Tetrahydrofuran → [3-(2-Pyridinylamino-carbonyl)-4-oxo-4-phenyl-butylidene]bisphosphonic acid tetraethyl ester

HRID 36159Notes

Reaction equation

HRID 36159 reaction equation
S(N1[CH2:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)C1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:22]([O:24][P:25]([C:30]([P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH2:31])(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1C[CH2:49][N:48]2[C:43](=[N:44][CH2:45][CH2:46][CH2:47]2)[CH2:42]C1.C1C[O:54]CC1>C(OCC)(=O)C.CCOCC>[CH2:37]([O:36][P:32]([CH:30]([P:25](=[O:29])([O:26][CH2:27][CH3:28])[O:24][CH2:22][CH3:23])[CH2:31][CH:20]([C:49]([NH:48][C:43]1[CH:42]=[CH:47][CH:46]=[CH:45][N:44]=1)=[O:54])[C:19](=[O:21])[C:18]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:39])[O:33][CH2:34][CH3:35])[CH3:38]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 5896332-tosyl-2,3-dihydroisoquinolin-4(1H)-oneHCID 11022954Tetraethyl vinylidene phosphonate

Product 1

HCID 54098047[3-(2-Pyridinylamino-carbonyl)-4-oxo-4-phenyl-butylidene]bisphosphonic acid tetraethyl ester

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolvent

Procedure

The amide (II, 2.52 g), ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), and DBU (0.25 ml) are heated to 50° C. in THF (20 ml) for 3 hrs. The reaction is cooled, diluted with ethyl acetate, then extracted with hydrochloric acid (10%, 3×). After back washing with ethyl acetate, the acidic fraction is neutralized with saturated sodium bicarbonate, extracted with methylene chloride, dried with magnesium sulfate, and concentrated under reduced pressure. The crude material is chromatographed eluting with ethyl acetate and acetone. The resulting oil is concentrated under reduced pressure from ether to give a solid. The solid is slurried in ether, filtered and dried under reduced pressure to give the title compound, mp 104°-105°; MS (m/e) 540, 435, 420, 403, 163, 121, 105 and 94; IR (mineral oil) 1705, 1679, 1596, 1578, 1543, 1435 and 1256 cm-1 ; NMR (CDCl3) 9.77, 8.28, 8.10, 7.60, 7.47, 7.01, 5.16, 4.16, 2.65, 1.34 and 1.26 δ; CMR (CDCl3) 202.9, 195.5, 167.6, 151.1, 147.6, 138.4, 136.0, 133.7, 128.9, 128.7, 119.9, 114.1, 63.0 (m), 54.1, 34.5, 25.9 and 16.3 δ.

Workup

  1. temperatureThe reaction is cooled
  2. extractionextracted with hydrochloric acid (10%, 3×)
  3. washAfter back washing with ethyl acetate
  4. extractionextracted with methylene chloride
  5. dry with materialdried with magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe crude material is chromatographed
  8. washeluting with ethyl acetate and acetone
  9. concentrationThe resulting oil is concentrated under reduced pressure from ether
  10. customto give a solid
  11. filtrationfiltered
  12. customdried under reduced pressure

Sources & evidence

ORD record
ord-a54911ce8eb44651870aa78c973b4842
Source dataset
uspto-grants-1995_05
Patent number
US05412141

Reaction notes

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