Hydrochloric Acid → Methyl 3-amino-6-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazine-2-carboxylate

HRID 736605Notes

Reaction equation

HRID 736605 reaction equation
B(OC(C)C)(OC(C)C)OC(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:43][C:44]1[C:45]([C:51]([O:53][CH3:54])=[O:52])=[N:46][C:47](Br)=[CH:48][N:49]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[C:45]([C:51]([O:53][CH3:54])=[O:52])=[N:46][C:47]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:48][N:49]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 21531Triisopropyl borateHCID 227251Methyl 3-Amino-6-bromopyrazine-2-carboxylateHCID 7107291-(4-Bromophenylsulfonyl)-4-methylpiperazineHCID 178418339Butyllithium

Product 1

HCID 68531416Methyl 3-amino-6-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazine-2-carboxylateYield 69%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Triisopropyl borate (2.7 mL, 11.6 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine in (1.24 g, 3.87 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (25 mL) at −78° C. under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (9.8 mL, 15.5 mmol). The resulting mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature. HCl (3 M aq, 7.8 mL, 23.2 mmol) was added and the mixture was stirred at room temperature for 10 min. Sodium carbonate (4.1 g, 38.7 mmol) was added followed by the addition of methyl 3-amino-6-bromo-2-pyrazinecarboxylate (0.79 g, 3.4 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949, 2798) and Pd(dppf)Cl2 (95 mg, 0.12 mmol). The resulting mixture was heated at 55° C. overnight. Silica was added, the solvent was evaporated and the crude mixture was purified by column chromatography on silica using chloroform/methanol, (99:1), as the eluent to give 0.923 g (69% yield) of the base as a yellow solid: 1HNMR (DMSO-d6) δ 9.0 (s, 1H), 8.22 (d, J=7 Hz, 2H), 7.80 (d, J=7 Hz, 2H), 7.62 (br s, 2H), 3.90 (s, 3H) 2.91 (m, 4H), 2.36 (m, 4H), 2.12 (s, 3H); 13C NMR (DMSO-d6) δ 166.2, 155.1, 145.8, 140.33, 127.5, 134.0, 128.1, 125.7, 109.1, 53.5, 52.3, 45.7, 45.2; MS (ESP) m/z 392 (M++1).

Workup

  1. temperatureto warm to room temperature
  2. stirringthe mixture was stirred at room temperature for 10 min
  3. temperatureThe resulting mixture was heated at 55° C. overnight
  4. additionSilica was added
  5. customthe solvent was evaporated
  6. customthe crude mixture was purified by column chromatography on silica

Sources & evidence

ORD record
ord-e3f1dd351bf94d45a450db16c86a60b4
Source dataset
uspto-grants-2009_09
Patent number
US07595319B2

Reaction notes

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