tributyl-(1,1-dioxo-4,5-dihydro-1H-1lambda6-thiophen-2-yl)-stannane → (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

HRID 1751242Notes

Reaction equation

HRID 1751242 reaction equation
[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41](=[O:46])(=[O:45])[CH2:42][CH2:43][CH:44]=1)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:45]=[S:41]1(=[O:46])[CH2:42][CH2:43][CH:44]=[C:40]1[C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:30])(=[O:29])[C:21]=2[CH:27]=1

Participants

5

Reactant 2

HCID 59853603tributyl-(1,1-dioxo-4,5-dihydro-1H-1lambda6-thiophen-2-yl)-stannaneHCID 136395898(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one

Product 1

HCID 136402479(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-oneYield 20%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 200 mg, 0.34 mmol) and tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (prepared as described in US patent application US 2008/0031852, 180 mg, 0.44 mmol) in anhydrous N,N-dimethylformamide (7 mL) under a nitrogen atmosphere, Pd(PPh3)4 (20 mg, 0.017 mmol) was added. The resulting mixture was stirred at 90° C. for 22 h, and then allowed to cool to 25° C. The reaction mixture was concentrated in vacuo and 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-4,5-dihydro-1H-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 (38 mg, 0.065 mmol, 20%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.42-1.61 (4H, m), 2.50 (1H, m), 2.65 (1H, m), 2.97 (2H, m), 3.05 (1H, m), 3.53 (3H, m), 4.43 (1H, d, J=14.4 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.33 (2H, m), 7.41 (1H, t, J=3.6 Hz), 7.66 (1H, d, J=9.2 Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C28H26FN3O6S2 583.12, found 584.2 [M+H+].

Workup

  1. temperatureto cool to 25° C
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. 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 @30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water]

Sources & evidence

ORD record
ord-65cf707d88554eaf97b01508fda8e733
Source dataset
uspto-grants-2015_10
Patent number
US09156832B2

Reaction notes

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