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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 4-(N-Boc-amino)piperidine; 4-(tert-Butoxycarbonylamino)piperidine; 4-(t-Butoxycarbonylamino)piperidine
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Canale, Vittorio ; Czekajewska, Joanna ; Klesiewicz, Karolina ; Papiez, Monika ; Kuziak, Agata ; Witek, Karolina , et al.
Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.
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Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane
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Purchased from AmBeed: 122536-76-9 ; 936-59-4 ; 135632-53-0 ; 404-71-7 ; 73874-95-0 ; 372-20-3 ; 98-17-9 ; 402-45-9 ; 57260-71-6 ; 122536-77-0 ; 444-30-4 ; 165800-03-3 ; 150-19-6 ; 1195-45-5 ; 2909-38-8 ; 165800-03-3
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CAS No. : | 73874-95-0 |
Formula : | C10H20N2O2 |
M.W : | 200.28 |
SMILES Code : | O=C(NC1CCNCC1)OC(C)(C)C |
Synonyms : |
4-(N-Boc-amino)piperidine; 4-(tert-Butoxycarbonylamino)piperidine; 4-(t-Butoxycarbonylamino)piperidine
|
MDL No. : | MFCD00798171 |
InChI Key : | CKXZPVPIDOJLLM-UHFFFAOYSA-N |
Pubchem ID : | 723833 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H315-H318-H335 |
Precautionary Statements: | P280-P301+P312+P330-P302+P352-P305+P351+P338+P310 |
* 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 |
---|---|---|
91% | at 20℃; for 16 h; Cooling with ice | 5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgS04 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1 -Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91 percent; ESI-MS: 279 [M+H]+ |
89% | With triethylamine In dichloromethane at 20℃; for 1 h; | EXAMPLE 4; Preparation of 4-(2-chloro-6-fluoro-benzoylamino)- 1 H-pyrazole-3 -carboxylic acid ( 1 -methanesulphonyl-piperidin-4-yl)-amide4A. 4-Amino-1H-pyrazole-3-carboxylic acid (l-methanesulphonyl-piperidin-4-yl) amideTo a stirred solution of 4-(N-BOC amino)piperidine (2.5 g, 12.5 mmoles) in dichloromethane (30 ml) was added triethylamine (2.1 ml, 15.0 mmoles), and then EPO <DP n="165"/>dropwise methanesulphonyl chloride (1.06 ml, 13.8 mmoles). The solution formed was stirred at room temperature for one hour. The reaction mixture was partitioned between EtOAc and water. The organic portion was washed with water, 2N HCl, brine, dried (MgSO4) filtered and evaporated in vacuo to give 4-(N-BOC-amino)-l- methanesulphonylpiperidine as a white solid (3.1g, 89percent). |
55% | With triethylamine In dichloromethane at 20℃; for 4 h; | General procedure: To a stirred solution of 2 (0.20 g, 1.00 mmol) in anhydrous DCM(5 mL) was added Et3N (0.42 mL, 3.00 mmol) at room temperature.Then 3a–i (3.96 mmol) was added in small portions at room temperature.The reaction was stirred for 4 h at this temperature and then quenched the reaction with saturated aqueous solution ofNaHCO3. The aqueous layer was extracted with ethyl acetate(3 10 mL). The combined organic layers were dried over anhydrousNa2SO4, filtered, and concentrated. Silica gel flash columnchromatography (EtOAc/hexanes = 1:2) of the residue gave 4a–ias the product. Dissolved 4a–i (0.34 g, 0.97 mmol) in 25 mL TFAat room temperature, the reaction was stirred at room temperature for 10 h. Distilled the TFA under vacuum and then diluted with saturated aqueous solution of NaHCO3. The aqueous layer wasextracted with ethyl acetate (3 10 mL). The combined organiclayers were dried over anhydrous Na2SO4, filtered, and concentrated.Silica gel flash column chromatography (EtOAc/hexanes =1:1) of the residue gave 5a–i as the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 1.5h;Microwave; | TEA (0.243 ML, 1.74 mmol) and 6-CHLORO-2-(METHYLTHIO) pyrimidin-4-amine (0.309 g, 