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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 1h;Product distribution / selectivity; |
Step 4a: To generate the acid chloride, 3-methyl-1 ,2-oxazole-4-carboxylic acid (95.53 mg, 0.75 mmol) was dissolved in CH2CI2 (10 mL). Oxalyl chloride (0.22 mL, 2.63 mmol) and a drop of DMF were added at 0C. The ice bath was removed and the mixture stirred for 1 h before the solvent and the unreacting oxalyl chloride was removed with a stream of nitrogen. The residue was further dried in vacuo. 10a-[4-(difluoromethoxy)phenyl]-2,3, 10, 10a- tetrahydro-1 H,5H-imidazo[1 ,2-a]pyrrolo[1 ,2-c ]pyrazin-5-one (60 mg, 0.19 mmol) was dissolved in pyridine (4 ml) and the solution added to the previously generated acid chloride in pyridine (1 mL) at 0 C. The ice bath was removed after 15 min and the mixture stirred at room temperature for 18 h. LCMS analysis showed only a trace amount of product. Further 4 equivalent of acid chloride were prepared as described above and added to the reaction mixture. The resultant mixture was then heated at 50 C until completion (28 h, monitored by LCMS). The resultant suspension was then concentrated in vacuo and the residue partitioned between CH2CI2 (20 mL) and a saturated aqueous solution of NaHC03 (10 mL). The organic layers were washed with further a saturated aqueous solution of NaHC03 (10 mL) and brine (5 mL), dried (MgS04), filtered and concentrated in vacuo to give a yellow residue. This residue was purified by flash column chromatography (Biotage SP4, 12g cartridge, 70-100 % EtOAc gradient in n-hexanes) to give 10a-[4-(difluoromethoxy)phenyl]-1 - [(3-methyl-1 ,2-oxazol-4-yl)carbonyl]-2,3, 10, 10a-tetrahydro-1 H,5H-imidazo[1 ,2-a]pyrrolo[1 ,2- c/]pyrazin-5-one compound (1 ) as a white solid (42 mg, yield 52%). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1.16667h;Inert atmosphere; |
Step 3: To generate the acid chloride: To a chilled (ice bath) suspension of 3- methylisoxazole-4-carboxylic acid (110 mg, 0.87 mmol) in dichloromethane (1.5 mL) was added oxalyl chloride (0.3 mL) followed by DMF (1 drop, catalytic) under an atmosphere of nitrogen. The mixture was stirred at 0 C for 10 minutes and then at room temperature for 1 hour. The resulting solution was concentrated under a stream of nitrogen to yield an oil. The oil was taken up in dichloromethane and re- concentrated to yield the acid chloride as a yellow oil which formed a thick suspension upon addition of pyridine. To a chilled (ice bath) suspension of the acid chloride (generated as above, 0.87 mmol) in pyridine (0.8 mL) was added a suspension of 10a-(4-fluorophenyl)- 2,3,10, 10a-tetrahydroimidazo[2,l-g][l,7]naphthyridin-5(lH)-one (50 mg, 0.18 mmol) in pyridine (1.0 mL). The mixture was allowed to gradually warm to room temperature. After 4 hours, LCMS indicated complete reaction so the mixture was poured into water (4 mL) and extracted with ethyl acetate (3 x 6 mL). The extracts were combined, dried (MgSO-Q, filtered and the filtrate concentrated in vacuo to yield a pale yellow oil. The material was purified by flash chromatography (80% acetone- hexanes to acetone) to yield the desired product (4) as an off-white solid after freeze- drying (59 mg, 84% yield). ESI-MI m/z [Mu+Eta]+ 392.99. lH NMR (400 MHz, CDC13) delta 8.66 (d, J= 4.3 Hz, 1H), 8.52 (s, 1H), 7.59 (d, J= 7.7 Hz, 1H), 7.50 (dd, J = 9.0, 5.1 Hz, 2H), 7.33 (dd, J= 1.1, 4.1 Hz, 1H), 6.98 - 6.86 (m, 2H), 4.75 (d, J= 16.1 Hz, 1H), 4.48 (ddd, J= 12.0, 8.7, 5.7 Hz, 1H), 4.06 (ddd, J= 9.4, 8.7, 5.8 Hz, 1H), 3.97 (ddd, J= 12.0, 8.3, 5.8 Hz, 1H), 3.87 - 3.73 (m, 2H), 2.42 (s, 3H). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃;Cooling; |
Step (c): To generate the acid chloride: To a chilled (ice bath) suspension of 3- methylisoxazole-4-carboxylic acid (140 mg, 1.1 mmol) in dichloromethane (3 mL) was added oxalyl chloride (0.23 mL, 2.7 mmol) followed by DMF (1 drop, catalytic). The mixture was allowed to warm to room temperature and stirred until the reaction was complete(suspension dissolved). The resulting solution was concentrated in vacuo and further dried under a stream of nitrogen to yield the crude acid chloride.To a chilled (ice bath) suspension of the acid chloride (generated as above, 1.1 mmol) in pyridine (2.4 mL) was added a suspension of 11a-(4-methoxyphenyl)-2,3,11 ,11a-tetrahydro- 1 H,5H-imidazo[1 ,2-a]thieno[3',2':4,5lpyrrolo[1 ,2-c/)pyrazin-5-one (75 mg, 0.22 mmol) in pyridine (3 mL). The mixture was allowed to warm to room temperature. After 2 hours, LCMS indicated complete reaction so the mixture was diluted with water and extracted with ethyl acetate (x 3). The extracts were combined, washed with brine, dried (Na2S04), filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography using the Biotage SP4 (0 to 10% methanol-ethyl acetate). The resulting material was dissolved in ethyl acetate and washed with sat. aq. NaHC03. The organic layer was concentrated in vacuo and resulting solid triturated with ethyl acetate-hexanes to yield 11a- (4-methoxyphenyl)-1 -[(3-methyl-1 ,2-oxazol-4-yl)carbonyl]-2,3,11,11 a-tetrahydro-1 H,5H- imidazo[1,2-a]thieno[3',2':4,5]pyrrolo[1 ,2-d]pyrazin-5-one (1) (44 mg, 44% yield) as a solid. ESI-MI m/z [M+H]* 449.16. 1H NMR (400 MHz, CDCI3) delta 8.54 (s, 1 H), 7.35 (d, J = 9.0 Hz, 2H), 7.14 (s, 1 H), 6.98 (d, J = 5.3 Hz, 1 H), 6.90 (d, J = 5.3 Hz, 1H), 6.78 (d, J = 9.0 Hz, 2H), 5.71 (d, J = 12.6 Hz, 1H), 4.62 (d, J = 12.6 Hz, 1 H), 4.44 - 4.30 (m, 1 H), 4.09 - 4.01 (m, 1 H), 3.94 - 3.79 (m, 2H), 3.73 (s, 3H), 2.46 (s, 3H). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Cooling with ice-brine; |
To a solution of <strong>[17153-20-7]3-methylisoxazole-4-carboxylic acid</strong> (10.0g, 78.6 mmol) in dichloromethane (310 ml_), cooled with an ice-brine bath, was added N,N-dimethylformamide (0.30 ml_, 3.9 mmol) followed dropwise by oxalyl chloride (7.55 ml_, 86.5 mmol). After stirring at room temperature overnight (meanwhile gas evolution had completely stopped), all volatiles were removed in vacuo to affor the crude acid chloride (11.0 g). |
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