Diisopropylethylamine → N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine

HRID 2420755Notes

Reaction equation

HRID 2420755 reaction equation
C([N:4](C(C)C)CC)(C)C.Cl.Cl.N[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[C:45]([NH2:48])=[NH:4])=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 6721532412-Amino-1-piperazin-1-yl-dodecan-1-one dihydrochlorideHCID 140329753methyl N-(3,5-diamino-6-chloropyrazine-2-carbonyl)carbamimidothioate;hydroiodide

Product 1

HCID 86634238N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
70 °C

Procedure

Diisopropylethylamine (1.67 mL, 9.59 mmol) was added to a suspension of 12-amino-1-piperazin-1-yl-dodecan-1-one dihydrochloride (11) (342 mg, 0.96 mmol) in absolute ethanol (10 mL). The resulting solution was stirred at 70° C. (oil bath) for 10 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (380 mg, 0.98 mmol) added in one portion. The reaction mixture was then stirred at this temperature for 3 hours and cooled to room temperature. The solvent was removed by rotary evaporation and the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin column was rinsed thoroughly with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with 0% to 20% of 9:1 methanol/ammonium hydroxide in dichloromethane to give N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine as a yellow solid. About half of this material was further purified by preparative HPLC using acetonitrile/water/0.05% TFA. The TFA salt obtained was co-evaporated twice with aqueous 2N HCl and further dried under high vacuum to give the desired compound 12 (123 mg, 45%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.28 (m, 14H), 1.52 (m, 4H), 2.29 (t, 2H), 3.00 (m, 4H), 3.30 (m, 2H), 3.68 (m, 4H), 7.40 (br, 4H), 8.96 (m, 2H), 9.25 (m, 11H), 9.50 (br, 2H), 10.50 (s, 1H). m/z (ESI) 496 [C22H38ClN9O2+H]+. mp 148-150° C.

Workup

  1. stirringThe reaction mixture was then stirred at this temperature for 3 hours
  2. temperaturecooled to room temperature
  3. customThe solvent was removed by rotary evaporation
  4. dissolutionthe resulting residue was dissolved in small volume of methanol
  5. washThe resin column was rinsed thoroughly with methanol
  6. concentrationthe methanol solution was concentrated in vacuo
  7. customThe resulting residue was purified by Biotage silica gel column chromatography
  8. washeluting with 0% to 20% of 9:1 methanol/ammonium hydroxide in dichloromethane

Sources & evidence

ORD record
ord-97dafcdf8c9d4cb0afeb8177310bbbf2
Source dataset
uspto-grants-2011_06
Patent number
US07956059B2

Reaction notes

Loading…