4,6-Dichloro-5-(2-propen-1-yl)pyrimidine

Pale yellow paint, liquid

To a solution of compound 3 (290 g, 1.91 mol) in MeCN (600 ml), N, N-dimethylaniline (60 ml) was added, then the mixture was warmed to 80°C and POCl3 (822 g, 5.36 mol) was added dropwise. The reaction mixture was refluxed for 3 h under nitrogen atmosphere. Then it was quenched with ice-water (500 ml) and concentrated to dryness under reduced pressure. The residue was extracted with 1, 2-dichloroethane (500 ml), washed with water (3×100 ml) and aqueous Na2CO3 (200 ml). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude, that was purified by vacuum distillation (94–96°C, 8 mmHg). Yield 306 g (85percent), light yellow oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz):8.64 (1H, s, H-2); 5.89–5.82 (1H, m, =CH); 5.17–5.09 (2H, m, =CH2); 3.64 (2H, d, J = 6.2, CH2). 13C NMR spectrum(CDCl3), δ, ppm: 162.0; 155.8; 131.0; 130.6; 118.2; 34.0. Mass spectrum, m/z (Irel, percent): 191 [M(35Cl, 37Cl)+H]+ (61), 189 [M(35Cl)+H]+ (100), Step 2 - Synthesis of compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (-260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was cooled to room temperature, poured over crushed ice, washed sequentially with sodium bicarbonate, brine and water, then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified using flash column chromatography on silica gel (100percent CHStep 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed with sodium bicarbonate, brine and water respectively and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to provide a crude residue which was purified using flash column chromatography on silica gel (100percent DCM) to provide compound 1C (9.73 g, 57.95percent).Step 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, . 77.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for 15 hours. The reaction mixture was cooled, poured over crushed ice and washed sequentially with saturated aqueous sodium bicarbonate, brine and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (CHA solution of Compound 1A (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) in acetonitrile (-260 mL) was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed sequentially with saturated aqueous sodium bicarbonate solution, brine and water, then extracted with ethy. acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (100percent Ch^C^) to provide Compound 1 B (9.73g, 57.95percent).Step 3:A 100ml three necked round bottom flask was charged with 5-allylpyrimidine- 4, 6-diol (4 g) and phosphorusoxychloride (25 mL) under nitrogen atmosphere. The reaction mixture was heated to 80°C for 3 hours. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The resulting oil was neutralized with saturated NaHCC solution and pH was adjusted to 8-9. The aqueous layer was diluted with dichloromethane (100 mL) and was extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous NaSynthesis of 5-allyl-4, 6-dichloropyrimidlne (8c): 4, 6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1 M in THE; 0.05 mL, 5 mol percent) was then slowly added at -20° C. Allyl bromide (242 mg, 2.0 mmol) was then slowly added at -60° C. The resulting mixture was then allowed to warm up slowly to 0° C. for 4 h. The reaction mixture was quenched with a sat. aq. NHThe alkylation step by conducted using a modified procedure: TMPMgCl·LiCl (0.8M, 11.0 mL, 8.8 mmol) was added to a solution of 2, 4, 6-trichloropyrimidine (1.47 g, 8.0 mmol) in anhydrous THF (20 mL) at -78 Step 2: 4, 6-Dichloro-5-(2-propen-1 -yl)pyrimidine (2)A round-bottomed flask was charged, under NIn a 1000 ml round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 60 g of compound I was added, 200 ml of ammonia water and 200 ml of ethanol were added, and the temperature was raised to 60 C and the reaction was incubated for 24 h.The progress of the reaction was monitored by TLC (ethyl acetate: petroleum ether = 5: 1). After the reaction was completed, spin-dry the solvent to obtain compound I50.1g, yield 93.4%.A mixture of compound 4 (100.9 g, 0.53 mol) and NH4OH (400 ml) in EtOH (300 ml) was stirred at 70C for 24 h in a sealed flask. The solvent was removed under reduced pressure and EtOH (300 ml) was added to the residue. The precipitated ammonium chloride was filtered off. The filtrate was concentrated under reduced pressure to give a solid product which was oven-dried and triturated with EtOAc. Yield 81.1 g (90%), white solid, mp 150-152C. IR spectrum, nu, cm-1: 3411, 3376, 3181, 1653, 1546, 901.1H NMR spectrum (DMSO-d6), delta, ppm (J, Hz): 8.13 (1H, s, H-2); 7.14 (2H, br. s, NH2); 5.89-5.79 (1H, m, =CH);5.07 (2H, t, J = 8.9, =CH2); 3.36 (2H, d, J = 5.8, CH2).13C NMR spectrum (DMSO-d6), delta, ppm: 163.1; 157.7;156.0; 132.7; 115.5; 111.1; 29.7. Found, m/z: 169.0406[M (35Cl)]+. C7H8ClN3. Calculated, m/z:169.0407.Under nitrogen protection, take 50g (I), 200ml ammonia water, 38 g of N-methyl-N-oxomorpholine and 200 ml of dichloromethane were added to the reaction flask. The reaction was placed in an oil bath and stirred to 35-40 C for 24 h. TLC tracks the progress of the reaction. When the raw material point disappears or does not change, the reaction was stopped and the solvent was removed to obtain 40.5 g of compound II with a yield of 90%.To a solution of compound 3 (290 g, 1.91 mol) in MeCN (600 ml), N, N-dimethylaniline (60 ml) was added, then the mixture was warmed to 80C and POCl3 (822 g, 5.36 mol) was added dropwise. The reaction mixture was refluxed for 3 h under nitrogen atmosphere. Then it was quenched with ice-water (500 ml) and concentrated to dryness under reduced pressure. The residue was extracted with 1, 2-dichloroethane (500 ml), washed with water (3×100 ml) and aqueous Na2CO3 (200 ml). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude, that was purified by vacuum distillation (94-96C, 8 mmHg). Yield 306 g (85%), light yellow oil. 1H NMR spectrum (CDCl3), delta, ppm (J, Hz):8.64 (1H, s, H-2); 5.89-5.82 (1H, m, =CH); 5.17-5.09 (2H, m, =CH2); 3.64 (2H, d, J = 6.2, CH2). 13C NMR spectrum(CDCl3), delta, ppm: 162.0; 155.8; 131.0; 130.6; 118.2; 34.0. Mass spectrum, m/z (Irel, %): 191 [M(35Cl, 37Cl)+H]+ (61), 189 [M(35Cl)+H]+ (100), Step 2 - Synthesis of compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (-260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was cooled to room temperature, poured over crushed ice, washed sequentially with sodium bicarbonate, brine and water, then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified using flash column chromatography on silica gel (100% CH2Cl2) to provide compound 1C (9.73 g, 57.95%).Step 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed with sodium bicarbonate, brine and water respectively and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to provide a crude residue which was purified using flash column chromatography on silica gel (100% DCM) to provide compound 1C (9.73 g, 57.95%).Step 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, . 77.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for 15 hours. The reaction mixture was cooled, poured over crushed ice and washed sequentially with saturated aqueous sodium bicarbonate, brine and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (CH2CI2) and the product 1C was isolated (9.73 g, 57.95%).A solution of Compound 1A (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) in acetonitrile (-260 mL) was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed sequentially with saturated aqueous sodium bicarbonate solution, brine and water, then extracted with ethy. acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (100% Ch^C^) to provide Compound 1 B (9.73g, 57.95%).Preparation of 5-Allyl-4, 6-dichloro-pyrimidine To a solution of 5-allyl-pyrimidine-4, 6-diol (16.64 g, 109.4 mmol), Diethyl-phenyl-amine (17.5 mL, 131.28 mmol), Benzyl-triethyl-ammonium chloride (50.4 g, 228.3 mmol) in CH3CN (270 mL), was added POCl3 (54 mL, 108.0 mmol) slowly. This was heated at 110 C. for o/n under argon. After the mixture was cooled to rt, it was poured into crushed ice (500 g) and stirred for 30 min. This was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography to yield 3.0 g of Step 3:A 100ml three necked round bottom flask was charged with 5-allylpyrimidine- 4, 6-diol (4 g) and phosphorusoxychloride (25 mL) under nitrogen atmosphere. The reaction mixture was heated to 80C for 3 hours. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The resulting oil was neutralized with saturated NaHCC solution and pH was adjusted to 8-9. The aqueous layer was diluted with dichloromethane (100 mL) and was extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2S04. Evaporation of solvents under reduced pressure gave crude compound, which was purified by column chromatography using MeOH/CHCls (0.4:9.6) as eluent to afford

Molecular Weight:189.04
XLogP3:3.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:187.9908036
Monoisotopic Mass:187.9908036
Topological Polar Surface Area:25.8
Heavy Atom Count:11
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes