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CAS No. : | 1780-26-3 |
Formula : | C5H4Cl2N2 |
M.W : | 163.00 |
SMILES Code : | C1=C(N=C(N=C1Cl)C)Cl |
MDL No. : | MFCD00090472 |
InChI Key : | FIMUTBLUWQGTIJ-UHFFFAOYSA-N |
Pubchem ID : | 234997 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With thionyl chloride; In acetonitrile; at 80℃; for 3h;Industrial scale; | <strong>[1194-22-5]4,6-dihydroxy-2-methylpyrimidine</strong> (5.0 g, 0.04 mol) was added to a mixed solution of thionyl chloride (18.9 g, 0.16 mol) and acetonitrile,The reaction was stirred at 80 C for 3 hours, and the plate was confirmed to disappear. The excess thiophenolate was distilled off under reduced pressure and the residue was poured into 50 g of ice water. The precipitated solid was filtered and purified by column chromatography to give 6.1 g (yield: 94%) of solid. |
69% | With trichlorophosphate;Heating / reflux; | A mixture of 4, 6-dihydroxy-2-methylpyrimidine (15 g, 120 mmol) and phosphorus oxychloride (150 ml) were heated at reflux overnight. After allowing to cool the reaction mixture was concentrated TO-30 ml and then poured onto ice. The reaction mixture was extracted with ethyl acetate (3 x 75 ml). The organic extracts were combined, washed with base, brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (13.4 g, 69%). |
36% | With N,N-diethylaniline; trichlorophosphate; for 2h;Heating / reflux; | Step 1 4,6-dichloro-2-methyl-pyrimidine To a stirred suspension of 2-methyl-pyrimidine-4,6-diol (10.0 g, 79.4 mmol) in phosphorous oxychloride (75 mL) was added N,N-diethylaniline (5 mL). This mixture was heated under reflux for two hours and then cooled to room temperature, after which the remaining phosphorous oxychloride was removed in vacuo. The residue was carefully diluted with cold water, extracted three times with 150 mL of diethyl ether, and the combined ether layers were dried on potassium carbonate. The solvent was removed in vacuo to yield an oil that solidified under vacuum to form a light yellow solid, 4.68 g (36%) of 4,6-dichloro-2-methyl-pyrimidine; ms (M+H) 164. |
With trichlorophosphate; for 4h;Heating / reflux; | A suspension of 2-methyl-pyrimidine-4,6-diol (20. 0 g) in POCI3 (162 mL) was stirred at reflux for 4 hr and cooled to ambient temperature. The mixture was poured into ice water (3 L). The aqueous layer was extracted with CHC13 (three times) The combined organic layer was dried over MgS04, filtrated, and concentrated under reduced pressure to give 4, 6-dichloro-2-methyl-pyrimidine (22. 37 g). CI MS m/e 163, M+ ;'H NMR (300 MHz, CDCl3) delta 2.71 (s, 3 H), 7.25 (s, 1 H). | |
With trichlorophosphate; for 3h;Heating / reflux; | 2-Methyl-4,6-dihydroxypyrimidine (42.0 g.; 333 mmol) was added to phosphoryl chloride (350 mL). The reaction mixture was heated at reflux for three hours. The solvent was removed under reduced pressure until the volume was approximately 100 mL, and the reaction mixture was then poured onto ice (500 mL) and stirred for ten minutes. Dichloromethane (200 mL ) was added, and after shaking, the organic layer was dried with sodium sulfate and evaporated to yield crude 2-methyl-4,6-dichloropyrimidine (41.8 g.; 256 mmol). | |
