Hydrochloric Acid → HCID 10254785, compound

HRID 736465Notes

Reaction equation

HRID 736465 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.[ClH:36].C(=O)([O-])[O-].[Na+].[Na+].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])=[O:52])=[N:46][C:47](Br)=[CH:48][N:49]=1>O1CCCC1.CO.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].C(OCC)C>[ClH:36].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])=[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

11

Reactant 6

HCID 313Hydrochloric Acid2×HCID 10340Sodium CarbonateHCID 21531Triisopropyl borateHCID 7107291-(4-Bromophenylsulfonyl)-4-methylpiperazineHCID 101082083-Amino-6-bromo-N-(3-methoxypropyl)-2-pyrazinecarboxamideHCID 178418339Butyllithium

Product 1

HCID 10254785HCID 10254785, compoundYield 19%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

Triisopropyl borate (0.82 mL, 3.6 mmol) was added to a stirred solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.380 g, 1.2 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965,8,548-550) in anhydrous tetrahydrofuran (15 mL) at −78° C. under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (2.4 mL, 3.6 mmol) over 10 min. The resulting mixture was allowed to warm up to room temperature and was stirred for another 10 min at ambient temperature. HCl (3 M, 1.9 mL, 6.0 mmol) was added and the mixture was stirred for another 10 min, followed by an addition of sodium carbonate (1.26 g, 11.9 mmol). After 30 min, 3-amino-6-bromo-N-(3-methoxypropyl)pyrazine-2-carboxamide (0.24 g, 0.83 mmol) and Pd(dppf)Cl2 (39 mg, 0.05 mmol) were added and the resulting mixture was heated at 65° C. for 22 h. The reaction mixture was evaporated and the residue was dissolved in NaHCO3 (aq. sat.)/ethyl acetate, the aqueous phase was extracted with ethyl acetate and the combined organic phases were evaporated. The crude product was purified on a silica gel column using methylene chloride/methanol/triethyl amine, (9:1:0.1), as the solvent. The product was eluated from the silica with methanol and the solvent was evaporated to give the free base. The base was dissolved in methanol (10 mL) and the mixture was treated with HCl (1.0 M in diethyl ether, 1 mL) followed by addition of diethyl ether (5 mL). The formed precipitate was filtered off and dried at 40° C. in vacuo to give 70 mg (19% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.02 (br s, 1H), 8.97 (s, 2H), 8.46 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz, 2H), 3.82 (d, J=13 Hz, 2H), 3.41 (m, 6H), 3.27 (s, 3H), 3.15 (m, 2H), 2.72 (m, 5H), 1.81 (m, 2H); MS (ES) m/z 449 (M++1).

Workup

  1. stirringthe mixture was stirred for another 10 min
  2. waitAfter 30 min
  3. temperaturethe resulting mixture was heated at 65° C. for 22 h
  4. customThe reaction mixture was evaporated
  5. dissolutionthe residue was dissolved in NaHCO3 (aq. sat.)/ethyl acetate
  6. extractionthe aqueous phase was extracted with ethyl acetate
  7. customthe combined organic phases were evaporated
  8. customThe crude product was purified on a silica gel column
  9. customthe solvent was evaporated
  10. customto give the free base
  11. filtrationThe formed precipitate was filtered off
  12. customdried at 40° C. in vacuo

Sources & evidence

ORD record
ord-8a3945abc0bc42ad8eb962e2ad8386d5
Source dataset
uspto-grants-2009_09
Patent number
US07595321B2

Reaction notes

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