Kilogram Synthesis of a Selective Serotonin Reuptake Inhibitor

Abstract

Process development of a selective serotonin reuptake inhibitor (1) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation of vinyl indole 2 with ethyldiazoacetate to install the trans-disubstituted cyclopropane. The active pharmaceutical ingredient (1) was prepared in 13 chemical steps with 9 isolations and proceeded in an overall yield of 34%.

Indole‐derived Donor‐acceptor Cyclopropanes

“…Meanwhile, a good choice of the appropriate catalyst allows one to synthesize IDDA cyclopropanes with high diastereo‐ and enantioselectivity. Thus, cyclopropanation of 3‐vinylindoles 29 , catalyzed with diazoacetates in the presence of ( R,R )‐Pybox Ru(II) complexes 30 , afforded trans ‐2‐(indolyl)cyclopropanecarboxylates 31 with 73–85 % yield and 81–88 % ee (Scheme ) ,…”

“…The most general transformation of this type is the oxidation of (2‐indolylcyclopropyl)methanols 40 to the corresponding aldehydes 41 (Scheme ). [16,26,27,36–39] In some cases, the obtained aldehydes were immediately introduced into further transformations ,,,. Similarly, 2‐(1‐tosylindol‐3‐yl)‐1‐propionylcyclopropane was obtained by the oxidation of the corresponding secondary alcohol with 2‐iodoxybenzoic acid .…”

“…Similarly, 2‐(1‐tosylindol‐3‐yl)‐1‐propionylcyclopropane was obtained by the oxidation of the corresponding secondary alcohol with 2‐iodoxybenzoic acid . Precursor alcohols can be obtained by the reduction of esters, or other acid derivatives,, cyclopropanation of allylic alcohols, and their silyl ethers, or other methods …”

“…Another important process is the reductive amination of aldehydes 41 , furnishing rigid analogues of homotryptamine or isomeric [2‐(aminomethyl)cyclopropyl]indoles (Scheme ) ,,,,. The Bristol‐Myers‐Squibb company disclosed 1‐[5‐cyanoindol‐3‐yl)‐2‐dimethylaminomethylcyclopropane (BMS‐505130) as an excellent selective serotonin reuptake inhibitor, and developed stereoselective synthesis of the most active (1 S ,2 S )‐enantiomer on the kilogram scale …”

Selective TEMPO‐Oxidation of Alcohols to Aldehydes in Alternative Organic Solvents

“…Nevertheless, a major disadvantage of the “classical” TEMPO‐oxidation using sodium hypochlorite as an oxidation agent and TEMPO as a catalyst is the strong limitation of the solvent system for selective oxidation of primary alcohols to aldehydes, which consists of a biphasic system of water and dichloromethane (DCM) , , , . Many studies were performed to find alternative solvents, but despite some examples for replacement no general solvent or solvent type was found to be suitable for the selective TEMPO‐catalysed oxidation of primary alcohols to aldehydes , , , , , . The Sheldon group, for example, investigated different systems for the selective oxidation of alcohols with aromatic residues to the corresponding aldehydes using alternative solvents like ethyl acetate (EtOAc) or methyl‐ tert ‐butyl ether (MTBE) .…”