Patent Watch

August 10, 2009

Produce duloxetine with high stereoselectivity. Duloxetine (2) is sold as its HCl salt under the trade name Cymbalta for treating major bouts of depression. Inventors M. A. Butchko, A. Merschaert, and K. P. Moder report that most processes for synthesizing 2 involve an arylation step that uses NaH and DMSO. These reagents produce the cation MeS(O)CH₂⁺ that can cause racemization during this step; only the (S)-enantiomer is desired. Use of these reagents with a phase-transfer catalyst such as 18-crown-6 prevents racemization, but the crown ether is toxic.

The inventors’ objective was to provide a process that avoids racemization by eliminating the use of NaH and by reducing the amount of DMSO used. Previously reported reactions using KOH as base can cause racemization, but the inventors found that KOH can be used in DMSO if toluene is also present. Alternatively, diglyme can be used as solvent with KOH as base.

One process for producing 2 is run at 85 °C in toluene that contains up to 25% DMSO (see figure). The enantiomeric excess of the (S)-isomer of the crude amine 2 is not reported in the patent, but the purity of the

product is given in terms of %ΔR. This is the difference in the amount of the unwanted (R)-enantiomer between the starting thiophene derivative 1 and product 2. The value of %ΔR is reported as 1.0, but this is not very meaningful without knowing the actual purity of 1 and 2 (although indications are that pure enantiomer 1 is used in the reaction, so the reaction does seem to be stereoselective).

The patent also describes the production of the H₃PO₄ adduct of the Me₂NH derivative 3. In this case, KOH–diglyme was used for the alkylation step. The adduct was isolated and had a %ΔR value of 0.2. The primary advantage of the new process is that it gives highly stereoselective reactions with a relatively small change in the existing process. (Eli Lilly [Indianapolis]. US Patent 7,538,232, May 26, 2009; Keith Turner)

View patent information from CAS.

What do you think of Patent Watch and Noteworthy Chemistry? Let us know.