Dichlorotriphenylphosphorane

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

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

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

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

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dichlorotriphenylphosphorane (1.65 g, 5.1 mmol) was added to a solution of 56 (1.34 g, 2.55 mmol) in pyridine (75 mL) and the solution stirred at 20° C. After 10 min more dichlorotriphenylphosphorane (2.06 g, 6.4 mmol) was added, and after a further 10 min the solution was poured into H2O and the mixture stirred for 5 min. The precipitated solid was filtered off, washed with H2O, and redissolved in CH2Cl2 (400 mL). This solution was filtered through Celite, eluting with CH2Cl2, and the filtrate was dried (Na2SO4) and evaporated. The resulting orange solid was recrystallized from CH2Cl2 giving methyl 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (31) as an orange powder (0.88 g, 64%), mp 246-247.5° C. The mother liquor was evaporated onto silica and purified by chromatography (50% EtOAc-petroleum ether) to give further 31 (0.50 g, 36%). 1H NMR (CDCl3) δ 10.39 (s, 1 H, NH), 9.42 (s, 1 H, NH), 9.39 (s, 1 H, H-4), 7.31 (d, J=2.2 Hz, 1 H, H-8), 6.97 (d, J=2.4 Hz, 1 H, H-3'), 6.86 (s, 1 H, H-4'), 4.80 (t, J=10.0 Hz, 1 H, H-2), 4.69 (dd, J=10.8, 4.4 Hz, 1 H, H-2), 4.32-42.3 (m, 1 H, H-1). 4.09 (s, 3 H, OMe), 4.05 (dd, J=11.4, 3.9 Hz, 1 H, CH2Cl), 4.02 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.77 (dd, J=11.4, 8.8 Hz, 1 H, CH2Cl); 13C NMR [(CD3)2SO] δ 160.5, 160.0, 149.2, 140.0, 139.0, 137.5, 133.6, 132.1, 131.3, 130.2, 127.7, 126.1, 125.5, 123.2, 111.3, 107.5, 106.4, 97.9, 61.1, 60.9, 55.9, 54.1, 52.3, 47.0, 42.0. Anal. Calculated for C25H23ClN4O8 : C, 55.3; H, 4.3; N, 10.3. Found: C, 55.4; H, 4.1; N, 10.3%. the mixture stirred for 5 min The precipitated solid was filtered off washed with H2O redissolved in CH2Cl2 (400 mL) This solution was filtered through Celite eluting with CH2Cl2 the filtrate was dried (Na2SO4) evaporated The resulting orange solid was recrystallized from CH2Cl2

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

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 1-(t-butoxycarbonyl)-4-(2-(2-pyridinyl)hydrazino)carbonyl-piperidine (320 mg, 1.0 mmol) and dichlorotriphenylphosphorane (666 mg, 2.1 mmol) in CH3CN (10 mL) was added Et3N (0.42 mL, 3.0 mmol). After refluxing for 2h, the solution was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration followed by flash chromatography eluting with 100% EtOAc, then 10% MeOH/CH2Cl2 afforded the title compound (180 mg) as a foamy solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 2.05˜2.11 (m, 4H), 3.03 (br s, 2H), 3.24 (m, 1H), 4.25 (br d, J=11.7 Hz, 1H), 6.86 (dt, J=6.9, 0.9 Hz, 1H), 7.25 (m, 1H), 7.78 (dt, J=9.4, 1.2 Hz, 1H), 7.95 (dt, J=6.8, 1.1 Hz, 1H), 7.79 (dd, J=7.3, 0.8 Hz, 1H). The aqueous layer was extracted with EtOAc (3×) Combined organic phase was washed with brine dried over anhydrous MgSO4 Concentration eluting with 100% EtOAc

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

Procedure: To a solution of 1-(t-butoxycarbonyl)-4-(2-(2-pyridinyl)hydrazino)carbonyl-piperidine (320 mg, 1.0 mmol) and dichlorotriphenylphosphorane (666 mg, 2.1 mmol) in CH3CN (10 mL) was added Et3N (0.42 mL, 3.0 mmol). After refluxing for 2h, the solution was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration followed by flash chromatography eluting with 100% EtOAc, then 10% MeOH/CH2Cl2 afforded the title compound (180 mg) as a foamy solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 2.05˜2.11 (m, 4H), 3.03 (br s, 2H), 3.24 (m, 1H), 4.25 (br d, J=11.7 Hz, 1H), 6.86 (dt, J=6.9, 0.9 Hz, 1H), 7.25 (m, 1H), 7.78 (dt, J=9.4, 1.2 Hz, 1H), 7.95 (dt, J=6.8, 1.1 Hz, 1H), 7.79 (dd, J=7.3, 0.8 Hz, 1H). The aqueous layer was extracted with EtOAc (3×) Combined organic phase was washed with brine dried over anhydrous MgSO4 Concentration eluting with 100% EtOAc

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Ethyl aniline (5.2 gm) was taken in chloroform (100 ml) and stirred for 10 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (26.6 gm) at 25-30° C. and the reaction mixture was stirred for 15 minutes. 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (10 gm) was added to the resulting mass at 25-30° C. followed by heating to reflux (40-45° C.) and then stirred for 3 hours at reflux. Chloroform was distilled out from the reaction mass under vacuum at below 55° C. The resulting residue was cooled to 25-30° C., followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. and the resulting mixture was stirred for 30 minutes at 25-30° C. The separated solid was filtered, washed with water and then dried to yield 12.95 gm of laquinimod (HPLC purity: 99.24%). the reaction mixture was stirred for 15 minutes by heating to reflux (40-45° C.) stirred for 3 hours at reflux Chloroform was distilled out from the reaction mass under vacuum at below 55° C The resulting residue was cooled to 25-30° C. followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. the resulting mixture was stirred for 30 minutes at 25-30° C The separated solid was filtered washed with water dried

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Ethyl aniline (5.2 gm) was taken in chloroform (100 ml) and stirred for 10 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (26.6 gm) at 25-30° C. and the reaction mixture was stirred for 15 minutes. 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (10 gm) was added to the resulting mass at 25-30° C. followed by heating to reflux (40-45° C.) and then stirred for 3 hours at reflux. Chloroform was distilled out from the reaction mass under vacuum at below 55° C. The resulting residue was cooled to 25-30° C., followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. and the resulting mixture was stirred for 30 minutes at 25-30° C. The separated solid was filtered, washed with water and then dried to yield 12.95 gm of laquinimod (HPLC purity: 99.24%). the reaction mixture was stirred for 15 minutes by heating to reflux (40-45° C.) stirred for 3 hours at reflux Chloroform was distilled out from the reaction mass under vacuum at below 55° C The resulting residue was cooled to 25-30° C. followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. the resulting mixture was stirred for 30 minutes at 25-30° C The separated solid was filtered washed with water dried