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A solution of lithium aluminum hydride (15.939 g, 10%w, 42 mmol) is added to a solution of 1-ethylpiperazine (6.85 g, 60 mmol) in tetrahydrofuran (98 ml) at about 25C over a period of about 1 hour followed by rinsing with tetrahydrofuran (2 ml). 4-[4-((R)-1-Phenyl-ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzoic acid ethyl ester (7.729 g, 20 mmol) is added at about 25C over a period of about 1 hour, followed by rinsing with tetrahydrofuran (5 ml). The mixture is heated to about 500C and stirring is continued for about 1 hour. The mixture is cooled to about 25C, then filter aid (Cellflock 40/Cellulose, 1.05 g) is added. Water (4.54 g, 252 mmol) is added over a period of about 1.5 hours and stirring continues for about 1hour. The solids are removed by filtration and the filter cake is washed with tetrahydrofuran. Acetic acid (10.31g, 171.5 mmol) is added to the stirred filtrate at about 25C. The solution is concentrated by distilling at a mantle temperature of about 500C and about 450-400 mbar. After cooling the concentrate to about 25C, sodium borohydride (0.227 g, 6 mmol) is added. Stirring is continued and after full conversion, water (54 g) is added. The solution is concentrated by distilling at a mantle temperature of about 500C and about 300-150 mbar, until distillation ceases. After cooling to about 25C, toluene (0.9 ml) is added followed by water (60 ml). Sodium hydroxide solution 30%w (approx. 13 ml, 130 mmol) is added over a period of about 1 hour, until a pH of about 8- about 9 is obtained. Stirring is continued. The precipitated solids are isolated by filtration and washed with water. The moist filter cake (ca. 17 g) is added to a stirred mixture of water (approx. 8 ml), ethyl acetate (5.81 ml) and acetic acid (1.31 g, 21.8 mmol) at about 300C. Stirring is continued for about 1h, then water ( 58 ml) is added and stirring is continued for 3h. Filter aid (Cellflock 40/Cellulose, 0.1 g) is added. After stirring, the solids are removed by filtration, and the filter EPO <DP n="10"/>cake is washed with water. The filtrate is extracted with ethyl acetate (41.5 ml), the organic layer is separated and the aqueous layer is extracted again with ethyl acetate (41.5 ml). The organic layer is removed and the aqueous layer is filtered. Sodium hydroxide solution 30%w (approx. 0.6 ml, 6 mmol) is added until a pH of about 6- about 6.5 is obtained. After stirring, sodium hydroxide solution 30%w (approx. 1.5 ml, 15 mmol) is added over a period of about 90 minutes, until a pH of about 8- about 9 is reached. Stirring is continued, then the precipitated solids are isolated by filtration, washed in portions with water and isopropanol (15 ml).The moist solids are added to stirred isopropanol (35 ml) at about 700C. The suspension is heated to about 80 to about 85C and stirred for about 1 hour, then cooled to about 00C within about 1 hour and stirred for about another hour. The solids are isolated by filtration, washed in portions with water and dried at about 70- about 800C to constant weight to give the title compound; m.p. 243-244C (dec), (sintering > 239C); MS-ES+: (M+H)+ = 441 ; HPLC purity > 99% area. |