Nicotinic Acid → 1,4-Dinicotinoylpiperazine

HRID 325860Notes

Reaction equation

HRID 325860 reaction equation
S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[C:26]([N:20]1[CH2:25][CH2:24][N:23]([C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=2)[CH2:22][CH2:21]1)(=[O:27])[C:16]1[CH:17]=[CH:18][CH:19]=[N:14][CH:15]=1

Participants

8

Reactant 5

HCID 938Nicotinic AcidHCID 1049PyridineHCID 4837PiperazineHCID 10340Sodium CarbonateHCID 24386Thionyl Chloride

Product 1

HCID 871151,4-Dinicotinoylpiperazine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
90 °C

Procedure

N,N'-Bis(nicotinoyl)piperazine (Example 34) was prepared by a procedure adapted from the one reported by Badgett et al. (J. Am. Chem. Soc., Vol. 67, pages 1135-1138 (1945)). Thus, thionyl chloride (71.4 g, 0.600 mole) was added dropwise to a cold stirred mixture of 73.9 g (0.600 mole) of nicotinic acid, 94.9 g (1.20 moles) of pyridine and 196 ml of toluene. After the reaction mixture was gradually heated to 90° C. and maintained at this temperature for 1-2 hr, 25.8 g (0.300 mole) of piperazine dissolved in 120 ml of hot toluene was dispensed gradually into the reaction mixture from a dropping funnel in which the solution was maintained hot by circulating steam or hot water through the funnel's jacket. The stirred mixture was maintained at 90° C. for a additional 1-2 hr, after which it was poured into 500 ml of ice water and the pH adjusted to 9.0 with sodium carbonate. The resulting suspension was extracted with a total of 950 mml of chloroform, the chloroform extract dried over anhydrous magnesium sulfate, the drying agent was removed, the filtered solution decolorized by boiling with charcoal and the charcoal removed by filtration through Celite. The filtrate was reduced in volume to 400 ml whereupon crystallization ensued, yielding the product with properties indicated in Table 1. As indicated in the tabulation, Ross (J. Med. Chem., Vol. 10. pages 257-259 (1967)) reported the preparation of this compound by a different procedure without recording the yield. The present method produced 42.2% of analytical grade product.

Workup

  1. temperaturemaintained at this temperature for 1-2 hr
  2. customwas dispensed gradually into the reaction mixture from a dropping funnel in which
  3. temperaturethe solution was maintained hot
  4. temperatureThe stirred mixture was maintained at 90° C. for a additional 1-2 hr
  5. extractionThe resulting suspension was extracted with a total of 950 mml of chloroform
  6. extractionthe chloroform extract
  7. dry with materialdried over anhydrous magnesium sulfate
  8. customthe drying agent was removed
  9. customthe charcoal removed by filtration through Celite
  10. customThe filtrate was reduced in volume to 400 ml whereupon crystallization
  11. customyielding the product with properties
  12. customthe preparation of this compound by a different procedure

Sources & evidence

ORD record
ord-986b598c011f4388b14f4dfe07ed51ea
Source dataset
uspto-grants-1984_04
Patent number
US04443450

Reaction notes

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