2-(4-ethoxyphenyl)acetyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 50ELH4 (0.11 g, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added and the vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeated and the product dissolved in dichloromethane (1 ml) and HCl (1 eq., 2 M in ether) is added. This mixture was added drop-wise to an excess of heptane whereupon the salt precipitated. Yield 31.1 mg (16%), UV/MS: 94/100 (M+ 385), tr (A, MS) 2.573. the vial was sealed The product was extracted in distilled water (made basic with potassium carbonate, pH 10) Dried with sodium sulfate concentrated Purified by HPLC The extraction drying concentration the product dissolved in dichloromethane (1 ml) precipitated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70° C. for 21/2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified. Thionylchloride was evaporated off

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70° C. for 21/2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified. Thionylchloride was evaporated off

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine (792 mg, 3.80 mmol) in dichloromethane (50 mL) at room temperature was added 4-ethoxy-benzeneacetyl chloride (795 mg, 4.00 mmol). The mixture was stirred for 10 hours. The mixture was concentrated in vacuo and the residue dissolved in dichloroethane (25 mL) and acetic acid (25 mL). The mixture was stirred for 48 hours at 85° C. The reaction was then cooled to room temperature and brought to pH=10 by addition of 1 M NaOH aqueous solution. The mixture was extracted with EtOAc (50 mL). The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2.5%. MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1.02 g of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine (76.0% yield from N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine). 1H-NMR (400 MHz, CDCl3): δ 0.44 (m, 2H), 0.52 (m, 2H), 1.10 (m, 1H), 1.40 (t, J=6.8 Hz, 3H), 4.01 (q, J=6.8 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.35 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 8.80 (d, J=2.3 Hz, 1H) 9.26 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 353. The mixture was concentrated in vacuo the residue dissolved in dichloroethane (25 mL) The mixture was stirred for 48 hours at 85° C brought to pH=10 by addition of 1 M NaOH aqueous solution The mixture was extracted with EtOAc (50 mL) The aqueous phase was back-extracted with additional EtOAc (2×50 mL) dried with MgSO4 filtered concentrated in vacuo The residue was purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (1.61 g, 6.50 mmol) in dichloromethane (50 mL) at 0° C. was added 4-ethoxy-benzeneacetyl chloride (1.35 g, 6.80 mmol). The mixture was stirred for 3 hours at room temperature. The reaction was then quenched with NaHCO3 saturated aqueous solution (100 mL) and extracted with dichloromethane (50 mL). The aqueous phase was back-extracted with additional dichloromethane (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2% MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1:69 g of the title compound 5-[[(4-ethoxyphenyl)acetyl]amino]-NN-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (63.3% yield from 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.18 (t,J=7.2 Hz, 6H), 1.41 (t,J=7.8 Hz, 3H), 3.42 (br s, 1H), 3.69 (s, 2H), 4.02 (m, 8H), 5.13 (m, 2H), 5.92 (m, 1 H), 6.90 (m, 2H), 7.27 (m, 2H), 7.34 (m, 1H), 8.00 (m, 1H). MS (ES) (M+H)+: 411. The reaction was then quenched with NaHCO3 saturated aqueous solution (100 mL) extracted with dichloromethane (50 mL) The aqueous phase was back-extracted with additional dichloromethane (2×50 mL) dried with MgSO4 filtered concentrated in vacuo The residue was purified to provide 1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring toluene solution (100 mL) of (3-Amino-4-nitrophenyl)methyl-carbamic acid, 1,1-dimethylethyl ester (1.10 g, 4.12 mmol) were added 4-ethoxyphenylacetyl chloride (980 mg, 1.2 eq) and zinc dust (400 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution was stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 2:1/hex:EtOAc on silica gel to yield the desired product [3-[[(4-Ethoxyphenyl)acetyl]amino]-4-nitrophenyl]methyl-carbamic acid, 1,1-dimethylethyl ester (1.18 g, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.11 (d, J=9.2 Hz, 1H), 7.22 (m, 3H), 6.93 (d, J=9.2 Hz, 2H), 4.40 (m, 2H), 3.75 (s, 2H), 3.33 (s, 3H), 1.50 (s, 9H), 1.42 (t, J=6.8 Hz, 3H). the solution was stirred at rt for another 24 h The solution was then filtered through celite rinsed with EtOAc The organic phase was washed with saturated NaHCO3 solution, brine dried over anhydrous MgSO4 The crude product was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring toluene solution (100 mL) of 3-amino-N,N-diethyl-4-nitro-benzamide (1.00 g, 4.21 mmol) were added 4-ethoxyphenylacetyl chloride (1.25 g, 1.5 eq) and zinc dust (415 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 1:1/hex:EtOAc on silica gel to furnish the desired product (1.52 g, 90% yield). 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.26 (m, 3H), 7.15 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.54 (q, J=6.8 Hz, 2H), 3.24 (q, J=6.8 Hz, 2H), 1.59 (br s, 1H), 1.42 (t, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 1.16 (t, J=6.8 Hz, 3H). the solution stirred at rt for another 24 h The solution was then filtered through celite rinsed with EtOAc The organic phase was washed with saturated NaHCO3 solution, brine dried over anhydrous MgSO4 The crude product was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure 2D, the freshly prepared (4-ethoxyphenyl)acetyl chloride (from 793 mg of acid, 4.4 mmol) and crude 3-amino-4-[(cyclopropylmethyl)amino]benzonitrile (750 mg, 4.01 mmol) were heated in acetic acid (HOAc) overnight. After work-up, the crude residue was purified by silica gel column chromatography to afford pure product (1.04 g, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.29 (s, 2H), 4.01 (d, J=7.6 Hz, 2H), 3.96 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H), 1.04–1.00 (m, 1H), 0.58–0.53 (m, 2H), 0.29–0.25 (m, 2H). MS (ESI) (M+H)+=332. Anal. Calcd for C21H21N3O.0.1H2O: C, 75.50; H, 6.41; N, 12.61. Found: C, 75.76; H, 6.72; N, 12.45. After work-up, the crude residue was purified by silica gel column chromatography