(8aR)-1,5,6,7,8,8a-hexahydro-[1,3]oxazolo[3,4-a]pyrazin-3-one

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

実験手順: The title compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of (R)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.800 g, 5.63 mmol), 1,6-dichlorophthalazine (0.516 g, 2.59 mmol) and N,N-diisopropylethylamine(1.40 mL, 8.04 mmol) in 3 mL 1-methyl-2-pyrolidone was heated at 140° C. After 4.5 h the reaction was cooled to RT, quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated onto silica gel and purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39) to give 1.18 g of a brown liquid. MS m/z: 305.1 [M+1]. After 4.5 h the reaction was cooled to RT quenched with H2O extracted with ethyl acetate (3×) The combined organic layers were dried over Na2SO4 filtered evaporated onto silica gel purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39)

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

実験手順: The title compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of (R)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.800 g, 5.63 mmol), 1,6-dichlorophthalazine (0.516 g, 2.59 mmol) and N,N-diisopropylethylamine(1.40 mL, 8.04 mmol) in 3 mL 1-methyl-2-pyrolidone was heated at 140° C. After 4.5 h the reaction was cooled to RT, quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated onto silica gel and purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39) to give 1.18 g of a brown liquid. MS m/z: 305.1 [M+1]. After 4.5 h the reaction was cooled to RT quenched with H2O extracted with ethyl acetate (3×) The combined organic layers were dried over Na2SO4 filtered evaporated onto silica gel purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39)

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

実験手順: To a cooled (0° C.) solution of (R)-tert-butyl 3-oxo-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.01 g, 12 mmol) in 100 mL CH2Cl2 was added TFA (75 mL, 973 mmol) dropwise. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2 to give 2.29 g of an orange oil. MS m/z: 143.1 [M+1]. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2

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

実験手順: To a cooled (0° C.) solution of (R)-tert-butyl 3-oxo-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.01 g, 12 mmol) in 100 mL CH2Cl2 was added TFA (75 mL, 973 mmol) dropwise. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2 to give 2.29 g of an orange oil. MS m/z: 143.1 [M+1]. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2

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

実験手順: Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (71 mg, 50%). Prepared

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

実験手順: Compound 285 is synthesized from Intermediate C and (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one according to General Method M. (LC/MS method 16: ES+ m/z 368.4 [M+H]+, Rt=2.52 min).