1,2-Dichloroethane → (S)-6,7-Difluoro-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochloride

HRID 131474Notes

Reaction equation

HRID 131474 reaction equation
[F:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[F:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:30])[C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1

Participants

5

Reactant 4

HCID 111,2-DichloroethaneHCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 135434034(S)-6,7-Difluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Product 1

HCID 136384230(S)-6,7-Difluoro-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochlorideYield 96%

Procedure

Dissolve (S)-6,7-difluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (26.1 g, 66.5 mmol) in 1,2-dichloroethane (DCE, 260 mL) with stirring at ambient temperature under nitrogen; cool to 10-15° C. Add aqueous 37% wt. formaldehyde (5.40 g×37%=2.00 g, 66.6 mmol) in one portion. Add powdered sodium triacetoxyborohydride (19.8 g, 93.4 mmol) in a few portions over 10-15 minutes, keeping the temperature below 20° C. Rinse in the residue with DCE (26 mL). Stir the reaction solution at ambient temperature for 1-2 hours. Add aqueous saturated sodium bicarbonate (260 mL) dropwise, and then stir at ambient temperature for 20-30 minutes. Separate the layers, and then extract the aqueous layer with methylene chloride (50 mL). Extract the combined organic layers with water (100 mL) then brine (100 mL). Dry the organic solution over magnesium sulfate with stirring, filter, and then concentrate under reduced pressure to an oily foam residue. Dissolve in methylene chloride and concentrate under reduced pressure to give 26.0 g (96%) of the free base of the title compound as a foam. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.75 (bm, 2H), 3.35 (m, 2H), 3.20 (s, 3H), 2.95 (bt, 1H), 2.75 (m, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.15 (bm, 2H), 1.82 (m, 1H), 1.50 (m, 1H). HRMS (ES) exact mass M+H calcd for C20H24F2N4OS 407.1717; found 407.1716.

Workup

  1. temperaturecool to 10-15° C
  2. customthe temperature below 20° C
  3. washRinse in the residue with DCE (26 mL)
  4. stirringStir the reaction solution at ambient temperature for 1-2 hours
  5. stirringAdd aqueous saturated sodium bicarbonate (260 mL) dropwise, and then stir at ambient temperature for 20-30 minutes
  6. customSeparate the layers
  7. extractionextract the aqueous layer with methylene chloride (50 mL)
  8. extractionExtract the combined organic layers with water (100 mL)
  9. dry with materialDry the organic solution over magnesium sulfate
  10. stirringwith stirring
  11. filtrationfilter
  12. concentrationconcentrate under reduced pressure to an oily foam residue
  13. dissolutionDissolve in methylene chloride
  14. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-1c1867b6786746d19932559ff3997abb
Source dataset
uspto-grants-2008_06
Patent number
US07384934B2

Reaction notes

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