1.74 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.35 g, 1.74 mmol) in NMP (4 ML). Using a Smith Microwave Synthesizer, the mixture was subjected to single- mode microwave at 150 °C for 90 minutes. The mixture was partitioned between water and EtOAc and washed (x2) with water. The organic phase was dried over magnesium sulphate and concentrated to give the title compound (0.294 g). MS (ES) (MH+) : 340 for CL6H26N402S |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In dimethyl sulfoxide; at 120℃; for 17h; | tert-Butyl {l-[4-(trifluoromethyl)pyridin-2-yl]piperidin"4-yl}carbamate; A solution of <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (1.0Og, 4.42mmol), tert-butyl piperidine-4- ylcarbamate (0.93g, 4.65mmol) and TEA (0.67mL, 4.86mmol) in DMSO (5mL) was heated at 1200C for 17h. The reaction mixture was evaporated to dryness, Et2O was added, and the organic phase was washed with water, brine and evaporated to dryness. The residue was purified using the Biotage Horizon HRFC system eluting with 22percent EtOAc in petroleum ether EPO <DP n="195"/>(40-60°C) to give the title compound (1.08g, 71percent) as a solid. 1H NMR(500MHz, CDCl3): 8.30 (d, IH), 6.82 (s, IH), 6.77 (d, IH), 4.49 (bs, IH), 4.36-4.22 (m, 2H), 3.74 (bs, IH), 3.06 (td, 2H), 2.10-2.04 (m, 2H), 1.56-1.38 (m, 11H); 13C NMR(CDCl3): 159.4, 155.4, 149.5, 140.1, 139.9, 124.5,122.4, 108.1, 102.7, 79.8, 48.3, 44.4, 32.3, 28.6; Mass Spectrum: M+H 5 346. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1) (1 g, 4.64 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1 .92 g, 13.92 mmol, 3 eq) and tert-buty piperidin-4-yl carbamate (2) (1 g, 5.35 mmol, 1.2 eq) at 0C. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water and extracted with Ethyl acetate (2 X 70 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and concentrated under reduced pressure to afford crude. The crude purified by trituration with diethyl ether to afford tert-butyl (l -(6,7-dimethoxyquinazolin-4-yl) piperidin-4-yl) carbamate (01) (1.45 g, yield: 88%) as white solid. TLC system MeOH:DCM (5:95), Rf value:0.25; LCMS (m/z): 389.3 (M+H)+; 'HNMR (400 MHz, DMSO-d6) d 8.52 (s, 1H), 7.20 (s, 1H), 7.08 (s, 1H), 6.92 (d, ./= 7.6 Hz, 1H), 4.1 1-4.07 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.57-3.75 (m, 1 H), 3.15 (t, ./ = 1 1.6 Hz, 2H), 1.91-1.89 (m, 2H), 1 .64-1 .54 (m, 2H), 1.40 (s, 9H). |
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | EXAMPLE 21; N-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-2-(4-isopropyl-phenyl)-acetamide (Compound No. 21); a. [1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester; To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h; | [1-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester.; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (50.0 mg, 0.197 mmol) in DMF (0.5 mL) is added piperidin-4-yl-carbamic acid fert-butyl ester (83.0 mg, 0.394 mmol) and K2CO3 (55.0 mg, 0.394 mmol) at rt. The reaction mixture is heated to 900C and stirred for 5 h.(Alternatively, the two reagents are heated at 90 0C for 3-5 h using pure 1-methyl-pyrrolidin-2- one as solvent and DIPEA as base). The reaction mixture is cooled to rt, diluted with EtOAc and washed with H2O. The organic layer is separated and the aqueous layer is extracted with EtOAc (3x). The combined organic layers are dried over MgSO4, filtered, and evaporated to dryness. The residue is purified by FCC (SiO2, gradient elution, CH2CI2 / MeOH 100:0 → 90:10, 26 min) to yield the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In tetrahydrofuran; at 50℃; for 2h; | Reference Example 35 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-nitropyridine-4-carboxylic acid [Show Image] A solution of <strong>[907545-47-5]2-chloro-5-nitropyridine-4-carboxylic acid</strong> (1.50 g, 7.41 mmol), tert-butyl piperidin-4-ylcarbamate (1.48 g, 7.41 mmol) and triethylamine (3.1 mL, 22.2 mmol) in THF (19 mL) was stirred with heating at 50°C for 2 hr. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1 to 1:0) to give the title compound (1.57 g, yield 58percent) as a powder. EI(pos) 311.1 [M+H-tBu]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; | 4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide To a cooled (0 degrees) mixture of 3.7 g (0.019 mole) of piperidin-4-yl-carbamic acid tert-butyl ester in 60 mL of dichloromethane, was added 2.1 g (0.020 mole) of triethylamine, followed by 4.2 g (0.017 mole) of <strong>[357913-53-2]3-(methylsulfonyl)-1-propanol-1-methanesulfonate</strong>. The mixture was stirred at room temperature for 18 hours, then diluted with water and the organic layer washed twice with 40 mL of water, once with 40 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with dichloromethane-methanol (gradient, 100:0-90:10) to give 3.6 g of [1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 0.5 g (2.8 mmol) of <strong>[60211-57-6]3,5-dichlorobenzyl alcohol</strong> and 0.55 g (3.4 mmol) of 1,1' carbonyldiimidazole (CDI) are dissolved in 10 ml of CH2Cl2 and stirred at RT for 3 h. 0.56 g (2.8 mmol) of 6 are then added and stirred at RT for 18 h. The mixture is washed with water. The organic phase is then dried over sodium sulfate, filtered off, and the solvent is evaporated in vacuo. The residue is purified by means of preparative HPLC, giving 1.0 g (88%) of 7 as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20.0℃; for 1.0h;Inert atmosphere; | Diisopropylethylamine (1.74 ml, 9.98 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.25 g, 1.25 mmol) in DCM (5 ml) at room temperature.To this mixture was added <strong>[64835-30-9]3-chloro-4-nitrobenzene sulfonyl chloride</strong> (0.32 g, 1.25 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour.After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated.The resulting residue was purified by flash column chromatography (elution: percent EtOAc: percent Heptane) to give the title compound (0.44 g, 84percent yield) as a white solid. deltaH (500 MHz, DMSO) 7.97-8.12 (m, 3H) 6.93 (d, J=7.72 Hz, 1H) 3.64 (d, J=12.77 Hz, 2H) 3.43 (d, J=3.94 Hz, 2H) 2.88-3.00 (m, 2H) 1.78 (d, J=10.40 Hz, 2H) 1.25-1.46 (m, 11H). Tr=2.22 min, m/z (ES+) (M+Na)+ 442. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 59 3,5-Dichlorophenethyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate The title compound was prepared from commercially available tert-butyl piperidin-4-ylcarbamate and <strong>[93427-13-5]2-(3,5-dichlorophenyl)ethanol</strong> analogously to Example 51 steps 2-4; LC-MS: Rt 1.24 mins; MS m/z 454.3, 456.3 [M+H]+; Method 2minLowpHv03 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; 1,1'-carbonyldiimidazole; In ethyl acetate; N,N-dimethyl-formamide; | Step 1: 3,5-Dichlorobenzyl 4-(tert-butoxycarbonylamino)piperidine-1-carboxylate A mixture comprising tert-butyl piperidin-4-ylcarbamate (5 g, 24.97 mmol), <strong>[60211-57-6]3,5-dichlorobenzyl alcohol</strong> (4.42 g, 24.97 mmol) and carbonyldiimidazole (4.05 g, 24.97 mmol) in DMF (83 ml) was heated at 50 C. with stirring for 3 days. The resulting mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and washed with 1M HCl, a saturated solution of sodium bicarbonate and brine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In acetonitrile; at 20℃; for 4h; | 4-N-Boc-aminopiperidine (0.96 g, 4.78 mmol) was added lot wise to a well stirred suspension of 2-bromo-5-nitro thiazole (1 g, 4.78 mmol) and potassium carbonate (0.79 g, 5.74 mmol) in acetonitrile (15 mL). The reaction mixture was then stirred at room temperature for about 4 h (monitored by TLC & LCMS for completion), and solvent evaporated under reduced pressure. The residue was further diluted with water (10 mL) and ethyl acetate (20 mL) and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2 * 15 mL) and the combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure and the residue purified by column chromatography using hexane/ethylacetate as eluent to give the desired product 2 (1.32 g, 84percent) as yellow solid. 