Hydrochloric Acid → HCID 10459419, compound

HRID 736464Notes

Reaction equation

HRID 736464 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][C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)=[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]>[ClH:36].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)=[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 Acid2×HCID 10340Sodium CarbonateHCID 21531Triisopropyl borateHCID 7107291-(4-Bromophenylsulfonyl)-4-methylpiperazineHCID 9996522HCID 9996522, compoundHCID 178418339Butyllithium

Product 1

HCID 10459419HCID 10459419, compoundYield 6%

Reagents, catalysts & solvents 2

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

Procedure

Triisopropyl borate (0.82 mL, 3.6 mmol) was added to a stirred solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.38 g, 1.2 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 549-550) in anhydrous tetrahydrofuran (115 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. Aqueous HCl (3 M, 1.9 mL, 6.0 mmol) was added and the mixture was stirred for 10 min, followed by an addition of sodium carbonate (1.26 g, 11.9 mmol). 3-Amino-6-bromo-N-(2-thien-2-ylethyl)pyrazine-2-carboxamide (0.272 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 1 h. The solvent was evaporated, the resulting residue dissolved in methylene chloride/water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were evaporated, methanol was added, and the insoluble material was filtered off. The solvent was evaporated and the residue was purified on a silica gel column using methylene chloride/methanol/triethyl amine, (98:2:0.1), as the eluent. The crude product was purified by re-crystallization from methanol to give the free base that was treated with HCl (1.0 M in diethyl ether, 0.6 mmol). The formed precipitate was filtered off and dried under vacuo to give 25 mg (6% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.55 (br s, 1H), 9.05 (m, 1H), 8.99 (s, 1H), 8.46 (d, J=8 Hz, 2H), 7.82 (d, J=8 Hz, 2H), 7.37 (d, J=5 Hz, 1H), 6.98 (m, 2H), 3.83 (m, 2H), 3.58 (m, 2H), 3.46 (m, 2H), 3.13 (m, 4H), 2.75 (s, 3H), 2.67 (m, 2H); MS (S) m/z 487 (M++1).

Workup

  1. stirringthe mixture was stirred for 10 min
  2. temperaturethe resulting mixture was heated at 65° C. for 1 h
  3. customThe solvent was evaporated
  4. dissolutionthe resulting residue dissolved in methylene chloride/water
  5. extractionthe aqueous phase was extracted with ethyl acetate
  6. customThe combined organic phases were evaporated
  7. additionmethanol was added
  8. filtrationthe insoluble material was filtered off
  9. customThe solvent was evaporated
  10. customthe residue was purified on a silica gel column
  11. customThe crude product was purified by re-crystallization from methanol
  12. customto give the free base that
  13. filtrationThe formed precipitate was filtered off
  14. customdried under vacuo

Sources & evidence

ORD record
ord-41918b3dcb554311afaaad26cdc688c4
Source dataset
uspto-grants-2009_09
Patent number
US07595321B2

Reaction notes

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