Potassium Iodide → N-{3-[(1R,2S,7R,8S)-6-hydroxy-4-oxo-3-(1-trifluoromethyl-cyclopropylmethyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

HRID 421503Notes

Reaction equation

CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.C(O[C:19]([C@H:21]1[C@@H:26]([NH2:27])[C@@H:25]2[CH2:28][C@H:22]1[CH2:23][CH2:24]2)=[O:20])C.[F:29][C:30]([F:47])([F:46])[C:31]1([CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1.C(N(CC)CC)C.[I-].[K+].[CH3:57][S:58]([NH:61][CH2:62][C:63]1[C:71]2[S:70](=[O:73])(=[O:72])[N:69]=[C:68]([CH2:74][C:75](O)=[O:76])[NH:67][C:66]=2[S:65][CH:64]=1)(=[O:60])=[O:59].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[OH:20][C:19]1[C@H:21]2[C@H:26]([C@H:25]3[CH2:28][C@@H:22]2[CH2:23][CH2:24]3)[N:27]([CH2:34][C:31]2([C:30]([F:29])([F:46])[F:47])[CH2:32][CH2:33]2)[C:75](=[O:76])[C:74]=1[C:68]1[NH:67][C:66]2[S:65][CH:64]=[C:63]([CH2:62][NH:61][S:58]([CH3:57])(=[O:59])=[O:60])[C:71]=2[S:70](=[O:73])(=[O:72])[N:69]=1

Participants

Conditions

Temperature: 75 °C

Procedure

(1R,2R,3S,4S)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-methanesulfonate (0.3 g, 0.72 mmol, prepared as described in WO08124450A1) was dissolved in N,N-dimethylformamide (4 mL). Toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (0.424 g, 1.44 mmol) was added followed by triethylamine (0.218 g, 2.16 mmol) and potassium iodide (approximately 0.05 g, 0.03 mmol). The mixture was shaken for 40 h at 75° C. Upon cooling, [7-(methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.254 g, 0.72 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.208 g, 1.08 mmol. The mixture was shaken at 25° C. for 16 h. Triethylamine (0.290 g, 2.88 mmol) was added and the mixture was shaken for at 75° C. for 24 h. Upon cooling to 25° C., the mixture was concentrated in vacuo to afford a thick oil. The oil was partitioned between dichloromethane (6 mL) and 1.0 M aqueous hydrochloric acid solution (10 mL). The organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (5 mL). The organic phase was directly purified by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes). The resulting solid was triturated with diethyl ether, filtered and dried in vacuo to afford N-{3-[(1R,2S,7R,8S)-6-hydroxy-4-oxo-3-(1-trifluoromethyl-cyclopropylmethyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.006 g, 0.01 mmol, 1.4%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.79-0.92 (3H, m), 1.00-1.21 (3H, m), 1.37-1.60 (4H, m), 2.49-2.56 (2H, m), 2.88 (3H, s), 2.97 (1H, d, J=9.6 Hz), 3.03 (1H, d, J=15.3 Hz), 3.67 (1H, d, J=9.3 Hz), 4.17 (2H, d, J=6.2 Hz), 4.53 (1H, d, J=15.6 Hz), 7.21 (1H, s), 7.59 (1H, t, J=6.3 Hz). LC-MS (ESI—negative mode) calculated for C22H25F3N4O6S3 594.09. found 593.25 [M−H].

Workup

temperatureUpon cooling
stirringThe mixture was shaken at 25° C. for 16 h
stirringthe mixture was shaken for at 75° C. for 24 h
temperatureUpon cooling to 25° C.
concentrationthe mixture was concentrated in vacuo
customto afford a thick oil
customThe oil was partitioned between dichloromethane (6 mL) and 1.0 M aqueous hydrochloric acid solution (10 mL)
washThe organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (5 mL)
customThe organic phase was directly purified by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes)
customThe resulting solid was triturated with diethyl ether
filtrationfiltered
customdried in vacuo

Sources & evidence

ORD record: ord-286be9d43bb0420fb03b493889806e44
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097613B2

Reaction notes

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