1H NMR (DMSO-d6): deltaH 1.39 (s, 9H), 1.44-4.03 (m, 9H), 8.38 (s, 1H), 13C NMR (DMSO-d6): deltac 171.9, 154.8, 147.6, 135.7, 77.8, 47.1, 46.1, 30.7, 28.2. ESI-MS m/z 329.1 (M+H)+. Anal. Calcd for C13H20N4O4S: C, 47.55; H, 6.14; N, 17.06. Found: C, 47.52; H, 6.11; N, 17.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 24h;Molecular sieve; | To 1 equivalent of tert-butyl piperidin-4-ylcarbamate (4) dissolved in DCM was added 1 equivalent of <strong>[17794-48-8]N-(3-(trifluoromethyl)benzoyl)glycine</strong>, 1 equivalent of PyBroP, 0.8 equivalents of 4-dimethylaminopyridine, 3 equivalents of N,N-diisopropylethylamine and molecular sieves 4 . The reaction mixture was stirred for 24 h at room temperature. The product was extracted with DCM/ 1 M NaOH. The organic layer was washed with brine, dried over MgSO4 and evaporated. The intermediate was purified by column chromatography (50/50 EtOAc in DCM). 1H NMR (400 MHz, CDCl3) delta: 8.13 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 (br s, 1H), 4.65-4.50 (m, 2H), 4.70 (dd, J = 22.4, 3.6, Hz, 2H), 3.82-3.72 (m, 2H), 3.23-3.15 (m, 1H), 2.88 (t, J = 12.0 Hz, 1H), 2.15-2.00 (m, 2H), 1.47 (s, 9H), 1.41-1.30 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Part F: tert-butyl (l-((7-bromo-4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2, 1- fjf 1, 2, 4]triazin-5-yl)methyl)piperidin-4-yl)carbamate To a solution of N-((7-bromo-4-chloropyrrolo[l,2- J[l,2,4]triazin-5- yl)methyl)-N,N-diethylethanaminium (0.5 g, 1.442 mmol) in dry acetonitrile (10 mL) in a microwave tube flushed with nitrogen was added <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (0.231 g, 1.442 mmol). The reaction tube was capped and heated in the microwave at 75C for 30 min. To the reaction mixture was added tert-butyl piperidin-4-ylcarbamate (0.289 g, 1.442 mmol) and DIEA (0.252 mL, 1.442 mmol). The reaction tube was capped again and heated in a microwave at 75C for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane/ethyl acetate/0.5% TEA) to obtain tert-butyl l-((7-bromo-4-(3- (oxazol-5 -yl)phenylamino)pyrrolo [ 1 ,2-f [ 1 ,2,4]triazin-5 -yl)methyl)piperidin-4- ylcarbamate (0.398 g, 0.700 mmol, 49 % yield). LCMS (ESI) m/e 568.2, 570.2 Br pattern [(M+H)+, calcd for C26H3iBrN703 568.2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Part B. tert-butyl (l-((4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2,l-fj [1,2,4] triazin- 5-yl)methyl)piperidin-4-yl)carbamate To a solution of N-((4-chloropyrrolo[l,2: ][l,2,4]triazin-5-yl)methyl)-N,N- diethylethanaminium, bromide salt (0.1 g, 0.288 mmol) in dry acetonitrile (4 mL) in a microwave tube flushed with nitrogen was added <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (0.046 g, 0.288 mmol). The reaction tube was capped and heated in a microwave at 75C for 30 min. To the reaction mixture was added 4-(N-BOC amino)-piperidine (0.058 g, 0.288 mmol) and DIEA (0.126 mL, 0.719 mmol). The reaction tube was capped again and heated in a microwave at 75C for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: ethyl acetate containing 0.5% TEA). Obtained tert-butyl 1 -((4-(3-(oxazol-5-yl)phenylamino)pyrrolo[ 1 ,2- J [1 ,2,4]triazin-5- yl)methyl)piperidin-4-ylcarbamate (0.099 g, 0.202 mmol, 70 % yield) as a yellow