CAS No. : | 479691-42-4 | MDL No. : | MFCD09743711 |
Formula : | C13H19ClN4O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SPSXSTDJXLNVJF-UHFFFAOYSA-N |
M.W : | 298.77 | Pubchem ID : | 46738270 |
Synonyms : |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-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 |
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With sodium hydrogencarbonate; In ethanol; at 100℃; for 1.0h;Heating / reflux;Product distribution / selectivity; | A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 50 ml of EtOH is heated at reflux for 1 hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, corresponding to tert-butyl 4-(4-chloro-2-pyrimidinyl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, corresponding to the compound of step A), of which 12.9 g are obtained, and which is used as it is; A) tert-Butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate and tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 90 ml of EtOH is heated at 100 C. for one hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, tert-butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate, of which 12.9 g are obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In methanol; diethyl ether; at 20℃; for 18.0h; | A mixture of 1.75 g of the less polar compound obtained in the preceding step and 100 ml of 2N hydrochloric ether solution in 10 ml of MeOH is left with stirring at AT for 18 hours. It is concentrated under vacuum, the residue is taken up in ether and the crystalline product formed is isolated with suction. This gives 1.6 g of the expected product. | |
With hydrogenchloride; In diethyl ether; at 20℃; for 1.0h;Inert atmosphere; | Preparation of compound 38: A solution of compound 37 in 20 ml of ether/HCl was allowed to stir at room temperature under nitrogen atmosphere for 1 h. The excess solvent was distilled off under reduced pressure and the crude material was washed with n-pentane and dried to yield 180 mg of compound 38 in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In ethanol; hexane; ethyl acetate; | Example 4 Preparation of Intermediate 4-[4-(3-Chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-4a): A mixture of <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2*18 mL). The combined organic extracts were washed with H2O (2*10 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluding solvent to afford the title compound I-4a (93 mg) as a colorless oil. 1H NMR (400 MHz, CD3OD) delta 7.69 (d, 1H); 7.32 (s, 1H); 7.28-7.19 (m, 3H); 5.88 (d, 1H); 4.49 (s, 2H); 3.64-3.61 (m, 4H); 3.37-3.29 (m, 4H); 1.45 (s, 9H). MS (ES+) Calc: 403.2, Found: 404.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; mineral oil; | Preparation of Intermediate 4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2b): 1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7 mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg, 60% dispersion in mineral oil, 0.20 mmol). This was stirred under nitrogen for 1 hour at ambient temperature, then the reaction was treated with <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (I-2a) (50 mg, 0.17 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (20 mL) and extracted with ethyl acetate (2*25 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7:13 ethyl acetate:hexanes) to afford 64.3 mg of the title product (I-2b). 1H NMR (400 MHz, CDCl3) delta 8.00 (d, 1H); 7.38-7.13 (m, 4H); 6.35 (q, 1H); 6.02 (d, 1H); 3.62 (m, 4H); 3.30 (m, 4H); 1.57 (d, 3H); 1.45 (s, 9H). MS (APCI+) Calc: 418, Found: 419.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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73% | In toluene; at 110℃; | A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 10 (109g, 73%) as a colorless powder. 1H NMR (300MHz, CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+. |
62% | In toluene; at 110℃;Product distribution / selectivity; | (2) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62%) as a solid. 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz). |
In water; toluene; | Example 2 Preparation of Intermediate 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2a): To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2*40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a). 1H NMR (400 MHz, CDCl3) delta 8.15 (d, 1H); 6.52 (d, 1H); 3.80 (m, 4H); 3.48 (m, 4H); 1.47 (s, 9H). MS (APCI+) Calc: 298, Found: 299.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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6% | With sodium hydrogencarbonate; In ethanol; for 1.5h;Heating / reflux;Product distribution / selectivity; | (1) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours. The reaction was filtered and the filtrate was concentrated. To the residue was added methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (6.30 g, 6%). 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.45-3.52 (4H, m), 3.75-3.83 (4H, m), 6.53 (1H, d, J=4.8 Hz), 8.16 (1H, d, J=4.8 Hz). |
With sodium hydrogencarbonate; In ethanol; for 1.0h;Reflux; | Preparation of compound 37: 2,4-dichloropyrimidine (801 mg, 0.0053 mole, 1 eq), N-Boc-piperazine (1.0 gm, 0.0053 mole, 1 eq) and sodium bicarbonate (903 mg, 0.0107 mole, 2 eq) were dissolved in ethanol (50 ml) and stirred at reflux for 1 h. Progress of the reaction was monitored by TLC. The excess solvent was removed, dissolved in water and extracted with DCM. The organic layer was washed with water, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 15% ethyl acetate-hexane to afford coupled product compound 37 (230 mg). |
Yield | Reaction Conditions | Operation in experiment |
