Potassium Iodide → N-{3-[(1R,2S,7R,8S)-3-(2-cyclopentyl-ethyl)-6-hydroxy-4-oxo-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 421504Notes

Reaction equation

C[C:2]1(C)[CH:6]2[CH2:7][CH2:8][C:3]1(CS(O)(=O)=O)[C:4](=O)[CH2:5]2.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.C1(CCOS(C2C=CC(C)=CC=2)(=O)=O)CCCC1.C(N(CC)CC)C.[I-].[K+].[CH3:56][S:57]([NH:60][CH2:61][C:62]1[C:70]2[S:69](=[O:72])(=[O:71])[N:68]=[C:67]([CH2:73][C:74](O)=[O:75])[NH:66][C:65]=2[S:64][CH:63]=1)(=[O:59])=[O:58].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:3]1([CH2:4][CH2:5][N:27]2[C:74](=[O:75])[C:73]([C:67]3[NH:66][C:65]4[S:64][CH:63]=[C:62]([CH2:61][NH:60][S:57]([CH3:56])(=[O:58])=[O:59])[C:70]=4[S:69](=[O:72])(=[O:71])[N:68]=3)=[C:19]([OH:20])[C@H:21]3[C@@H:26]2[C@H:25]2[CH2:28][C@@H:22]3[CH2:23][CH2:24]2)[CH2:2][CH2:6][CH2:7][CH2:8]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 (0.15 g, 0.36 mmol, prepared as described in WO08124450A1) was dissolved in N,N-dimethylformamide (4 mL). Toluene-4-sulfonic acid 2-cyclopentyl-ethyl ester (0.193 g, 0.72 mmol) was added followed by triethylamine (0.109 g, 1.08 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; 0.127 g, 0.36 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol. The mixture was shaken at 25° C. for 16 h. Triethylamine (0.145 g, 1.44 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 (4 mL) and 1.0 M aqueous hydrochloric acid solution (6 mL). The organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (2 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)-3-(2-cyclopentyl-ethyl)-6-hydroxy-4-oxo-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 (0.015 g, 0.026 mmol, 7.2%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.11-1.18 (1H, m), 1.18-1.27 (1H, m), 1.27-1.34 (1H, m), 1.42-1.66 (10H, m), 1.67-1.81 (4H, m), 2.50-2.54 (1H, m), 2.61-2.63 (1H, m), 2.96-3.11 (5H, m), 3.58-3.68 (2H, m), 4.24 (2H, d, J=6.2 Hz), 7.28 (1H, s), 7.66 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C24H32N4O6S3 568.1. found 569.3 [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 (4 mL) and 1.0 M aqueous hydrochloric acid solution (6 mL)
washThe organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (2 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-2a0e5c625cb444739fd69b1c61c7e397
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097613B2

Reaction notes

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