A novel and practical asymmetric synthesis of dapoxetine hydrochloride

Summary A novel and practical asymmetric synthesis of dapoxetine hydrochloride by using the chiral auxiliary (S)-tert-butanesulfinamide was explored. The synthesis was concise, mild, and easy to perform. The overall yield and stereoselectivity were excellent.


Introduction
Premature ejaculation (PE) is the most frequent form of ejaculatory dysfunction with a distribution of 39% of the general male population [1,2]. Dapoxetine hydrochloride (1, (S)-(+)-N,Ndimethyl-[3-(naphthalen-1-yloxy)-1-phenylpropyl]amine hydrochloride, Figure 1) was approved by EMA in 2009 for the special treatment of PE [3,4]. By virtue of its fast acting property and rapid elimination from the body, it is one of the more effective and safe drugs for treating PE.
For this reason, the synthesis of this interesting drug has attracted great attention, especially asymmetric synthesis approaches. However, only a few methods have been reported for the synthesis of enantiopure dapoxetine hydrochloride. The earlier methods included chiral/enzymatic resolution [5], whereas the newer approaches encompass asymmetric dihydroxylation of trans-methyl cinnamate or cinnamyl alcohol [6], chiral azetidin-2,3-dione [7], asymmetric C-H amination reactions of a prochiral sulfamate [8], oxazaborolidine reduction of 3-chloropropiophenone or ketone [9], and an imidazolidin-2- one chiral auxiliary mediated acetate aldol reaction [10]. However, these methods are undermined by poor yield, low enantioselectivity, and complex synthetic procedure.
Chiral tert-butanesulfinamide, developed by García Ruano and Ellman, has been proven to be a broadly useful reagent for the preparation of chiral amines via the chiral N-tert-butanesulfinylimine intermediates [11,12]. Due to its high diastereoselectivity and convenient cleavage of the N-tert-butanesulfinyl group, it has become an excellent chiral auxiliary in the synthesis of chiral amine compounds [13]. This work was devoted to develop an efficient synthetic route for the synthesis of (S)dapoxetine (1) through this chiral auxiliary.

Results and Discussion
Herein, a novel and practical synthesis of 1 (Scheme 1) based on (S)-tert-butanesulfinamide (2) was developed.
The diastereoselective reduction of imine 4 (Scheme 2) was the key step in this route. Accordingly, various conditions were screened and the results are presented in Table 1.
Following a procedure reported in the literature [14], the reduction of 4 was carried out with NaBH 4 in THF at 25 °C for 1 h ( Table 1, entry 1). However, the main product was proven to be the denaphthalenyloxy compound 5'' by 1 H NMR and MS while the desired sulfinamide 5 was obtained only in a yield of 28%. The amount of denaphthalenyloxy was greatly reduced when the reaction temperature was decreased to −30 °C ( Table 1, entry 2), but no significant improvement was achieved by further decreasing the temperature (Table 1, entry 3). It was assumed that after reduction, the basicity resulting from NaBH 4 might lead to the denaphthalenyloxylation. Therefore, AcOH was used as an additive in the reaction. The results showed that the denaphthalenyloxylation was almost negligible, but the diastereoselectivity was not good enough ( Then purified 5 was hydrolyzed in methanol with HCl/EtOH solution at room temperature and dissociated with NaHCO 3 to give the primary amine 6 in 90.0% yield. The reductive amination of 6 under Eschweiler-Clarke conditions furnished (S)dapoxetine 7 with excellent enantiopurity (99.3% ee) in 74.7% yield. After salt formation and recrystallization, the target com-pound 1 was obtained. The optical rotation value of compound 1 was consistent with that previously reported [15], which confirmed that the S-enantiomer of dapoxetine hydrochloride was synthesized successfully by using this route.

Conclusion
In summary, a novel and stereoselective synthesis of dapoxetine hydrochloride starting from commercially available 3-(naphthalen-1-yloxy)-1-phenylpropan-1-one in five linear steps (33.5% overall yield) via introduction of the chiral auxiliary (S)-tert-butanesulfinamide was developed. This method was easy to perform and both the purity and yield of the product were excellent.

Experimental
All solvents and reagents were of reagent grade and used without further purification. 1 H and 13 C NMR spectra were recorded using a Bruker 400 MHz spectrometer with TMS as an internal standard. HPLC analyses were recorded with on a Dionex Ultimate 3000 chromatograph and chiral HPLC analyses were recorded with an Agilent 1100 Series spectrometer.

Preparation of (S)-2-methyl-N-((S)-3-(naphthalen-1-yloxy)-1-phenylpropyl)propane-2-sulfinamide (5):
To a suspension of 4 (20 g, 53 mmol) in diisopropyl ether (300 mL), BH 3 /THF (10 mL, 42.2 mmol) was added dropwise at −5 to 0 °C. After this addition, the reaction mixture was stirred for 1.5 h. The color of the reaction changed from yellow to white and TLC showed the complete consumption of 4. Then, ethyl acetate (200 mL) and water (100 mL) were added and the mixture was stirred for 5 min and then separated. The organic phase was washed with brine, dried over Na 2 SO 4 , and filtered and concentrated to obtain the crude product. The crude product was crystallized from an n-heptane/ethyl acetate mixture (9:1) to get pure 5 as an off-white solid. Yield 15.

Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (6):
To a solution of 5 (12 g, 31.5 mmol) dissolved in methanol (60 mL), 28% HCl/EtOH (9 mL, 63 mmol) was added at 10-20 °C. The mixture was stirred for 1 h at room temperature. Then, the mixture was concentrated and the obtained crude residue was resuspended with MTBE (70 mL) to give pure hydrochloride 6. The solid was suspended in DCM (50 mL), and saturated aqueous NaHCO 3 solution (15 mL) was added and stirred until the mixture was no longer turbid. The organic phase was washed with brine, dried over Na 2 SO 4 , and filtered and concentrated to give 6 as a pale yellow oil. Yield