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

HRID 1350482Notes

Reaction equation

HRID 1350482 reaction equation
[C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[NH:32][CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:46])([F:45])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1>CO.ClC(Cl)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[N:32]([CH3:1])[CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:45])([F:46])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 136005622(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Product 1

HCID 136005576(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azuleneYield 60.1%

Reagents, catalysts & solvents 1

HCID 22036585Dichloroethane methanolSolvent

Procedure

Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueous formaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1 yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours, concentrate the reaction under reduced pressure to remove methanol, and then dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.48 (s, 1H), 7.19–7.10 (m, 1H), 6.97–6.81 (m, 3H), 6.76–6.67 (m, 4H), 3.96–3.76 (br. m, 2H), 3.68 (s, 3H), 3.15–3.02 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.69 (m, 1H), 2.65–2.34 (m, 2H), 2.27–2.04 (m, 5H), 1.91–1.75 (m, 1H), 1.66–1.48 (m, 1H).

Workup

  1. concentrationconcentrate
  2. customthe reaction under reduced pressure
  3. customto remove methanol
  4. additiondilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane
  5. customseparate the layers
  6. extractionExtract the aqueous layer with dichloromethane (2×)
  7. dry with materialdry (sodium sulfate)
  8. filtrationfilter
  9. concentrationconcentrate under reduced pressure to a residue
  10. customPurify the residue by flash chromatography
  11. washeluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol
  12. additionadded (40–100% in hexane over 30 minutes

Sources & evidence

ORD record
ord-42707cc7f1c14aba8dcb53de650a999b
Source dataset
uspto-grants-2007_05
Patent number
US07214673B2

Reaction notes

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