solid. LCMS (ESI) m/e 490.2 [(M+H)+, calcd for C26H32N7O3 490.3]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130.0℃; for 16.0h;Inert atmosphere; | [0188] To a stirred solution of 4-iodo-6-methoxypyrimidine (500 mg, 2.12 mmol) in (0423) NMP (5 mL) was added diisopropylethylamine (383 mg, 2.96 mmol) and tert-butyl piperidin- (0424) 4-ylcarbamate (550 mg, 2.75 mmol) and purged with argon for 15 min. The reaction mixture was heated to 130 C and stirred for 16 h. After consumption of the starting materials (0425) (monitored by TLC), the mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 10-30% EtOAc:hexanes to afford tert-butyl (l-(6-methoxypyrimidin- (0426) 4-yl) piperidin-4-yl) carbamate (400 mg, 61%) as an off-white solid. 1H-NMR (DMSO-< 5, 500 MHz): delta 8.22 (s, 1H), 6.84-6.82 (m, 1H), 6.06 (s, 1H), 4.24-4.21 (m, 2H), 3.81 (s, 3H), 3.51 (br s, 1H), 2.94 (t, 2H), 1.75-1.73 (m, 2H), 1.38 (s, 9H), 1.30-1.22 (m, 2H); LC-MS: 308.9 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 2.45 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 mupiiota); RT 1.67 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc:hexanes (Rf. 0.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
900 mg | With acetic acid; In chloroform; at 20℃; for 1h; | (1) To a solution of the compound 1 (2.0 g) in chloroform (5 mL) were added the compound 2 (1.24 g) and aceticacid (0.63 mL), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, and then extracted 3 times with chloroform. The resultingorganic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol; gradient:100:0-95:5), and dried to give the compound 3 (900 mg) as a brown solid.MS (APCI) 296 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
102.5 g | With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 25 - 75℃; for 5h; | <strong>[182438-98-8]9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide</strong> compound of formula-4a (100 gm) and sodium iodide (3.5 gm) were added to a mixture of tert-butyl piperidin-4-ylcarbamate compound of formula-S (47 gm), diisopropylethyl,amine (121 gm) and N,N-dimethylformamide (300 ml) at 25-30C. Heated the reaction mixture to 70-75Cand stirred for 5 hrs at thesame temperature. Cooled the reaction mixture to 25-30C, water was added and stirred for 15 mm at the same temperature. Ethyl acetate was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilledwith n-heptane under reduced pressure. Cooled the reaction mixture to 25-30C, tetrahydroftiran (200 ml) was added and stirred for 15 mm at the same temperature. nHeptane (800 ml) was added to the reaction mixture at 25-30C. Heated the reaction mixture to 75-80C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25- 30C. Filtered the reaction mixture through hyflow bed and washed with n-heptane. Distilledoff the solvent completely from the filtrate and under reduced pressure. Tetrahydrofuran (50 ml) and n-heptane (400 ml) were added to the obtained compound at 25-30C. Heated the reaction mixture to 95-100C and stirred for 40 mm at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 40 mm at the same temperature. Filtered the precipitated solid and washed with a mixture of tetrahydrofuran and n-heptane and then driedthe material to provide the title compound. PXRD pattern of obtained compound is shown in figure-6. Yield: 102.5 gm; M.R: 135-138C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In acetonitrile;Reflux; | General procedure: A mixture of the protected 4-(N-Boc-amino)piperidine (1.2 equiv), the corresponding fluorinated derivatives (Ia-d) (1.0 equiv), K2CO3 (1.5 equiv) and acetonitrile (30mL) was heated at reflux for 24h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50mL) and washed with water (3×30mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by