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Intermediate 90:N-{6-[bis(ethyloxy)methyl]-2-[(phenylmethyl)thio]-4-pyrimidinyl}[1,3]thiazolo[5,4- b]pyridin-2-amineIn an atmosphere of nitrogen, an ice-cooled solution of a mixture of 6-[bis(ethyloxy)methyl]-2-[(phenylmethyl)thio]-4-pyrimidinamine (15g, 47.0mmol) and 2- bromo[1,3]thiazolo[5,4-b]pyridine (10.6Og, 49.3mmol) in dry N,N-dimethylformamide (20OmL) was treated portionwise over 5 minutes with sodium hydride (60% w/w in oil) (3.76g, 94mmol) and the mixture was stirred with cooling for 3 hours and at ambient temperature for a further 2 hours. The mixture was treated cautiously with water (25OmL) and the precipitated material was filtered off. The filtered solid was washed with water and dried to afford the title compound (19.6g, 43.2mmol, 92% yield). LCMS (Method A): Rt 1.32 minutes; m/z 454 (MH+).
Intermediate 37:W-[6-chloro-4-([(1 ,1 -dimethylethyl)(dimethyl)silyl]oxy}methyl)-2- pyridinyl][1 ,3]thiazolo[5,4-£>]pyridin-2 -amineUnder an atmosphere of nitrogen, an ice-cooled mixture of 6-chloro-4-([(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinamine [intermediate 40] (2g, 7.33mmol) and 2-bromo[1 ,3]thiazolo[5,4-b]pyridine (1 .58g, 7.33mmol) in dry N,N-dimethylformamide (20mL) was treated portionwise over 5 minutes with sodium hydride (60% in oil) (0.586g, 14.7mmol) and the mixture was stirred for 3 hours whilst being allowed to warm to ambient temperature. The mixture was then treated cautiously with saturated aqueous ammonium chloride (20mL) and water (30mL). The precipitated solid was filtered, washed with water and dried to afford the title compound (2.87g, 7.05mmol, 96% yield). LCMS (Method A): Rt 1 .51 minutes; m/z 407 (MH+).
96%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 3.08333h;Inert atmosphere; Cooling with ice;
Intermediate 93:W-te-chloro^-U i.l-dimethylethylKdimethylJsilylloxylmethyl)^- pyridin-2-amineUnder an atmosphere of nitrogen, an ice-cooied mixture of 6-chloro-4-([(1 , 1- dimethylethy.)(dimethyl)silyl]oxy}methyj)-2-pyridinamine (2 g, 7.33 mmol) and 2- bromo[1 ,3]thiazoio[5,4-fo]pyridine (1 .58 g, 7.33 mmol) in anhydrous N,N- dimethyiformamide (20 mL) was treated portionwise over 5 minutes with sodium hydride (60% w/w in mineral oil, 0.586 g, 14.7 mmol) and the mixture was stirred for 3 hours whilst being allowed to warm to ambient temperature. The mixture was then treated cautiously with saturated aqueous ammonium chloride (20 mL) and water (30 mL). The precipitated solid was filtered, washed with water and dried to afford the title compound (2.87 g, 7.05 mmol, 96% yield). LCMS (Method A): Rt 1.51 minutes; m/z 407 (MH+).
