(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1lambda6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one → (1R,2S,7R,8S)-5-[7-(1,1-dioxo-tetrahydro-1lambda6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one

HRID 884241Notes

Reaction equation

[O:1]=[S:2]1(=[O:40])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CO.[Pd]>[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:21]34[CH2:28][CH:24]([CH2:23][CH2:22]3)[CH:25]3[CH:20]4[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:18](=[O:37])[CH:17]=[C:26]3[OH:27])=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1.[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1

Participants

Conditions

Temperature: 25 °C

Procedure

(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 20, 30 mg, 0.05 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, rinsed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (26 mg, 0.044 mmol, 86%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.40-1.60 (4H, m), 2.12 (1H, m), 2.67 (1H, m), 2.36 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 3.03 (1H, m), 3.23 (1H, m), 3.32 (1H, m), 3.53 (1H, d, J=10.0 Hz), 4.42 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=11.6, 6.8 Hz), 4.97 (1H, d, J=15.6 Hz), 7.14 (2H, m), 7.33 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz); LC-MS (ESI) calcd for C28H28FN3O6S2 585.14, found 586.3 [M+H+].

Workup

customThe flask was degassed
washrinsed with 10% methanol/dichloromethane
concentrationthe filtrate was concentrated in vacuo
customThe residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min

Sources & evidence

ORD record: ord-4e1260cc50f84c70ae4e7a9b8789778e
Source dataset: uspto-grants-2012_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08236948B2

Reaction notes

Loading…