* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1994, vol. 59, # 8, p. 1841 - 1852
[2] Collection of Czechoslovak Chemical Communications, 1994, vol. 59, # 8, p. 1841 - 1852
2
[ 6214-64-8 ]
[ 188781-08-0 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 105℃; for 0.5 h;
General procedure: A solution of compound 2 (10 mmol) in phosphorous oxychloride (10 mL) was heated under reflux for 30 min. The resulting reaction mixture was distilled under reduced pressure to remove excess phosphorous oxychloride. Last traces of phosphorous oxychloride were removed by azeotrophic distillation with dry benzene and crude product was purified by column chromatography to afford pure product 3.
13.18%
at 80℃; for 12 h; Inert atmosphere
To a solution of ethyl 6-methyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate (62 g 340 mmol) stirred under N2 at 20 was added POCl3 (496 g 3233 mmol) slowly. The reaction mixture was stirred at 80 for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine dried over Na2SO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 Rf 0.7) were combined and concentrated to yield a yellow solid of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (9 g 44.9 mmol 13.18yield) 1H NMR (400 MHz CDCl3) δ 9.01 (s 1H) 4.41 (q J 7.2 Hz 2H) 2.82 (s 3H) 1.41 (t J 7.2 Hz 3H) .
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2290 - 2294
[2] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 70
[3] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 314 - 323
3
[ 6214-64-8 ]
[ 188781-08-0 ]
Yield
Reaction Conditions
Operation in experiment
45%
for 2 h; Reflux
A mixture of POCI3 (10ml) and 2-hydroxy-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (Frontier, lg, 5.49mmol) was heated to reflux for 2h. Excess POCI3 and diethyl iso-propylamine were removed by evaporation under vacuum. The residue was partitioned between 10percent NaOH and EtOAc. The organic extract was washed with water and brine, dried over Na2S04, filtered and concentrated to give the desired product (498mg, 45percent yield).
Reference：
[1] Patent: WO2012/123467, 2012, A1, . Location in patent: Page/Page column 30
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2573 - 2577
[3] Patent: US5935966, 1999, A,
[4] Patent: US5811428, 1998, A,
5.2. General procedure for the synthesis of compound 3
General procedure: A solution of compound 2 (10 mmol) in phosphorous oxychloride (10 mL) was heated under reflux for 30 min. The resulting reaction mixture was distilled under reduced pressure to remove excess phosphorous oxychloride. Last traces of phosphorous oxychloride were removed by azeotrophic distillation with dry benzene and crude product was purified by column chromatography to afford pure product 3.
13.18%
With trichlorophosphate at 80℃; for 12h; Inert atmosphere;
2 Step 2 Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate
To a solution of ethyl 6-methyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate (62 g 340 mmol) stirred under N2 at 20 was added POCl3 (496 g 3233 mmol) slowly. The reaction mixture was stirred at 80 for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine dried over Na2SO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 Rf 0.7) were combined and concentrated to yield a yellow solid of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (9 g 44.9 mmol 13.18yield) 1H NMR (400 MHz CDCl3) δ 9.01 (s 1H) 4.41 (q J 7.2 Hz 2H) 2.82 (s 3H) 1.41 (t J 7.2 Hz 3H) .
Stage #1: ethyl acetoacetate; orthoformic acid triethyl ester; urea at 80℃; for 28h; Inert atmosphere;
Stage #2: With sodium ethanolate In ethanol at 80℃; for 2h;
1 Step 1 Ethyl 6-methyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate
A solution of urea (50 g 833 mmol) ethyl 3-oxobutanoate (119 g 916 mmol) in triethoxymethane (136 g 916 mmol) was stirred for 28 h while distilling off EtOH at 80 under N2atmosphere. Then the mixture was cooled to 20 and EtOH (800 mL) was added NaOEt (85 g 1249 mmol) in EtOH (500 mL) was added to above mixture and the mixture was stirred for 2 h at 80 the mixture was cooled to 20 followed by addition of water (400 mL) AcOH (60 mL) was added at 20-30 then the mixture was filtered the solid was washed with water (200 mL) and then dried to give ethyl 6-methyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate (70 g 384 mmol 46.2yield) .1HNMR(400 MHz DMSO-d6) δ 8.81 (s 1H) 4.31 (q J 7.2 Hz 2H) 2.64 (s 3H) 1.35 (t J 7.2 Hz 3H) LCMS m/z 183.2 (M+H) .
1-(2-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-methylpyrimidin-5-yl)-3-(4-((3-methyloxetan-3-yl)methyl)-3-(trifluoromethyl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1.1: trichlorophosphate / 12 h / 80 °C / Inert atmosphere
2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere
3.1: lithium hydroxide; water / tetrahydrofuran / 12 h / 50 °C / Inert atmosphere
3.2: pH 7
4.1: diphenyl phosphoryl azide; triethylamine / 1,4-dioxane / 0.5 h / 25 °C
4.2: 3 h / 80 °C
1-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-methylpyrimidin-5-yl)-3-(4-((3-methyloxetan-3-yl)methyl)-3-(trifluoromethyl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1.1: trichlorophosphate / 12 h / 80 °C / Inert atmosphere
2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere
3.1: lithium hydroxide monohydrate / tetrahydrofuran / 12 h / 60 °C / Inert atmosphere
3.2: pH 7
4.1: diphenyl phosphoryl azide; triethylamine / 1,4-dioxane / 0.5 h / 25 °C
4.2: 3 h / 80 °C
1-(4-(2-cyano-2-methylpropyl)-3-(trifluoromethyl)phenyl)-3-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)-1,6-dihydropyridin-3-yl)-4-methylpyrimidin-5-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1.1: trichlorophosphate / 12 h / 80 °C / Inert atmosphere
2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere
3.1: lithium hydroxide monohydrate / tetrahydrofuran / 12 h / 60 °C / Inert atmosphere
3.2: pH 7
4.1: diphenyl phosphoryl azide; triethylamine / 1,4-dioxane / 0.5 h / 25 °C
4.2: 3 h / 80 °C
ethyl 2-(4-isobutylphenoxy)-4-methylpyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.7%
Stage #1: ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 1h;
Stage #2: 4-isobutylphenol In N,N-dimethyl-formamide at 75℃; for 1h;
208.1
[00713] A mixture of ethyl 2-hydroxy-4-methyl-pyrimidine-5-carboxylate (50.0 mg, 0.27mmol), PyAOP (485.5 mg, 1.1 mmol) and Cs2CO3 (179 mg, 0.55 mmol) in N,Ndimethylformamide (5 mL) was stirred at 25 °C for 1 h, then 4-isobutylphenol (164.9 mg, 1.1 mmol) and Cs2CO3 (179 mg, 0.55 mmol) were added. The reaction was stirred in the microwave at 75 °C for 1 h, diluted with water (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL x 3), dried over Na2SO4 andconcentrated. The residue was purified by prep-TLC (10% EtOAc in petroleum ether) to give ethyl 2-(4-isobutylphenoxy)-4-methylpyrimidine-5-carboxylate (110 mg, 63.7% yield).
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