2-methylpropyl piperazine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.1 g, 0.34 mmol), isobutyl piperazine-1-carboxylate (0.06 g, 0.34 mmol), and Et3N (0.096 mL, 0.68 mmol) in DMF (1.2 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.14 g, 47% yield). LC/MS: m/z 441.3 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was cooled The solution was washed with water dried over Na2SO4 concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperazine-1-carboxylate (0.10 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.11 g, 55% yield). LC/MS: m/z 427.5 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was cooled The solution was washed with water dried over Na2SO4 concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3.40 g 2-chloro-5,6-dimethoxy benzimidazole, 7.50 g piperazine N-carboxylic acid isobutyl ester (described in U.S. 3,635,979, Example LVII) and 25 ml 2-methoxyethanol were reacted as in Example I to give the base of the desired product as a gum. This was washed free of starting amine with water, then dissolved in isopropyl alcohol and acidified with HCl gas to give 5.30 g product HCl salt, mp 248°-250° C

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-bromo chlorobenzene (434 mg, 2.3 mmol), isobutyl piperazine-1-carboxylate 6 (324 mg, 1.7 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), t-BuONa (251 mg, 2.6 mmol), and Xantphos (60 mg, 0.11 mmol) in dry toluene (5 mL) were sealed in a microwave vessel and heated by microwave irradiation at 140° C. for 40 seconds. The reaction mixture was cooled and diluted with 10 mL of CH2Cl2, washed with water (5 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)); LC/MS: m/z 297.4 (M+H)+, r.t: 3.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), to give 13. The reaction mixture was cooled washed with water (5 mL) dried over Na2SO4 evaporated under reduced pressure The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene sollution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C. to remove the water as it formed the solution extracted with potassium carbonate and water The benzene sollution was treated with magnesium sulfate and charcoal filtered concentrated the residue crystallized from isopropyl alcohol and ether to give 5.50 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene sollution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C. to remove the water as it formed the solution extracted with potassium carbonate and water The benzene sollution was treated with magnesium sulfate and charcoal filtered concentrated the residue crystallized from isopropyl alcohol and ether to give 5.50 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.1 g, 0.34 mmol), isobutyl piperazine-1-carboxylate (0.06 g, 0.34 mmol), and Et3N (0.096 mL, 0.68 mmol) in DMF (1.2 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.14 g, 47% yield). LC/MS: m/z 441.3 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was cooled The solution was washed with water dried over Na2SO4 concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperazine-1-carboxylate (0.10 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.11 g, 55% yield). LC/MS: m/z 427.5 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was cooled The solution was washed with water dried over Na2SO4 concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperazine-1-carboxylate (0.10 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.11 g, 55% yield). LC/MS: m/z 427.5 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was cooled The solution was washed with water dried over Na2SO4 concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene solution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C. to remove the water as it formed the solution extracted with potassium carbonate and water The benzene solution was treated with magnesium sulfate and charcoal filtered concentrated the residue crystallized from isopropyl alcohol and ether to give 5.50 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene solution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C. to remove the water as it formed the solution extracted with potassium carbonate and water The benzene solution was treated with magnesium sulfate and charcoal filtered concentrated the residue crystallized from isopropyl alcohol and ether to give 5.50 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of piperazine (8.61 g, 0.1 mol) in 1M HCl (200 mL) at room temperature was treated with isobutyl chloroformate (13.66 g, 13 mL, 0.1 mol), adjusted to pH 3 with 1M NaOH over 1 to 2 hours, stirred for 18 hours, quenched with 4M KOH, and extracted with dichloromethane (2×100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to provide 10.9 g (59%) the desired product. MS (ESI(+)) m/e 187 (M+H)+. quenched with 4M KOH extracted with dichloromethane (2×100 mL) The combined extracts were dried (MgSO4) filtered concentrated