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Stage #1: acetonitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl cyclobutylcarboxylate In tetrahydrofuran at -78℃; for 4h; |
Synthesis of CK01: Cyclobutyl-3-oxo-propionitrile
A 1L 4 neck round bottom flask was equipped with 2 dropping funnels and a septum on top of the apparatus. The whole system was flame-dried (heat gun) for 10 minutes under vacuum and then cooled down to RT under a positive stream of nitrogen (balloon). A low-temperature thermometer was adapted under a positive stream of nitrogen, then a 1N LiHMDS solution in THF (468.0 mL, 468.0 mmol, 1.5 equiv) was cannulated into the flask using a positive stream of nitrogen. The solution was cooled down to -78 °C (dry ice/acetone cooling bath) as confirmed with the thermometer. Dry MeCN (24.4 mL, 468.0 mmol, 1.5 equiv) was added via syringe into the first dropping funnel, and then added dropwise (over 20 min) into the reaction mixture. After the end of the addition, the mixture was stirred at -78 °C for 1 h. At this point, cyclobutanecarboxylic acid ethyl ester (CAS: 14924-53-9, 43.1 mL, 312.1 mmol, 1.0 equiv) as a solution in dry THF (106 mL) was introduced into the second dropping funnel. This solution was slowly added over 2 h into the reaction mixture at -78 °C. The mixture was stirred at -78 °C for 2 h. The reaction mixture was poured into 300 mL of cold water, stirred for 30 min and allowed to warm to RT. The mixture was then partitioned between ethyl acetate and H2O. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic phases were discarded. The aqueous layer was then acidified with 100 mL of 2 N HCl, then extracted with ethyl acetate (3 x 300 mL), washed with 50 mL of brine, dried over MgSO4 filtered and concentrated in vacuo to afford the titled compound which was used without further purification. |
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With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; |
Illustrative Synthesis of CKO1:Cyclobutyl-3-Oxo-Propionitrile+
General procedure: 11446] A 1 L 4 neck round bottom flask was equipped with2 dropping thnnels and a septum on top of the apparatus. The whole system was flame-dried (heat gun) for 10 minutes under vacuum and then cooled down to RT under a positive stream of nitrogen (balloon). A low-temperature thermometer was adapted under a positive stream of nitrogen, then a 1 N LiHMDS solution in THF (468.0 mE, 468.0 mmol, 1.5 equiv) was cannulated into the flask using a positive stream of nitrogen. The solution was cooled down to -78° C. (dry ice/acetone cooling bath) as confirmed with the thermometet Dry MeCN (24.4 mE, 468.0 mmol, 1.5 equiv) was added via syringe into the first dropping funnel, and then added dropwise (over 20 mm) into the reaction mixture. Afier the end of the addition, the mixture was stirred at -78° C. for 1 h. At this point, cyclobutanecarboxylic acid ethyl ester (CAS:14924-53-9, 43.1 mE, 312.1 mmol, 1.0 equiv) as a solution in dry THF (106 mE) was introduced into the second dropping funnel. This solution was slowly added over 2 h into the reaction mixture at -78° C. The mixture was stirred at -78° C. for 2 h. The reaction mixture was poured into 300 mE of cold water, stirred for 30 mm and allowed to warm to RT. The mixture was then partitioned between ethyl acetate and H20. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3x300 mE). The combined organic phases were discarded. The aqueous layer was then acidified with 100 mE of 2 N HC1, then extracted with ethyl acetate (3x300 mE), washed with 50 mE of brine, dried over Mg504, filtered and concentrated in vacuo to afford the titled compound which was used without further purification. |
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Stage #1: acetonitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl cyclobutylcarboxylate In tetrahydrofuran at -78℃; for 4h; Inert atmosphere; |
1.1; i 1.1. Step i: Cyclobutyl-3-oxo-propionitrile
A 1 L 4 neck round bottom flask was equipped with 2 dropping funnels and a septum on top of the apparatus. The whole system was flame-dried (heat gun) for 10 min under vacuum and then cooled down to RT under a positive stream of nitrogen (balloon). A low-temperature thermometer was adapted under a positive stream of nitrogen, then a 1 N LiHMDS solution in THF (468.0 mL, 468.0 mmol, 1.5 equiv) was cannulated into the flask using a positive stream of nitrogen. The solution was cooled down to -78°C (dry ice/acetone cooling bath) as confirmed with the thermometer. Dry MeCN (24.4 mL, 468.0 mmol, 1.5 equiv) was added via syringe into the first dropping funnel, and then added dropwise (over 20 min) into the reaction mixture. After the end of the addition, the mixture was stirred at -78°C for 1 h. At this point, cyclobutanecarboxylic acid ethyl ester (CAS 14924-53-9, 43.1 mL, 312.1 mmol, 1.0 equiv) as a solution in dry THF (106 mL) was introduced into the second dropping funnel. This solution was slowly added over 2 h into the reaction mixture at -78°C. The mixture was stirred at -78°C for 2 h. The reaction mixture was poured into 300 mL of cold water, stirred for 30 min and allowed to warm to RT. The mixture was then partitioned between ethyl acetate and H2O. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 300 mL). The combined organic phases were discarded. The aqueous layer was then acidified with 100 mL of 2 N HC1, then extracted with ethyl acetate (3 c 300 mL), washed with 50 mL of brine, dried over MgSCfi, filtered and concentrated in vacuo to afford the titled compound which was used without further purification. |
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Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: ethyl cyclobutylcarboxylate In tetrahydrofuran; hexane at -78 - -45℃; for 2.5h; |
4 AcN? (2S)-N-[2-[[2-[4-(cyanoinethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin- 4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (compound 4)
To a solution of MeCN (6.41 g, 156.04 mmol, 8.21 mL) in THF (200 mL) was added n-BuLi (2.5 M in hexane, 62.4 mL) stirred at -78°C for 0.5 h. After that a solution of ethyl cyclobutanecarboxylate (10 g, 78.02 mmol, 10.78 mL) in THF (200 mL) added into the mixture and stirred at -78°C for 0.5°C. Then the mixture was warmed to -45°C and stirred for 2 h. The mixture was quenched by addition of 0 (50 mL) at 25°C, and then diluted with 0 (100 mL) and extracted with EtOAc (80 c 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford 3-cyclobutyl-3-oxo-propanenitrile (10 g, crude) as yellow oil, which would be used directly in the next step. 1H NMR (400 MHz, DMSO-ty,): d - 3.6 (s, 2H), 2.98-2.96 (m, 1H), 2.90-2.89 (m, 1H), 2.8 (s, 2H), 2.72 -2.70 (m, 2H), 2.55-2.52 (m, 2H). |
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