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Stage #1: N2-[4-(diethylamino)butyl]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine-2,7-diamine With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h;
Stage #2: Tert-butyl isocyanate In N,N-dimethyl-formamide at 20℃; for 16h;
Multi-step reaction with 3 steps
1.1: 18.30 g / 2-(phenylsulfonyl)-3-phenyloxaziridine / CHCl3 / 24 h / 20 °C
2.1: 72 percent / dioxane / 50 °C
3.1: NaH / dimethylformamide / 1.5 h / 20 °C
3.2: 80 percent / dimethylformamide / 16 h / 20 °C
Multi-step reaction with 2 steps
1.1: 72 percent / dioxane / 50 °C
2.1: NaH / dimethylformamide / 1.5 h / 20 °C
2.2: 80 percent / dimethylformamide / 16 h / 20 °C
Multi-step reaction with 4 steps
1.1: NaH / tetrahydrofuran / 1.5 h / 20 °C
1.2: tetrahydrofuran / 20 °C
2.1: 18.30 g / 2-(phenylsulfonyl)-3-phenyloxaziridine / CHCl3 / 24 h / 20 °C
3.1: 72 percent / dioxane / 50 °C
4.1: NaH / dimethylformamide / 1.5 h / 20 °C
4.2: 80 percent / dimethylformamide / 16 h / 20 °C
Multi-step reaction with 4 steps
1.1: NaH / tetrahydrofuran / 1.5 h / 20 °C
1.2: tetrahydrofuran / 20 °C
2.1: 18.30 g / 2-(phenylsulfonyl)-3-phenyloxaziridine / CHCl3 / 24 h / 20 °C
3.1: 72 percent / dioxane / 50 °C
4.1: NaH / dimethylformamide / 1.5 h / 20 °C
4.2: 80 percent / dimethylformamide / 16 h / 20 °C
With sulfuryl dichloride In acetonitrile at 0℃; for 2h;
17 Example 17: Synthesis of COMPOUND 55
Example 17: Synthesis of COMPOUND 55. In a dried vessel, sulfuryl chloride (2 equiv.) is added to a solution of 1-(tert-butyl)-3-(2- ((4-(diethylamino)butyl)amino)-6- (3 ,5-dimethoxyphenyl)pyrido [2,3-d]pyrimidin-7-yl)urea (1 equiv.) in anhydrous acetonitrile at 0°C. After stirring for 2 hours, the reaction mixture is dilutedwith dichloromethane and washed with aqueous saturated sodium bicarbonate solution. The crude product, 1 -(tert-butyl)-3 -(6- (2,6-dichloro-3 ,5-dimethoxyphenyl)-2- ((4- (diethylamino)butyl)amino)pyrido[2,3-d]pyrimidin-7-yl)urea, is used in the next step without further purification.
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2h;
16 Example 16: Synthesis of COMPOUND 52
Example 16: Synthesis of COMPOUND 52 The starting material 1- (tert-butyl)-3- (2- ((4- (diethylamino)butyl)amino)-6- (3,5- dimethoxyphenyl)pyrido [2,3-d]pyrimidin-7-yl)urea (PD 173074) can be purchased from, e.g., SelleckChem.com. In a dried vessel, acryloyl chloride (2 equiv.) and diisopropylethylamine (4.3 equiv.) are added to a solution of 1 -(tert-butyl)-3- (2-((4- (diethylamino)butyl)amino)-6-(3 ,5 -dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (1 equiv.) in anhydrous dichloromethane at0°C. After stuffing at room temperature for 2 hours, the reaction mixture is concentrated, diluted with DMSO and purified by reverse phase HPLC (5-95% water/acetonitrile). After concentrating the fractions, the product N- (7 -(3- (tert-butyl)ureido)-6-(3 ,5 - dimethoxyphenyl)pyrido [2,3-d]pyrimidin-2-yl)-N- (4- (diethylamino)butyl)acrylamide is obtainedas a pale yellow foam. LCMS (M+1) = 578.2.