* 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.
B) to a 25 ml round-bottom flask is sequentially added in the compound B (1g, 5.29mmol), phosphorus oxychloride (4.82 ml, 52 . 9mmol) and phosphorus pentachloride (1.10g, 5 . 29mmol), then 106 °C reflux overnight, to evaporate the solvent, saturated sodium bicarbonate for adjusting to pH 7 - 8, ethyl acetate (40 ml * 2) extraction, the combined organic layer, sequentially water 80 ml, saturated salt water 80 ml extraction, anhydrous sodium sulfate drying. Residues rapidly through the silica gel column chromatography purification, using petroleum ether/ethyl acetate (V/V=8:1) elution, get compound C 0.96g, is a white solid, yield 80percent.
49%
With triethanolamine; trichlorophosphate In water; toluene
4,6-Dichloro-2-pyridin-2-yl-pyrimidine POCl3 (2.7 ml, 28.97 mmol) was added dropwise to a solution of 2-pyridin-2-yl-pyrimidine-4,6-diol 140 (532 mg, 2.81 mmol) in toluene (3.7 ml) at 0° C. TEA (1.57 ml, 11.25 mmol) was added dropwise and the mixture was allowed to warm to room temperature before being heated at 110° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was quenched by the addition of ice/water (10 ml). The aqueous phase was extracted with EtOAc (*3). The combined organic phases were washed with NaHCO3 and water, dried (Na2SO4) and concentrated in vacuo to give the title compound (310 mg, 49percent).
Reference：
[1] Patent: CN106608869, 2017, A, . Location in patent: Paragraph 0104; 0105; 0107
[2] Patent: US2012/202806, 2012, A1,
[3] Patent: US6372751, 2002, B1, . Location in patent: Example Pr3
6-Chloro-2-pyridin-2-yl-pyrimidin-4-ylamine NH4OH (35percent solution in water, 2.0 ml, 18.58 mmol) was added to a solution of 4,6-dichloro-2-pyridin-2-yl-pyrimidine (210 mg, 0.93 mmol) in EtOH (2 ml) in a microwave tube and the mixture was heated at 100° C. for 30 min in the microwave. The reaction mixture was concentrated in vacuo and the resulting residue was purified by trituration from iso-propyl alcohol to give the title compound (135 mg, 70percent).
C. In a similar manner, the following compounds of formula (H) are made: ... 2-(4-(dimethylamino)phenyl)-4,6-dichloropyrimidine; 2-(4-(aminocarbonyl)phenyl)-4,6-dichloropyrimidine; 2-(1-(benzyloxycarbonyl)piperidin-4-yl)-4,6-dichloropyrimidine; 2-(1-ethylpiperidin-4-yl)-4,6-dichloropyrimidine; 2-(pyridin-2-yl)-4,6-dichloropyrimidine; 2-(imidazolin-2-yl)-4,6-dichloropyrimidine; and 2-(piperidin-1-yl)methyl-4,6-dichloropyrimidine.
3
[ 10235-65-1 ]
N,N-dimethyl<6-ethylthio-2-(pyridin-2'-yl)pyrimidin-4-yl>amine[ No CAS ]
With phosphorus pentachloride; trichlorophosphate; at 106℃;
B) to a 25 ml round-bottom flask is sequentially added in the compound B (1g, 5.29mmol), phosphorus oxychloride (4.82 ml, 52 . 9mmol) and phosphorus pentachloride (1.10g, 5 . 29mmol), then 106 C reflux overnight, to evaporate the solvent, saturated sodium bicarbonate for adjusting to pH 7 - 8, ethyl acetate (40 ml * 2) extraction, the combined organic layer, sequentially water 80 ml, saturated salt water 80 ml extraction, anhydrous sodium sulfate drying. Residues rapidly through the silica gel column chromatography purification, using petroleum ether/ethyl acetate (V/V=8:1) elution, get compound C 0.96g, is a white solid, yield 80%.
49%
With triethanolamine; trichlorophosphate; In water; toluene;
4,6-Dichloro-2-pyridin-2-yl-pyrimidine POCl3 (2.7 ml, 28.97 mmol) was added dropwise to a solution of 2-pyridin-2-yl-pyrimidine-4,6-diol 140 (532 mg, 2.81 mmol) in toluene (3.7 ml) at 0 C. TEA (1.57 ml, 11.25 mmol) was added dropwise and the mixture was allowed to warm to room temperature before being heated at 110 C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was quenched by the addition of ice/water (10 ml). The aqueous phase was extracted with EtOAc (*3). The combined organic phases were washed with NaHCO3 and water, dried (Na2SO4) and concentrated in vacuo to give the title compound (310 mg, 49%).
