4-chloro-N-methylaniline

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: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 2.51 g (˜0.017 mole) of freshly distilled 4-chloro-N-methylaniline (b.p. 102-103° C.) is added 4.26 g (˜0.017 mole) of 2-bromo-benzenesulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. The 2-bromo-4′-chloro-N-methylbenzene-sulfonanilide is formed as viscous liquid. It is washed with water several times until the wash water is neutral. The compound is dried overnight at room temperature. The yield is 4.2 g (69% yield). 1H NMR (deuterioacetone): δ 6.8-7.9 (m, 8 ArH), 3.2 (s, 3H, N—CH3). with stirring until the solution

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one. The compound thus obtained The suspension thus obtained After the termination of dropwise addition with stirring for 6 minutes to obtain a mixture To the mixture thus obtained with stirring in 5 minutes The reaction mixture was stirred at room temperature for 17 hours concentrated to half the initial volume under reduced pressure poured into about 500 ml of ice-water The resulting crystal was collected by filtration washed with water dried under reduced pressure The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol) recrystallized from ethanol

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

Procedure: The reaction procedure of Example 57 was followed except that 2.175 g (12.68 mmol) of 2-chloro-6-methylnicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 1.01 g of ammonium thiocyanate, 15 ml of acetone, 1.81 g of N-methyl-4-chloroaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 1.58 g of 2-[N-(4-chlorophenyl)-N-methylamino)-7-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one. The reaction procedure of Example 57 The resulting crude product was then recrystallized from ethanol

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

Procedure: 2.5 g of 4,7-dichloroquinazoline and 2.2 g of p-chloro-N-methylaniline were added to 10 ml of ethanol and then the mixture was heated. The mixture became a homogeneous solution which solidified soon after. After cooling, the solidified crystals were collected and recrystallized from ethanol to give the desired compound in the form of its hydrochloride (Compound No. 68). The crystals of hydrochloride were crushed and added to a dilute aqueous solution of sodium hydroxide, with stirring, to precipitate the free base. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 2.4 g (yield 65%) of the desired Compound No. 67 in the form of colourless plates melting at 129°-131° C. the mixture was heated After cooling the solidified crystals were collected recrystallized from ethanol

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1 mmol) in DMF (or DMSO) (5 ml) are added 4-chloro-N-methylaniline (1.2 mmol) and potassium carbonate (2.4 mmol). The mixture is heated at 50° C. for 13 h. The reaction mixture is diluted with AcOEt, washed with water and brine, dried over sodium sulfate and concentrated. The crude product is purified by HPLC (n-hexane:AcOEt) to give the product in 27% yield. Rf=0.69(n-hexane:AcOEt=1:1). 1H NMR(400 MHz, CDCl3) δ 1.06(s, 9H), 3.03(s, 3H), 4.13(s, 2H), 4.71(s, 2H), 6.40(s, 1H), 6.62-6.69(m, 2H), 7.17-7.23(m, 2H), 8.84(s, 1H). washed with water and brine dried over sodium sulfate concentrated The crude product is purified by HPLC (n-hexane:AcOEt) to give the product in 27% yield