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PROCESS FOR PREPARING 3-(3-TRIFLUOROMETHYLPHENYL)PROPANAL

IP.com Disclosure Number: IPCOM000191229D
Publication Date: 2009-Dec-22
Document File: 3 page(s) / 69K

Publishing Venue

The IP.com Prior Art Database

Abstract

An improved method for preparing 3-(3-trifluoromethylphenyl)propanal, a key intermediate for the synthesis of cinacalcet hydrochloride, has been developed through an one-pot process comprising a Heck coupling between 3-bromobenzotrifluoride and acrolein diethyl acetal, catalyzed by palladium (II) acetate, followed by a hydrogenation reaction, using the same palladium compound as a catalyst, and a final acetal deprotection. Cinacalcet Hydrochloride is a calcimimetic compound which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and also for the treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is marketed as Sensipar® in United States and as a Mimpara® and Parareg® in Europe.

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PROCESS FOR PREPARING 3-(3-TRIFLUOROMETHYLPHENYL)PROPANAL

Introduction

            An improved method for preparing 3-(3-trifluoromethylphenyl)propanal, a key intermediate for the synthesis of cinacalcet hydrochloride, has been developed through an one-pot process comprising a Heck coupling between 3-bromobenzotrifluoride and acrolein diethyl acetal, catalyzed by palladium (II) acetate, followed by a hydrogenation reaction, using the same palladium compound as a catalyst, and a final acetal deprotection.

            Cinacalcet Hydrochloride is a calcimimetic compound which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and also for the treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is marketed as Sensipar® in

United States

and as a Mimpara® and Parareg® in

Europe

.

Background

US 6,211,244 discloses a cinacalcet synthesis by condensation of 1-acetyl naphthalene and 3-[3-(trifluoromethyl)phenyl]propylamine in the presence of titanium (IV) isopropoxide and subsequent reduction of the resulting imine with sodium cyanoborohydride. The resulting racemic cinacalcet is then resolved by a chiral chromatographic column.

Drugs of the Future (2002), 27(9), page 831, reports a similar preparation of cinacalcet, starting from (R)-1-(1-naphthyl)ethylamine and 3-(3-trifluoromethylphenyl) propanal, again by imine formation and subsequent reduction with sodium cyanoborohydride, as depicted in Scheme 1.

       

                                                           Scheme 1

A known synthetic route for the preparation of the above starting material, 3-(3-trifluoromethylphenyl)propanal, is disclosed in a footnote in Tetrahedron Letters (2004), 45(45), page 8355, from commercially available 3-trifluoromethylcinnamic acid (Scheme 2):

                                

                                                           Scheme 2

The process involves hydrogenation of the double bound of trans-3-trifluoromethylcinnamic acid followed by reduction (LiAlH4) of the carboxylic moiety to the corresponding alcohol, which is then oxidized to aldehyde by Swern oxidation. The last reaction involves reagents such as oxalyl chloride and DMSO which are not environmentally friendly.

PCT patent application WO2008/035212 describes a method to synthesize the same aldehyde by oxidation of 3-(3-trifluoromethylphenyl)propan-1-ol with an oxidizing agent (sodium hypochlorite) using a nitroxyl compound as catalyst (TEM...