Odentegravir

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Odentegravir

CAS 2495436-99-0

MF C20H18F3N3O4 MW421.4 g/mol

(7S)-12-hydroxy-1,11-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,4,5,6,7,11-hexahydro-3H-2,7-
methanopyrido [1,2-a][1,4]diazonine-10-carboxamide

(7S)-1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
(7S)-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-1,4,5,6,7,11-HEXAHYDRO-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE, 1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-, (7S)-

antiviral, H8B26JZ4A4, orb2664247

Odentegravir is a small molecule drug classified as a

HIV integrase inhibitor, indicated by the “-tegravir” stem in its name. It is a chemical compound with the molecular formula

has been used in research for its antiviral properties.

Drug Class: HIV integrase inhibitor
Chemical Formula: C20H18F3N3O4cap C sub 20 cap H sub 18 cap F sub 3 cap N sub 3 cap O sub 4𝐶20𝐻18𝐹3𝑁3𝑂4
Molecular Weight: 421.12421.12421.12 Da (monoisotopic)
Classification: Small molecule drug

SYN

WO-2020197991

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020197991&_cid=P12-MHY8KB-06018-1

Example 23: Preparation of racemic-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-

methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1) and (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2):

Synthesis of 12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26):

[0335] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) with (2,4,6-trifluorophenyl)methanamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added and the mixture was stirred at room

temperature. After overnight reaction, the reaction was concentrated to dryness, purified by silicon gel chromatography to obtain compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) MS (m/z) 512.06 [M+H]⁺.

[0336] Compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) (7 mg, 0.014 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stirred at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26). MS (m/z) 422.091 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) d 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.24 – 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9 Hz, 1H), 4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 – 3.79 (m, 1H), 3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06 – 1.91 (m, 1H), 1.89 – 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J = 12.7 Hz, 1H).

Synthesis of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1):

[0337] Racemic 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) was separated by chiral HPLC separation (SFC chromatography on an IB 4.6X100mm 5mic column using MeOH(20) as co-solvent) to obtain compounds (7R)-12-(Benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) and (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2)

[0338] Compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2) (20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-2). (MS (m/z) 422.123 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) d 10.59 (s, 1H), 10.39 (d, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 4.72 (s, 1H), 4.59 – 4.48 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.69 – 3.59 (m, 1H), 3.05 (ddd, J = 11.3, 6.7, 3.6 Hz, 1H), 1.97 (m, 1H), 1.87 – 1.71 (m, 3H), 1.67 – 1.55 (m, 1H), 1.10 (m, 1H).

[0339] Compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) ((20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-1). MS (m/z) 422.116 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) d 10.58 (s, 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H), 4.73 (s, 1H), 4.58 – 4.49 (m, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 – 3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d, J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 – 1.05 (m, 1H).

SYN

WO-2023196875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023196875&_cid=P12-MHY8FJ-02517-1

PAT