Synthesis of a Potent Pan-Serotype Dengue Virus Inhibitor Having a Tetrahydrothienopyridine Core

Abstract

A synthesis of the first-in-class pan-serotype dengue virus inhibitor NITD-688 is presented. The Gewald reaction of N-(tert-butoxycarbonyl)-6,6-dimethylpiperidin-3-one with malononitrile and sulfur in the presence of l-proline as a catalyst gave tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate. This was coupled with [4-(aminosulfonyl)phenyl]acetic acid by using propane­phosphonic acid anhydride. A subsequent reductive alkylation with cyclohexanecarboxaldehyde gave NITD-688. Preliminary results of our attempts to control the regioselectivity of the Gewald synthesis of the 2-amino-3-cyanothiophene core are also presented.

Key words

medicinal chemistry - Gewald reaction - tetrahydrothienopyridines - regioselectivity - dengue virus inhibitors

Publication History

Received: 26 October 2020

Accepted after revision: 26 November 2020

Accepted Manuscript online:
26 November 2020

Article published online:
21 December 2020

• References and Notes

• 1 Current address: Novartis (Singapore) Pte Ltd, 20 Pasir Panjang Road #10-25/28 Mapletree Business City, Singapore 117439.
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• 18 tert-Butyl 2-Amino-3-cyano-6,6-dimethyl-6,7-dihydro­thieno- [3,2-c]pyridine-5(4H)-carboxylate (12) l-Proline (12.66 g, 110 mmol, 1.0 equiv) and sulfur (5.27 g, 165 mmol, 1.5 equiv) were added sequentially to a solution of 11 (25 g, 110 mmol) in DMF (100 mL) at rt, and the mixture was stirred at rt for 10–15 min. Malononitrile (8 g, 121 mmol, 1.1 equiv) was added, and mixture was stirred at 55–60 °C for 10–12 h. When the reaction was complete, the mixture was washed with hexane (3 × 50 mL). The bottom DMF layer was slowly added to cold H₂O (250 mL), and the precipitated solids were collected by filtration, washed with H₂O (50 mL), and dried. The wet product was purified by column chromatography (silica gel, CH₂Cl₂–MeOH) to give 12 as a pale brown color solid; yield: 8 g (26 mmol, 24%) (96.1% pure; 96.22:0.75 isomeric mixture based on HPLC). ¹H NMR (400 MHz, DMSO-d ₆): δ = 17.13 (br s, 2 H), 4.18 (s, 2 H), 3.31 (s, 2 H), 2.54 (s, 2 H), 1.40 (s, 9 H), 1.38 (s, 6 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 1163.71, 154.76, 128.71, 115.51, 114.31, 80.68, 79.24, 55.22, 42.66, 37.85, 28.06, 27.40. HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₂₀N₃O₂S: 306.1271; found: 306.1281.
• 19 2-Amino-5-benzyl-6,6-dimethyl-4,5,6,7-tetrahydro­thieno[3,2-c]pyridine-3-carbonitrile (19): Regiocontrolled Synthesis Pyridinium tribromide (382 mg, 1.194 mmol, 1.2 equiv) was added to a 0.1 M solution of silyl enol ether 17 (330 mg, 0.995 mmol, 1.0 equiv) in CH₂Cl₂ (10 mL) at 23 °C, and the mixture was stirred for 15 min. The reaction was then quenched with sat. aq Na₂S₂O₃ and extracted with CH₂Cl₂ (×3). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated in vacuo to provide bromide 18, which was used immediately in the next step without further purification. Anhyd DMF (3.32 mL, 0.1 M) was added to the crude bromide 18 (1.0 equiv), NaSH (27.9 mg, 0.498 mmol, 1.5 equiv), malononitrile (24.1 mg, 0.365 mmol, 1.1 equiv), and l-proline (38.2 mg, 0.332 mmol, 1.0 equiv) under an inert atmosphere at 23 °C, and the mixture was stirred at 23 °C for 2 h. When the reaction was complete it was quenched with sat. aq Na₂S₂O₃ and sat. aq NaHCO₃, and the mixture was extracted with EtOAc (×3). The combined organic layers were washed sequentially with H₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The residual crude mixture was redissolved in CH₂Cl₂ at 23 °C, silica gel (3 g) was added, and the mixture was stirred for 4 h. The solvent was then removed in vacuo and the crude residue was purified by flash column chromatography on an ISCO machine [silica gel, heptane–EtOAc (0–50%)] to give the cyano derivative 19 as a yellow solid; yield: 21 mg (20%, 0.071). ¹H NMR (500 MHz, CDCl₃): δ = 17.36–7.28 (m, 4 H), 7.30–7.22 (m, 1 H), 4.59 (s, 2 H), 3.66 (s, 2 H), 3.39 (t, J = 2.0 Hz, 2 H), 2.51 (d, J = 2.2 Hz, 2 H), 1.23 (s, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 160.56, 139.92, 129.78, 128.52 (2 C), 128.36 (2 C), 126.91, 118.51, 100.45, 86.83, 53.94, 53.05, 46.93, 37.46, 24.21 (2 C). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₀N₃S: 298.1372; found: 298.1374.