Ammonia → tert-Butyl (3R)-4-[3-(2-{[2-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-ethoxy)pyridin-3-yl]oxy}ethoxy)pyrazin-2-yl]-3-methylpiperazine-1-carboxylate

HRID 1765092Notes

Reaction equation

HRID 1765092 reaction equation
O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:13][CH:14]=[CH:15][CH:16]=1.N.CC(C)([O-])C.[K+].Cl[C:39]1[C:40]([N:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@H:46]2[CH3:58])=[N:41][CH:42]=[CH:43][N:44]=1>CC(O)=O.[Cl-].[Na+].O.O.[Cl-].[Na+].O.C(#N)C>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][C:12]1[C:11]([O:10][CH2:9][CH2:8][O:7][C:39]2[C:40]([N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@H:46]3[CH3:58])=[N:41][CH:42]=[CH:43][N:44]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:30])([CH3:29])([CH3:28])[CH3:27]

Participants

9

Reactant 4

HCID 222AmmoniaHCID 23665647Potassium tert-butoxideHCID 86591089tert-Butyl {2-[2-({3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}carbamateHCID 86591091(R)-tert-butyl 4-(3-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 86591090tert-Butyl (3R)-4-[3-(2-{[2-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-ethoxy)pyridin-3-yl]oxy}ethoxy)pyrazin-2-yl]-3-methylpiperazine-1-carboxylateYield 40.9%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 6342AcetonitrileSolventHCID 23713072Sodium chloride dihydrateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
50 °C

Procedure

tert-Butyl {2-[2-({3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}carbamate (from Step 1; 0.74 g, 1.7 mmol) was suspended in 2 M HOAc (5 mL) and acetonitrile (1 mL) and heated at 50° C. for two days. The solution was neutralized with concentrated aqueous ammonia. Brine was added (3 mL) and the mixture was extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The remaining oil was dissolved in dry DMSO (10 mL), potassium tert-butoxide (0.36 g, 3.2 mmol) was added followed by tert-butyl (3R)-4-(3-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate (from Example 5; 0.59 g, 1.9 mmol) and the mixture was heated at 50° C. for 20 minutes. The reaction mixture was diluted with water/brine (90:10) and extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4), the solvent was removed under reduced pressure and the remaining oil was chromatographed on a column of silica with hexane/EtOAc (70:30) as eluent to give 0.43 g (40%) of the title compound as a colorless oil. LC-UV purity: system (A) 100%. HRMS m/z calcd for C30H46N6O8 (M)+ 618.3377. found 618.3381. Step 3: {2-[2-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}amine, bis(trifluoroacetate).

Workup

  1. extractionthe mixture was extracted with CHCl3 (×3)
  2. dry with materialThe combined organic phases were dried (MgSO4)
  3. customthe solvent was removed under reduced pressure
  4. dissolutionThe remaining oil was dissolved in dry DMSO (10 mL)
  5. extractionextracted with CHCl3 (×3)
  6. dry with materialThe combined organic phases were dried (MgSO4)
  7. customthe solvent was removed under reduced pressure
  8. customthe remaining oil was chromatographed on a column of silica with hexane/EtOAc (70:30) as eluent

Sources & evidence

ORD record
ord-ac43c76598564435954e6bf2c483f564
Source dataset
uspto-grants-2007_06
Patent number
US07226925B2

Reaction notes

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