Methanol → HCID 86613798, compound

HRID 2378117Notes

Reaction equation

HRID 2378117 reaction equation
[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:14]([CH3:17])[CH:15]=2)[C@H:10](N(CC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C#N)[CH2:9][C@@H:8]1[CH2:44][CH3:45])=[O:6])([CH3:3])[CH3:2].[N-]=[N+]=[N-].[Na+].Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:14]([CH3:17])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[CH2:44][CH3:45])=[O:6])([CH3:3])[CH3:2]

Participants

9

Reactant 6

HCID 887MethanolHCID 11130Triethylamine hydrochloride2×HCID 11776TriphenylphosphineHCID 33557Sodium Azide2×HCID 5363146Diisopropyl azodicarboxylateHCID 86613799HCID 86613799, compound

Product 1

HCID 86613798HCID 86613798, compoundYield 31.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

Heat at 110° C. a mixture of (+/−)-cis-6-benzylamino-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (110 mg, 0.174 mmol), sodium azide (16 mg, 0.244 mmol) and triethyl amine hydrochloride (33 mg, 0.244 mmol) in dry toluene under a nitrogen atmosphere for 15 h. Then add more sodium azide (10 mg) and triethyl amine hydrochloride (25 mg) and heat the mixture for 20 h. Cool to room temperature, dilute with ethyl acetate, and wash with 1 N HCl. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate. Dissolve the residue in dry dichloromethane (1 mL), add triphenylphosphine (38 mg, 0.146 mmol), methanol (22 mg, 0.66 mmol) followed by diisopropylazodicarboxylate (0.046 mL, 0.104 mmol) and stir the mixture for 15 h at room temperature. Remove the solvent in vacuo and purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester [15 mg, 16%, MS (ES+): 691 (M+H)] and (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester [20 mg, 22%, MS (ES+): 691 (M+H)].

Workup

  1. temperatureheat the mixture for 20 h
  2. temperatureCool to room temperature
  3. washwash with 1 N HCl
  4. dry with materialDry the organic layer over anhydrous sodium sulfate
  5. filtrationfilter
  6. customremove the solvent under reduced pressure
  7. customPurify the residue by flash chromatography
  8. washeluting with hexanes/ethyl acetate
  9. dissolutionDissolve the residue in dry dichloromethane (1 mL)
  10. customRemove the solvent in vacuo
  11. custompurify the residue by silica gel chromatography
  12. washeluting with ethyl acetate/hexanes

Sources & evidence

ORD record
ord-f5c0915661fd4d019913f0def874ebe9
Source dataset
uspto-grants-2008_12
Patent number
US07470705B2

Reaction notes

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