Cesium carbonate → Methyl 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate

HRID 600553Notes

Reaction equation

HRID 600553 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 536296172-(Azetidin-1-ylcarbonyl)-5-bromopyridineHCID 59761136methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate2×

Product 1

HCID 59761163Methyl 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoateYield 52%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), azetidin-1-yl-(5-bromopyridin-2-yl)methanone (CAS no. 845306-16-3) (531 mg, 2.2 mmol), caesium carbonate (1.956 g, 6 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (373 mg, 0.4 mmol) in DMA (5 mL) was stirred at 160° C. for 6 hours. The DMA was evaporated under reduced pressure and the residue was dissolved in water (520 mL) washed with ethyl acetate (3×20 mL). The aqueous fraction was acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×100 mL), the combined organic layers were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in THF (6 mL) and methanol (3 mL) and was treated dropwise with 2M (trimethylsilyl)diazomethane in hexane (1.1 mL). The reaction was stirred for 30 min then treated with 1 drop of acetic acid, stirred for another 15 minutes and evaporated to dryness under reduced pressure. The residue was purified by chromatography eluting with 0-100% ethyl acetate/hexane to give afford the product (439 mg, 52%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.24 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.56 (m, 2H), 3.89 (s, 3H), 4.25 (t, 2H), 4.70 (t, 2H), 4.91 (t, 1H), 6.99 (s, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.53 (s, 1H), 8.10 (d, 1H), 8.31 (s, 1H); m/z 426 (M+H)+.

Workup

  1. customThe DMA was evaporated under reduced pressure
  2. dissolutionthe residue was dissolved in water (520 mL)
  3. washwashed with ethyl acetate (3×20 mL)
  4. extractionextracted with ethyl acetate (3×100 mL)
  5. washthe combined organic layers were washed with water (2×20 mL) and brine (20 mL)
  6. dry with materialdried (MgSO4)
  7. customthe solvent removed under reduced pressure
  8. dissolutionThe residue was dissolved in THF (6 mL)
  9. additionmethanol (3 mL) and was treated dropwise with 2M (trimethylsilyl)diazomethane in hexane (1.1 mL)
  10. additionthen treated with 1 drop of acetic acid
  11. stirringstirred for another 15 minutes
  12. customevaporated to dryness under reduced pressure
  13. customThe residue was purified by chromatography
  14. washeluting with 0-100% ethyl acetate/hexane
  15. customto give

Sources & evidence

ORD record
ord-a2d23166bb4043848c4755ca8e2f72c3
Source dataset
uspto-grants-2011_03
Patent number
US07902200B2

Reaction notes

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