Ammonium Chloride → [5-Methyl-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester

HRID 1992646Notes

Reaction equation

HRID 1992646 reaction equation
CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58](=[O:68])[CH2:59][C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62](Cl)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54].[CH3:69][N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1.[NH4+].[Cl-]>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:53]([O:57][C:58](=[O:68])[CH2:59][C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62]([N:73]2[CH2:74][CH2:75][N:70]([CH3:69])[CH2:71][CH2:72]2)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54]

Participants

9

Reactant 5

HCID 25517Ammonium ChlorideHCID 531671-MethylpiperazineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 86623475(2-Chloro-5-methyl-pyridin-4-yl)-acetic acid tert-butyl ester

Product 1

HCID 66869033[5-Methyl-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Sodium tert-butoxide (227 mg, 2.37 mmol) is dried under high vacuum at approximately 80° C. After purging with argon and cooling to RT, palladium acetate (39 mg, 0.17 mmol), rac-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (rac-BINAP, 54 mg, 0.09 mmol) and (2-chloro-5-methyl-pyridin-4-yl)-acetic acid tert-butyl ester (520 mg, 2.15 mmol) are added. The mixture is dissolved in dioxane (7 ml, degassed with three freeze-thaw cycles under HV/argon), and 1-methyl-piperazine (237 mg, 2.37 mmol) is added. The round bottom flask containing the reaction mixture is immersed into a pre-heated oil bath (T=85° C.). After 30 minutes, TLC analysis indicated almost complete conversion of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (CH2Cl2/MeOH, slow gradient from 98:2 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.43 (s, 9H), 2.14 (s, 3H), 2.34 (s, 3H), 2.51 (m, 4H), 3.44 (s, 2H), 3.49 (m, 4H), 6.51 (s, 1H), 7.96 (s, 1H). ES+−MS: 306.4 [M+H]+.

Workup

  1. customAfter purging with argon
  2. additionThe round bottom flask containing the reaction mixture
  3. customis immersed into a pre-heated oil bath
  4. custom(T=85° C.)
  5. customThe organic layer is separated
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. customthe solvent is evaporated
  9. customThe residue is purified by FCC (CH2Cl2/MeOH, slow gradient from 98:2 to 90:10)

Sources & evidence

ORD record
ord-6e9e9c8202b0485c9fe9c158cac4222d
Source dataset
uspto-grants-2010_01
Patent number
US07648989B2

Reaction notes

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