Acetic Acid → Nevirapine

HRID 1510816Notes

Reaction equation

HRID 1510816 reaction equation
[H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:23])[CH:7]=[CH:6][N:5]=1.C(O)(=O)C.O>CC1C=CC=CC=1C.COCCOCCOC>[CH3:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]=12

Participants

7

Reactant 4

HCID 176Acetic Acid2×HCID 962WaterHCID 24758Sodium hydrideHCID 9972204N-(2-Chloro-4-methylpyridin-3-yl)-2-(cyclopropylamino)nicotinamide

Product 1

HCID 4463Nevirapine

Reagents, catalysts & solvents 2

HCID 7237O-XyleneSolventHCID 8150DiglymeSolvent

Conditions

Temperature
132.5 °C

Procedure

Sodium hydride (9.15 g, 65% w/w) was suspended in o-xylene (187.5 ml) at 25-30° C. under nitrogen atmosphere and slowly heated to 130-135° C. N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide (25 g) was dissolved in diglyme (50 ml) at 70-80° C. and added to the above suspension over a period of 10-20 min at 135-138° C. and stirred for 1 h at 135-140° C. Thereafter the reaction mixture was cooled to 5° C. and acetic acid (8.75 ml) was added slowly below 15° C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15° C. and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-10° C. The temperature of the reaction mixture was raised to 20-25° C. and stirred for 1 h at 20-25° C. and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 70° C., a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-65° C.). Filtrate was concentrated under reduced pressure at 50-55° C. up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-10° C. and stirred for 30 min at 5-10° C. The product obtained was filtered and washed with cold DM water (25 ml, 5-10° C.), suck dried and dried at 65-70° C. under reduced pressure.

Workup

  1. additionadded to the above suspension over a period of 10-20 min at 135-138° C.
  2. temperatureThereafter the reaction mixture was cooled to 5° C.
  3. temperatureThe temperature of the reaction mixture was raised to 20-25° C.
  4. stirringstirred for 1 h at 20-25° C.
  5. customproduct crystallizes out
  6. customThe product obtained
  7. filtrationwas filtered
  8. washwashed with DM water (75 ml)
  9. dry with materialwith cyclohexane (50 ml) and suck dried the product under suction for 10 min
  10. additionThe wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml)
  11. temperatureheated
  12. temperatureto reflux at 70° C.
  13. customa clear solution formed
  14. additionCarbon (2.5 g) was added
  15. stirringstirred for 30 min
  16. temperatureat reflux
  17. filtrationFiltered the carbon in hot condition
  18. washwashed with hot methanol (50 ml, 60-65° C.)
  19. concentrationFiltrate was concentrated under reduced pressure at 50-55° C. up to residual weight
  20. temperatureThereafter cooled the concentrated mass to 5-10° C.
  21. stirringstirred for 30 min at 5-10° C
  22. customThe product obtained
  23. filtrationwas filtered
  24. washwashed with cold DM water (25 ml, 5-10° C.), suck
  25. customdried
  26. customdried at 65-70° C. under reduced pressure

Sources & evidence

ORD record
ord-a1a4ec155a1f42198466c4be8c0c70f8
Source dataset
uspto-grants-2012_07
Patent number
US08212025B2

Reaction notes

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