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CAS No. : | 5305-59-9 | MDL No. : | MFCD00053576 |
Formula : | C4H4ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DUKKRSPKJMHASP-UHFFFAOYSA-N |
M.W : | 129.55 | Pubchem ID : | 238012 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.45 |
TPSA : | 51.8 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.51 cm/s |
Log Po/w (iLOGP) : | 1.26 |
Log Po/w (XLOGP3) : | 0.82 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | -0.05 |
Log Po/w (SILICOS-IT) : | 0.98 |
Consensus Log Po/w : | 0.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.71 |
Solubility : | 2.5 mg/ml ; 0.0193 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.49 |
Solubility : | 4.19 mg/ml ; 0.0324 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.87 |
Solubility : | 1.74 mg/ml ; 0.0135 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
88% | With ammonia In isopropyl alcohol at 25℃; for 1 h; | General procedure: To a suspension of 4,6-dichloropyrimidine 53 (3.0 g, 20 mmol) in isopropanol (40 mL) was added appropriate amine at such a rate that the internal temperature did not rise above 40 °C. After completion of the addition, the reaction mixture was stirred for 1 h at 25 °C. Water (30 mL) was added, and the resulting suspensio nwas cooled in an ice bath to 0 °C. The precipitated product was filtered off and washed with cold isopropanol/water (2:1, 50 mL) and water. The collected material was dried in vacuo to afford the title compounds. |
81% | at 30℃; for 15 h; | A mixture of 4, 6-dichloropyrimidine (20 g, 0.14 mol) and NH4OH (200 mL) was heated at 30 °C for 15 hours with stirring. The resulting precipitate was collected via filtration, and the filter cake was washed with water (100 mL). The resultant solid was purified by silica gel column chromatography, eluting with EtOAc to give the desired product as a white solid ( 14 g, 81 percent yield) . LCMS (ESI) m/z : 130.1 [M+H+] . |
80% | at 100℃; Sealed tube | Step 1: 6-chloropyrimidin-4-amine Intermediate 14 4,6-Dichloropyrimidine (7.5 g, 50 mmol) was suspended in ammonium hydroxide (64 mL) in a sealed tube. The tube was sealed and heated at 100° C. in an oil bath overnight. The reaction mixture was cooled to rt. The solid was removed by filtration, washed with water and dried under high vacuum to afford 6-chloropyrimidin-4-amine (5.23 g, 80percent) LC-MS (AA) ES+ 130. |
77% | With ammonia In ethanol at 80℃; for 1.5 h; | Compound 1-1-1 (10 g, 67.1 mmol) was disposed into a stainless steel vessel, and EtOH saturated with NH3 (g) in advance (40 mL) was added. The reaction mixture was heated to 80° C., reacted for 1.5 h, and then cooled down to r.t., concentrated in vacuo and stripped to give a crude product which was triturated with water and filtered to afford compound 8-6 (6.7 g, Yield 77percent). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.20 (s, 1H), 7.22 (s, 2H), 6.45 (s, 1H) |
71% | With ammonia In ethanol at 100℃; for 1.5 h; In a stainless pressure vessel | 4, 6-Dichloropyrimidine (10.0 g, 67. 1 mmol) in ammonia saturated ethanol (40 mL) was heated to 100°C in a stainless steel pressure vessel for 1.5 h. Removal of the solvent in vacuo gave a solid which was triturated with water (270 mL) then filtered to give 6-amino-4-chloropyrimidine (1) (6. 18 g, 71percent) as white crystals. APCI-MS Found [M + H] + = 130, 132. |
67% | With ammonia In methanol at 85℃; for 16 h; | 4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +. |
67% | With ammonia In methanol at 85℃; for 16 h; | 4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogen iodide; sodium iodide In water at 70℃; for 0.5 h; | Description 93; 6-IodoPvrimidin-4-amine-",; A mixture of 4-amino-6-chloropyrimidine [WO-A-0245652] (1. 00 g, 7.72 mmol), sodium iodide (5.79 g, 38.6 mmol) and 40percent HI (20 ml) were heated at 70°C for 30 min, then allowed to cool to room temperature. The precipitate was removed by filtration, and partitioned between dichloromethane and sat. NaHCO3. The organic layer was separated, and dried over Na2SO4, filtered, and evaporated to give the title compound (1.2 g, 70percent). 1H NMR (400 MHz, DMSO-d6) 6.89 (1 H, s), 7.04 (2 H, br s), 8.04 (1 H, s). |
65% | With hydrogen iodide In water at 0 - 20℃; for 18.5 h; | 6-Chloropyrimidin-4-ylamine (450 mg) was added in portions to HI (57percent wt. aq. , 20 mL) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C and then at ambient temperature for 18 hours. The reaction mixture was treated with NaHC03 (sat. aq. ) until pH8 was achieved and then the product extracted with EtOAc (2 x 30 mL). The combined organics were washed with NaOH (2M, aq. ), dried (MgS04), filtered and then concentrated. The crude product was used directly without further purification (500 mg, 65percent); lH NMR (CDCl3) ; 6.90 (s, 1H), 7.03 (s, 2H), 8.05 (s, 1H); MS m/e MHs 221. |
47% | With hydrogen iodide In water at 0 - 20℃; for 3 h; | General procedure: 2-Amino-4-chloropyrimidine (55) (13.0g, 100mmol) was added to a 57wt.percent aqueous solution of hydriodic acid (115ml, 1.00mol) at 0°C and the mixture was stirred at room temperature for 3h. The mixture was cooled to 0°C and the resulting precipitate was removed by filtration and taken up in cold 5N aqueous Na2CO3 (200ml). The mixture was extracted with EtOAc (3×500ml) and the combined organic layers were concentrated under reduced pressure to deliver 2-amino-4-iodopyrimidine (21.1g, 95.0mmol, 95percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h; | The 400mg4-amino-6-chloro-pyrimidine, 1.51g (1.5equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, adding 405 μ L (1.5equiv) morpholine, heating to 100 °C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/50 elution, to get the yellow solid 245 mg, yield 44percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | at 125℃; for 0.333333 h; Microwave irradiation | Step A: 6-(pyridin-3-yl)pyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3- ylboronic acid (0.384 g, 3.13 mmol), Na2C03 (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water. The mixture was heated in the microwave synthesizer at 125 °C for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60 percent ethyl acetate in hexanes, then 5-25 percent 9: 1methanol: ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4- amine (0.17 g, 0.987 mmol, 40 percent yield) as an off-white solid. LCMS R.T. = 0.31; [M+H]+ = 173.11. |
40% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 125℃; for 0.333333 h; Microwave irradiation | A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), pyridin-3-ylboronic acid (0.384 g, 3.13 mmol),Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin a mixture ofDME/EtOH/water. The mixture was heated inthe microwave synthesizer at 125° C. for 20 min and concentrated.The residue was purified by silica gel chromatography(10-60percent ethyl acetate in hexanes, then 5-25percent 9: I methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3yl)pyrimidin-4-amine (0.17 g, 0.987 mmol, 40percent yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With Iodine monochloride In N,N-dimethyl-formamide at 45℃; | To a solution of 3.03 g (23.39 mmol) of 6-chloropyrimidin-4-amine in 60 mL of dimethylformamide was added dropwise a solution of iodine monochloride (2.34 mL, 46.70 mmol) in 40 mL of dimethylformamide. Then the mixture was stirred at 45 °C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a 4percent aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0percent to 20percent, methanol-dichloromethane) to obtain 4.28 g (72percent yield) of the title compound. LRMS (m/z): 256 (M+1 )+. |
47% | With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; for 8 h; | To a solution of 6-chloropyri.midin-4-amme (1 ,29 g, 10 mmol) in DMF (8 mL) was added N-iodosuccinimide (2.25 g, 10 mmol) in one portion to give an orange mixture. The reaction mixture was stirred at 100 °C for 8 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL), and the resulted mixture was washed successively with a mixture of saturated \a --S;O; aqueous solution and saturated NaHC03 aqueous solution (1/2 (v/v), 100 mL x 3), water (150 mL x 3) and brine (100 mL). Then the organic phase was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (1.20 g, yield 47.0percent). MS (ESI, pos. ion) m/z: 255.8 [M+H]+; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-Λ) δ (ppm): 8.12 (s, 1H). |
46.97% | With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; for 8 h; | The compound 6-chloropyrimidine-4-amino (1.29 g, 10 mmol) was dissolved in DMF (8 mL), and thenNIS (2.25 g, 10 mmol) was added and the reaction mixture was stirred at 100 ° C for 8 hours, then cooled to room temperature and concentrated under reduced pressureShrink The residue was dissolved in EtOAc (300 mL) and the resulting mixture was washed with a mixture of saturated aqueous Na2S204 / saturated aqueous NaHCO3 (v / v, 1/2, 100 mL x 3) followed by water (150 mL x 3) and brine (100 mL)The resulting organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE /EtOAc (v / v) = 5/1) to give the title compound as a white solid (1.20 g, 46.97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In toluene; for 24h;Heating; | General procedure: To a solution of 6-chloropyrimidin-4-amine intoluene was added substituted amine (2.5 eq). The mixture was heatedat 105 C for 24 h and concentrated in vacuo. The residue was purifiedby flash column chromatography. |
44% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 400mg<strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong>, 1.51g (1.5equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, adding 405 mu L (1.5equiv) morpholine, heating to 100 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/50 elution, to get the yellow solid 245 mg, yield 44%. |