With trichlorophosphate; at 95℃; for 18h; | Example Bl. {4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2- methyl-phenoxy}-acetic acid. [00127] Step A:; 4,6-Dihydroxy-2-methylpyrimidine 21 (1.03 g, 8.1 mmol) is suspended in 2.5 mL phosphorus oxychloride (27.3 mmol). The mixture is heated to 95C for 18 hours. Upon cooling, the mixture is diluted with dichloromethane (100 mL) and filtered. It is then washed with water, saturated aqueous sodium bicarbonate and brine, then concentrated to yield 4,6-dichloro-2-methylpyrimidine 22 as a white powder. IH-NMR (400MHz, CDCl3) 8 = 7.45 (s, 1H), 2.77 (s, 3H). MS calculated for C5H5Cl2N2 (M+H+) 162.99, found 163.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.8% | Example 1: synthesis of 2-(4-(6-chloro-2-methylpyrimidin-4-yl) piperazin-1-yl) ethanol (Compound 4); 1-(2-hydroxyethyl) piperazine (Compound 3) (16.6g, 127.6mmol)) and 2-methyl-4,6-dichloropyrimidine (Compound 2) (10.4g, 63.8mmol) were mixed with methylene dichloride (80mL) in reaction flask to be stirred for 2.5h at 30C, and then triethylamine (1.8mL) was added with the reaction overnight in thermal insulation. After vacuum filtration, the cake was rinsed by methylene dichloride. The filtrate was vacuum condensed to dry, and then n-hexane (40mL) was added to grow the grains for 1h by stirring. After vacuum filtration, the cake was rinsed by n-hexane (20mL) and dried at 40C to constant weight to give white solid target Compound 4 (14.7g, yield: 89.8%). Element analysis: C11H17ClN4O, Calculated: C, 51.46; H, 6.67; N, 21.82; Found: C, 51.45; H, 6.69; N, 21.82. | |
89.8% | [0138]1-(2-hydroxyethyl)piperazine (Compound 3) (16.6 g, 127.6 mmol)) and 2-methyl-4,6-dichloropyrimidine (Compound 2) (10.4 g, 63.8 mmol) were mixed with methylene dichloride (80 mL) in reaction flask to be stirred for 2.5 h at 30 C., and then triethylamine (1.8 mL) was added with the reaction overnight in thermal insulation. After vacuum filtration, the cake was rinsed by methylene dichloride. The filtrate was vacuum condensed to dry, and then n-hexane (40 mL) was added to grow the grains for 1 h by stirring. After vacuum filtration, the cake was rinsed by n-hexane (20 mL) and dried at 40 C. to constant weight to give white solid target Compound 4 (14.7 g, yield: 89.8%).[0139]Element analysis: C11H17ClN4O, Calculated: C, 51.46; H, 6.67; N, 21.82. Found: C, 51.45; H, 6.69; N, 21.82. | |
85% | In dichloromethane; at 20℃; | General procedure: 4,6-dichloro-2-methylpyrimidine 10a (1 mmol) and corresponding piperazine (2 mmol) were mixed in CH2Cl2 (40 mL) and stirred at room temparature overnight. The mixture was purified by flash chromatography (DCM: MeOH = 20:1) to give the product 1e-g. |
85% | In dichloromethane; at 20℃; | A mixture of 4,6-dichloro-2-methylpyrimidine (162 mg, 1 mmol) and 1-(2-ethanol)-ylpiperazine (260 mg, 2 mmol) was stirred in dichloromethane (40 mL) at room temperature overnight. After the nucleophilic substitution reaction, after TLC monitoring the reaction, The product 1c (218mg) was isolated through a silica gel column, a white solid, melting point: 72 C, The yield was 85% and the purity was 95%. |
83% | To a solution of 4,6-dichloro-2-methylpyrimidine (2.86 g, 17.5 mmol) in 1,4- dioxane (200 niL) was added 2~(piperazin-l-yl)ethanol (1.14 g, 1.08 mmol) and N5N- diisopropylethylamine (12.2 mL, 70 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in EtOAc (150 mL) and washed with saturated NaHCO3 (2 x 50 mL). The organic layer was dried (Na2SO4). The solvent was removed in vacuo to afford the crude product (1.86 g, 83%) as yellow oil. | |
39% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;Heating / reflux; | Example 145 Synthesis of 2-(4-{6-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-2-methyl-pyrimidin-4-yl}-piperazin-1-yl)-ethanol To synthesize the title compound (CLXIX), two intermediate compounds 62 (2-[4-(6-chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol) and 63 (7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine) shown below were used. To synthesize compound 62, to a solution of 4,6-dichloro-2-methyl-pyrimidine (5.0 g, 31 mmol) and 2-piperazin-1-yl-ethanol (2.7 g, 21 mmol) in dioxane (25 mL) was added DIPEA (3.0 mL, 17 mmol). The mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and poured into water. The reaulting aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford compound 62 as a brown liquid (2.1 g, 39%). MS (ESI+): m/z 257. |
39% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 16h;Heating / reflux; | Example 127. 2-[4-(6-Chloro-2-methvl-pyrimidin-4-vl)-piperaziii-l-vll-ethanoϖ71); [0307] To a solution of 4,6-dichloro-2-methyl-pyrimidine (5.0 g, 31 mmol) and 2- piρerazin-1-yl-ethanol (2.7 g, 21 mmol) in dioxane (25 mL) was added DEPEA (3.0 mL, 17 mmol). The mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and poured into water. The resulting aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford the title compound as a brown liquid (2.1 g, 39%). MS (ES+): m/z 257 (M+H)+. |
2-Piperazin-1-yl-ethanol (8.2g, 63.1 mmol) was added to a solution of 4,6-dichloro-2- methylpyrimidine (5.2g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5h. Filtration gave 7C (8.13g) as a white solid | ||
4.08 g | To a solution of 4,6-dichloro-2-methylpyrimidine (3.00 g) in dichloromethane (35 mL) was added 2-(piperazin-1-yl)ethanol (4.51 mL) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture was added triethylamine (0.513 mL) at room temperature, and the reaction mixture was stirred overnight. The resulting solid was collected by filtration, washed with dichloromethane, and dried under reduced pressure to give the title compound (4.08 g). 1H NMR (400 MHz, CDCl3) δ 2.48 (3H, s), 2.55-2.63 (6H, m), 3.63-3.73 (6H, m), 6.34 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | To a suspension of <strong>[6633-61-0]methyl 2-aminothiazole-5-carboxylate</strong> (4.90 g, 31.0 mmol) and NaH (60% dispersion in mineral oil, 1.36 g, 34.1 mmol) in DMF at O0C is added 4,6-dichloro-2-methyl-pyrimidine (5.05 g, 31.0 mmol) in DMF and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer is dried over MgSO4, and concentrated in reduced pressure. The crude product is crystallized from MeOH to give methyl 2-(6-chloro-2-methyl-pyrimidin-4-ylamino)-thiazole-5-carboxylate as a white solid. [0065] To a stirred solution of methyl 2-(6-chloro-2-methyl-pyrimidin-4- ylamino)-thiazole-5-carboxylate (3.97 g, 14.0 mmol) in MeOH is added 4 N NaOH (15 mL) and the mixture is stirred for 12 hours at 6O0C. The reaction mixture is neutralized with 1 N HCl and the resulting precipitate is filtered and washed with MeOH to give 2-(6-chloro-2- methyl-pyrimidin-4-ylamino)-thiazole-5-carboxylic acid in a white solid. [0066] To a solution of 2-(6-chloro-2-methyl-pyrimidin-4-ylamino)-thiazole-5- carboxylic acid (230 mg, 0.85 mmol), N-(3-Amino-4-methyl-phenyl)-3- trifluoromethylbenzamide (250 mg, 0.85 mmol), and diisopropylethylamine (0.59 mL, 3.4 mmol) in DMF is added O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (355 mg, 0.93 mmol), and the mixture is stirred for 12 hours at room temperature. The reaction mixture is diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The crude product is purified by preparative HPLC to give 2-(6-chloro-2- methyl-pyrimidin-4-ylamino)-thiazole-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl- benzoylamino)-phenyl] -amide as a white solid.