1,1'-Carbonyldiimidazole → N-[3-carbamoyl-5-ethyl-1-(2-Pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide

HRID 1700134Notes

Reaction equation

HRID 1700134 reaction equation
[CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:41][C:42]1[C:43]([C:56]([NH2:58])=[O:57])=[N:44][N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[C:46]=1[CH2:47][CH3:48]>C(OCC)(=O)C>[C:56]([C:43]1[C:42]([NH:41][C:6](=[O:7])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:46]([CH2:47][CH3:48])[N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[N:44]=1)(=[O:57])[NH2:58]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3386966ImidazolateHCID 46689282-Ethoxy-5-[(4-ethylpiperazino)sulfonyl]nicotinic acidHCID 220522374-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide

Product 1

HCID 12114162N-[3-carbamoyl-5-ethyl-1-(2-Pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamideYield 90.7%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (0.875 Kg, 2.55 mol) was charged followed by ethyl acetate (7L, 8 ml/g) to the reaction vessel and 2 ml/g was distilled off at atmospheric pressure to ensure the reaction system was dry. The slurry was cooled to room temperature under a nitrogen atmosphere and carbonyldiimidazole (0.43 Kg, 2.65 mol) added in one portion. The slurry was heated to 35° C. and held for half an hour. The reaction was further heated to 45-50° C. and held for a further half hour. The reaction was then heated to reflux, stirring at reflux for one hour. On confirmation of complete imidazolide formation the reaction was cooled to 45-50° C. under nitrogen and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (0.59 Kg, 2.42 mol) charged in one portion before returning to reflux and a further 1 ml/g was distilled off at atmospheric pressure. The reaction was stirred at reflux for 16 hours with crystallisation of product occurring after 4 hours. The reaction was cooled to 10-15° C. and granulated for one hour. The reaction slurry was filtered and washed (ethyl acetate) which was dried under vacuum at 50° C. to afford the title compound (1.252 Kg, 90.7%) as a white solid. Mpt 178-179° C. ? (CDCl3): 1.04 (3H, t), 1.06 (3H, t), 1.59 (3H, t), 240 (2H, q), 2.50 (4H, q), 2.90 (4H, q), 3.08 (4H, m), 2.78 (2H, q), 5.35 (1H, s) 5.48 (2H, s), 6.68 (1H, s), 6.92 (1H, d), 7.22 (IH, m), 7.65 (1H, m), 8.58 (1H, d), 8.64 (1H, d), 8.83 (1H, d). m/z (Found:571 [M+H]+, 100%. C26H34N8O5S requires 571.67).

Workup

  1. distillationwas distilled off at atmospheric pressure
  2. customwas dry
  3. temperatureThe slurry was heated to 35° C.
  4. waitheld for half an hour
  5. temperatureThe reaction was further heated to 45-50° C.
  6. temperatureThe reaction was then heated
  7. temperatureto reflux
  8. temperatureat reflux for one hour
  9. temperatureto reflux
  10. distillationa further 1 ml/g was distilled off at atmospheric pressure
  11. stirringThe reaction was stirred
  12. temperatureat reflux for 16 hours with crystallisation of product
  13. waitoccurring after 4 hours
  14. temperatureThe reaction was cooled to 10-15° C.
  15. waitgranulated for one hour
  16. filtrationThe reaction slurry was filtered
  17. washwashed (ethyl acetate) which
  18. customwas dried under vacuum at 50° C.

Sources & evidence

ORD record
ord-5ce164f57bd3418580fbdf2cfe2aeeaa
Source dataset
uspto-grants-2002_02
Patent number
US06350751B1

Reaction notes

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