In water; toluene; | EXAMPLE 22 A mixture of 8.0 g (0.062 mole) of <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> and 10.8 g (0.124 mole) of morpholine in 100 ml of toluene was heated at its reflux temperature for 20 hours, and was then cooled. The solid was separated by filtration, washed with toluene, and slurried in 100 ml of water followed by filtration. Recrystallization from water provided yellow crystals of 4-amino-6-(4-morpholino)pyrimidine, m.p. 198-201 C. Analysis: Calculated for C8 H12 N4 O: %C,53.3; %H,6.7; %N,31.1; Found: %C,53.5; %H,6.5; %N,31.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,4-dioxane; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,4-dioxane; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; In tetrahydrofuran; at 20℃; | The Preparation of Compound 8: Compound 8A (20 g, 0.15 mol) and dimethylaminopyridine (DMAP, 1.9 g, 15.4 mmol) were added to tetrahydrofuran (THF, 750 mL) and stirred. To the solution di-tert-butyl dicarbonate ((Boc)2O, 75 g, 0.34 mol) was added dropwise. Then the reaction mixture was stirred at room temperature overnight. The reaction was monitored via TLC (PE/EA=3:1). After the reaction was completed, the reaction mixture was concentrated and resuspended in a mixture solvent PE/EA (10:1, 200 mL), filtrated to obtain a purified compound 8 (50 g, 100%) as a white solid. |
100% | With dmap; In tetrahydrofuran; at 20℃; | Compound 8A (20 g, 0.15 mol) and dimethylaminopyridine (DMAP, 1.9 g, 15.4 mmol) were added to tetrahydrofuran (THF, 750 mL) and stirred. To the solution di-tert-butyl dicarbonate ((Boc)2O, 75 g, 0.34 mol) was added dropwise. Then the reaction mixture was stirred at room temperature overnight. The reaction was monitored via TLC (PE/EA=3:1). After the reaction was completed, the reaction mixture was concentrated and resuspended in a mixture solvent PE/EA (10:1, 200 mL), filtrated to obtain a purified compound 8 (50 g, 100%) as a white solid. |
90% | With dmap; In tetrahydrofuran; at 20℃; for 6h; | Method 2: Example 93 :l-{6-[2-(2,6-Dichlorophenyl)-2H^yrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-ethanol Step 1 :(6-Chloropyrimidin-4-yl)-Z>/s-carbamic acid tert-butyi ester<strong>[5305-59-9]4-Amino-6-chloropyrimidine</strong> (10.0 g, 77.2 mmol) was suspended in THF (450 mL) and di-ferf-butyl dicarbonate (36.4 g, 162 mmol) was added, followed by DMAP (471 mg, 3.86 mmol). The resultant yellow solution was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the residue was dried under reduced pressure overnight. This was purified by silica gel flash chromatography (0-30% ethyl acetate in cyclohexane) to afford the title compound as a white solid (22.9 g, 90% yield). NMR (300 MHz, CDCl 3 ): 5 8.66 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 1.55 (s, 18H). |
60% | With dmap; In acetonitrile; at 20℃; for 72h; | 6-Chloropyrimidin-4-amine (4.1 g, 31.6 mmo1)was suspended in acetonitrile. DMAP (0.966 g, 7.91 mmo1) anddi-tert-butyl dicarbonate (14.74 g, 67.5 mmo1) were addedand the mixture was stirred at rt for 3 days. The solvent wasevaporated and the residue was purified by silica gel using0-15% ethyl acetate in hexanes to give 6[bis(tert-butoxycarbony1)amino ]-4-ch1oropyrimidine as a white solid (6.27 g,19.01 mmo1,60%). |
1.13 g | With dmap; In acetonitrile; at 10 - 35℃; for 72h; | To a solution of 6-chloropyrimidin-4-amine (500 mg) and N,N-dimethylaminopyridine (47.2 mg) in acetonitrile (5.0 mL) was added di-tert-butyl dicarbonate (2.24 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 days, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.13 g). MS (ESI+) : [M+H]+330.2 |
With dmap; In tetrahydrofuran; at 20℃; for 16h; | Synthesis of tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2) To a stirred solution of 6-chloropyrimidin-4-amine (1, 1 g, 7.75 mmol) in tetrahydrofuran (20 mL), 4-(dimethylamino)pyridine (0.047 g, 0.387 mmol) and di-tert-butyl dicarbonate (3.55 g, 16.27 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2) which was used for the next step without further purification. Yield: 1.3 g, 51%; MS (ESI) m/z 330 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonia; In isopropyl alcohol; at 25℃; for 1h; | General procedure: To a suspension of 4,6-dichloropyrimidine 53 (3.0 g, 20 mmol) in isopropanol (40 mL) was added appropriate amine at such a rate that the internal temperature did not rise above 40 C. After completion of the addition, the reaction mixture was stirred for 1 h at 25 C. Water (30 mL) was added, and the resulting suspensio nwas cooled in an ice bath to 0 C. The precipitated product was filtered off and washed with cold isopropanol/water (2:1, 50 mL) and water. The collected material was dried in vacuo to afford the title compounds. |
81% | With ammonium hydroxide; at 30℃; for 15h; | A mixture of 4, 6-dichloropyrimidine (20 g, 0.14 mol) and NH4OH (200 mL) was heated at 30 C for 15 hours with stirring. The resulting precipitate was collected via filtration, and the filter cake was washed with water (100 mL). The resultant solid was purified by silica gel column chromatography, eluting with EtOAc to give the desired product as a white solid ( 14 g, 81 % yield) . LCMS (ESI) m/z : 130.1 [M+H+] . |
80% | With ammonium hydroxide; at 100℃;Sealed tube; | Step 1: 6-chloropyrimidin-4-amine Intermediate 14 4,6-Dichloropyrimidine (7.5 g, 50 mmol) was suspended in ammonium hydroxide (64 mL) in a sealed tube. The tube was sealed and heated at 100 C. in an oil bath overnight. The reaction mixture was cooled to rt. The solid was removed by filtration, washed with water and dried under high vacuum to afford 6-chloropyrimidin-4-amine (5.23 g, 80%) LC-MS (AA) ES+ 130. |
77% | With ammonia; In ethanol; at 80℃; for 1.5h; | Compound 1-1-1 (10 g, 67.1 mmol) was disposed into a stainless steel vessel, and EtOH saturated with NH3 (g) in advance (40 mL) was added. The reaction mixture was heated to 80 C., reacted for 1.5 h, and then cooled down to r.t., concentrated in vacuo and stripped to give a crude product which was triturated with water and filtered to afford compound 8-6 (6.7 g, Yield 77%). 1H NMR (400 MHz, DMSO-d6): delta ppm 8.20 (s, 1H), 7.22 (s, 2H), 6.45 (s, 1H) |
71% | With ammonia; In ethanol; at 100℃; for 1.5h;In a stainless pressure vessel; | 4, 6-Dichloropyrimidine (10.0 g, 67. 1 mmol) in ammonia saturated ethanol (40 mL) was heated to 100C in a stainless steel pressure vessel for 1.5 h. Removal of the solvent in vacuo gave a solid which was triturated with water (270 mL) then filtered to give 6-amino-4-chloropyrimidine (1) (6. 18 g, 71%) as white crystals. APCI-MS Found [M + H] + = 130, 132. |
67% | With ammonia; In methanol; at 85℃; for 16h; | 4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67% yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +. |
With ammonia; In water; isopropyl alcohol; at 55℃; | A solution of 0.46 ml (2.2 mMol) hexamethyldistannane in toluene is added dropwise to a stirred mixture of 343 mg (2 mMol) N-(6-chloro-pyrimidin-4-yl)-acetamide (obtainable from4,6-dichloropyrimidine by reaction with NH3 in water and isopropanol at 55 0C and acetylation of the resulting 4-amino-6-chloro-pyrimidine with acetanhydride in the presence of LiCI at 1100C) and 92 mg (0.08 mMol) tetrakis(triphenylphosphine)palladium in 20 ml toluene under an argon atmosphere. The reaction mixture is then heated at 120 0C for 6 h. After cooling to rt, the solvent is evaporated off under reduced pressure to give the title compound as a brown residue which is used in the next Step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In toluene;Heating / reflux; | 4-amino-6-hydroxy-2-thiopyrimidine was treated with Raney nickel (RaNi) in water and ammonia and heated to reflux for 2 h. Purification afforded the 4-amino-6-hydroxypyrimidine, which was combined with phosphorus oxychloride and N,N-diethylaniline and heated at reflux for 4 h to give 4-amino-6-chloropyrimidine. This product was combined with diphenylborinic acid ethanolamine ester in toluene with diisopropylethylamine and heated to reflux overnight to produce the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.6% | With sodium hydride; In dimethyl sulfoxide; at 20 - 100℃; for 4.5h; | Sodium hydride (200 mg, 5.00 mmol) was suspended in dimethyl sulfoxide (8 ml); while stirring at room temperature, <strong>[2380-86-1]6-hydroxyindole</strong> (666 mg, 5.00 mmol) and 6-amino-4-chloropyrimidine (518 mg, 4.00 mmol) were added thereto one by one; and the reaction mixture was stirred at 60 C for 2 hours, at 80 C for 1 hour, and at 100 C for 1.5 hours. After cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane: ethyl acetate = 1: 1, ethyl acetate, then ethyl acetate: methanol = 98: 2); the obtained crystals were suspended in ethyl acetate (50 ml) and stirred at room temperature overnight, filtered off, washed with diethyl ether, and dried to yield the title compound (322 mg, 1.42 mmol, 35.6%) as pale yellow crystals.1H-NMR Spectrum (DMSO-d6) delta (ppm) : 5.56 (1H, s), 6.44 (1H, s), 6.72 (2H, s), 6.76 (1H, d, J=8.4 Hz), 7.12 (1H, s), 7.34 (1H, s), 7.55 (1H, d, J=8.4 Hz), 8.05 (1H, s), 11.13 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogen iodide; sodium iodide; In water; at 70℃; for 0.5h; | Description 93; 6-IodoPvrimidin-4-amine-«,; A mixture of 4-amino-6-chloropyrimidine [WO-A-0245652] (1. 00 g, 7.72 mmol), sodium iodide (5.79 g, 38.6 mmol) and 40% HI (20 ml) were heated at 70C for 30 min, then allowed to cool to room temperature. The precipitate was removed by filtration, and partitioned between dichloromethane and sat. NaHCO3. The organic layer was separated, and dried over Na2SO4, filtered, and evaporated to give the title compound (1.2 g, 70%). 1H NMR (400 MHz, DMSO-d6) 6.89 (1 H, s), 7.04 (2 H, br s), 8.04 (1 H, s). |
65% | With hydrogen iodide; In water; at 0 - 20℃; for 18.5h; | 6-Chloropyrimidin-4-ylamine (450 mg) was added in portions to HI (57% wt. aq. , 20 mL) at 0 C. The reaction mixture was stirred for 30 minutes at 0 C and then at ambient temperature for 18 hours. The reaction mixture was treated with NaHC03 (sat. aq. ) until pH8 was achieved and then the product extracted with EtOAc (2 x 30 mL). The combined organics were washed with NaOH (2M, aq. ), dried (MgS04), filtered and then concentrated. The crude product was used directly without further purification (500 mg, 65%); lH NMR (CDCl3) ; 6.90 (s, 1H), 7.03 (s, 2H), 8.05 (s, 1H); MS m/e MHs 221. |
