Sodium Hydroxide → 1,1-Dimethylethyl 4-(6-bromo-5-methoxy-3-pyridinyl)-1-piperazinecarboxylate

HRID 969297Notes

Reaction equation

HRID 969297 reaction equation
[Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[N:24][C:25]([Br:1])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 67184N-bromobutanimideHCID 11652254HCID 11652254, compound

Product 1

HCID 115236021,1-Dimethylethyl 4-(6-bromo-5-methoxy-3-pyridinyl)-1-piperazinecarboxylate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of 3-chloro-5-methoxypyridine (40.0 g, 0.279 mol), piperazine (48.0 g, 0.557 mol), potassium-tert-butoxide (62.5 g, 0.557 mol) and tetrakis-(triphenylphosphine)palladium(0) (1.6 g, 1.39 mmol) was refluxed for 2 hours. The workup procedure was performed according to method A. 1-(5-Methoxy-3-pyridyl)piperazine fumaric acid salt was isolated as intermediate product. Yield 22.6 g (26%). A mixture of 1-(5-methoxy-3-pyridyl)-piperazine fumaric acid salt (23.1 g, 74.7 mmol), aqueous sodium hydrogen carbonate (224 ml, 1 M), di-tert-butyldicarbonate (16.3 g, 74.7 mmol) and dichloromethane (200 ml) was stirred at room temperature for 1 hour. The phases were separated. The organic phase gave 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine in quantitative yield. N-Bromosuccinimide (1.82 g, 10.2 mmol) was added to a mixture of 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine (3.0 g, 10.2 mmol) and acetonitrile (50 ml) at 0° C. The reaction was allowed to reach room temperature and was stirred for 2 hours. Aqueous sodium hydroxide (100 ml, 4 M) was added followed by extraction twice with ethyl acetate (2×100 ml). Chromatography on silica gel with ethyl acetate:petroleum (1:3) gave 4-tert-butoxycarbonyl-1-(6-bromo-5-methoxy-3-pyridyl)-piperazine as free base. Yield 2.6 g, 68%. This compound (2.32 g, 6.23 mmol) was deprotected by stirring with a mixture of trifluoroacetic acid (4.8 ml) and dichloromethane (30 ml) for 6 hours. The mixture was evaporated, and aqueous sodium hydroxide (100 ml, 1 M) was added. The mixture was extracted three times with ethyl acetate (3×100) and gave the title compound as the free base. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid in quantitative yield. Mp 202-218° C.

Workup

  1. customto reach room temperature
  2. extractionfollowed by extraction twice with ethyl acetate (2×100 ml)

Sources & evidence

ORD record
ord-92fc52ee3fe245778ae181c639ba29c2
Source dataset
uspto-grants-2007_12
Patent number
US07307087B2

Reaction notes

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