[0067] To a stirred solution of 2-(6-chloro-2-methyl-pyrimidin-4-ylamino)- thiazole-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (25 EPO <DP n="27"/>mg, 46 mumol) in l,3-dimethyl-2-imidazolidinone (0.2 mL) is added excess 2-piperazin-l-yl- ethanol (100 mg) in l,3-dimethyl-2-imidazolidinone (0.2 mL) and the mixture is stirred for 4 hours at 60 C . The crude product is diluted with DMSO (1 mL) and purified by preparative HPLC to give 2-{6-[4-(2-Hydroxyethyl)-piperazin-l-yl]-2-methylpyrimidin-4-ylamino}- thiazole-5-carboxylic acid [2-methyl-5-(3-trifluoromethylbenzoylamino)-phenyl]-amide in a TFA salt form: 1H NMR 400 MHz (MeOH-d_0 delta 8.26 (s, IH), 8.20 (d, IH), 8.15 (s, IH), 7.90 (d, IH), 7.83 (s, IH), 7.74 (t, IH), 7.55 (d, IH), 7.31 (d, IH), 6.20 (br, IH), 3.93 (dd, 2H), 3.50 (br, 8H), 3.35 (dd, 2H), 2.53 (s, 3H), 2.31 (s, 3H); MS m/z 641.5(M + 1). | |
62.89 g | With sodium hydride; In tetrahydrofuran; N,N-dimethyl acetamide; at -5℃; for 3h; | In a reaction flask, 49.49 g 4,6-dichloro-2-methylpyrimidine (0.303 mol), 40.00 g methyl 2-aminothiazol-5-carboxylic acid (0.253 mol), and 200 ml N,N-dimethylacetamide were charged, the temperature was brought to -5 C. and 18.20 g sodium hydride (0.455 mol) in 90 ml tetrahydrofuran were added dropwise and the reaction mixture was kept under these conditions for about three hours. At the end of the reaction, 250 ml of a solution of hydrochloric acid 2N were added, the temperature was brought to the room value, the formed solid was filtered and washed with water (4×200 ml) and dried in oven under vacuum at a temperature of 55 C. for about eight hours, to give 62.89 g methyl 2-(6-chloro-2-methylpyrimidin-4-yl-amino)thiazol-5-carboxylic acid.1H-NMR (DMSO, 300 MHz): delta 8.13 (1H, s), 6.97 (1H, s), 3.82 (3H, s), 2.59 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In water; | 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-morpholine A mixture of morpholine (2.36 ml, 27.0 mmol) and 4,6-dichloro-2-methyl-pyrimidine (2.0 g, 12.3 mmol) in water (20 ml) was heated at 100 C. for 2 h. The reaction was allowed to cool to room temperature and was diluted with water (20 ml). The resulting precipitate was collected by filtration to give the title compound (1.90 g, 72% yield). |
4.84 g (72%) | In water; | Part A Preparation of 4-Chloro-2-methyl-6-(4-morpholino)pyrimidine by Scheme I, Step (5) A solution of 5.00 g (31.7 mmole) of 4,6-dichloro-2-methylpyrimidine and 6.00 g (68.9 mmole) of morpholine in 50 ml of water was heated on a steam cone for about 18 hours. The mixture was diluted with water and cooled. The white solid was separated by filtration, washed with water and dried to provide 4.84 g (72%) of 4-chloro-2-methyl-6-(4-morpholino)pyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses. |
4.84 g (72%) | In water; | Part A. Preparation of 4-Chloro-2-methyl-6-(4-morpholino)pyrimidine by Scheme I, Step (5) A solution of 5.00 g (31.7 mmole) of 4,6-dichloro-2-methylpyrimidine and 6.00 g (68.9 mmole) of morpholine in 50 ml of water was heated on a steam cone for about 18 hours. The mixture was diluted with water and cooled. The white solid was separated by filtration, washed with water and dried to provide 4.84 g (72%) of 4-chloro-2-methyl-6-(4-morpholino)pyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses. |
