5-chloro-2-hydroxy-3-methoxybenzaldehyde

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: A solution of sulfuryl chloride (15 mL, 190 mmol) in toluene (20 mL) is added dropwise over 1.5 h to a solution of o-vanillin (25.0 g, 164 mmol) in toluene (90 mL) and the reaction is then stirred 16 h. Water (30 mL) is added over 10 minutes with ice-bath cooling. The solid is filtered, washed with water and dried to provide the title compound. MS (EI) 186 (M)+. cooling The solid is filtered washed with water dried

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

Procedure: A solution of sulfuryl chloride (15 mL, 190 mmol) in toluene (20 mL) is added dropwise over 1.5 h to a solution of o-vanillin (25.0 g, 164 mmol) in toluene (90 mL) and the reaction is then stirred 16 h. Water (30 mL) is added over 10 minutes with ice-bath cooling. The solid is filtered, washed with water and dried to provide the title compound. MS (EI) 186 (M)+. cooling The solid is filtered washed with water dried

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

Procedure: 5-Chloro-2-hydroxy-3-methoxy-benzaldehyde (see J. Org. Chem. 56; 1991; 5451; 20.0 g, 107 mmol) was suspended in hydrobromic acid (100 mL of 47% in water). The mixture was refluxed for 6 h and then cooled to room temperature before dilution with water (300 mL). The formed precipitate was collected by filtration and then washed with water. After air drying, the solid material was purified by soaking with CH2Cl2 (4×150 mL). There was obtained 6.0 g (32%) of 5-chloro-2,3-dihydroxybenzaldehyde as a solid. 1H NMR (300 MHz, CDCl3): 5.7 (s, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 9.8 (s, 1H), 11.0 (s, 1H). The mixture was refluxed for 6 h The formed precipitate was collected by filtration washed with water After air drying the solid material was purified

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

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

Conditions: temp:61.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-Chloro-2-hydroxy-3-methoxybenzaldehyde (275 g, 1.47 mol) and DMF were stirred as potassium carbonate (411 g, 2.97 mol) was added over 5 minutes. The mixture temperature rose from 22 to 29° C. over 10 minutes. Dimethylsulfate (283 g, 2.24 mol) was added over 15 minutes causing a temperature rise from 28 to 47° C. The mixture was then heated with a heating mantle to 61° C. over 15 minutes and stirred at 61° C. for 1.5 hours; the reaction was complete by TLC. The reaction mixture was cooled to 22° C., transferred to a 22-L flask and diluted with water (8.2 L) over 5 minutes; the temperature rose to 38° C. The light yellow mixture was filtered and the flask and filter cake rinsed with 1.5 L water. The solid was dried under vacuum for 15 hour at 50° C. The material contained inorganic salts and was suspended in water (3 L) for 1.5 hours. After filtration and a 500 mL water rinse, the filter cake was dried under by suction and overnight at 65° C. under vacuum. Yield: 305 g (100% yield, 99.1% purity). was added over 5 minutes from 28 to 47° C The reaction mixture was cooled to 22° C. transferred to a 22-L flask rose to 38° C The light yellow mixture was filtered the flask and filter cake rinsed with 1.5 L water The solid was dried under vacuum for 15 hour at 50° C was suspended in water (3 L) for 1.5 hours After filtration a 500 mL water rinse the filter cake was dried under by suction and overnight at 65° C. under vacuum

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

Procedure: To a solution of 5-chloro-2-hydroxy-3-methoxy-benzaldehyde (7 g, 37.5 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. was added a solution of BBr3 in CH2Cl2 (1 M, 93.7 mL, 93.7 mmol) and the reaction mixture was stirred overnight at room temperature. The solution was diluted with CH2Cl2 (200 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure generating the title compound (6.2 g, 36.0 mmol, 96%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.02 (s, 1H), 9.83 (s, 1H), 7.18 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 5.71 (s, 1H). washed with water, brine dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of 5-chloro-2-hydroxy-3-methoxy-benzaldehyde (7 g, 37.5 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. was added a solution of BBr3 in CH2Cl2 (1 M, 93.7 mL, 93.7 mmol) and the reaction mixture was stirred overnight at room temperature. The solution was diluted with CH2Cl2 (200 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure generating the title compound (6.2 g, 36.0 mmol, 96%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.02 (s, 1H), 9.83 (s, 1H), 7.18 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 5.71 (s, 1H). washed with water, brine dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: 6-[4-(5-Chloro-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-hydroxy-3-methoxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.50-2.55 (m, 4H), 3.60-3.66 (m, 4H), 3.70 (s, 2H), 3.88 (s, 3H), 5.39 (s, 1H), 6.61-6.62 (m, 1H), 6.80-6.81 (m, 1H), 7.84 (s, 1H), 12.40 (br s, 1H). Mass spectrum (ES) MH+=351.

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: o-Vanillin (100.5 g, 660 mmol), acetic acid (504 mL) and N-chlorosuccinimide (83.8 g, 627 mmol) were mixed and heated to 105° C. over 30 minutes. A rapid exotherm from 55 to 105° C. occurred over 7 minutes. The mixture refluxed for a few minutes and was allowed to cool slowly to room temperature (2.5 h). Water (1 L, 2 volume equivalents) was added to the mixture slowly over 10 minutes. The mixture was stirred for 5 minutes, filtered and the crude product air dried to afford 146.9 g of wet cake as a light yellow powder with 90% product, 3% o-vanillin and 7% dichlorovanillin Recrystallization from 200 g ethanol afforded 61 g (52% yield). The mixture refluxed for a few minutes to cool slowly to room temperature (2.5 h) filtered the crude product air dried to afford 146.9 g of wet cake as a light yellow powder with 90% product, 3% o-vanillin and 7% dichlorovanillin Recrystallization from 200 g ethanol afforded 61 g (52% yield)