Pyridine → N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo [6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6 benzo[1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

HRID 2408770Notes

Reaction equation

HRID 2408770 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1.C(N(CC)CC)C.N1C=CC=CC=1.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl.C(OCC)(=O)C.O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:16]2[C:15](=[O:34])[C:14]([C:9]3[NH:8][C:7]4[CH:35]=[CH:36][C:4]([CH2:3][NH:2][S:51]([CH3:50])(=[O:53])=[O:52])=[CH:5][C:6]=4[S:11](=[O:13])(=[O:12])[N:10]=3)=[C:23]([OH:24])[C@H:22]3[C@@H:17]2[C@H:18]2[CH2:25][C@@H:21]3[CH2:20][CH2:19]2)=[CH:32][CH:31]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 136395900(1R,2S,7R,8S)-5-(7-Aminomethyl-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 hydrochloride

Product 1

HCID 135936819N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo [6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6 benzo[1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamideYield 31%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

(1R,2S,7R,8S)-5-(7-Aminomethyl-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 hydrochloride (crude from previous step, ˜0.77 mmol) was dissolved in methylene chloride (10 mL). Triethylamine (2 mL) and pyridine (2 mL) were added. Methane sulfonyl chloride (2 mL) was added and the mixture stirred at 25° C. for 20 min. Water (50 mL) was added and the mixture stirred for 5 min. The solution was diluted with ethyl acetate (200 mL) and washed with 1.0 M aqueous hydrochloric acid solution (3×300 mL), saturated aqueous ammonium chloride solution (2×200 mL) and saturated aqueous brine solution (200 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.139 g, 0.238 mmol, 31%) as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.19-1.25 (1H, m), 1.40-1.64 (5H, m), 2.50-2.54 (1H, m), 2.64 (1H, d, J=2.5 Hz), 2.92 (3H, s), 3.04 (1H, d, J=8.8 Hz), 3.53 (1H, d, J=9.5 Hz), 4.25 (2H, d, J=6.2 Hz), 4.42 (1H, d, J=15.8 Hz), 4.97 (1H, d, J=14.7 Hz), 7.12-7.17 (2H, m), 7.33 (2H, dd, J1=7.7 Hz, J2=5.4 Hz), 7.52 (1H, d, J=8.7 Hz), 7.63-7.70 (2H, m), 7.81 (1H, s). LC-MS (ESI) calculated for C26H27FN4O6S2 574.14. found 575.3 [M+H+].

Workup

  1. stirringthe mixture stirred for 5 min
  2. washwashed with 1.0 M aqueous hydrochloric acid solution (3×300 mL), saturated aqueous ammonium chloride solution (2×200 mL) and saturated aqueous brine solution (200 mL)
  3. dry with materialThe organic phase was dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto afford a clear oil
  7. customPurification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes)
  8. concentrationfollowed by concentration in vacuo

Sources & evidence

ORD record
ord-4341011b90e040c89b9b64b48dfc5e8d
Source dataset
uspto-grants-2014_08
Patent number
US08815847B2

Reaction notes

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