Nitric Acid → 4-(2-Amino-3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester

HRID 493109Notes

Reaction equation

HRID 493109 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N+:9]([O-:12])(O)=[O:10].C([O-])([O-])=O.[Na+].[Na+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>OS(O)(=O)=O.CS(C)=O.C(OCC)(=O)C.CCCCCC>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=2[N+:9]([O-:12])=[O:10])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]

Participants

9

Reactant 5

HCID 944Nitric AcidHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 5818662-Amino-4-chloropyridine

Product 1

HCID 576808314-(2-Amino-3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl esterYield 13%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 1118Sulfuric AcidSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
0 °C

Procedure

Following the procedure of Recl. Trav. Chim. Pays-Bas 88(11): 1263 (1969), 4-Chloro-pyridin-2-ylamine (A) (6.8 g, 67 mmol) was carefully dissolved in H2SO4 (45.2 ml) at 0° C. Nitric acid (2.3 ml) was added, maintaining the temperature at 0° C. The solution was stirred at 5° C. for 2 days. After it was judged complete by TLC (40% ethyl acetate/hexane), the mixture was carefully made basic with the addition of solid Na2CO3. The mixture was then extracted with ethyl acetate several times. The ethyl acetate was dried over magnesium sulfate and the solvents were removed under vacuum. The resulting crude was dissolved in DMSO (25 ml) with t-butyl-1-piperazine carboxylate (14.3 g, 75 mmol) and DIEA (10.3 g, 80 mmol). This mixture was heated to 50° C. for 3 hours before it was judged complete by MS. The mixture was purified by HPLC Method E to yield the title product 5 (2.8 g (13%), 8.6 mmol). 1H NMR (DMSO-d6): δ 7.82 (d, J=5.8 Hz, 1H), 6.98 (bs, 2H), 6.31 (d, J=5.8 Hz, 1H), 3.41 (m, 4H), 3.13 (m, 4H), 1.41 (s, 9H). MS (ESI-POS): [M+H]+=324.

Workup

  1. extractionThe mixture was then extracted with ethyl acetate several times
  2. dry with materialThe ethyl acetate was dried over magnesium sulfate
  3. customthe solvents were removed under vacuum
  4. temperatureThis mixture was heated to 50° C. for 3 hours before it
  5. customThe mixture was purified by HPLC Method E

Sources & evidence

ORD record
ord-5b4c7ddf50b94af585985b3af63181bc
Source dataset
uspto-grants-2009_05
Patent number
US07534796B2

Reaction notes

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