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Stage #1: for 1 h; Heating / reflux Stage #2: at 45℃; Heating / reflux
Intermediate 1A : Preparation of 4-chloro-6-phenylpyrimidin-2-amine; A suspension of guanidine carbonate (3.60 g, 20 mmol) in ethanol (120 mL) and toluene (20 mL) was refluxed under nitrogen for 1 h, during which time about 50 mL of solvent was removed by distillation. After the mixture was cooled to 45 °C, ethyl 3-oxo-3- phenylpropanoate (7.68 g, 40 mmol) was added and the solution was heated at reflux overnight. The desired product precipitated as a white solid during the reaction. Water (50 mL) was added to the reaction and the mixture was refluxed for an additional 30 min. After cooling to rt, the mixture was neutralized with 1N HC1 and placed in the refrigerator for 6 h. The solid was filtered, washed with water followed by ether and dried at 60 °C under vacuum to give the product as white solid (6.45 g, 86percent). MS ES: 188 (M+H) +, calcd 188; RT = 0.91 min; TLC (CH2C12/2M NH3 in MeOH 95/5) Rf = 0.10. A mixture of the above product (6.0 g, 32 mmol) and POC13 (100 mL) was heated at reflux for 1 h. The majority of the POC13 was removed in vacuo and the residue was diluted with EtOAc and poured over an ice/saturated NaHC03 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude organic concentrate was re-crystallized from EtOAc/ether to give the product 1A as an off-white powder (2. 8 g, 43percent). MS ES: 206 (M+H) +, calcd 206; RT = 2.49 min; TLC (CH2C12/2M NH3 in MeOH 95/5) Rf = 0.72. (Reference 1: H. L. Skulnick, S. D. Weed, E. E. Edison, H. E. Renis, W. Wierenga, and D. A. Stringfellow, J ; Med. Cllem. 1985, 28,1854-1869).
General procedure: To a suspension of guanidine carbonate (1.5-5 eq) in ethanol (2 mL/mmol) was added γ-aryl-β-ketoester (1.43-26.6 mmol), and the reaction mixture heated at 80 °C for 15-64 h. Followingreaction completion by TLC, the mixture was cooled to ambient temperature, filtered and thesolid triturated with water (5-20 mL) and acetone (5-20 mL) to give the title compound.
Reference：
[1] Tetrahedron, 2015, vol. 71, # 39, p. 7339 - 7343
[2] Journal of the American Chemical Society, 1998, vol. 120, # 27, p. 6761 - 6769
[3] Justus Liebigs Annalen der Chemie, 1891, vol. 262, p. 365
[4] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 47, p. 203
3
[ 614-27-7 ]
[ 113-00-8 ]
[ 56741-94-7 ]
Yield
Reaction Conditions
Operation in experiment
800 mg
With sodium methylate In methanol at 65℃; Inert atmosphere
A mixture of methyl 3-oxo-3-phenylpropanoate (2.0 g) , guanidine (2.02 g) and sodium methanolate (1.12 g) in methanol (50 mL) was stirred at 65°C overnight under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was purified by washed with methanol: ethyl acetate (1:10) as eluent to give the desired compound (800 mg) as a white solid. LC-MS m/z [M+H]+ = 188 (calc=188) (ES+)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1315 - 1321
With bromine; acetic acid; at 20 - 70℃;Inert atmosphere;
To a suspension of 2-amino-6-phenylpyrimidin-4(3H)-one 6 (200 mg, 1.07 mmol) in glacialacetic acid (2 mL) at 70 C was slowly added a solution of bromine (57.0 muL, 1.12 mmol) inglacial acetic acid (2 mL). The reaction mixture was allowed to cool to ambient temperature and stirred for 4 h, and then the solvent removed under reduced pressure. The residue was trituratedwith ether (10 mL) and recrystallized from ethanol to give the title compound as a colourlesssolid (171 mg, 60%); mp 275-277 C (lit.,2 mp 285-287 C); (Found: M+H+, 264.9847.C10H979BrN3O+ requires 264.9845); numax (CHCl3)/cm-1 3691, 3607, 3012, 1692, 1602, 1473,1440, 1328, 1240; deltaH (400 MHz; DMSO-d6) 7.56-7.53 (2 H, m, ArH), 7.45-7.43 (3 H, m, ArH),6.87 (2 H, br s, NH2); deltaC (100 MHz; DMSO-d6) 158.6 (C), 153.2 (2xC), 136.3 (C), 129.7 (CH),128.5 (CH), 128.0 (CH), 97.3 (C) ; m/z (ESI) 264/266 (M+H+, 34/35%).Spectroscopic data in agreement with those previously reported.2
