis of arimoclomol has been reported in the literature. 10 It is known that the (R)-enantiomer of arimoclomol has the desirable biological activities. 11 Enzymes are used as an alternative catalysts compared to chemical ones. Lipases are used as catalysts for many chemical reactions, due to their robust nature in terms of stability, substrate and product tolerance, broad specificity, and non requirement of cofactors. 12 Lipases are well established in our laboratory for transesterification reactions with secondary alcohols. 13 Ionic liq- uids are seen as the ‘green’ reaction media of the future. These salts, which consist of an organic cation and an inorganic anion, have melting temperatures of less than 100 °C, and are often fluid at room temperature. 14 Ionic liquids are considered to be ‘designer solvents’, due to their ability to tune their properties with regard to hydrophobicity, polarity, and solvent miscibility by selecting suit- able cation/anion combinations. Ionic liquids have been used in the lipase-catalyzed resolution of fatty acids, 1-phenylethanol, carbohydrate derivatives, malonates, biodiesel, nucleoside drugs (inosine, cytarabine, and ribavirin), and ibuprofen, and as catalysts in ammonolysis and perhydrolysis reactions. 15 Ionic liquids and organic solvents, or mixtures of the two, have been used in the resolution of chiral esters, amines, and alcohols with immobilized lipase B from Candida antarctica or lipase from Pseudomonas cepacia (native), and are highly effective. 16 The effect of different reaction parameters on the activity and enantioselectivity of the enzyme preparation of PAL have been reported in the literature. 13 Herein we report the use of this biocatalyst for the resolution of (RS)-3 in ionic liquids and organic solvents as media using vinyl acetate as the acyl donor. The dependence of the enantioselectivity and the rate of acetylation on the reaction media, acyl donor, 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.10.008 ⇑ Corresponding author. Tel.: 91 172 2214682/85x2142; fax: 91 172 2214692. E-mail address: ucbanerjee@niper.ac.in (U.C. Banerjee). Tetrahedron: Asymmetry 23 (2012) 1564–1570 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy