Hydrochloric Acid → n-{[4-Hydroxy-2-oxo-1-(phenylmethyl)-1,2-dihydro-1,7-naphthyridin-3-yl]carbonyl}glycine

HRID 598216Notes

Reaction equation

HRID 598216 reaction equation
[CH2:1]([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH2:10]([N:12](CC)CC)[CH3:11].[O-][CH2:18]C.[Na+].[Na+].[NH2:22][CH2:23][C:24]([O-:26])=[O:25].N12C[CH2:36][CH2:35][N:34]=[C:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2.Cl.[OH2:39]>C(Cl)Cl>[OH:39][C:1]1[C:2]2[C:35](=[CH:36][N:12]=[CH:10][CH:11]=2)[N:34]([CH2:33][C:32]2[CH:18]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:5])[C:3]=1[C:7]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:8]

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 962WaterHCID 8471TriethylamineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 2723922Sodium ethoxideHCID 4684308Sodium GlycinateHCID 109209242-Ethylpropanedioyl dichloride

Product 1

HCID 54721173n-{[4-Hydroxy-2-oxo-1-(phenylmethyl)-1,2-dihydro-1,7-naphthyridin-3-yl]carbonyl}glycineYield 32%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of the compound from Example 6a) (0.500 g, 1.90 mmol) in methylene chloride (20.0 mL) was treated with (4-dimethylamino)pyridine (0.040 mL, 0.38 mmol) followed by ethyl malonyl chloride (0.260 mL, 2.09 mmol). The mixture was stirred overnight at ambient temperature, followed by addition of triethylamine (1.00 mL, 7.17 mmol). Following stirring 1 h at ambient temperature, the reaction mixture was concentration in vacuo. The residue was dissolved in ethanol (2.0 mL), treated with sodium ethoxide (0.700 mL, 1.90 mmol, 21% solution in ethanol) at ambient temperature, and stirred overnight. The solution was concentrated in vacuo, filtered through a plug of silica with ethyl acetate, and concentrated in vacuo. The resulting residue was dissolved in ethanol (3.0 mL) and treated with glycine sodium salt (0.110 g, 1.54 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.230 mL, 1.54 mmol) and heated to 180° C. for 30 min. in a Biotage Initiator microwave synthesizer. The reaction was diluted with water, acidified with 1 N aqueous hydrochloric acid, and the resulting precipitate was filtered, washed with methanol, and dried in vacuo to afford the title compound as a light brown solid (0.175 g, 32%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 13.0 (br. s., 1H), 10.5 (t, J=5.6 Hz, 1H), 8.75 (dd, J=4.7, 1.9 Hz, 1H), 8.54 (dd, J=8.0, 1.9 Hz, 1H), 7.31-7.43 (m, 3H), 7.14-7.30 (m, 3H), 5.75 (s, 2H), 4.20 (d, J=5.6 Hz, 2H). MS(ES+) m/e 354 [M+H]+.

Workup

  1. stirringFollowing stirring 1 h at ambient temperature
  2. concentrationconcentration in vacuo
  3. dissolutionThe residue was dissolved in ethanol (2.0 mL)
  4. stirringstirred overnight
  5. concentrationThe solution was concentrated in vacuo
  6. filtrationfiltered through a plug of silica with ethyl acetate
  7. concentrationconcentrated in vacuo
  8. dissolutionThe resulting residue was dissolved in ethanol (3.0 mL)
  9. temperatureheated to 180° C. for 30 min. in a Biotage Initiator microwave synthesizer
  10. filtrationthe resulting precipitate was filtered
  11. washwashed with methanol
  12. customdried in vacuo

Sources & evidence

ORD record
ord-1597bf4e734b47af96b8b174e24a251b
Source dataset
uspto-grants-2011_03
Patent number
US07897612B2

Reaction notes

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