1-Methylpiperazine → HCID 178463571, compound

HRID 243374Notes

Reaction equation

HRID 243374 reaction equation
[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCC[O:28]3)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:62][N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH4+:6].[OH-:28].[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([CH:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35]([N:66]1[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]1)=[O:36]

Participants

8

Reactant 4

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 681574615-Fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid

Product 2

HCID 14923Ammonium HydroxideHCID 178463571HCID 178463571, compoundYield 118.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (100 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol), 1-methylpiperazine (33 μL, 0.3 mmol) and DIPEA (69 μL, 0.4 mmol) in DCM (2 mL) was stirred at RT for 1 h. The crude mixture was diluted with water and extracted with DCM. The aqueous phase was further extracted with DCM and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in MeOH (1 mL) and 4N HCl in dioxane (0.25 mL) and the mixture stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue purified by HPLC (Waters C18 XBridge, on a 20 min gradient 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 202 (59 mg, 59%). LCMS (Method K): RT 2.02 min [M+H]+ 500.1. 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 12.45 (1H, s), 8.52 (1H, br s), 8.44 (1H, d, J=6.07 Hz), 7.85-7.80 (1H, m), 7.56-7.27 (5H, m), 7.24-7.17 (1H, m), 5.67 (1H, br s), 3.76-3.52 (1H, m), 3.49-3.37 (1H, m), 3.34-2.87 (7H, m), 2.81 (3H, s), 1.71-1.64 (3H, m)

Workup

  1. extractionextracted with DCM
  2. extractionThe aqueous phase was further extracted with DCM
  3. dry with materialthe combined organic fractions were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. dissolutionThe resulting residue was dissolved in MeOH (1 mL)
  6. stirring4N HCl in dioxane (0.25 mL) and the mixture stirred at RT for 30 min
  7. customThe volatiles were removed under reduced pressure
  8. customthe resulting residue purified by HPLC (Waters C18 XBridge

Sources & evidence

ORD record
ord-9fd62289fce34fff8916b5e60a91eca1
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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