Dimethylformamide → HCID 10078275, compound

HRID 441186Notes

Reaction equation

HRID 441186 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:25])[NH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[Si:33]([O:40][CH:41]([C:51]([F:54])([F:53])[F:52])[CH:42]([NH:46][C:47](=[O:50])[CH2:48]I)[CH:43]([CH3:45])[CH3:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CCCCCC.CCOCC>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:25])[N:14]([CH2:48][C:47]([NH:46][CH:42]([CH:43]([CH3:45])[CH3:44])[CH:41]([O:40][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:51]([F:52])([F:54])[F:53])=[O:50])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 10089516HCID 10089516, compoundHCID 10479059HCID 10479059, compound

Product 1

HCID 10078275HCID 10078275, compoundYield 63.9%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8058HexaneSolvent

Procedure

To a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a nitrogen inlet were added 3-benzyloxycarbonylamino-6-(2-chlorophenyl)pyrid-2-one (158.0 g, 0.445 mol) and N,N-dimethyformamide (dried over molecular sieves, 3.0 L) giving a tan suspension. Sodium hydride (60% mineral oil dispersion, 19.6 g, 0.490 mol) was added in one portion at ambient temperature. The reaction mixture was stirred at room temperature for 1.5 h, gradually becoming a clear amber solution; then it was was cooled with an ice/water bath to 5° C. N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (222.5 g, 0.490 mol) was added in one portion as a dry solid and washed down with N,N-dimethylformamide (200 mL). The reaction flask was packed in ice and the mixture stirred over the weekend (50 h), gradually warming to room temperature. For analysis of the reaction mixture an aliquot was partitioned between IN hydrochloric acid and ethyl acetate for TLC: dichloromethane:ethyl acetate (95:5), Rf (starting pyridone)=0.15, Rf (N-alkyated pyridone)=0.70, Rf (O-alkylated pyridone)=0.75. The reaction mixture was treated with water (100 mL) and acetic acid (25 mL) to neutralize any excess sodium hydride; then it was evaporated under pump vacuum at a bath temperature of 35° C. to remove most of the N,N-dimethylformamide. The residue was diluted with water (4 L) yielding a gummy precipitate. The aqueous mixture was extracted with ethyl acetate (1 L, followed by 4×500 mL). The combined extracts were washed successively with IN hydrochloric acid (2×500 mL), saturated sodium bicarbonate solution (2×500 mL), and brine (500 mL); dried (MgSO4), and evaporated to yield a thick amber syrup which was then pumped down under high vacuum. The crude syrup was redissolved in a mixture of hexane (1000 mL) and ether (200 mL) and seeded with authentic product. Crystallization ensued, and the mixture was stirred periodically with a spatula to complete the crystallization. The mixture was allowed to stand overnight at room temperature before collecting the crystals. The crystals were suction filtered, washed with ether/hexane (1:9) (3×200 mL) then dried in the vacuum oven at 50° C. to yield the N-alkylated product 2-[3-benzyloxycarbonylamino-6-(2 -chlorophenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as off-white crystals (193.5 g, 63.9%); mp 139°-141° C.

Workup

  1. customTo a 5 liter, 3-necked flask equipped with a mechanical stirrer
  2. customgiving a tan suspension
  3. temperaturethen it was was cooled with an ice/water bath to 5° C
  4. washwashed down with N,N-dimethylformamide (200 mL)
  5. stirringthe mixture stirred over the weekend (50 h)
  6. temperaturegradually warming to room temperature
  7. customFor analysis of the reaction mixture an aliquot was partitioned between IN hydrochloric acid and ethyl acetate for TLC
  8. additionThe reaction mixture was treated with water (100 mL) and acetic acid (25 mL)
  9. customthen it was evaporated under pump vacuum at a bath temperature of 35° C.
  10. customto remove most of the N,N-dimethylformamide
  11. additionThe residue was diluted with water (4 L)
  12. customyielding a gummy precipitate
  13. extractionThe aqueous mixture was extracted with ethyl acetate (1 L, followed by 4×500 mL)
  14. washThe combined extracts were washed successively with IN hydrochloric acid (2×500 mL), saturated sodium bicarbonate solution (2×500 mL), and brine (500 mL)
  15. dry with materialdried (MgSO4)
  16. customevaporated
  17. customto yield a thick amber syrup which
  18. customCrystallization
  19. stirringthe mixture was stirred periodically with a spatula
  20. customthe crystallization
  21. waitto stand overnight at room temperature
  22. custombefore collecting the crystals
  23. filtrationfiltered
  24. washwashed with ether/hexane (1:9) (3×200 mL)
  25. customthen dried in the vacuum oven at 50° C.

Sources & evidence

ORD record
ord-1d0b0529142f4c57bc1ee5a22be4507f
Source dataset
uspto-grants-1996_05
Patent number
US05521179

Reaction notes

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