trans-4-[4-[(tetrahydro-2H-pyran-4-ylamino)methyl]-6-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)-2-pyridinyl]amino}cyclohexanol (2Z)-2-butenedioate[ No CAS ]
Intermediate 3:W-[6-[(methyloxy)methyl]-2-(methylthio)-4-pyriamine A solution of 6-[(methyloxy)methy.]-2-(methylthio)-4-pyrimidinamine (10 g, 54 mmol) in /V,W-dimethylformamide (100 mL) was cooled down to 0 C and sodium hydride (60 % w/w in mineral oil) (3.24 g, 81 mmol) was carefully added under nitrogen. The reaction was stirred for 20 minutes until the effervescence had stopped. 2-bromo[1 ,3]thiazolo[5,4- 0]pyridine (1 1.61 g, 54 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 C, sodium hydride (60 % w/w in mineral oil) (1.08 g, 27 mmol) was added and the reaction slowly warmed up to 40 C and stirred for 4 hours. Aqueous ammonium chloride was added and the reaction was stirred for 10 minutes. The mixture was poured into water and the light brown precipitate was then filtered off, dried overnight under reduced pressure in the oven to afford the title compound (18.4 g, 57.6 mmol, >100 % yield) as a light brown solid. LCMS (Method A): Rt 0.90 minutes; m/z 320 (MH+).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1.08333h;Inert atmosphere; Cooling with ice;
Intermediate 51 ;W-[6-chloro-4-(4-morpholinylmethyl}-2-pyridinyl][1 ,3]thia2olo[5,4-J ]pyridin-2-amine A mixture of 6-chioro-4-(4-morpholiny.methyl)-2-pyridinamine (0.96g, 4.22 mmol) and 2- bromo[1 ,3]thiazolo[5,4-j ]pyridine (1.088 g, 5.06 mmol) was dissolved in anhydrous N,N- dimethylformamide (10 mL), placed in an atmosphere of nitrogen and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 0.337 g, 8.43 mmol) was added portionwise over 5 minutes and the mixture stirred for 1 hour whilst being allowed to warm to ambient temperature. The reaction mixture was then partitioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was dried using a hydrophobic frit, evaporated to dryness to give a yellow solid. The product was purified by chromatography on silica using a gradient elution from 0 to 100 % ethyl acetate in cyclohexane followed by 0 to 20 % methanol in ethyl acetate wash to afford the title compound (1 g, 2.763 mmol, 65 % yield) as a yellow solid. LC S: (Method B): Rt 2.51 minutes; m/z 362 ( H+).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 17h;Inert atmosphere; Cooling with ice;
Intermediate 67:-(4-morpholinylmethyl)-A/-[1 ,3]i/) azo/o[5,4-fa]pyridin-2-yl-2I6-pyridinediA round bottom flask was charged with 4-(4-morpholinylmethy.)-2,6-pyridinediamine (900 mg, 4.32 mmol) and 2-bromo[1 ,3]thiazolo[5,4-jb]pyridine (1.022 g, 4.75 mmol) in anhydrous N,/V-dimethy.formamide (10 mL). The reaction was placed in an atmosphere of nitrogen and cooled in an ice bath. Sodium hydride (60 % w/w in mineral oil, 519 mg, 12.96 mmol) was added portionwise over 5 minutes and the mixture stirred for 1 hour whilst being allowed to warm to ambient temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between dichloromethane and water. After separation, the organic .ayer was dried using an hydrophobic frit and evaporated to dryness to give a black oil. The product was purified by chromatography on aminopropyl (NH2) silica using a gradient elution from 0 to 100 % ethyl acetate In cyc.ohexane to afford the title compound (417 mg, 1.218 mmol, 28 % yield) as an off-white soiid. LCMS: (Method D): Rt 0.74 minutes; m/z 343 (MH+).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1.58333h;Inert atmosphere; Cooling with ice;
Intermediate 78:W-(2-chloro-6-[c/*s-2f6-dimethyl-4-morpholinyI]methyl}-4- pyrimidinyl)[1 ,3]thiazoio[5,4-f>]pyridin-2-amineUnder an atmosphere of nitrogen, an ice-cooled solution of 2-chloro-6-[c/s-2,6-dimethyi- 4-morpholinyl]methyl}-4-pyrimidinamine (500 mg, 1.948 mmol) and 2- bromo[1 ,3]thiazoio[5,4-6]pyridine (419 mg, 1.948 mmol) in dry V,A/-dimethyjformamide (10 mL) was treated portionwise over 5 minutes with sodium hydride (60 % w/w in mineral oil) (156 mg, 3.90 mmol). The reaction mixture was stirred with cooiing for 30 minutes and at ambient temperature for a further 1 hour. The mixture was treated cautiously with saturated aqueous ammonium chloride (3 ml_). Saturated aqueous sodium carbonate was added (aqueous pH 1 1 ) and the product was extracted with dichloromethane (2 x 50 m._).The solvent was evaporated to dryness to afford the title compound (767 mg, 1.96 mmol, >100 % yield) as a white solid. LCMS (Method D): Rt 0.87 minutes; m/z 391 (MH+).
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