gradient elution glass-column chromatography on silica gel using DCM/MeOH (v/v) as an eluent or gradient elution automated flash chromatography eluting with DCM/MeOH (v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 7h;Inert atmosphere; | General procedure: Solid K2CO3 (2 equiv) was added to a solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (1 equiv) and amine (1 equiv) in DMF(20 mL), and the resulting solution was stirred at 110 °C for 7 h.The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (ethyl acetate: hexane= 4:1) to yield pure product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 17h; | Step 1: tert-Butyl 1-(2-cyano-6-fluorophenyl)piperidin-4-ylcarbamate A mixture of <strong>[425379-16-4]2-bromo-3-fluoro-benzonitrile</strong> (3.00 g, 15.00 mmol), tert-butyl N-(4-piperidyl)carbamate (3.61 g, 18.00 mmol), Pd2(dba)3 (1.37 g, 1.50 mmol), BINAP (932.95 mg, 1.50 mmol) and tBuONa (2.16 g, 22.50 mmol) in toluene (50.00 mL) was charged with N2 for three times, then stirred at 90 C. for 17 h. The reaction mixture was cooled down to rt and concentrated to give a residue which was purified by a flash column (10% to 22% of EtOAc in PE) to afford tert-butyl N-[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]carbamate (4.00 g, 83% yield) as a yellow solid. MS (EI+, m/z): 320.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.666667h; | A mixture of <strong>[1008451-58-8]4-chloro-3-formyl-2-methoxypyridine</strong> (0.43 g, 2.51 mmol), 4- Boc-aminopiperidine (0.7 g, 3.5 mmol), and DIEA (1.0 mL, 2.5 eq.) in ACN (14 mL) was stirred at 100 C for 40 min. After removal of the volatile solvent, the residue was purified by column chromatography to afford the title compound (0.84 g, 100%). MS (M+H)+: 336.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl acetamide; at 120℃; | tert- Butyl piperidin-4-ylcarbamate (commercial, 500 mg, 3.22 mmol) was dissolved in DMA (10 ml_) and <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (552 mg, 3.22 mmol) was added followed by potassium carbonate (2.23 g, 16.1 mmol). The suspension was heated to 120C and stirred overnight before cooling and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and subsequently dried (anh. MgS04) and concentrated in vacuo to give the crude product (1.1 g, 78%) as an orange solid which was taken on as such into the next step. LCMS (Method B): RT = 1.45 min, m/z = 352 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
950 mg | With potassium carbonate; In acetonitrile; at 85℃; for 5h; | Dissolve 2-fluoro-3chloronitrobenzene (750mg, 4.27mmol), N-Boc-4-aminopiperidine (855.69mg, 4.27mmol), potassium carbonate (1.18g, 8.54mmol) in 20mL acetonitrile,React at 85C for 5h. After the temperature dropped to room temperature, ethyl acetate and water were added for extraction, the organic layer was dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain 950 mg of brown solid and used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.75 g | With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 4h; | A solution of <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (560 mg, 3.0 mmol), TEA ( 0.6 g, 6.0 mmol) and tert-butyl piperidin-4-ylcarbamate (1.2 g, 6.0 mmol) in DMF (5 mL) was stirred at 80oC for 4 hrs. The DMF was removed under reduced pressure. The residue was purified by silica gel column (PE/EA = 1/1) to give tert-butyl (1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin- 4-yl)carbamate (0.75 g, yield: 71%) as a white solid. MS: m/z 349.2 (M+H+). |
Tags: 4-Boc-Aminopiperidine | 4-(N-Boc-amino)piperidine | Piperidines | Amines | Amides | Carbamates | Organic Building Blocks | Heterocyclic Building Blocks | 73874-95-0
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