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Sunday, 27 September 2015

Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine

Tolterodine is chemically known as (R)-N,N-disiopropyl-3-(2-hydroxy-5-methyl phenyl)-3-phenyl propyl amine. Tolterodine acts as a muscarinic receptor antagonist. It is useful in the treatment of urinary incontinence [1]. Tolterodine tartrate acts by relaxing the smooth muscle tissues in the walls of the bladder by blocking cholinergic receptors[2]. Tolterodine tartrate [3] is marketed by Pharmacia & Upjohn in the brand name of Destrol®.
The present invention relates to a novel process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4); a key intermediate for the preparation of Tolterodine (1). Some different approaches have been published [4-8] for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4). These methods involve multistep synthesis using hazardous, expensive reagents and some of the methods [6] involve activators like Grignard reagents, LDA, n-butyl lithium, Lewis acids. Hence there is a need to develop an alternative, plant friendly procedure for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) from 3,4-dihydro-6-methyl-4-phenylcoumarin (2) (Fig1).

Tolterodine (1), Methyl 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanoate (3) and N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4).

Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine

Ring opening reactions of dihydrocoumarins are well known in literature[9-11]. But in the present invention, we have described a new methodology (Scheme 1 & Scheme2) for the preparation ofN,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) by using inexpensive and commercially vailable starting materials like 3, 4-dihydro-6-methyl 4-phenylcoumarin (2), which was synthesized from p-cresol and trans-cinnamic acid [12].

Scheme 1
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4.

Scheme 2
N-Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 5.

3,4-Dihyhydro-6-methyl 4-phenylcoumarin (2) reacts with diisopropylamine (6) in presence of acetic acid gives N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) at room temperature. This process of compound 4 is very useful for commercialization of Tolterodine 1 in plant.

General procedure for the synthesis of compounds 4-4c & 5-5c

To a solution of 3,4-dihyhydro-6-methyl 4-phenylcoumarin 2 (10 g, 42 mmol) in diisopropylether (200 mL), N,N-diisopropylamine (33.95 g, 336 mmol) and acetic acid (10 g, 168 mmol) were added at room temperature. The suspension was stirred for 16 h at room temperature. The reaction mass was concentrated, the resulting residue was crystallized with D.M.Water (50 mL) and diisopropyl ether (50 mL) mixture to gave N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4 (10.6 g, 75% yield).

N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4

IR (KBr) cm^-1: 3024 (Aromatic C-H, str.), 2949, 2904, 2869 (Aliphatic C-H, str.), 1630 (C═O, str.), 1609, 1555, 1510 (C═C, str.), 1469, 1459 (CH₂ bending), 1270 (C-N, str.), 1072 (C-O, str.), 788, 769 (Aromatic CH Out-of-plane bend). ¹H NMR (300 MHz, DMSO-d₆) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). ¹³C NMR (125 MHz, DMSO-d₆) δ 19.39, 20.36, 45.69, 115.33, 125.70, 127.20, 128.15, 130.60, 144.43, 152.23, 173.37. MS m/z: 340 [(M + H)⁺].

Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine

Garaga Srinivas¹²^*, Ambati V Raghava Reddy¹, Koilpillai Joseph Prabahar¹, Korrapati venkata vara Prasada Rao¹, Paul Douglas Sanasi² and Raghubabu Korupolu²

*Corresponding author: Garaga Srinivas srinivasgaraga@yahoo.com

¹Chemical Research and Development Department, Aurobindo Pharma Ltd, Survey No:71&72, Indrakaran Village, Sangareddy Mandal, Medak district, Hyderabad 502329, Andhra Pradesh, India

²Engineering Chemistry Department, AU college of Engineering, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India

Sustainable Chemical Processes 2014, 2:2 doi:10.1186/2043-7129-2-2

The electronic version of this article is the complete one and can be found online at:http://www.sustainablechemicalprocesses.com/content/2/1/2
http://www.sustainablechemicalprocesses.com/content/2/1/2/additional