In dichloromethane; at -78 - 20℃; | The crude 2-methyl-4,6-dichloropyrimidine (41.8 g.; 256 mmol) was dissolved in dichloromethane (200 mL) and chilled to -78C in an inert atmosphere. Morpholine (48 g.; 550 mol) dissolved in dichloromethane (100 mL) was added slowly. The reaction was allowed to warm to room temperature while stirring overnight. The organic layer was washed with saturated ammonium chloride (2x100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyrimidine (48.5 g.; 227 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 18h;Sealed tube; | Example 2: Synthesis of 6-(4-chlorophcnyl)-2-methyI-N-[(l R)-l , 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine (Compound 138).Step 1 :[00341 ] A pressure vessel was charged with 4,6-dichloro-2-methylpyrimidine (3.87 g, 23.7 mmol, 1.5 eq), (R)-l ,2,3.4-tetrahydronaphthalen-l -amine (2.33 niL, 15.8 mmoL 1.0 eq), DMA (25.0 mL). and D1EA (5.51 mL, 31.7 mmol, 2.0 eq). The reaction vessel was sealed and stirred at room temperature for 18 hours. The reaction was then partitioned between water and EtOAc, and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, dried over Na2S04. and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography (80:20 to 75:25 hexanes/ethyl acetate) to afford (R)-6-chloro-2-methyl-N-( l ,23,4-telrahydronaphthalen- l - yl)pyrimidin-4-amine as a yellow solid (3.82 g, 88% yield). NMR (400 MHz. d6-DMSO): 7.97 (d, 1 H), 7.15 (m, 3H), 6.34 (s: l H), 5.31 (br d, 1 H), 2.76 (m, 2H), 2.36 (s, 3H), 1 .93 (m, 2H), 1.86 (m, 1 H), 1.76 (m, 2H); MS (EI) for C, 5H 16CIN3: 274.1 (ΜΙΤ' ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 90℃; for 15h;Sealed tube; Inert atmosphere; | 00141 ] Example 1 : Synthesis of 3-] l-( {6-|2-chloro-3-(methyloxy)phenyl]-2- mcthylpynmidin-4-yl}amino)ethyl] bcnzcncsulfonaniide (Compound 49) Step 1[00142] A pressure vessel was charged witli 4,6-dichloro-2-methyl-pyrimidine (1 .0g, 6.0 mmol. 1 .0 eq.), 2-(2-chloro-3-methoxyphenyl)-4.4.5,5-tetramethyl-[l ,3,2]dioxaborolane ( 1.6 g, 6.0 mmol, 1 .0 eq.), 1 ,2 DME ( 15 mL), and I Na2COj (2.0 mL). The reaction was purged with nitrogen before adding Pd(dppf)2Cl2CH2Cl2 (400 mg, 0.49 mmol, 0.08 eq.), then sealed and heated to 90 C for 15 hours. The reaction was then cooled to it and partitioned between water and EtOAc. The organic layer was dried with Na2S04 and concentrated under vacuum to give the crude product as a brown oil. The product was purified by Si02 flashchromatography (80:20 hexanes/ethyl acetate) to afford 4-chloro-6-(2-chloro-3- methoxyphenyl)-2-methylpyrimidine as a white solid (878 mg, 55% yield). NMR (400MHz, dfi-DMSO): 7.78 (s, 1 H), 7.46 (t, 1 H), 7.33 (d, 1H), 7.19 (d, 1 H), 3.88 (s, 3 H), 2.64 (s, 3H); MS (EI) for C |2H ioCl2N20: 433.1 (MI-f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 66h; | 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (Intermediate 2) 4,6-dichloro-2-methylpyrimidine(2-1) (137.8 g, 845 mmol), <strong>[7343-34-2]3,5-dimethyl-1H-1,2,4-triazole</strong> (2-2)[0080] (82 g, 845 mmol), and Cs2CO3 (275 g, 845 mmol) were suspended in DMF (1L) and the resulting mixture wasstirred at room temperature for 66 h. The mixture was then poured into water (2L) and stirred for 1 hour. The precipitatewas filtered, washed with water (2x) and dried under vacuum to afford Intermediate 2 as an off-white solid (130 g, 69percent).MS: m/z = 224.2 (M+H). |
