1-methylsulfonylpiperazine;hydrochloride

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

実験手順: To 1-(methylsulfonyl)piperazine hydrochloride (150 g, 632 mmol) in DCE (3.5 L) was added TEA (192 g, 1.90 mol). The mixture was stirred at rt for 1 h and then acetic acid (94.8 g, 1.58 mol) and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (251 g, 1.26 mol) was added. After stirring another h, the reaction was cooled with an ice water bath and NaBH(OAc)3 (294 g, 1.39 mol) was added in four portions. The mixture was stirred overnight at rt. The reaction mixture was neutralized with saturated Na2CO3 to pH 8-9. The organic phase was washed with brine and H2O, dried (Na2SO4), and rotovapped down to provide the crude Boc-protected amine (A combination of 3 batches, 720 g). This amount was split into 2 batches and used without further purification. To 1,1-dimethylethyl 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinecarboxylate (360 g, 1.04 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L). The mixture was stirred at rt for 30 min. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step C (A combination of 2 batches, 600 g, 1.87 mol, 89% over 2 steps). 1H NMR (400 MHz, D2O) δ 1.87-1.91 (m, 2H), 2.33-2.36 (m, 2H), 2.97 (s, 3H), 2.99-3.05 (m, 2H), 3.45-3.59 (m, 11H). After stirring another h the reaction was cooled with an ice water bath The mixture was stirred overnight at rt The organic phase was washed with brine and H2O dried (Na2SO4) to provide the crude Boc-protected amine (A combination of 3 batches, 720 g) This amount was split into 2 batches used without further purification The mixture was stirred at rt for 30 min The resultant precipitate was filtered washed with MeOH dried on high vacuum

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

実験手順: To 1,1-dimethylethyl 4-(methylsulfonyl)-1-piperazinecarboxylate (360 g, 1.36 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L) dropwise. The mixture was stirred at rt for 1 h. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step B (A combination of 2 batches, 570 g) which was used without further purification. 1H NMR (400 MHz, D2O) δ 2.95 (s, 3H), 3.27-3.29 (m, 4H), 3.42-3.46 (m, 4H). The resultant precipitate was filtered washed with MeOH dried on high vacuum

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

実験手順: To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. at reflux for 16 h washed with saturated aqueous sodium hydrogencarbonate solution The organics were dried (MgSO4) purified on silica

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

実験手順: Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of the desired product after purification. Prepared

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

実験手順: Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of the desired product after purification. Prepared

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

実験手順: 4.92 g (24.5 mmol) of 1-methylsulfonylpiperazine hydrochloride and 2.7 ml (24.5 mmol) of NMM was dissolved in 50 ml of DMF. After addition of 4 g (29.6 mmol) of HOBt and a solution of 5.93 g (20.4 mmol) of Boc-3-cyano-(L)-phenylalanine in 200 ml of THF, the mixture was cooled to O° C. 5.1 g (24.7 mmol) of DCC were added and the mixture was stirred for 48 hours at room temperature. Afterwards, the precipitated dicyclohexyl urea was filtered off, the THF moiety of the solution evaporated under reduced pressure, filtered and the filtrate poured into a mixture of 100 ml of 5% sodium bicarbonate solution and 200 ml of ice water. The formed precipitate was filtered off, washed with water, dissolved in methanol and the solvent was evaporated under reduced pressure. To remove the still present water, a co-distillation with toluene/isopropanol was performed several times. The only slightly impure product was processed in this form. Yield: 7.9 g (89%) Afterwards, the precipitated dicyclohexyl urea was filtered off the THF moiety of the solution evaporated under reduced pressure filtered the filtrate poured into a mixture of 100 ml of 5% sodium bicarbonate solution and 200 ml of ice water The formed precipitate was filtered off washed with water dissolved in methanol the solvent was evaporated under reduced pressure To remove the still present water

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

実験手順: Reaction between 1-methanesulfonyl-piperazine HCL salt and 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde 33 using General Procedure C yielded 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.

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

実験手順: To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. at reflux for 16 h washed with saturated aqueous sodium hydrogencarbonate solution The organics were dried (MgSO4) purified on silica

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

実験手順: To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. at reflux for 16 h washed with saturated aqueous sodium hydrogencarbonate solution The organics were dried (MgSO4) purified on silica

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

実験手順: Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of the desired product after purification. Prepared

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

実験手順: To 1-(methylsulfonyl)piperazine hydrochloride (150 g, 632 mmol) in DCE (3.5 L) was added TEA (192 g, 1.90 mol). The mixture was stirred at rt for 1 h and then acetic acid (94.8 g, 1.58 mol) and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (251 g, 1.26 mol) was added. After stirring another h, the reaction was cooled with an ice water bath and NaBH(OAc)3 (294 g, 1.39 mol) was added in four portions. The mixture was stirred overnight at rt. The reaction mixture was neutralized with saturated Na2CO3 to pH 8-9. The organic phase was washed with brine and H2O, dried (Na2SO4), and rotovapped down to provide the crude Boc-protected amine (A combination of 3 batches, 720 g). This amount was split into 2 batches and used without further purification. To 1,1-dimethylethyl 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinecarboxylate (360 g, 1.04 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L). The mixture was stirred at rt for 30 min. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step C (A combination of 2 batches, 600 g, 1.87 mol, 89% over 2 steps). 1H NMR (400 MHz, D2O) δ 1.87-1.91 (m, 2H), 2.33-2.36 (m, 2H), 2.97 (s, 3H), 2.99-3.05 (m, 2H), 3.45-3.59 (m, 11H). After stirring another h the reaction was cooled with an ice water bath The mixture was stirred overnight at rt The organic phase was washed with brine and H2O dried (Na2SO4) to provide the crude Boc-protected amine (A combination of 3 batches, 720 g) This amount was split into 2 batches used without further purification The mixture was stirred at rt for 30 min The resultant precipitate was filtered washed with MeOH dried on high vacuum

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

実験手順: To 1-(methylsulfonyl)piperazine hydrochloride (150 g, 632 mmol) in DCE (3.5 L) was added TEA (192 g, 1.90 mol). The mixture was stirred at rt for 1 h and then acetic acid (94.8 g, 1.58 mol) and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (251 g, 1.26 mol) was added. After stirring another h, the reaction was cooled with an ice water bath and NaBH(OAc)3 (294 g, 1.39 mol) was added in four portions. The mixture was stirred overnight at rt. The reaction mixture was neutralized with saturated Na2CO3 to pH 8-9. The organic phase was washed with brine and H2O, dried (Na2SO4), and rotovapped down to provide the crude Boc-protected amine (A combination of 3 batches, 720 g). This amount was split into 2 batches and used without further purification. To 1,1-dimethylethyl 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinecarboxylate (360 g, 1.04 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L). The mixture was stirred at rt for 30 min. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step C (A combination of 2 batches, 600 g, 1.87 mol, 89% over 2 steps). 1H NMR (400 MHz, D2O) δ 1.87-1.91 (m, 2H), 2.33-2.36 (m, 2H), 2.97 (s, 3H), 2.99-3.05 (m, 2H), 3.45-3.59 (m, 11H). After stirring another h the reaction was cooled with an ice water bath The mixture was stirred overnight at rt The organic phase was washed with brine and H2O dried (Na2SO4) to provide the crude Boc-protected amine (A combination of 3 batches, 720 g) This amount was split into 2 batches used without further purification The mixture was stirred at rt for 30 min The resultant precipitate was filtered washed with MeOH dried on high vacuum