1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-(2-Bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

HRID 1804463Notes

Reaction equation

HRID 1804463 reaction equation
[CH2:1]([C:3]1[C:4]([C:14]([OH:16])=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:38][C:39]1[CH:56]=[C:55](/[C:57](=[N:59]/O)/[NH2:58])[CH:54]=[CH:53][C:40]=1[CH2:41][N:42]1[CH2:45][CH:44]([C:46]([O:48]C(C)(C)C)=[O:47])[CH2:43]1>CN(C=O)C>[Br:38][C:39]1[CH:56]=[C:55]([C:57]2[N:59]=[C:14]([C:4]3[C:3]([CH2:1][CH3:2])=[C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[O:6][N:5]=3)[O:16][N:58]=2)[CH:54]=[CH:53][C:40]=1[CH2:41][N:42]1[CH2:43][CH:44]([C:46]([OH:48])=[O:47])[CH2:45]1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 548465634-Ethyl-5-phenylisoxazole-3-carboxylic acidHCID 58537202HCID 58537202, compound

Product 1

HCID 585371751-(2-Bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

A solution of 4-ethyl-5-phenylisoxazole-3-carboxylic acid, Int.5-D (7.83 mg, 0.036 mmol), EDCI (6.91 mg, 0.036 mmol), and HOBt (5.52 mg, 0.036 mmol) in DMF (2 mL) was stirred at RT for 5 minutes before being transferred to a flask containing (Z)-tert-butyl 1-(2-bromo-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.5-B (12.60 mg, 0.033 mmol). The reaction was placed in an oil bath and heated overnight at 55° C. then the temperature was raised to 90° C. for 3 hours. The solution was cooled and the volatiles were removed under vacuum. The resulting residue was treated with TFA (2 mL) at RT for 3 hours. The TFA was evaporated and the residue was treated with triethylamine (3-4 mL) before again being evaporated to dryness. The residue was loaded onto a 4 g silica gel Isco cartridge (which had been pre-equilibrated with DCM) and purified by flash chromatography. Eluent: 0-20% MeOH in DCM (plus 5% NH4OH). The product containing fractions were evaporated and placed under high vacuum to afford 1-(2-bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid as a pale yellow solid (13.1 mg, 0.024 mmol). The compound had an HPLC retention time=3.97 min.−Column: PHENOMENEX® Luna 3 u C18 4.6×30 mm (5 min. gradient; 4 mL/min); Solvent A=10% MeOH, 90% H2O, 0.05% TFA; Solvent B=90% MeOH, 10% H2O, 0.05% TFA. LC/MS M+1=509/511. 1H NMR (500 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.11 (q, J=7.5 Hz, 2H), 3.36-3.44 (m, 1H), 3.92 (dd, J=8.5 Hz, 8.5 Hz 2H), 4.01 (dd, J=8.8 Hz, 9.0 Hz 2H), 4.26 (s, 2H), 7.56-7.72 (m, 4H), 7.81-7.83 (m, 2H), 8.22 (dd, J=6.3, 1.8 Hz, 1H), 8.42 (d, 1.8 Hz).

Workup

  1. custombefore being transferred to a flask
  2. customThe reaction was placed in an oil bath
  3. temperaturethe temperature was raised to 90° C. for 3 hours
  4. temperatureThe solution was cooled
  5. customthe volatiles were removed under vacuum
  6. additionThe resulting residue was treated with TFA (2 mL) at RT for 3 hours
  7. customThe TFA was evaporated
  8. additionthe residue was treated with triethylamine (3-4 mL)
  9. custombefore again being evaporated to dryness
  10. custompurified by flash chromatography
  11. additionThe product containing fractions
  12. customwere evaporated

Sources & evidence

ORD record
ord-eb6e27a6976f44658aabab48ddf4bfab
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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