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 90℃; for 1h;Inert atmosphere; Microwave radiation;
-Chloro-6-[5-(3-methoxy-phenyl)-pyridin-3-yl]-2-pyridin-2-yl-pyrimidine A solution of 5-(3-methoxy-phenyl)-pyridine boronic acid hydrochloride (Int. D) (1 eq, 59 mg) in DME (1 ml) and 2M sodium carbonate (0.4 ml) is treated with 4,6-dichloro- 2-pyridin-2-yl-pyrimidine (Int. C) (1 eq, 50 mg) and placed under an atmosphere of argon. PdCl2(dppf).DCM (0.1 eq. 16 mg) is added and the reaction mixture is heated using microwave radiation at 90 C for 1 h. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgStheta4) and concentrated in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute C18, 0-100% acetonitrile in water - 0.1% TFA) and the appropriate fractions are combined and concentrated in <n="44"/>vacuo. The residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+ = 375/377.
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 90℃; for 1.5h;Inert atmosphere; Microwave radiation;
A solution of (4-Isopropylpiperazin-l-yl)(4-(5-(4,4,5,5-tetramethyl-[l,3,2]- dioxaborolan-2-yl)pyridin-3-yl)-phenyl)-methanone (Int. I) (1.5 eq, 402 mg) in DME (1 ml) and 2M sodium carbonate (0.62 ml) is treated with 4,6-dichloro-2-pyridin-2-yl- pyrimidine (Int. C) (1 eq, 139 mg) and placed under an atmosphere of argon. PdCl2(dppf).DCM (0.1 eq. 45 mg) is added and the reaction mixture is heated using microwave radiation at 900C for 90 minutes. After cooling to room temperature, the mixture is partitioned between DCM/water and the organic portion is separated, washed with brine, dried (MgSCM) and concentrated in vacuo. The crude residue is purified by chromatography on silica eluting with 0-10 % MeOH in DCM to afford the title compound [M+H]+ = 499/501 as a solid.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;
To a solution of <strong>[10235-65-1]4,6-dichloro-2-(2-pyridinyl)pyrimidine</strong> (500 mg, 2.212 mmol) in 1 ,4-Dioxane (5 mL), was added DIPEA (1 .159 mL, 6.64 mmol) and ethyl beta-alaninate hydrochloride (374 mg, 2.433 mmol) and the reaction heated in a Biotage microwave at 80 C for 2 h. A further portion of ethyl b-alaninate hydrochloride (34.0 mg, 0.221 mmol) was added and the reaction mixture heated in a Biotage microwave at 80 C for 2 h in total. The reaction mixture was then partitioned between DCM and water. The aqueous layers were re-extracted, the organics were combined, passed through a hydrophobic frit and the solvent removed by vacuum to give a brown oil (688mg). The product was left under high vacuum overnight to give ethyl A/-[6-chloro-2-(2-pyridinyl)-4-pyrimidinyl]-p-alaninate as a brown solid (533mg, 79%).LCMS (Method A): rt = 0.69 min, MH+ = 307.06
Sodium Hydride (31 .8 mg, 0.796 mmol) was added to DMF (1 mL), followed by 3,4-dihydro-1 (2H)- isoquinolinone (107 mg, 0.730 mmol). The resulting suspension was stirred at r.t. for 5 min, then 4,6- dichloro-2-(2-pyridinyl)pyrimidine (150 mg, 0.664 mmol) was added and resulting mixture was stirred at r.t. for 45 min.The mixture was partitioned between EtOAc and water then the aqueous layer extracted with DCM three times. The organic layers were combined, filtered throught a phase separator and volatiles removed under reduced pressure to afford 212 mg of a white-brown powder.The crude material was purified by column chromatography, eluting with a 0 to 100% EtOAc in cyclohexane, to give the title compound, 121 mg (54%) as an off white powder.LCMS (Method A) Rt 1 .05 min, MH+=337.0
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere; Microwave irradiation;
Tetrakis(triphenylphosphine)palladium (109.0 mg, 0.09 mmol) was added to a suspension of 1 - benzothien-2-ylboronic acid (201 .0 mg, 1 .13 mmol), <strong>[10235-65-1]4,6-dichloro-2-(2-pyridinyl)pyrimidine</strong> (213.0 mg, 0.94 mmol) and Cs2C03 (614.0 mg, 1 .88 mmol) in 1 ,4-dioxane (3 mL) and water (0.75 mL). The mixture was degassed with nitrogen for 30 min and heated to 100 C in a Biotage initiator microwave for 0.5 hr. The reaction mixture was concentrated under reduced pressure and the product purified by column chromatography, eluting with 0-40% cyclohexane-EtOAc. The resulting material was dissolved with DCM (10 mL), then thiourea silica (1 .71 g) was added. After 1 hr of stirring at r.t., the silica was filtered off using a hydrophobic frit, under vacuum. The filtrate was concentrated under reduced pressure to give the title compound as a colourless oil, 167.0 mg (55%).LCMS (Method A): Rt = 1 .18 min, MH+ 324.0.
Intermediate 134: 4-chloro-2-(2-pyridi vdro-2-naphthalenyloxy)pyrimidine1 ,2,3,4-tetrahydro-2-naphthalenol (164.0 mg, 1 .1 1 mmol) was added to a cold (0C) solution of sodium hydride (48.7 mg, 1 .22 mmol) in A/,A/-dimethylformamide (10 ml_). After 30 min of stirring under nitrogen at 0 C, <strong>[10235-65-1]4,6-dichloro-2-(2-pyridinyl)pyrimidine</strong> (250.0 mg, 1 .1 1 mmol) was added. After 16 hr of stirring at r.t., the reaction mixture was cooled at 0 C and sodium hydride (24.0 mg, 0.60 mmol) was added. After 2 hr of stirring under nitrogen at room temperature, water (50 ml_) was added to the reaction mixture, followed by EtOAc (50 ml_). The aqueous layer was further extracted with EtOAc (50 ml_). The combined organic layers was dried through a hydrophobic frit and concentrated to dryness to give a brown oil. The crude was purified by column chromatography eluting with a gradient from 0-50% of EtOAc-cyclohexane to give the impure product (278.0 mg). 168 mg of the impure product was dissolved in 1 :1 MeOH:DMSO (2 mL) and purified by MDAP (Method E). The solvent was evaporated in vacuo to give the title compound as a yellow oil, 64.2 mg (17%).LCMS (Method A): Rt = 1 .25 min, MH+ 338.1 .
6-Chloro-2-pyridin-2-yl-pyrimidin-4-ylamine NH4OH (35% solution in water, 2.0 ml, 18.58 mmol) was added to a solution of 4,6-dichloro-2-pyridin-2-yl-pyrimidine (210 mg, 0.93 mmol) in EtOH (2 ml) in a microwave tube and the mixture was heated at 100 C. for 30 min in the microwave. The reaction mixture was concentrated in vacuo and the resulting residue was purified by trituration from iso-propyl alcohol to give the title compound (135 mg, 70%).
Ethyl N-[6-chloro-2-(2-pyridinyl)-4-pyrimidinyl]-beta-alaninate Hunig's base (11.94 mL, 68.3 mmol) was added over 1 min to a stirred suspension of 4,6-dichloro-2-(pyridin-2-yl)pyrimidine (5.15 g, 22.78 mmol) and ethyl 3-aminopropanoate hydrochloride (3.85 g, 25.06 mmol) in 1,4-Dioxane (55 mL) at rt under N2. The resultant suspension was heated at 60 C for 6 h by which time a solution had formed and then allowed to stand at rt for 72 h. The solution was then reheated to 60 C for 3 h. Upon cooling, the solvent was evaporated under reduced pressure to give an orange oil. The oil was dissolved in CH2Cl2 (400 mL) and then washed with sat. aq. NaHCO3 (2 x 100 mL), brine (100 mL) and then passed through a hydrophobic frit. The solution was evaporated under reduced pressure to give an orange oil which was then dried under high vaccum at 40 C for 12 h to give the title compound as an orange solid (6.94 g, 99%).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 4h;
C) compound C (0.83g, 3 . 67mmol) dissolved in 5 ml dioxane, adding 3 - aminopropionitrile (0.33 ml, 4 . 41mmol) and N, N - diisopropyl ethylamine (0.13 ml, 7 . 34mmol), 80 C reaction 4 hours, cooling to room temperature, ethyl acetate (40 ml * 2) extraction, the combined organic layer, sequentially water 80 ml, saturated salt water 80 ml extraction, anhydrous sodium sulfate drying. Residues rapidly through the silica gel column chromatography purification, using petroleum ether/ethyl acetate (V/V=2:1) elution, get compound D 0.29g, is a white solid, yield 30%.
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