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70% | With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 14.0h;Heating / reflux; | (2) 4-phenyl-2-piperazin-1-ylpyrimidine Dihydrochloride To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (6.30 g, 20.7 mmol) and phenylboric acid (3.75 g, 31.1 mmol) in anhydrous toluene (250 ml) was added potassium phosphate (9.20 g, 41.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (480 mg, 0.83 mmol) and trisdibenzylideneacetone dipalladium (119 mg, 0.21 mmol) under nitrogen atmosphere, and the reaction was degassed and heated under reflux for 14 hours. The reaction was distilled off under reduced pressure and to the residue was added to methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate (5.00 g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20 - 95℃; | (1) 4-(2-fluorophenyl)-2-piperazin-1-ylpyrimidine Dihydrochloride To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (10 g, 33.5 mmol), 2-fluorophenyl boronic acid (7.02 g, 50.2 mmol), and 2 N aqueous sodium carbonate solution (45 ml) in 1,2-dimethoxyethane (300 ml) was added tetrakistriphenylphosphine palladium (4.64 g, 40.2 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred at 95 C. overnight. The reaction was poured into the saturated saline, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl 4-[4-(2-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
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87% | With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; hexane; water; at 20 - 60℃; for 2.0h; | (1) Tert-butyl 4-[4-(2,6-difluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (6.00 g, 20.1 mmol), 2,6-difluorophenyl boronic acid (3.80 g, 24.1 mmol), potassium fluoride (3.5 g, 60.3 mmol) in tetrahydrofuran-water (10:1)(66 ml) was added trisbenzylidene acetone dipalladium (1.80 g, 2.01 mmol) and tri-tert-butylphosphine (10 wt % in hexane) (8.4 g, 4.02 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred at 60 C. for 2 hours. The reaction solution was cooled to the room temperature, and concentrated. To the residue was poured water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain the title compound (6.60 g, 87%) as a solid. 1H-NMR (CDCl3) delta: 1.42 (9H, s), 3.32-3.42 (4H, m), 3.72-3.75 (4H, m), 6.84-6.85 (1H, m), 7.22-7.26 (2H, m), 7.54-7.62 (1H, m), 8.51 (1H, d, J=4.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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71% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 20 - 100℃; | (3) Tert-butyl 4-[4-(2,4-difluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate To a mixture of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (1.0 g, 3.35 mmol), 2,4-difluorophenylboric acid (793 mg, 5.02 mmol), 2N aqueous sodium carbonate solution (13.4 ml) and toluene (33 ml) was added tetrakistriphenylphosphine palladium (464 mg, 0.402 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 100 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (894 mg, 71%) as an oily material. 1H NMR (CDCl3) delta: 1.50 (9H, s), 3.46-3.58 (4H, m), 3.85-3.93 (4H, m), 6.83-7.08 (3H, m), 8.08-8.22 (1H, m), 8.39 (1H, d, J=5.3 Hz). |
71% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 100℃;Inert atmosphere; | General procedure: A mixture of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (1.80g, 6.02mmol), (2,4-difluorophenyl)boronic acid (1.43g, 9.04mmol), 1M aq Na2CO3 (24 mL, 48.2 mmol), tetrakis(triphenylphosphine)palladium (0) (835mg, 0.723mmol), and toluene (60mL) was stirred at 100C overnight under N2 atmosphere. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 8 (907mg, 40%) as a colorless viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine; In isopropyl alcohol; for 2.0h;Heating; Reflux; | Production Example 1062-{ 4- [2- (6~piperazin-l-ylpyrimidin-4- yl) ethyl] phenyl }acetohydrazide tetrahydrochloride step 1[0323] [0324]To a solution (60 ml) of 4, 6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs . The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 1:2) to give tert-butyl 4- ( 6-chloropyrimidin-2-yl) piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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16% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide;Inert atmosphere; | Step 4: tert-butyl 4-(4-(3-(tert-butyl)-4-(cyclopentylamino)phenyl)pyrimidin-2- yl)piperazine- 1 -carboxylate:To a solution of 2-(ie -butyl)-/V-cyclopentyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)aniline (390 mg, 1 .136 mmol) in DMF (2 ml) was added a mixture of terf-butyl 4-(2- chloropyrimidin-4-yl)piperazine-1 -carboxylate and terf-butyl 4-(4-chloropyrimidin-2- yl)piperazine-1 -carboxylate (339 mg, 1 .136 mmol) and 2M aq. Na2C03 (1 .136 ml, 2.272 mmol). The reaction mixture was degassed by bubbling nitrogen through the mixture for 10 min and then PdCI2(dppf)-CH2CI2 (93 mg, 0.1 14 mmol) was added. The mixture was heated for 16 h at 80 C under nitrogen. After cooling to RT the reaction mixture was diluted with EtOAc. The mixture was washed with brine. The organic layer was dried with Na2S04, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si02, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound (89 mg, 16%).LCMS (Method F): RT = 2.02 min, M+H+ = 480; H-NMR (500 MHz, CDCI3): 8.26 (1 H, d), 8.03 (1 H, d), 7.82 (1 H, dd), 6.88 (1 H, d), 6.73 (1 H, d), 4.25 (1 H, d), 3.96-3.93 (1 H, m), 3.90-3.88 (4H, m), 3.54-3.52 (4H, m), 2.10-2.04 (2H, m), 1 .77-1 .67 (4H, m), 1 .57-1 .55 (2H, m), 1 .50 (9H, s), 1 .45 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
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With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 95℃;Inert atmosphere; | A mixture of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (10.0g, 33.5mmol), (3,4-difluorophenyl)boronic acid (7.90 g, 50.2 mmol), 1M aq Na2CO3 (45 mL, 90.0 mmol), tetrakis(triphenylphosphine)palladium (0) (4.6 g, 4.02 mmol), and DME (300 mL) was stirred at 95 C overnight under N2 atmosphere. After cooling to room temperature, the mixture was stirred at room temperature for 15h, diluted with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo to give 14 as a brown oil. This product was used for next reaction without further purification. |