47% | With hydrogen iodide; In water; at 0 - 20℃; for 3.0h; | General procedure: 2-Amino-4-chloropyrimidine (55) (13.0g, 100mmol) was added to a 57wt.% aqueous solution of hydriodic acid (115ml, 1.00mol) at 0C and the mixture was stirred at room temperature for 3h. The mixture was cooled to 0C and the resulting precipitate was removed by filtration and taken up in cold 5N aqueous Na2CO3 (200ml). The mixture was extracted with EtOAc (3×500ml) and the combined organic layers were concentrated under reduced pressure to deliver 2-amino-4-iodopyrimidine (21.1g, 95.0mmol, 95% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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9% | In 1,3-dimethyl-2-imidazolidinone; at 130℃; for 6.5h; | A solution of 6-amino-4-chloropyrimidine (1) (0.504 g, 3.89 mmol) and N- <strong>[6092-47-3]chloroacetylurethane</strong> (0.770 g, 4.65 mmol) in 1, 3-dimethyl-2-imidazolidinone (10 mL) was heated to 130C under nitrogen for 3 h. N-Chloroacetylurethane (0.770 g, 4.65 mmol) was added and the mixture was heated to 130C under nitrogen for a further 3.5 h. The black oily solution was poured onto ice (200 g) and the aqueous solution was extracted with ethyl acetate (3 x 250 mL). The organic fractions were combined, removal of solvent in vacuo gave an oily solid which was triturated with ether. Filtration of the solid and washing with ether gave urethane (2) (88 mg, 9%) as a solid. APCI-MS Found [M + H] + = 241,243. |
Yield | Reaction Conditions | Operation in experiment |
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88.5% | With potassium hydroxide; potassium iodide; In 1-methyl-pyrrolidin-2-one; at 130℃; for 13h; | Step 112.4: 6-[(6-Aminopyrimidin-4-yl)oxy1-Lambda/-[4-(4-morpholin-4-ylcvclohexyl)phenyll-1- naphthamide; To a 100-mL flask, charge 6-hydroxy-/V-[4-(4-morpholin-4-ylcyclohexyl)phenyl]-1- naphthamide (2.34 g, 5.9 mmol), <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (0.80 g, 6.2 mmol), potassium hydroxide (0.418 g, 7.45 mmol), potassium iodide (0.979 g, 5.9 mmol), and N- methylpyrrolidone (45 mL). Hold at 135 0C for 13 h. Cool to 50 and slowly add water (90 mL), and hold at 50 0C for 30 min. Cool to room temperature filter and rinse with water. Dry at 65 0C in a vacuum oven to obtain crude 6~[(6-aminopyrimidin-4-yl)oxy]-Lambda/-[4-(4-morpholin- 4-ylcyclohexyl)phenyl]-1-naphthamide 2.19 g (Y. 71%, purity.88.5%). The crude product was purified by chromatography on silica gel using CH2CI2 / MeOH / Et3N = 95 / 5 / 1. MS. [M+ 1]+ = 524 |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 4-amino-6-chloropyrimidine; N,N-diethylaniline With hydrogenchloride In water; isopropyl alcohol at 90℃; for 36h; Stage #2: With potassium carbonate In water; ethyl acetate; isopropyl alcohol at 20℃; | 105.A A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 4-amino-N,N-diethylaniline (0.82mL, 5 mmol), 2-propanol (5 mL) and HCl cone. (0.225 mL, ~2.5 mmol) is shaken for 36 h at90°C. After cooling to room temperature, the reaction mixture is distributed between half-saturated K2CO3-solution and ethyl acetate. The precipitate thus formed is filtered off,washed with H2O and ethyl acetate and dried in vacuo to afford the title compound.Greyish solid, HPLC: tR = 2.37 min (gradient F), ESI-MS: 258.3 [MHf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
mixture of 6-chloro-pyrimidin-4-yl)-amine (500 mg, 3.87 mmol, 1.3 eq.) and <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (611 mg, 2.98 mmol) in water (3.0 ml) and glacial acetic acid (10ml) is heated to 100C for 15h. The reaction mixture is diluted with DCM and brine. Theaqueous layer is made basic by addition of sodium bicarbonate. The aqueous layer isseparated and extracted with DCM. The organic phase is washed with brine, dried (sodiumsulfate), filtered and concentrated. Purification of the crude product by trituration in EEaffords the title compound: ESI-MS: 299.2 [MHf; tR= 1.05 min (gradient J). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tert-butyl 4-[(6-aminopyrimidin-4-yl)(methyl)amino]methyl}piperidine-1-carboxylate (19-2) 710 mg (3.10 mmol) of 4-chloro-6-aminopyrimidine 7-2 and 402 mg (3.10 mmol) of <strong>[138022-02-3]tert-butyl 4-[(methylamino)methyl]piperidine-1-carboxylate</strong> 19-1 were used to obtain desired product 19-2 as a brown oil/solid. MS M+1=323. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetic acid; at 100℃; for 16h; | Step 1.1 : N-[4-(2-Morpholin-4-yl-ethoxy)-phenyll-pyrimidine-4,6-diamineA mixture of 6-chloro-pyrimidin-4-ylamine (194 mg, 1.5 mmol, 1.3 equiv), 4-(2-morpho.in-4- yl-ethoxy)-phenylamine (256 mg, 1.15 mmol) in H2O (1 mL) and glacial acetic acid (5 mL) is stirred for 16h at 1000C. After solvent evaporation, the residue is taken up in DCM and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (NaaSO4), filtered and concentrated. The residue is triturated in EtOAc to provide the title compound as a grey solid: ESI-MS: 316.2 [MH]+; tR= 1.00 min (purity: 95%, system 1 ); TLC: Rf = 0.22 (DCM/MeOH + 1 % NH3aq, 93:7). |
Yield | Reaction Conditions | Operation in experiment |
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With N,N-diethylaniline; trichlorophosphate; for 4h;Heating / reflux; | 4-amino-6-hydroxy-2-thiopyrimidine was treated with Raney nickel (RaNi) in water and ammonia and heated to reflux for 2h. Purification afforded the <strong>[1193-22-2]4-amino-6-hydroxypyrimidine</strong>, which was combined with phosphorus oxychloride and N,N-diethylaniline and heated at reflux for 4h to give 4-amino-6-chloropyrimidine. This product was combined with diphenylborinic acid ethanolamine ester in toluene with diisopropylethylamine and heated to reflux overnight to produce the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In toluene;Heating / reflux; | 4-amino-6-hydroxy-2-thiopyrimidine was treated with Raney nickel (RaNi) in water and ammonia and heated to reflux for 2h. Purification afforded the 4-amino-6-hydroxypyrimidine, which was combined with phosphorus oxychloride and N,N-diethylaniline and heated at reflux for 4h to give 4-amino-6-chloropyrimidine. This product was combined with diphenylborinic acid ethanolamine ester in toluene with diisopropylethylamine and heated to reflux overnight to produce the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 12h;Heating / reflux; | To a solution of <strong>[213211-69-9]2-ethoxyphenylboronic acid</strong> (II) (1.73 g, 10.4 mmol) in 30 ml of 1 , 4- dioxane 10 ml of saturated aqueous sodium carbonate solution were added. Argon gas was purged for 10 min at room temperature. 6-Chloro-pyhmidin-4-ylamine (I) (1.50 g, 11.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol) were added to the reaction mixture simultaneously and argon gas was bubbled in for another 5 min. The reaction mixture was heated to reflux for 12 hours. After completion of the reaction as indicated by TLC the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by column chromatography eluting with 15% ethyl acetate in dichloromethane to provide 6-(2-ethoxy-phenyl)- pyrimidin-4-ylamine (III) (2.17 g, 87.3%). 1H NMR (CDCI3) delta = 8.64 (1 H, s), 7.90-7.86 (1 H, m), 7.41 -6.88 (4H, m), 4.85 (2H, bs), 4.15 (2H, q), 1.40 (3H, t). MS: m/z = 216 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; In N,N-dimethyl-formamide; at 90℃; | Reference Example 9 6-Aminopyrimidine-4-carboxylic acid propyl ester A mixture of 6-chloro-4-aminopyrimidine (2.00 g, 15.4 mmol), palladium acetate (361 mg, 1.61 mmol), 1,3-bis(diphenylphosphino)propane (631 mg, 1.52 mmol), and potassium carbonate (2.55 g, 18.5 mmol) in n-propanol (45 mL) and DMF (15 mL) was stirred at 90C under carbon monoxide atmosphere. The mixture was allowed to stand and cool to room temperature, and then filtered through Celite. Aqueous sodium bicarbonate solution was added to the filtrate, which was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (chloroform/methanol = 100/1 to 50/1) to give the title compound (1.86 g, 10.3 mmol, yield 67%). 1H-NMR (delta ppm, CDCl3): 8.71 (d, J = 1.2 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.16 (br, 2H), 4.35 (t, J = 6.9 Hz, 2H), 1.83 (tq, J = 7.4, 6.9 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125.0℃; for 0.333333h;Microwave irradiation; | Step A: 6-(pyridin-3-yl)pyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3- ylboronic acid (0.384 g, 3.13 mmol), Na2C03 (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water. The mixture was heated in the microwave synthesizer at 125 C for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60 % ethyl acetate in hexanes, then 5-25 % 9: 1methanol: ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4- amine (0.17 g, 0.987 mmol, 40 % yield) as an off-white solid. LCMS R.T. = 0.31; [M+H]+ = 173.11. |
40% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 125.0℃; for 0.333333h;Microwave irradiation; | A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), pyridin-3-ylboronic acid (0.384 g, 3.13 mmol),Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin a mixture ofDME/EtOH/water. The mixture was heated inthe microwave synthesizer at 125 C. for 20 min and concentrated.The residue was purified by silica gel chromatography(10-60% ethyl acetate in hexanes, then 5-25% 9: I methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3yl)pyrimidin-4-amine (0.17 g, 0.987 mmol, 40% yield) as an off-white solid. |
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; ethanol; water; at 125.0℃; for 0.333333h;Microwave irradiation; | EXAMPLE 11; ( 3R, 4R)-N-( 6-(Pyridin-3-yl)pyrimidin-4-yl)-4'H-l-azaspiro[bicyclo[2.2.1 Jheptane-oxazolJ-2 '-amine; Step A: 6-(Pyridin-3-yl)pyrimidin-4-amine; A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3- ylboronic acid (0.385 g, 3.13 mmol), Na2C03 (0.795 g, 7.5 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dioxane/EtOH/water. The mixture was heated in the microwave synthesizer at 125 C for 20 min (reaction was run twice) and concentrated. The residue was purified on by silica gel chromatography using a 10-60% ethyl acetate/hexanes gradient, followed by a 5-25% 9: 1 methanohammonium hydroxide in ethyl acetate gradient. The desired fractions were concentrated to give an off- white solid. MS(LC/MS) R.T. = 0.28; (M+H = 173.13). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 6-(3-Methoxyphenyl)pyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-methoxyphenylboronic acid (0.475 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.050 mmol) was suspended in DME/EtOH/water (15:2:3 mL), heated in the microwave synthesizer at 125 C. for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60% ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70% yield) as an off-white solid. LCMS R.T.=1.28; [M+H]+=201.98. |
70% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 6-(3-Methoxyphenyl)pyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3- methoxyphenylboronic acid (0.475 g, 3.13 mmol), a2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in DME/EtOH/water(15:2:3 mL), heated in the microwave synthesizer at 125 C for 20 min and concentrated. The residue was purified by silica gel chromatography (10- 60 % ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70 % yield) as an off-white solid. LCMS R.T. = 1.28; [M+H]+ = 201.98. |
70% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), 3-methoxyphenylboronic acid (0.475 g, 3.13mmol), Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin DME/EtOH/water (15:2:3 ml.), heated in themicrowave synthesizer at 125 C. for 20 min and concentrated.The residue was purified by silica gel chromatography(10-60% ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70% yield) as anoff-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5% | (Reference example H-5) 4-Amino-6-(4-amino-2,5-difluorophenoxy)pyrimidine Production method - 1 <strong>[120103-19-7]4-Amino-2,5-difluorophenol</strong> (2.15 g) was dissolved in dimethyl sulfoxide (12.5 ml) at room temperature under a nitrogen flow. Potassium tert-butoxide (1.66 g) was added thereto, followed by stirring at room temperature for 5 min. 4-Amino-6-chloropyrimidine (1.55 g) was added, and the resultant mixture was stirred at 100 C for 18.5 hr under a nitrogen flow. The reaction mixture was allowed to cool to room temperature, then partitioned between ethyl acetate (100 ml) and a 1N aqueous solution of sodium hydroxide (50 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (50 ml, 3 times) and brine (50 ml). The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate = 1:2). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale yellow powder (271 mg, 9.5 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 3.76 (2H, br), 4.97 (2H, br), 5.94 (1H, d, J = 0.8 Hz), 6.60(1H, dd, J = 8.0, 11.2 Hz), 6.87 (1H, dd, J = 7.2, 11.2 Hz), 8.26 (1H, d, J = 0.8 Hz). ESI-MS (m/z): 239 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; ethanol; water; at 125℃; for 2h; | A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), phenylboronic acid (0.381 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and Bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) were suspended in a mixture of Dioxane (15 mL)/EtOH (2 mL)/water (3 mL). The mixture was heated a heating block at 125 C for 2 h and concentrated. The residue was purified on the silica gel using 100 % ethyl acetate, then 10% methanol in ethyl acetate. The desired fractions were concentrated to give an off-white solid (0.25 g, 58 %).1H NMR (400 MHz, DMSO-d6) d ppm 8.44 (1 H, d, J=1.26 Hz), 7.93 - 8.00 (2 H, m), 7.42 - 7.52 (3 H, m), 6.91 (2 H, s), 6.88 (1 H, d, J=1.26 Hz). LCMS (method D) tR, 2.58min., MH+ = 172.1. |
39% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 6-Phenylpyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.32 g, 2.5 mmol), phenylboronic acid (0.38 g, 3.13 mmol), saturated aqueous sodium carbonate (0.80 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dimethoxyethane (15 mL)/ethanol (2 mL)/water (2 mL). The mixture was heated in the microwave at 125 C. for 20 min then concentrated in vacuo. The residue was purified by column chromatography (10-60% ethyl acetate/hexanes) to afford 6-phenylpyrimidin-4-amine (167 mg, 0.98 mmol, 39% yield) as an off-white solid. MS (LC/MS) R.T.=0.99; [M+H]+=172.23. |
39% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 6-Phenylpyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.32 g, 2.5 mmol), phenylboronic acid (0.38 g, 3.13 mmol), saturated aqueous sodium carbonate (0.80 g, 7.50 mmol) and bis(triphenylphosphine)palladium(H) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dimethoxyethane (15 mL)/ethanol (2 mL)/water (2mL). The mixture was heated in the microwave at 125 C for 20 min then concentrated in vacuo. The residue was purified by column chromatography (10-60 % ethyl acetate/hexanes) to afford 6-phenylpyrimidin-4-amine (167 mg, 0.98 mmol, 39 %yield) as an off-white solid. MS (LC/MS) R.T. = 0.99; [M+H]+ = 172.23. |
39% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 125℃; for 0.333333h;Microwave irradiation; | A mixture of 6-chloropyrimidin-4-amine (0.32 g,2.5 mmol), phenylboronic acid (0.38 g, 3.13 mmol), saturatedaqueous sodium carbonate (0.80 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol)were suspended in a mixture of dimethoxyethane (15 mL)1ethanol (2 mL)/water (2 mL). The mixture was heated in themicrowave at 125 C. for 20 min then concentrated in vacuo.The residue was purified by column chromatography (1060%ethyl acetate/hexanes) to afford 6-phenylpyrimidin-4amine(167 mg, 0.98 mmol, 39% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium; at 20 - 140℃; | Step A: 6-Phenoxypyrimidin-4-amine 6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol) was added to a solution of sodium (0.197 g, 8.57 mmol) in phenol (11.29 g, 120 mmol) at 55 C. The mixture was heated at 140 C. for 2 h, then held at room temperature for 20 h. The reaction mixture was poured into 32% aqueous NaOH on ice/water keeping the mixture temperature below 20 C. The mixture was extracted with chloroform and the organic extract dried over calcium chloride and concentrated. The residue was purified by silica gel chromatography (2-20% ethyl acetate in hexanes) to afford 6-phenoxypyrimidin-4-amine (0.6 g, 3.21 mmol, 75% yield) as a white solid. LCMS R.T.=1.37; [M+H]+=197.95. |
75% | Step A: 6-Phenoxypyrimidin-4 -amine 6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol) was added to a solution of sodium (0.197 g, 8.57 mmol) in phenol (1 1.29 g, 120 mmol) at 55 C. The mixture was heated at 140 C for 2 h, then held at room temperature for 20 h. The reaction mixture was poured into 32% aqueous NaOH on ice/water keeping the mixture temperature below 20 C. The mixture was extracted with chloroform and the organic extract dried over calcium chloride and concentrated. The residue was purified by silica gel chromatography (2-20 % ethyl acetate in hexanes) to afford 6- phenoxypyrimidin-4-amine (0.6 g, 3.21 mmol, 75 % yield) as a white solid. LCMS R.T. = 1.37; [M+H]+ = 197.95. | |
75% | With sodium; at 55 - 140℃; for 2h; | 6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol)was added to a solution of sodium (0.197 g, 8.57 mmol) inphenol (11.29 g, 120mmol) at 55 C. The mixture was heatedat 140 C. for 2 h, then held at room temperature for 20 h. Thereaction mixture was poured into 32% aqueous NaOH onice/water keeping the mixture temperature below 20 C. Themixture was extracted with chloroform and the organicextract dried over calcium chloride and concentrated. Theresidue was purified by silica gel chromatography (2-20%ethyl acetate in hexanes) to afford 6-phenoxypyrimidin-4amine(0.6 g, 3.21 mmol, 75% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Description 137; 6-Quinoxalin-6-vlpvrimidin-4-amine; 6-Bromoquinoxaline (210 mg, 1.44 mmol), potassium acetate (141 mg, 1.44 mmol), bis (pinacolato) diboron (383 mg, 1.51 mmol) and [1, 1'- bis (diphenylphosphino) ferrocene] palladium (II) chloride (52 mg, 0.072 mmol) were suspended in dioxane (10 ml) and heated to 100C for 16 hours. 4-Amino-6- chloropyrimidine [WO-A-0245652] (186 mg, 1.44 mmol), [l, 1'- bis (diphenylphosphino) ferrocene]-palladium (II) chloride (52 mg, 0.072 mmol) and 2M Na2CO3 (aq) (2ml) were added and the mixture was heated at 100 oC for a further 16 hours. The mixture was partitioned between EtOAc and water, the aqueous phase was extracted with EtOAc, the combined organic phases were washed (brine), dried (sodium sulfate) and concentrated under reduced pressure. The residue was triturated with EtOAc to give a white solid, which was used in the next step without purification (170 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With Iodine monochloride; In N,N-dimethyl-formamide; at 45.0℃; | To a solution of 3.03 g (23.39 mmol) of 6-chloropyrimidin-4-amine in 60 mL of dimethylformamide was added dropwise a solution of iodine monochloride (2.34 mL, 46.70 mmol) in 40 mL of dimethylformamide. Then the mixture was stirred at 45 C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a 4% aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 20%, methanol-dichloromethane) to obtain 4.28 g (72% yield) of the title compound. LRMS (m/z): 256 (M+1 )+. |
47% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 100.0℃; for 8h; | To a solution of 6-chloropyri.midin-4-amme (1 ,29 g, 10 mmol) in DMF (8 mL) was added N-iodosuccinimide (2.25 g, 10 mmol) in one portion to give an orange mixture. The reaction mixture was stirred at 100 C for 8 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL), and the resulted mixture was washed successively with a mixture of saturated a --S;O; aqueous solution and saturated NaHC03 aqueous solution (1/2 (v/v), 100 mL x 3), water (150 mL x 3) and brine (100 mL). Then the organic phase was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (1.20 g, yield 47.0%). MS (ESI, pos. ion) m/z: 255.8 [M+H]+; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-Lambda) delta (ppm): 8.12 (s, 1H). |
47% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 100.0℃; for 8h; | The compound 6-chloropyrimidin-4-amine (1.29 g, 10 mmol) was dissolved in DMF (8 mL), and then N-iodosuccinimide (2.25 g, 10 mmol) was added in one portion to give a yellow mixture. The reaction mixture was stirred at 100 C for 8 hours, then cooled to EtOAc. The solution (1/2 (v/v), 100 mL x 3) was washed and washed with water (150 mL x 3) and brine (100 mL).The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting residue (5/1 PE / EtOAc (v / v) =) purified by silica gel column chromatography to give the title compound as a white solid (1.20g, 47.0% ). |
46.97% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 100.0℃; for 8h; | The compound 6-chloropyrimidine-4-amino (1.29 g, 10 mmol) was dissolved in DMF (8 mL), and thenNIS (2.25 g, 10 mmol) was added and the reaction mixture was stirred at 100 C for 8 hours, then cooled to room temperature and concentrated under reduced pressureShrink The residue was dissolved in EtOAc (300 mL) and the resulting mixture was washed with a mixture of saturated aqueous Na2S204 / saturated aqueous NaHCO3 (v / v, 1/2, 100 mL x 3) followed by water (150 mL x 3) and brine (100 mL)The resulting organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE /EtOAc (v / v) = 5/1) to give the title compound as a white solid (1.20 g, 46.97%). |