Intermediate 1A : Preparation of 4-chloro-6-phenylpyrimidin-2-amine; A suspension of guanidine carbonate (3.60 g, 20 mmol) in ethanol (120 mL) and toluene (20 mL) was refluxed under nitrogen for 1 h, during which time about 50 mL of solvent was removed by distillation. After the mixture was cooled to 45 C, ethyl 3-oxo-3- phenylpropanoate (7.68 g, 40 mmol) was added and the solution was heated at reflux overnight. The desired product precipitated as a white solid during the reaction. Water (50 mL) was added to the reaction and the mixture was refluxed for an additional 30 min. After cooling to rt, the mixture was neutralized with 1N HC1 and placed in the refrigerator for 6 h. The solid was filtered, washed with water followed by ether and dried at 60 C under vacuum to give the product as white solid (6.45 g, 86%). MS ES: 188 (M+H) +, calcd 188; RT = 0.91 min; TLC (CH2C12/2M NH3 in MeOH 95/5) Rf = 0.10. A mixture of the above product (6.0 g, 32 mmol) and POC13 (100 mL) was heated at reflux for 1 h. The majority of the POC13 was removed in vacuo and the residue was diluted with EtOAc and poured over an ice/saturated NaHC03 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude organic concentrate was re-crystallized from EtOAc/ether to give the product 1A as an off-white powder (2. 8 g, 43%). MS ES: 206 (M+H) +, calcd 206; RT = 2.49 min; TLC (CH2C12/2M NH3 in MeOH 95/5) Rf = 0.72. (Reference 1: H. L. Skulnick, S. D. Weed, E. E. Edison, H. E. Renis, W. Wierenga, and D. A. Stringfellow, J ; Med. Cllem. 1985, 28,1854-1869).
3.49 g (86%)
With ammonium hydroxide; In ice-water; trichlorophosphate;
b 4-Chloro-6-phenyl-pyrimidin-2-ylamine A stirred suspension of 3.69 g (19.7 mmol) 2-amino-6-phenyl-3H-pyrimidin-4-one in 4.5 ml (49.2 mmol) phosphorus oxychloride was heated at reflux for 2 h. The reaction mixture was then cooled to about 70 C. and poured cautiously onto 20 ml rapidly stirred ice-water. The mixture was briefly warmed to room temperature and then was recooled to 0 C. 100 ml 25% ammonium hydroxide solution was added and the resulting crystals were collected by filtration and washed with ice-cold water and then with a little ether to afford 3.49 g (86%) 4-chloro-6-phenyl-pyrimidin-2-ylamine as a pale yellow crystalline solid. EI-MS m/e (%): 207 (M{37Cl}+, 35), 206 ([M{37Cl}-H]+, 30)., 205 (M{35Cl}+, 100), 204 ([M{35Cl}-H]+, 56), 170 ([M-Cl]+, 35), 128 (([M-C6H5]+, 85).
With trichlorophosphate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
Example 1 Synthesis of 4-chloro-6-phenyl-2-pyrimidinamine; 2-amino-4-chloro-6-phenylpyrimidine To 10.0 g (53 mM) of 6-phenylisocytosine is added 80 ml of phosphorus oxychloride. The mixture is heated to reflux, and refluxed until solution is complete (about 30 minutes). The solution is then cooled and evaporated to dryness under vacuum at 45 C. The resulting oil is poured into 300 ml of ice water, with vigorous stirring, and the remaining oil washed into the aqueous mixture with additional 100 ml of water. The entire aqueous mixture is neutralized to pH 8 with concentrated ammonium hydroxide, filtered, and solids washed well with water until water wash is neutral. Dry at 60 in a vacuum oven to yield 9.2 g of 4-chloro-6-phenyl-2-pyrimidinamine.
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