Methyl triflate → (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

HRID 1350478Notes

Reaction equation

HRID 1350478 reaction equation
[F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C@H:38]2[CH2:43][NH:42][CH2:41][CH2:40][NH:39]2)[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C@@H:38]2[NH:39][CH2:40][CH2:41][N:42]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:43]2)[CH:33]=[CH:34][CH:35]=1

Participants

4

Reactant 3

HCID 9526Methyl triflateHCID 21093516HCID 21093516, compoundHCID 21093648(S)-2-(2-(3-Fluoro-phenyl)-ethyl)-piperazine

Product 1

HCID 136005588(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azuleneYield 52.9%

Procedure

Following a method similar as described in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to formed the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine and then (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.62 g, 3.0 mmol), followed by two chromatographic purifications, the first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane); and the second with a pre-packed cation exchange column, loading with methanol, and then eluting the product with increasing concentrations of 2M ammonia in methanol, in dichloromethane gives the title compound (0.754 g): mass spectrum (APCI+, m/e): 476 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.45 (s, 1H), 7.33–7.23 (m, 1H), 7.05–6.80 (m, 6H), 6.74–6.68 (m, 1H), 4.06–3.80 (br. m, 2.94–2.76 (m, 2H), 2.74–2.52 (m, 5H), 2.35 (br. s, 1H), 1.67–1.49 (m, 2H).

Workup

  1. customto formed the methylated intermediate
  2. washthe first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane)
  3. washeluting the product
  4. temperaturewith increasing concentrations of 2M ammonia in methanol

Sources & evidence

ORD record
ord-dedc34f7643a40c29c2ac142c66e8a76
Source dataset
uspto-grants-2007_05
Patent number
US07214673B2

Reaction notes

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