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | To a slurry of 4,6-dichloro-2-methylpyrirnidine (1-1) (5.00 g, 30.67 mmol, 1.0 eq.) and cesium carbonate (15.0 g, 46.05 mmol, 1.5 eq.) in DMF (250 mL) at 0 °C under nitrogen was added a solution of 3,5-dimethyl-lH-l,2,4-triazole (2.98 g, 30.67 mmol, 1.0 eq.) in DMF (50 mL) via a dropping funnel over 1 hour. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of water (500 mL) and extracted with ethyl acetate (3 x 400 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-30percent ethyl acetate in hexanes) to afford 4-chloro-6-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-2-methylpyrimidine (1-2) as a white solid. 'Eta NMR (300 MHz, CDC13) delta 7.75 (s, 1H), 2.91 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H). LRMS mlz (M+Ff) 224 found, 224 required. | |
With caesium carbonate; In tetrahydrofuran;Reflux; | Intermediate 2 4-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-6-iodo-2-methylpyrimidine (Intermediate 2) A mixture of 4,6-dichloro-2-methylpyrimidine (505 mg, 3.1 mmol), 3,5-dimethyl-lH-l,2,4- triazole (300 mg, 3.1 mmol) and CS2CO3 (1.54 g, 4.7 mmol) in THF (20 mL) was heated at reflux overnight. The mixture was filtered and the filtrate was concentrated to give 4-chloro-6- (3,5-dimethyl-lH-l,2,4-triazol-l-yl)-2-methylpyrimidine that was used without further purification. MS: m/z = 224.1 (M+H). To a mixture of 4-chloro-6-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-2-methylpyrimidine (2.00 g, 8.9 mmol), KI (4.44 g, 26.8 mmol) was added 57percent aq. HI solution (20 mL, 89.2 mmol). After heating at 70 °C for 5 min, water (20 mL) was added to the reaction mixture. The white solid was filtered, rinsed with water, and dried under vacuum to give Intermediate 2 as a white solid. XH NMR (400 MHz, DMSO) delta 8.06 (s, 1H), 2.78 (s, 3H), 2.62 (s, 3H), 2.30 (s, 3H). MS: m/z = 316.1 (M+H). |
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | 4-chloro-6-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)-2-methylpyrimidine (1-2) To a slurry of 4,6-dichloro-2-methylpyrimidine (1-1) (5.00 g, 30.7 mmol) and cesium carbonate (15.0 g, 46 mmol) in DMF (250 mL) at 0 °C was added a solution of 3,5-dimethyl-lH- 1,2,4- triazole (2.98 g, 30.7 mmol) in DMF (50 mL) via a dropping funnel over 1 h. The reaction was then warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of water (500 mL) and extracted with ethyl acetate (3 x 400 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-30percent EtOAc/hexanes) to afford 4-chloro-6-(3,5-dimethyl-lH- l,2,4-triazol-l-yl)-2-methylpyrimidine (1-2) as a white solid. XH NMR (400 MHz, CDC13) delta 7.75 (s, 1H), 2.91 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H); MS mlz = 224 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; | General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 4 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel (n-hexane:ethyl acetate = 1:1). The purified material was dried in vacuo to afford the corresponding product 5a-g. |
Tags: 4,6-Dichloro-2-methylpyrimidine | Pyrimidines | Chlorides | Organic Building Blocks | Heterocyclic Building Blocks | 1780-26-3
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