To a suspension of 6-chloropyrimidin-4-amine (5.29 g, 40.8 mmol) and trifluoro-methane sulfonic acid (40 mL, 452 mmol) was added N-iodosuccinimide (9.19 g, 40.8 mmol). The mixture was stirred for 3 h at rt. The mixture was poured into 50 mL of ice containing 15 g of NaOH with stirring for 10 min. The resulting precipitate was filtered washed with water, triturated in DCM and collected by filtration to give 6-chloro-5-iodopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) delta 8.11 (s, 1H); LC-MS (ESI) m/z 255.9 [M+H]+. | ||
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 100.0℃; for 0.5h;Microwave irradiation; | To a solution of 6-chloropyrimidin-4-amine (1 g, 7.8 mmol) in 5 mL N,N-dimethylformamide was added N-iodosuccinimide (2.6 g, 11.6 mmol) and the mixture subjected to microwave irradiation (Biotage Initiator) at 100 C. for 30 minutes. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 25% ethyl acetate in hexane) afforded the title compound. LCMS: 255.91 (M+1)+. | |
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 100.0℃; for 0.5h;Microwave irradiation; | To a solution of 6-chloropyrimidin-4-amine (1 g, 7.8 mmol) in 5 mL N,N-dimethylformamide was added N-iodosuccinimide (2.6g, 11.6 mmol) and the mixture subj ected to microwave irradiation (Biotage Initiator) at 100C for 30 minutes. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 25% ethyl acetate in hexane) afforded the title compound. LCMS : 255.91 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water at 90℃; Inert atmosphere; | 14.A A mixture of 6-chloropyrimidin-4-amine (260.0 mg, 2.0 mmol), dibutyl vinylboronate (0.66 mL, 3.0 mmol), (Ph3P)2PdCl2 (70.2 mg, 0.1 mmol), Na2CO3 (1.48 g, 14 mmol) in 8.0 mL of THF and 2.0 mL of H2O was degassed and purged with nitrogen, then heated at 90°C overnight. The reaction mixture was partitioned between EtOAc and brine, the combined organic extracts were dried (Na2SO4), concentrated in vacuo, followed by chromatography (EtOAc/ Hexanes: 0-30%) to afford 6-vinylpyrimidin- 4-amine. ESI-MS mlz 122.1(MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water at 90℃; Inert atmosphere; | 18.A A mixture of 6-chloropyrimidin-4-amine (260.0 mg, 2.0 mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (0.66 mL, 3.0 mmol), (Ph3P)2PdCl2 (70.2 mg, 0.1 mmol), Na2CO3 (1.48 g, 14 mmol) in 8.0 mL of THF and 2.0 mL of H2O was degassed and purged with nitrogen, then heated at 90°C overnight. The reaction mixture was partitioned between EtOAc and brine, the combined organic extracts were dried (Na2SO4), concentrated in vacuo, followed by chromatography (EtOAc/ Hexanes: 0-30%) to afford 6-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine. ESI-MS ml z 230.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 6-(Pyridin-4-yl)pyrimidin-4-amine 6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-4-ylboronic acid (0.384 g, 3.13 mmol), Na2C03 (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) were suspended in a mixture of DME/EtOH/water(15:2:3 mL). The mixture was heated in the microwave synthesizer at 125 C for 20 min and concentrated. The residue was purified by silica gel chromatography (5-25 % [9: 1 methanol: ammonium hydroxide]- ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35 % yield) as an off-white solid. LCMS R.T. = 0.30; [M+H]+ = 173.11. |
35% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | 6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol),pyridin-4-ylboronic acid (0.384 g, 3.13 mmol), Na2C03(0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) were suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125 C. for 20 min andconcentrated. The residue was purified by silica gel chromatography(5-25% [9: I methanol:ammonium hydroxide]ethylacetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine(0.15 g, 0.871 mmol, 35% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | Step A: 2'-methoxy-4,5'-bipyrimidin-6-amine6-Chloropyrimidin-4-amine (0.35 g, 2.70 mmol), 2-methoxypyrimidin-5- ylboronic acid (0.520 g, 3.38 mmol), Na2C03 (0.859 g, 8.11 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.038 g, 0.054 mmol) were suspended in a mixture of DME/EtOH/water. (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125 °C for 20 min and concentrated. The residue was purified by silica gel chromatography (0-5 percent 9: 1 methanol: ammonium hydroxide- ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.28 g, 1.378 mmol, 51 percent yield) as an off-white solid. LCMS R.T. = 0.53; [M+H]+ = 204.11. |
51% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | 6-Chloropyrimidin-4-amine (0.35 g, 2.70 mmol),<strong>[628692-15-9]2-methoxypyrimidin-5-ylboronic acid</strong> (0.520 g, 3.38 mmol),Na2CO3 (0.859 g, 8.11 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.038 g, 0.054 mmol) were suspendedin a mixture of DME/EtOH/water. (15:2:3 mL). Themixture was heated in the microwave synthesizer at 125° C.for 20 min and concentrated. The residue was purified bysilica gel chromatography (0-5percent 9:1 methanol:ammoniumhydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin4-amine (0.28 g, 1.378 mmol, 51percent yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 140℃; for 1.5h;Inert atmosphere; microwave irradiation; | To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)-lH-imidazo[4,5-c]-pyridine (0.100 g, 0.29 mmol), 2-chloro-6-isopropylpyrimidin-4-amine (0.034 g, 0.26 mmol), Pd2(dba)3 (0.026 g, 0.029 mmol), XantPhos (0.034 g, 0.058 mmol), Cs2C03 (0.189 g, 0.58 mmol) and dioxane (3 niL). The mixture was degassed with N2 for 1 min. The resulting mixture was irradiated in a microwave reactor at 140 C for 1.5 hours and cooled to room temperature. The mixture was filtered and the filtrate was concentrated and purified by column chromatography on silica gel with EtOAc/petroleum ether (1 :1.5) to give the desired product (50 mg, 44% yield). ¾ NMR (MeOH- 4, 500 MHz): delta 8.56 (s, 1H), 8.22 (m, 1H), 7.66 - 7.59 (m, 4H), 7.37 (d, J= 5.0 Hz, 1H). LCMS(ESI) m/z: 391.6 [M+H+]. |
44% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃; for 1.5h;Microwave irradiation; Inert atmosphere; | To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)-1H-imidazo[4,5-c]-pyridine(100mg, 0.290mmol), 2-chloro-6-isopropylpyrimidin-4-amine (34mg, 0.26 mmol), Pd2(dba)3(26mg, 0.029 mmol), XantPhos (34mg, 0.058 mmol), Cs2CO3(189mg, 0.580mmol), and dioxane (3.0mL).The mixture was degassed with N2for 1 min. The resulting mixture was irradiated in a microwave reactor at 140 C for 1.5 hours and cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue waspurified bysilica gelcolumn chromatographyelutingwithEtOAc/petroleum ether (1:1.5) to give thetitle compound(50 mg, 44% yield).1H NMR (500 MHz,MeOH-d4):delta8.56 (s, 1H), 8.23 - 8.21(m, 1H), 7.66-7.59 (m, 4H), 7.37 (d,J= 5.0 Hz, 1H). LCMS(ESI) m/z: 391.6 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In water; butan-1-ol; at 110℃; for 3h; | General procedure: A mixture of 3-chloro-4-(3-fluorobenzyloxy)aniline (5.00 g, 19.86 mmol) and compound 2 (4.17 g, 16.55 mmol) with two drops concd HCl in n-BuOH (30 mL) was heated at 110 C and kept stirring for 3 h. As the mixture cooled, the formed yellow solid was filtered through washing with n-BuOH followed by saturated NaHCO3 aqueous solution. After being dried overnight at vacuum drying oven at 40 C, the solid was purified by column chromatography on silica gel eluted with EtOAc/petroleum ether (1:2) to give 3 as a yellowish green solid (6.18 g, 13.24 mmol, 80% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃; under 15201.0 Torr; for 24h; | A mixture of 6-chloropyrimidin-4-amine (10.0 g, 77.2 mmol), PdCl2(dppf) (6.0 g, 8.2 mmol), Et3N (30 mL), MeOH (30 mL) in DMF (100 mL) was heated 100 C for 24 h under 20 atm CO (g) atmosphere. The solvents were removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL) three times. The combined organic phase was dried over Na2S04 and concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give the desired product as a gray solid (5.0 g, 42% yield). i-NMR (500 MHz, DMSO-t¾: delta 8.44 (d, J = 0.5 Hz, 1H), 7.27 (s, 2H), 7.03 (d, J = 1.5 Hz, 1H), 3.84 (s, 3H). LCMS (ESI) m/z: 154.1 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 15h;Inert atmosphere; | A mixture of 6-chloropyrimidin-4-amine (6.5 g, 0.050 mol), 4,4,5, 5-feframethyl-2-vinyl-l,3,2-dioxaborolane (9.24 g, 0.060 mol), fefrafc(triphenylphosphine)- palladium(O) (3.9 g, 0.0030 mol) and sodium carbonate (21 g, 0.20 mol) in dioxane (300 mL) and H20 (30 mL) was stirred at 90 C under nitrogen for 15 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (400 mL) and water (150 mL). The organic layer was separated, dried over Na2S04, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with DCM/MeOH (20: 1) to give the desired product as a white solid (4.8 g, 80% yield). LCMS (ESI) m/z: 122.1 [M+H+]. |
80% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 20 - 100℃; for 20h;Inert atmosphere; | Method 2:Example 22:4-[4-(6-Azetidin-l-ylmethylpyrimidin-4-ylamino)pyrazStep 1 : 6-Vinylpyrimidin-4-ylamineA mixture of <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (2.5 g, 19.2 mmol), l,r-6/s(diphenylphosphino)ferrocene palladium dichloride (810 mg, 1.2 mmol), sodium carbonate (8.14 g, 76.8 mmol) and vinyl borane pinacol ester (3.9 mL, 23 mmol) in dioxane (11.5 mL) and water (11.5 mL) under nitrogen, was heated at 100 C for 20 hours then cooled to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% methanol in DCM) to afford the title compound as a yellow solid (1.87 g, 80% yield). NMR (300 MHz, DMSO-d6): delta 8.30 (s, 1H), 6.83 (s, 2H), 6.57 (dd, J = 17.2, 10.5 Hz, 1H), 6.36 (s, 1H), 6.26 (dd, J = 17.2, 2.1 Hz, 1H), 5.48 (dd, J = 10.5, 2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 70℃; for 4h;Inert atmosphere; | A mixture of 4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.250 g, 0.65 mmol), 4-amino-6-chloropyridine (0.080 g, 0.62 mmol), Pd2(dba)3 (0.030 g, 0.033 mmol), XantPhos (0.038 g, 0.065 mmol) and cesium carbonate (0.530 g, 1.60 mmol) in dioxane (6.5 mL) was degassed with nitrogen then heated at 70 C for 4 hours. The resulting mixture was diluted with DCM and water, and then filtered through Celite. The layers of the filtrate were separated and the organic layer, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0- 25% EtOAc in pentane and 0-10% EtOAc in DCM to give the desired compound as a yellow solid (0.215 g, 76% yield). ¾ NMR (300 MHz, DMSO-t¾: delta 11.16 (s, 1H), 8.65 (s, 1H), 8.52 (d, J= 5.6 Hz, 1H), 8.39 (s, 2H), 7.97 (s, 1H), 7.91 (d, J= 5.6 Hz, 1H). LCMS (Method E): RT = 3.83 min, m/z: 433 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; oil; at 0 - 70℃; for 23.1667h; | Step 1-Synthesis of 6-(6-iodoindazol-1-yl)pyrimidin-4-amine To a solution of <strong>[261953-36-0]6-iodoindazole</strong> (500 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion, 131.12 mg, 3.28 mmol) at 0 C. The mixture was stirred at 0 C. to RT for 10 minutes before addition of 6-chloropyrimidin-4-amine (477.78 mg, 3.69 mmol) and stirring at 60 C. for 17 hr and then transferred to a pressure tube and heated at 70 C. for a further 6 hr. The reaction mixture was cooled and quenched by the addition of water (10 ml) and EtOAc (a few drops) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum to give the title intermediate (248 mg): LC-MS: m/z=+338.20 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: To the solution of alcohol 4b (0.50 g, 2.67 mmol) and DMSO (0.41 g, 5.34 mmol) in ethyl acetate (5 ml) was added T3P (1.84 g, 6.68 mmol, 2.5 equiv, 50% solution in ethyl acetate) at 0 C. The resulting mixture was allowed to warm to RT and stirred for 1 h. Pyrazine-2-amine 3a (0.254 g, 2.67 mmol) was added to the above mixture and stirred for 15 min, which was followed by the addition of isocyanide 1c (0.33 g, 4.01 mmol) at room temperature and stirring for 4 h. Progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and neutralized with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (25 mL × 2), the combined organic phases were washed with water, brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford a crude product, which was purified on silica gel using ethyl acetate and petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: cuminol With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dimethyl sulfoxide; ethyl acetate at 0 - 20℃; for 1h; Stage #2: 4-amino-6-chloropyrimidine In dimethyl sulfoxide; ethyl acetate for 0.25h; Stage #3: tert-butylisonitrile In dimethyl sulfoxide; ethyl acetate at 20℃; for 5h; | Typical procedure for the synthesis of (4d) General procedure: To the solution of alcohol 4b (0.50 g, 2.67 mmol) and DMSO (0.41 g, 5.34 mmol) in ethyl acetate (5 ml) was added T3P (1.84 g, 6.68 mmol, 2.5 equiv, 50% solution in ethyl acetate) at 0 °C. The resulting mixture was allowed to warm to RT and stirred for 1 h. Pyrazine-2-amine 3a (0.254 g, 2.67 mmol) was added to the above mixture and stirred for 15 min, which was followed by the addition of isocyanide 1c (0.33 g, 4.01 mmol) at room temperature and stirring for 4 h. Progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and neutralized with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (25 mL × 2), the combined organic phases were washed with water, brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford a crude product, which was purified on silica gel using ethyl acetate and petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 180℃; for 1h;Microwave irradiation; | A microwave vial was charged with <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1.0 g, 7.72 mmol), and pyrrolidine (10 mL) was added. The vial was sealed, and heated in the microwave at 180 C for 1 h. After cooling, the reaction was diluted with methanol (30 mL), and silica (15.0 g) was added. All solvents were removed in vacuo, and the remaining silica slurry loaded on a 40.0 g silica column. Elution with a 0% to 10% methanol in dichloromethane gradient yielded 6-(pyrrolidin-1-yl)pyrimidin-4-amine (1.22 g, 96% yield). MS (ESI) calcd for C8H14N4: 164.11 |
96% | at 180℃; for 1h;Microwave irradiation; Sealed tube; | A microwave vial was charged with <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1.0 g, 7.72 mmol), and pyrrolidine (10 mL) was added. The vial was sealed, and heated in the microwave at 180 C for 1 h. After cooling, the reaction was diluted with methanol (30 mL), and silica (15.0 g) was added. All solvents were removed in vacuo, and the remaining silica slurry loaded on a 40.0 g silica column. Elution with a 0% to 10% methanol in dichloromethane gradient yielded 6-(pyrrolidin-1-yl)pyrimidin-4-amine (1.22 g, 96% yield). MS (ESI) calcd for C8H14N4: 164.11. |
54% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 400mg<strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong>, 1.51g (1.5equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, adding 507 mu L (2.0equiv),pyrrolidine heating to 100 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/50 elution, to get the yellow solid 274 mg, yield 54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.8% | With pyridine; In tetrahydrofuran; at 20 - 60℃; for 3.16667h; | Add in the reaction flask<strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (6 g, 46.5 mmol),Tetrahydrofuran (75 mL) and pyridine (9.0 mL).Cyclopropylcarbonyl chloride (5.3 g, 50.7 mmol) was added dropwise at room temperature.10 minutes after the drop finished,The reaction solution was heated to 60 C,The reaction was incubated for 3 hours.After the reaction solution was cooled,Diluted with water (100 mL)Ethyl acetate was extracted twice,The organic phase was combined and used1N hydrochloric acid and saturated brine and dried.After concentration,Heated with n-hexane,To give N- (6-chloropyrimidin-4-yl)Cyclopropylcarboxamide(Pale yellow solid, 4.2 g, 45.8%). |
45% | With potassium carbonate; In tetrahydrofuran; at 70℃;Inert atmosphere; | Compound 6-chloropyrimidine-4-amine 67a (129 mg, 1.0 mmol)Soluble in tetrahydrofuran (5mL),Add cyclopropanecarbonyl chloride (208 mg, 2.0 mmol) at room temperature.Potassium carbonate (414 mg, 3.0 mmol) was reacted at 70 C overnight.The crude product was obtained under reduced pressure, and the title product was obtained by flash column chromatography (ethyl acetate / petroleum ether = 1:0-1:1)N-(6-chloropyrimidin-4-yl)cyclopropanecarboxamide67b (88.6 mg, 0.3 mmol, white solid), yield: 45%. |
With pyridine; In tetrahydrofuran; at 0 - 60℃; for 4h; | Add slowly cyclopropanecarbonyl chloride (10.6 g, 102.3 mmol) to a mixture of <strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong> (12 g, 91 mmol), pyridine (18 g, 227.5 mmol) in THF (150 mL) at 0C. Stir the reaction at 60C for 4 hrs. TLC (DCM:MeOH= 20:1) shows that the reaction is complete. Cool the reaction to 0C, add water (100 mL), extract with EtOAc (100 mLx2). Combine the organic layers, wash with diluted aqueous HC1 (1M, 150 mL) and brine sequentially, dry over anhydrous Na2S04. Evaporation under reduced pressure affords crude product (16 g, crude yield 88.8%). MS: (M+l): 198.1. Use crude product directly in next step without further purification. |
With pyridine; In tetrahydrofuran; at 0 - 60℃; for 4h; | Add slowly cyclopropanecarbonyl chloride (10.6 g, 102.3 mmol) to a mixture of <strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong> (12 g, 91 mmol), pyridine (18 g, 227.5 mmol) in THF (150 mL) at 0 C. Stir the reaction at 60 C. for 4 hrs. TLC (DCM:MeOH=20:1) shows that the reaction is complete. Cool the reaction to 0 C., add water (100 mL), extract with EtOAc (100 mL*2). Combine the organic layers, wash with diluted aqueous HCl (1M, 150 mL) and brine sequentially, dry over anhydrous Na2SO4. Evaporation under reduced pressure affords crude product (16 g, crude yield 88.8%). MS: (M+1): 198.1. Use crude product directly in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 10h;Reflux; Inert atmosphere; | A solution of 54b (1.3 g, 10 mmol), N-Boc-piperazine (2.0 g, 11 mmol), and N,N-diisopropylethylamine (3.9 g, 30 mmol) in n-BuOH (50 mL) was heated to refluxing under a nitrogen atmosphere for 10 h. The reaction mixture was concentrated under vacuum, and the crude residue was purified by silica gel chromatographyto afford the title compound (2.15 g, 77%) as a white solid, mp: 187-189 C. 1H NMR (500 MHz, CDCl3) d 8.18 (s, 1H), 5.56 (s,1H), 4.66 (s, 2H), 3.54 (s, 4H), 3.50 (s, 4H), 1.48 (s, 9H). ESI-MS (m/z):280 [M + 1]+. |
67% | In toluene; for 24h;Heating; | General procedure: To a solution of 6-chloropyrimidin-4-amine intoluene was added substituted amine (2.5 eq). The mixture was heatedat 105 C for 24 h and concentrated in vacuo. The residue was purifiedby flash column chromatography. |
55% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 16h; | A mixture of 6-chloropyrimidin-4-amine (680 mg, 5.25 mmol), tert-butyl piperazine-1-carboxylate (1.17 g, 6.30 mmol) and D1PEA (2.6 mL. 16 mmol) in n-butanol (5 mL) was heated at 140C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 10: 1 :0.1 DCM/ methanol/ammonium hydroxide) to afford tert-butyl 4-(6-aminopyrimidin-4-y]) piperazine- 1-carboxylate 194b (0.81 g, 55%) as an off-white solid. 1H NMR (400 MHz, CD3OD): delta 8.00 (s, 1H), 5.73 (s, i l l). 3.60-3.53 (m, 4H), 3.53-3.46 (m, 4H), 1.47 (s, 9H); ESI MS m/z 280 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | The 200mg<strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong>, 219 mg (1.2equiv) benzimidazole, 604 mg (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to obtain light yellow solid 173 mg, yield 53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | The 300mg4-amino-6-chloro-pyrimidine, 372 mg (1.1equiv) 4-polybromide imidazole, 905 mg (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/30 elution, to get the yellow solid 250 mg, yield 45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | Example 18 preparation of 6 - (4-iodo -1H-imidazol-1-yl) pyrimidin-4-amine (intermediate II-18) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12h; | 19 Example 19 preparation of 6 - (4,5-dichloro -1H-imidazol-1-yl) pyrimidin-4-amine (intermediate II-19) The 300mg4-amino-6-chloro-pyrimidine, 347 mg (1.1equiv) 4,5- two chlorine imidazole, 905 mg (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 °C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/30 elution, to get the yellow solid 64 mg, yield 12%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 1g4-amino-6-chloro-pyrimidine, 1.05g (1.1equiv) 4-nitro imidazole, 1.28g (1.2equiv) potassium carbonate into the flask, 20mLN, N '-dimethyl formamide as a solvent, heating to 100 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to get the yellow solid 500 mg, yield 31%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 400mg4-amino-6-chloro-pyrimidine, 462 mg (1.1equiv) 4-trifluoro methyl imidazole, 1.2g (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, heating to 100 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to get the yellow solid 219 mg, yield 31%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | The 400mg4-amino-6-chloro-pyrimidine, 428 mg (1.1equiv) imidazole 4-carboxylic acid methyl ester, 512 mg (1.2equiv) potassium carbonate into the flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to get the yellow solid 142 mg, yield 21%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In toluene; for 24h;Heating; | General procedure: To a solution of 6-chloropyrimidin-4-amine intoluene was added substituted amine (2.5 eq). The mixture was heatedat 105 C for 24 h and concentrated in vacuo. The residue was purifiedby flash column chromatography. |
64% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 400mg<strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong>, 1.51g (1.5equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, adding 515 mu L (1.5equiv) N-methyl piperazine, heating to 100 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/30 elution, to get the yellow solid 382 mg, yield 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | The 200 mg (1equiv) <strong>[5305-59-9]4-amino-6-chloro-pyrimidine</strong>, 152 mg (1.2equiv) 4-methyl imidazole, 604 mg (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to get the yellow solid 176 mg, yield 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | The 400mg4-amino-6-chloro-pyrimidine, 317 mg (1.0equiv) <strong>[15965-31-8]4-chloro-imidazole</strong>, 1.2g (1.2equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, the temperature is increased to 120 C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/20 elution, to get the yellow solid 368 mg, yield 61% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | The 0.96 g (10 mmol) of 1H-imidazole-4-carbaldehyde was dissolved in 20 ml of DMF, and 1.30 g (10 mmol) of <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong>, 2.07 g (15 mm1) of potassium carbonate was added successively 100 C, stirring reaction 12h. The appropriate amount of water was added and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and then filtered to remove the solvent under reduced pressure. The residue was purified by silica gel column The eluent was methanol: dichloromethane = 1: 30 to give 0.87 g of a white solid (compound represented by the formula Pialpha) in a yield of 46% |
46% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | General procedure: A mixture of imidazole derivatives (4a-c, 10mmol), <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1.30g, 10mmol), and K2CO3 (2.07g, 15mmol, for 5a) or Cs2CO3 (3.91g, 12mmol, for 5b-c) was stirred in DMF (20mL) at 100C (for 5a) or at 140C (for 5b-c) for 12h. Water (100mL) was then added. The mixture was extracted with EtOAc (3×50mL). The organic layer was separated and dried over Na2SO4. Removal of the solvents produced a residue which was purified using column chromatography and eluted with a mixture of MeOH:CH2Cl2 (1:30, v:v) to afford 5a-c. 4.1.2.1 1-(6-Aminopyrimidin-4-yl)-1H-imidazole-4-carbaldehyde (5a) White solid, 46% yield. 1H NMR (400MHz, DMSO-d6) delta 9.83 (s, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 8.37 (s, 1H), 7.35 (s, 2H), 6.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | 1-Chloro-N,N,2-trimethylpropenylamine (3.26 mL, 24.7 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (5.00 g, 20.6 mmol; prepared as in Example 2) in DCM (50 mL) and the resulting mixture stirred for 90 min at r.t. Then 6-chloropyrimidin-4-amine (2.66 g, 20.6 mmol) and pyridine (2.0 mL, 25 mmol) were added, and the resulting mixture was stirred under these conditions for 18 h. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with 0 to 100% (10% methanol in ethyl acetate) in heptane. Product fractions were combined and concentrated under reduced pressure to give tert-butyl ((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (1.0 g, 14%) as a white solid. m/z: ES-[M-H]-353. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 12h; | A solution of 1.12 g (10 mmol) of 2- (1 H-imidazol-4-yl) ethan-1-ol was dissolved in 20 ml of DMF, 1.30 g of (lOmmol) of 4-amino-6-chloroetine, g (12 mmol) of cesium carbonate, the temperature was raised to 140 C and the reaction was stirred for 12 h. And the residue was purified by silica gel column chromatography. The eluent was methanol: dichloromethane = 1: 30 to give 1.19 g of the compound as shown on the white solid (yield of the compound of the formula IIb-1) in a yield of 58%. |
58% | With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 12h; | General procedure: A mixture of imidazole derivatives (4a-c, 10mmol), 4-amino-6-chloropyrimidine (1.30g, 10mmol), and K2CO3 (2.07g, 15mmol, for 5a) or Cs2CO3 (3.91g, 12mmol, for 5b-c) was stirred in DMF (20mL) at 100C (for 5a) or at 140C (for 5b-c) for 12h. Water (100mL) was then added. The mixture was extracted with EtOAc (3×50mL). The organic layer was separated and dried over Na2SO4. Removal of the solvents produced a residue which was purified using column chromatography and eluted with a mixture of MeOH:CH2Cl2 (1:30, v:v) to afford 5a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | General procedure: To a mixture of (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-benzo[d]imidazole derivatives (7 mmol, 1 eq.), which was commercially available or prepared according to the literature procedure [WO2016192630], amino aromatic chloride (1.1 eq.) in DMF (20 mL) was added Na2CO3 aq. (3 eq.). The mixture was bubbled with Ar for 15 mins and then Pd(dppf)Cl2 (0.1 eq.) was added. The mixture was heated to 80oC and stirred for 4-6 hours under Ar atmosphere, then cooled to room temperature and concentrated to remove the organic solvent after reaction completion. The residue was diluted with water (100 mL) and extracted with EA (150 mL×3). The organic layer was separated and washed with saturated brine, then dried with anhydrous Na2SO4. The organic phase was then concentrated and the residue was further purified with flash chromatography or preparative HPLC to afford the desired intermediate compounds 3a-3j, which were characterized by LC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.34 g | With pyridine; trichlorophosphate; at 0℃; for 0.166667h; | To a solution of 4-amino-6-chloropyrimidine (CAS Number 5305-59-9; 0.145 g, 1 .12 mmol) in pyridine (4.06 ml) was added (R)-N-BOC-morpholine-2-carboxylic acid (CAS Number 884512-77-0; 0.310 g, 1 .34 mmol) at 0C. POCI3 (0.514 g, 3.36 mmol) was added drop wise to reaction mixture at 0C. The reaction mixture was stirred at 0C for 10 min. The reaction was diluted with water (40 ml) extracted with EtOAc (2 x 30 ml). The combined organic phase was washed with saturated citric acid solution (50 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (32% EtOAc in hexane) to yield tert-butyl (R)-2-((6-chloropyrimidin-4-yl)carbamoyl)morpholine-4- carboxylate (0.340 g, 0.99 mmol). LCMS: Method C, 1 .992 min, MS: ES+ 287.35 (M-56). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 0.333333h;Microwave irradiation; | A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), 3-chlorophenylboronic acid (0.489 g, 3.13mmol), Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin a mixture ofDME/EtOH/water (15:2:3 mL). Themixture was heated in the microwave synthesizer at 125 C.for 20 min and concentrated. The residue was purified bysilica gel chromatography (30-70% ethyl acetate in hexanes)to afford: 6-(3-chlorophenyl)pyrimidin-4-amine (0.47 g,2.286 mmol, 91% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: Take a dry three-mouth reaction bottle and place the magnet.Add <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1 eq), KI (0.5 eq),It was dissolved in absolute ethanol (35 mL).After stirring for 10 min on a magnetic stirrer,Trifluoroacetic acid (200 mL) was added. activation.After about 1 h, a solution of the substituted aniline (0.8 eq) dissolved in absolute ethanol (15 mL) was added.Note that you have to add it by drop,In order to achieve long-term excess reaction,The dropping time is controlled at around 1h. Step 2: The progress of the reaction and the reaction effect were examined by the TLC method.Generally, after 36 hours of reaction, the reaction is almost complete.After the reaction is completed, the solvent is dried in absolute ethanol.Then a certain amount of ethyl acetate was added to dissolve.First remove the acid with an appropriate amount of 20% sodium bicarbonate solution.Then add a certain amount of 50% sodium chloride solution to extract the layering.Collect the organic layer and spin it to a certain amount.Add an appropriate amount of anhydrous sodium sulfate and remove water overnight. Step 3: suction filtration, sand making,Weigh 15 to 20 times the total amount of raw materials and install the column silica gel powder column, and collect the product points through the column.Generally use petroleum ether: ethyl acetate = 2:1 to pass the first point (aniline point),Petroleum ether: ethyl acetate = 1:1 over the second point (pyrimidine point),Ethyl acetate or methanol is washed out of the product.The spin-dried product points were collected, dried in an oven, mass spectrometrically and nuclear magnetically verified. | ||
