Limnetrelvir

CAS 2923500-04-1

MF C₂₇H₂₃F₄N₅O₄ MW 557.50

N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide

N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-
(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamide
antiviral, ABBV-903, ABBV 903, 4TPS988XGG

Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research.

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION

Example 1 – Synthesis of Compound (2) (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide

Compound 2F – Synthesis of 8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid

[00035] A suspension of 7-fluoroindoline-2,3-dione (55 g, 333 mmol), malonic acid (41.6 g, 400 mmol) and sodium acetate (68.3 g, 833 mmol) in acetic acid (500 mL) was heated at 112 °C overnight. The reaction mixture was cooled to room temperature and poured into cold 0.4 M aqueous HCl (2200 mL). The precipitate was collected by filtration and rinsed thoroughly with ice-cold water (~250 mL) followed by methyl tert-butyl ether (~100 mL) and then concentrated twice from acetonitrile with high vacuum. The materials were largely dissolved into 1 M aqueous NaOH (370 mL) and filtered through diatomaceous earth with a 0.1 M aqueous NaOH (50 mL) rinse. Then the filtrate was washed thrice with dichloromethane (3 x 200 mL) which removed the color. After this aqueous layer was filtered again through diatomaceous earth, it was acidified by the dropwise addition of concentrated aqueous HCl (33 mL, ~0.4 moles). The material was collected by filtration. After prolonged drying under heat and vacuum, the material was treated with water (1 L) and the mixture was made acidic by the addition of a small amount of 1 M aqueous HCl. The suspension was heated to 80 °C and then allowed to slowly cool to room temperature. The resulting material was collected by filtration, washed with 0.01 M aqueous HCl (150 mL) and dried under vacuum at 80 °C to provide the title compound (2F).¹H NMR (500 MHz, DMSO-d6) δ ppm 14.00 (bs, 1H), 12.07 (bs, 1H), 8.00 (dd, J = 8.2, 1.2 Hz, 1H), 7.49 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.23 (ddd, J = 8.2, 8.1, 5.2 Hz, 1H), 6.95 (s, 1H); ¹³C NMR (101 MHz, DMSO-d6, 90 °C) δ ppm 165.75 – 165.73 (m), 160.30, 148.75 (d, J = 246.0 Hz), 140.85 – 140.80 (m), 128.11 (d, J = 13.7 Hz), 123.85, 121.60 – 121.53 (m), 121.53 – 121.43 (m), 117.70 – 117.65 (m), 115.33 (d, J = 17.2 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆, 90 °C) δ ppm -130.47 (dd, J = 10.9, 5.3 Hz); MS (APCI, M+H⁺) m/z 208.

Compound 2G – Synthesis of (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (2)

00036] To a mixture of Compound 2F (29.84 g, 144 mmol) in anhydrous N,N-dimethylformamide (360 mL) was added DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-

methylmorpholinium chloride) (43.17 g, 156 mmol) over twelve minutes at room temperature. After the suspension had been stirred forty minutes, it was added over eight minutes to a suspension of Compound 2E (≤120 mmol) and N-methylmorpholine (16 mL, 146 mmol) in N,N-dimethylformamide (120 mL) with a N,N-dimethylformamide (20 mL) rinse. After forty minutes, the reaction mixture was added to rapidly stirred 0.1 M aqueous K2HPO4 (2.5 L) and extracted four times with 4:1 isopropyl acetate / heptanes then once with isopropyl acetate alone. The product, which had begun to precipitate out from the combined extracts, was separated by decantation and filtration, then washed with dichloromethane. The remaining aqueous phase was extracted twice more with isopropyl acetate and all the organic extracts were combined, then washed with additional 0.1 M aqueous K₂HPO₄ followed by water, dried (Na₂SO₄), and filtered. The filtrate was concentrated with the dichloromethane wash of the material collected above. The residue was concentrated, dissolved in acetonitrile / CH2Cl2, filtered, and purified by chromatography on silica (20 to 100% acetonitrile / CH2Cl2). The collected fractions were concentrated to a small volume, and stirred in ethyl acetate overnight.

[00037] The suspension was heated at 70 °C for twenty minutes, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether followed by methyl tert-butyl ether before being dried under vacuum with heat. The material obtained previously from the early extracts were also stirred in ethyl acetate, heated at 70 °C, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether rinse followed by methyl tert-butyl ether. The material was dried overnight under vacuum to provide the title compound (2).¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.96 (s, 1H), 9.03 – 8.84 (m, 1H), 8.21 – 8.18 (m, 1H), 7.98 – 7.93 (m, 1H), 7.56 – 7.50 (m, 1H), 7.49 – 7.43 (m, 1H), 7.21 – 7.15 (m, 1H), 6.66 – 6.59 (m, 1H), 4.51 – 4.40 (m, 1H), 3.73 – 3.55 (m, 6H), 3.54 – 3.22 (m, 6H), 2.29 – 2.18 (m, 1H), 2.07 – 1.95 (m, 1H); ¹H NMR (400 MHz, DMSO-d₆, 90 °C) δ ppm 11.47 (bs, 1H), 8.77 – 8.47 (m, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.1, 1.2 Hz, 1H), 7.39 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.15 (ddd, J = 8.1, 8.1, 5.1 Hz, 1H), 6.60 (s, 1H), 4.54 – 4.43 (m, 1H), 3.74 – 3.20 (m, 12H), 2.31 – 2.21 (m, 1H), 2.06 – 1.96 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆, 90 °C) δ

ppm 166.61, 165.97, 161.31, 149.59 (d, J = 246.3 Hz), 148.95, 146.10 – 146.03 (m), 136.00, 135.65, 133.13 (q, J = 6.1 Hz), 128.84 – 128.63 (m), 123.76 (q, J = 273.7 Hz), 122.19, 122.16, 122.12, 121.60, 118.99 – 118.91 (m), 117.75, 116.17 (d, J = 17.3 Hz), 105.57, 66.04, 57.95, 51.06, 50.35, 47.74, 42.35, 31.54; ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -57.54 – -58.10 (m), -130.02 – -130.15 (m); ¹⁹F NMR (376 MHz, DMSO-d6, 90 °C) δ ppm -58.37 – -58.97 (m), -130.96 (dd, J = 11.0, 5.1 Hz). MS (APCI, M+H⁺) m/z 558.

PAT

• Pyrrolidine Main Protease Inhibitors as Antiviral AgentsPublication Number: US-2024158368-A1Priority Date: 2022-10-14
• Pyrrolidine main protease inhibitors as antiviral agentsPublication Number: WO-2024081351-A1Priority Date: 2022-10-14

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