58.7% |
In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h;Product distribution / selectivity; |
To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g).This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea, L-lactate salt (5.7 g) as a beige solid.; l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-rhoyrazol- 4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L5 5.0vol) and ethyl acetate (8.0OL, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to 25C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 25C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L, 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 850C, cooled to 65 to 700C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 250C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45C to yield 1- cyclopropyl-3 - [3-(5 -morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4- yl]-urea l-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm"1.Without wishing to be bound by any theory, it is believed that the infra red peaks can be assigned to structural components of the salt as follow:Peak: Due to:3229 cm"1 N-H2972 cm"1 aliphatic C-H1660 cm"1 urea C=O EPO <DP n="197"/> |
58.7% |
In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h; |
To a solution of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1 , 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g). <n="296"/>This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying 1 -cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea, ..-?lactate salt (5.7 g) as a beige solid.7-Morpholin-4-ylmethyl-2,4-dihydro-1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5-one (0.797Kg, 2.46mol, 1.0wt) and 1-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.351wt) was added at 15 to 300C under nitrogen. The contents were heated to 95 to 105C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was cooled to 10 to 200C and ethyl acetate (8.00L, 10.0vol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, theta.Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, O.deltavol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 45C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55C and activated carbon (0.080Kg, 0.1wt) was charged. The mixture was stirred at 45 to 55C for 30 to 40 minutes and then hot filtered at 45 to 55C. The filter- cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, 0.1 wt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 55C for 30 to 40 minutes. The mixture was hot filtered at 45 to 55C and the filter-cake washed with propan-2-ol (0.40L, O.deltavol). The filtrates and wash were concentrated under vacuum at 35 to 45C. Ethyl acetate (8.00, 10.0vol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to 35C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 45C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, 1.Ovol) and pulled dry for 1delta to 30 minutes. The solid was dried under vacuum at 3delta to 4deltaC to yield 1-cyclopropyl-3-[3-(delta-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (O.delta33Kg, delta6.8%, 93.20% by HPLC area) as a brown solid. |
58.7% |
In ethyl acetate; isopropyl alcohol; at 15 - 25℃; for 2 - 24h;Product distribution / selectivity; |
Stage 11; Synthesis of l-cvclopropyl-S-rS-CS-mophiholin^-ylmethyl-lH-benzoimidazol^-ylV lH-pyrazol-4-yll-urea L-lactate salt; To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-yhnethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1:1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g).This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, L- lactate salt (5.7 g) as a beige solid.; Stage 11 : Preparation of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yll-ureaZ-lactic acid salt; L-Laotic acidC19H23N7O2 C22H29N7O5 FW: 381.44 FW: 471.52 l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L, 5.0vol) and ethyl acetate (8.00L, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to <n="250"/>250C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 250C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L5 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 85C, cooled to 65 to 7O0C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 250C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45C to yield l-cyclopropyl-3-[3-(5-morpholin-4-yhnethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-ureaZ-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.1H NMR data (400 MHz, CD3OD) delta 8.08 (s, IH, pyrazole-CH), 7.66 (s, IH, aryl-CH), 7.60 (d, J= 8.0 Hz, IH, aryl-CH), 7.29 (d, J= 8.5 Hz, IH, aryl-CH), 4.15 (q, J= 7.0 Hz, IH, lactate- CH), 3.96 (s, 2H, benzyl-CH2), 3.79 - 3.77 (m, 4H, morpholino-(CH2)2), 2.82 - 2.80 (m, 4H, morpholino-(CH2)2), 2.74 - 2.68 (m, IH, cyclopropyl-CH), 1.38 (d, J= 7.0 Hz, 3H, lactate- CH3), 0.98 (br s, 2H, cyclopropyl-CHa), 0.68 (br s, 2H, cyclopropyl-CH2).The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm"1. |