step one:Take a dry three-neck reaction flask and place the magnet.Add <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1 eq), KI (0.5 eq),It was dissolved in absolute ethanol (35 mL). On the magnetic stirrer,After stirring for 10 min, trifluoroacetic acid (200 mL) was added. activation. After about 1h,The reaction was carried out by adding a substituted aniline (0.8 eq) dissolved in absolute ethanol (15 mL). note,It should be added dropwise to achieve long-term excess reaction.The dropping time is controlled at around 1h.Step two:The progress of the reaction and the effect of the reaction were examined by the TLC method.Generally, after 36 hours of reaction, the reaction is almost complete. After the reaction is complete, the solvent is dried in absolute ethanol.Then a certain amount of ethyl acetate was added to dissolve.First remove the acid with an appropriate amount of 20% sodium bicarbonate solution.Then add a certain amount of 50% sodium chloride solution to extract the layering.Collect the organic layer and spin it to a certain amount, add an appropriate amount of anhydrous sodium sulfate,Remove water overnight.Step three:Drain filtration, sand making, and weigh 15 to 20 times the total amount of raw materials, column silica gel powder column,The product points are collected through the column. Generally use petroleum ether: ethyl acetate = 2:1 to pass the firstPoint (aniline point), petroleum ether: ethyl acetate = 1:1 over The second point (pyrimidine point), ethyl acetate or methanol is washed out of the product point.Collect the spin-dry product points, dry in an oven, mass spectrometry and nuclear magnetics, and verify. | ||
General procedure: Step 1: Take a dry three-mouth reaction bottle and place the magnet.Add <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (1 eq), KI (0.5 eq),It was dissolved in absolute ethanol (35 mL).After stirring for 10 min on a magnetic stirrer, trifluoroacetic acid (200 mL) was added.activation. After about 1 h, add absolute ethanol (15 mL)The dissolved substituted aniline (0.8 eq) was reacted. Note that it should be added in the form of dropping to achieve the effect of long-term excessive reaction, and the dropping time is controlled at about 1 h. Step 2: The progress of the reaction and the reaction effect were examined by the TLC method. Generally, after 36 hours of reaction, the reaction is almost complete. After the reaction is completed, the solvent is dried in absolute ethanol, and then a certain amount of ethyl acetate is added to dissolve. First remove the acid with an appropriate amount of 20% sodium bicarbonate solution, then add a certain amount of 50% sodium chloride solution to extract the layer, collect the organic layer and spin dry to a certain amount, add an appropriate amount of anhydrous sodium sulfate, Water overnight.Step 3: suction filtration, sand making, weigh 15 to 20 times of the total amount of raw materials, and collect the product points through the column. Generally use petroleum ether: ethyl acetate = 2:1 to pass the first point (aniline point), petroleum ether: ethyl acetate = 1:1 to pass the second point (pyrimidine point), ethyl acetate Or methanol rushed out of the product point. The spin-dried product points were collected, dried in an oven, mass spectrometrically and nuclear magnetically verified. |
General procedure: <strong>[5305-59-9]4-amino-6-chloropyrimidine</strong> (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene; for 24h;Heating; | General procedure: To a solution of 6-chloropyrimidin-4-amine intoluene was added substituted amine (2.5 eq). The mixture was heatedat 105 C for 24 h and concentrated in vacuo. The residue was purifiedby flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100.0℃; for 18.0h; | 5- (6-aminopyrimidin-4-yl)-2-fluorobenzonitrile: To a solution of 2-fluoro-5-(tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile (570 mg, 2.31 mmol) in 1,4-dioxane (120 niL) was added 6- chloropyrimidin-4-amine (302 mg, 2.33 mmol), Pd(Pcy3)2Cl2 (170 mg, 0.23 mmol) and a solution of sodium carbonate in water (10 M, 4.6 mL, 46 mmol) at the room temperature. The resulting solution was stirred for 18 h at 100 C. When the reaction was done, the solids in the reaction mixture were filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 80% gradient) to yield 5-(6-aminopyrimidin-4-yl)-2-fluorobenzonitrile as yellow solid (441 mg, 89%). MS: m/z = 215.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h; | 5-(6-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile: To a solution of 2-(oxan-4-yloxy)-5- (tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (525 mg, 1.59 mmol) in 1,4-dioxane (16 mL) was added 6-chloropyrimidin-4-amine (1.64 g, 12.63 mmol), Pd(pcy3)2Cl2 (324 mg, 0.44 mmol) and a solution of sodium carbonate in H20 (1.9 M, 4 mL, 7.60 mmol) at room temperature. The resulting mixture was stirred for 16 h at 100 C. When the reaction was done, the solids in the reaction mixture were filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with MeOH in EtOAc (0% to 50% gradient) to yield 5-(6-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile as light yellow solid (448 mg, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In 1,4-dioxane; ethyl acetate at 20℃; for 2h; | 82.1 Step 1: 2-(5-Chloro-2-methoxy-phenyl)-N-(6-chloropyrimidin-4-yl)acetamide A suspension of 6-chloropyrimidin-4-amine (250 mg, 1.93 mmol) and 2-(5-chloro-2- methoxy-phenyl)acetic acid (0.14 mL, 2.03 mmol) in 1 ,4-dioxane (2.5 mL) was treated wih DIPEA (1.01 mL, 5.79 mmol) followed by T3P (50% in EtOAc) (2754 pL, 2.32 mmol) andthe mixture was stirred at room temperature for 2 hours. The resulting mixture was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL) and the organic portion was separated, washed with water, dried over Na2504 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane followed by 0 to 100% MeOH in EtOAc to afford the titledcompound as an orange powdery solid.1H NMR (500 MHz, DMSO-d6) O 11.40 (5, 1H), 8.77 (d, J = 1.0 Hz, 1H), 8.07 (d, J = 1.0Hz, 1H), 7.33-7.29 (m, 2H), 7.03-6.98 (m, 1H), 3.79 (5, 2H), 3.74 (5, 3H).LC-MS (Method E): Rt 1.14 mins; MS m/z 311.9/313.9 = [M+H]+ (100% 215nm) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | General procedure: To a round-bottom flask was charged with the correspondingaromatic halogen (1.0 equiv), the corresponding boronic acid(1.05-1.25 equiv), Pd(dppf)Cl2 (0.05 equiv) and base Na2CO3 (2.0equiv) under nitrogen atmosphere, then 1,4-dioxane (14 mL) andwater (2 mL) were added and the vessel was immediately sealed tightly. The resulting mixture was heated at 95 C for a period time (usually 2-6 h) until the completion of the reaction as monitoredby TLC. The cooled mixture was diluted with water and exhaustively extracted with ethyl acetate (30 mL 3). The organic phase was washed by brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether as the eluent to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | General procedure: To a round-bottom flask was charged with the correspondingaromatic halogen (1.0 equiv), the corresponding boronic acid(1.05-1.25 equiv), Pd(dppf)Cl2 (0.05 equiv) and base Na2CO3 (2.0equiv) under nitrogen atmosphere, then 1,4-dioxane (14 mL) andwater (2 mL) were added and the vessel was immediately sealed tightly. The resulting mixture was heated at 95 C for a period time (usually 2-6 h) until the completion of the reaction as monitoredby TLC. The cooled mixture was diluted with water and exhaustively extracted with ethyl acetate (30 mL 3). The organic phase was washed by brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether as the eluent to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | General procedure: To a round-bottom flask was charged with the correspondingaromatic halogen (1.0 equiv), the corresponding boronic acid(1.05-1.25 equiv), Pd(dppf)Cl2 (0.05 equiv) and base Na2CO3 (2.0equiv) under nitrogen atmosphere, then 1,4-dioxane (14 mL) andwater (2 mL) were added and the vessel was immediately sealed tightly. The resulting mixture was heated at 95 C for a period time (usually 2-6 h) until the completion of the reaction as monitoredby TLC. The cooled mixture was diluted with water and exhaustively extracted with ethyl acetate (30 mL 3). The organic phase was washed by brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether as the eluent to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In water monomer; isopropanol for 3h; Reflux; | 3.1 Step 1: Synthesis of Compound 7-chloroimidazo[1,2-c]pyrimidine 4-amino-6-chloropyrimidine (0.84g, 6.5mmol) and 40% aqueous solution of chloroacetaldehyde (2.55g, 19.5mmol) were added in 15mL isopropanol. The mixture was heated to reflux for 3 hrs. The reaction solution was rotary evaporated to remove the solvent, diluted with 30 mL water, and extracted with EtOAc (20mL*3). The organic phases were combined, washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and separated by silica gel column chromatography to afford a pale yellow solid, 0.79g, yield: 80%. ESI-MS: 154[M++1]. |
80% | In water monomer; isopropanol for 3h; Reflux; | 3.1 Step 1: Synthesis of Compound 7-chloroimidazo[1,2-c]pyrimidine 4-amino-6-chloropyrimidine (0.84g, 6.5mmol) and 40% aqueous solution of chloroacetaldehyde (2.55g, 19.5mmol) were added in 15mL isopropanol. The mixture was heated to reflux for 3 hrs. The reaction solution was rotary evaporated to remove the solvent, diluted with 30 mL water, and extracted with EtOAc (20mL*3). The organic phases were combined, washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and separated by silica gel column chromatography to afford a pale yellow solid, 0.79g, yield: 80%. ESI-MS: 154[M++1]. |
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Precautionary Statements-General | |
Code | Phrase |
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P103 | Read label before use |
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Code | Phrase |
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P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
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P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
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P378 | |
P380 | Evacuate area. |
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P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
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P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
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P401 | |
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Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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