Dichloromethane → 1020634-41-6

HRID 2278701Notes

Reaction equation

HRID 2278701 reaction equation
ClCCl.[CH2:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][CH:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[CH:13][N:14]=2)[C:9](=[O:26])[C:8]([C:27](O)=[O:28])=[CH:7]1)[CH3:5].C(Cl)(=O)C(C)(C)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(N(CC)CC)C>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:12]1[CH:11]=[C:10]2[C:15](=[N:14][CH:13]=1)[N:6]([CH2:4][CH3:5])[CH:7]=[C:8]([C:27]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:28])[C:9]2=[O:26]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 8083MorpholineHCID 62493Pivaloyl chlorideHCID 24954055HCID 24954055, compound

Product 1

HCID 247721651020634-41-6

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
12.5 °C

Procedure

160.0 L of dichloromethane (water content should be no more than 0.1%), 1-ethyl-6-(indan-2-ylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acid (4.0 kg) and triethylamine (3.5 kg) were sequentially added to reactor at 25-30° C. under nitrogen atmosphere and the reaction mixture was cooled to 10-15° C. Pivaloyl chloride (4.1 kg) was slowly added to reaction mixture keeping the reaction temperature at 10-15° C. Then, the reaction temperature was raised to 25-30° C. and stirred. The reaction progress was monitored by TLC for disappearance of starting material. After completion of reaction (3-4 h), the reaction mixture was again cooled to 15-20° C. and morpholine (6.0 kg) was added with stirring, keeping the reaction temperature at 15-20° C. N,N-Dimethyl-4-aminopyridine (194 g) and DMF (2.0 L) were added to the reaction mixture at 15-20° C. and heated to reflux. The reaction progress was monitored by TLC for the disappearance of intermediate pivaloyl ester and found to be complete within 12-13 h. The reaction mixture was cooled to 15-20° C. and then quenched by addition of aqueous sodium bicarbonate solution (prepared by dissolving 5.6 kg of sodium bicarbonate in 56.0 L of water) with stirring. The organic layer was separated and washed with aqueous sodium chloride solution (prepared by dissolving 23.0 kg of sodium chloride in 57.0 L of water). The organic layer was separated and dried by stirring with anhydrous sodium sulphate (4.0 kg). The organic layer was filtered through a Nutsche filter and the sodium sulphate was washed with dichloromethane. The filtrate was transferred into a flask and evaporated under vacuum below 40° C. The resulting material in the flask was cooled to 25-30° C. and suspended in diethyl ether (40.0 L). The solid separated was filtered using a Nutsche filter and washed with diethyl ether (8.0 L) and the isolated wet solid was dissolved in dichloromethane (20.0 L). The solution (10.0 L) was then filtered through a silica gel plug (10.0 kg) with dichloromethane (36.0 L), followed by 10 L of 10% methanol in dichloromethane. The silica gel filter was dried under vacuum. Similarly, the remaining portion of solution (10.0 L) was filtered through another silica gel plug (10.0 kg). The combined filtrate was evaporated under vacuum below 40° C. and then residual solid was suspended in ethyl acetate (20.0 L) with stirring at 25-30° C. The solid separated was filtered through Nutsche filter and washed with ethyl acetate (4.0 L). The filter was dried under vacuum and then material was transferred to drying trays and dried at 40-45° C. Yield (2.36 kg). 1H NMR (DMSO-d6, 500 MHz): 1.49 (3H, t, J=7.2 Hz), 2.91(2H, dd, J=3.5 Hz, 16.0 Hz), 3.42-3.47(4H, m), 3.80(6H, s), 4.25-4.26(1H, bd), 4.40-4.48(3H, m), 7.20-7.25(4H, m), 7.82(1H, d, J=3.0 Hz), 8.09 (1H, s), 8.18(1H, d, J=3.0 Hz). 13C NMR (CDCl3, 150 MHz): 15.27, 39.87, 43.05, 46.66, 48.09, 53.93, 66.80, 67.40, 113.27, 116.71, 123.22, 124.92, 126.78, 140.87, 141.46, 141.83, 141.90, 143.84, 166.27, 173.38.

Workup

  1. customat 10-15° C
  2. temperatureThen, the reaction temperature was raised to 25-30° C.
  3. customAfter completion of reaction (3-4 h)
  4. temperaturethe reaction mixture was again cooled to 15-20° C.
  5. stirringwith stirring
  6. customat 15-20° C
  7. temperatureheated to reflux
  8. temperatureThe reaction mixture was cooled to 15-20° C.
  9. customquenched by addition of aqueous sodium bicarbonate solution (prepared by dissolving 5.6 kg of sodium bicarbonate in 56.0 L of water)
  10. stirringwith stirring
  11. customThe organic layer was separated
  12. washwashed with aqueous sodium chloride solution (prepared by dissolving 23.0 kg of sodium chloride in 57.0 L of water)
  13. customThe organic layer was separated
  14. customdried
  15. stirringby stirring with anhydrous sodium sulphate (4.0 kg)
  16. filtrationThe organic layer was filtered through a Nutsche
  17. filtrationfilter
  18. washthe sodium sulphate was washed with dichloromethane
  19. customThe filtrate was transferred into a flask
  20. customevaporated under vacuum below 40° C
  21. temperatureThe resulting material in the flask was cooled to 25-30° C.
  22. customThe solid separated
  23. filtrationwas filtered
  24. filtrationfilter
  25. washwashed with diethyl ether (8.0 L)
  26. dissolutionthe isolated wet solid was dissolved in dichloromethane (20.0 L)
  27. filtrationThe solution (10.0 L) was then filtered through a silica gel plug (10.0 kg) with dichloromethane (36.0 L)
  28. filtrationThe silica gel filter
  29. customwas dried under vacuum
  30. filtrationSimilarly, the remaining portion of solution (10.0 L) was filtered through another silica gel plug (10.0 kg)
  31. customThe combined filtrate was evaporated under vacuum below 40° C.
  32. stirringwith stirring at 25-30° C
  33. customThe solid separated
  34. filtrationwas filtered through Nutsche
  35. filtrationfilter
  36. washwashed with ethyl acetate (4.0 L)
  37. customThe filter was dried under vacuum
  38. customto drying trays
  39. customdried at 40-45° C
  40. customYield (2.36 kg)

Sources & evidence

ORD record
ord-05fad48f05fd41ee8c25bbd1c8811411
Source dataset
uspto-grants-2015_09
Patent number
US09133188B2

Reaction notes

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