A Two Hour Synthesis of the Anti-Parkinson Drug Safinamide Methanesulfonate

Abstract

The critical moment of the COVID-19 outbreak requires a real-time supply of therapeutic agents. Thus, time economy in the synthesis of biologically active compounds has become increasingly decisive. In this work, we developed a two hour synthesis of the anti-Parkinson drug safinamide methanesulfonate in four steps with a 64% overall yield. Microwave irradiation was used in the first three steps in a one-pot fashion. In fact, the protocol can provide safinamide free base in one hour without a chromatographic purification step. Also, green solvents such as methanol and ethyl acetate are used.

Key words

medicinal chemistry - microwave heating - time economy - safinamide mesylate - green chemistry

Publication History

Received: 19 May 2021

Accepted after revision: 22 June 2021

Accepted Manuscript online:
22 June 2021

Article published online:
09 July 2021

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• 17 Safinamide methanesulfonate (1) An Ace-type Teflon-threaded pressure tube was charged with 4-hydroxybenzaldehyde (2; 0.5 mmol, 61 mg), DIPEA (1 mmol, 174 μL), and 1-(bromomethyl)-3-fluorobenzene (3; 0.5 mmol, 68 μL). The tube was capped and then subjected to microwave irradiation (maximum power: 200 W) for 25 min at 70 °C. The mixture was then cooled and MeOH (200 μL) and l-alaninamide hydrochloride (0.5 mmol, 62 mg) were added. The tube was recapped and subjected to microwave irradiation (maximum power: 200 W) for 15 min at 55 °C. The mixture was cooled to r.t. and NaBH₃CN (1 mmol, 62 mg) was added to the tube. The tube was recapped once more and then subjected to microwave irradiation (maximum power: 200 W) for 20 min at 55 °C. The mixture was diluted with EtOAc (30 mL) and washed with H₂O (2 × 10 mL). The organic phase was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was transferred to a round-bottomed flask, and dissolved in EtOAc (4 mL). MsOH (0.6 mmol, 39 μL) was added, and the mixture was stirred for 60 min at 50 °C then filtered in a Pasteur pipette to give a white solid; yield: 128 mg (64%); mp 213 °C (dec) (lit.8 mp 210 °C (dec)) °C; [α]_D ²⁴ +12.5 (c 1.0, AcOH) {Lit.¹² [α]_D ²⁶ +12.9° (c 1.0, AcOH)}. ¹H NMR (500 MHz, DMSO-d ₆): δ = 9.01 (br s, 2 H), 7.90 (s, 1 H), 7.62 (s, 1 H), 7.46–7.39 (m, 3 H), 7.30–7.26 (m, 2 H), 7.18–7.14 (m, 1 H), 7.09–7.06 (m, 2 H), 5.17 (s, 2 H), 4.04–4.00 (m, 2 H), 3.75–3.71 (m, 1 H), 2.32 (s, 3 H), 1.41 (d, J = 5 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 170.4, 163.1, 161.2, 158.5, 139.9, 139.8, 131.6, 130.4, 123.8, 123.4, 114.9, 114.7, 68.3, 54.1, 47.9, 15.8. The NMR data agree with those reported in the literature (see ref. 12).