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CAS No. : | 87120-72-7 | MDL No. : | MFCD01076201 |
Formula : | C10H20N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LZRDHSFPLUWYAX-UHFFFAOYSA-N |
M.W : | 200.28 | Pubchem ID : | 1268291 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.9 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 59.3 |
TPSA : | 55.56 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) : | -7.0 cm/s |
Log Po/w (iLOGP) : | 2.44 |
Log Po/w (XLOGP3) : | 0.73 |
Log Po/w (WLOGP) : | 0.96 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | 0.32 |
Consensus Log Po/w : | 1.06 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.34 |
Solubility : | 9.08 mg/ml ; 0.0453 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.48 |
Solubility : | 6.7 mg/ml ; 0.0335 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.92 |
Solubility : | 24.1 mg/ml ; 0.12 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.12 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
47% | Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17 h; Stage #2: With acetic acid In dichloromethane at 0 - 20℃; for 16 h; |
tert-Butyl 4-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-1-carboxylate; tert-Butyl 4-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-1-carboxylate was synthesised as described in J. Med. Chem., 2005, 48, 5921. A solution of 2-bromo-1-phenylethanone (5 g, 25 mmol) in DCM (10 ml) was added dropwise to a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (6 g, 30 mmol) and DiPEA (9.84 ml, 57.5 ml) in DCM (50 ml) over 1 hour, the reaction mixture was then stirred at room temperature for 16 hours. Sodium cyanate (3.41 g, 52.5 mmol) was added, the reaction mixture was then cooled to 0° C., the pH was brought to pH 4 with acetic acid and the reaction mixtures was stirred from 0° C. to RT over 16 hours. The reaction mixture was poured into water and extracted with DCM (3.x.). Organics combined, washed with water (3.x.), brine, dried (MgSO4) and evaporated to dryness. The residue was triturated with ether, filtered and the solid was washed with ether to give a pale yellow solid (4.04 g, 47percent). LC/MS (10percent to 99percent): M/Z (M+H)+ (obs)=344; tR=3.01. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine In pyridine 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 MgSO4 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: 91percent; ESI-MS: 279 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃; for 0.666667h;microwave irradiation; | Step 2: 2-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester A mixture of <strong>[149849-94-5]2-chloro-pyrimidine-4-carboxylic acid methyl ester</strong> (0.62 g, 3.59 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 4.31 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (0.73 mL, 0.56 g, 4.31 mmol, 1.2 equiv) in acetonitrile (60 mL) was heated by microwave irradiation to 110 C. After stirring for 40 min, the reaction mixture was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluding with a gradient of heptane/ethyl acetate providing 0.48 g (34%) of the title compound. MS (ISP): 337.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 25℃; for 16h; | Step 1: 4-(4-Chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester To a stirred solution of <strong>[3638-04-8]2,4-dichloro-6-methoxy-1,3,5-triazine</strong> (10.0 g, 55.6 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 55.6 mmol, 1.0 equiv) in acetonitrile (300 mL) was added drop by drop N-ethyl diisopropylamine (48.5 mL, 36.6 g, 278 mmol, 5.0 equiv) keeping the temperature below 25 C. After stirring the reaction mixture at rt for 16 h, the heterogeneous mixture was poured onto ice water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluding with a gradient of dichloromethane/methanol to give 11.4 g (60%) of the title compound as a off-white foam. MS (ISP): 344.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In N,N-dimethyl-formamide; at 60℃; for 4h; | A mixture of <strong>[94741-69-2]4-amino-2-chloro-pyrimidine-5-carbonitrile</strong> (2.0 g, 12.94 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 15.53 mmol, 1.2 equiv; commercially available) in anhydrous DMF (20 mL) was heated to 60 C. for 4 h. The organic phase was concentrated under reduced pressure and the crude product purified by crystallization from ethyl acetate providing 3.02 g (74%) of the title compound. MS (ISN): 317.1 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine; In acetonitrile; at 150℃; for 0.5h;microwave irradiation; | A mixture of <strong>[22536-62-5]2-chloro-5-phenyl-pyrimidine</strong> (1.2 g, 6.29 mmol, 1.0 equiv; commercially available from Acme Bioscience Inc., USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.52 g, 12.59 mmol, 2.0 equiv; commercially available) and triethylamine (1.75 mL, 1.27 g, 12.59 mmol, 2.0 equiv) in anhydrous acetonitrile (5 mL) was heated by microwave irradiation to 150 C. for 30 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluding with a gradient of heptane/ethyl acetate providing 1.06 g (48%) of the title compound. MS (ISP): 355.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[175278-17-8]2-bromo-4-(trifluoromethyloxy)aniline</strong> (5.1 g), in 1 ,4-dioxane (30 ml.) was treated with bis(trichloromethyl) carbonate (2.2g). The mixture was heated to 1000C to give a clear solution then allowed to cool to ambient temperature. The solvent was evaporated and the residue was dissolved in dichloromethane (70ml) and 1 ,1- dimethylethyl 4-amino-1 -piperidinecarboxylate (4.0 g) was added. The mixture was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was loaded onto a silica gel chromatography column which was eluted with hexane/ethyl acetate 0-100% followed by chromatography on silica gel eluted with dichloromethane/methanol 0-10% to give the title compound as a white solid from diethyl ether (4.3 g).1HNMR delta (DMSO, 400 MHz): 1.25 (2H, m), 1.40 (9H, s), 1.79 (2H, m), 2.93 (2H, broad), 3.64 (1 H, m), 3.80 (2H, m), 7.21 (1 H, d), 7.35 (1 H, d), 7.66 (1 H, s), 7.91 (1 H, s), 8.19 (1 H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | To the solution of compound 8 (0.23g, 1.2mmol) in THF (5mL) was added DIPEA (1.8mmol) and bicyclic amine or piperidin amine (1.44mmol). The reaction was stirred at r.t. for overnight. Then the mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography to give the product. 4.1.4 40 tert-butyl 4-((2-chloro-6, 7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (9) (0018) Yellow solid, 87% yield. 1H NMR (600MHz, CDCl3) delta (pmm): 4.35 (d, J=7.6Hz, 1H), 4.27-4.01 (m, 3H), 3.02-2.83 (m, 4H), 2.60 (t, J=7.4Hz, 2H), 2.20-2.09 (m, 2H), 2.08-1.98 (m, 2H), 1.46 (s, 9H), 1.33(m, 2H). MS-ESI: [M-H]-:351.2. |
47% | Step 2: 4-(2-Chloro-6,7-dihydro-5Jf-cyclopentapyrimidin-4-ylamino)-piperidine-l- carboxylic acid tert-butyl ester; A mixture of 2,4-dichloro-6,7-dihydro-5Jf-cyclopentapyrimidine (2.71 g, 14.34 mmol, 1.0 equiv) and 4-amino-piperidine-l -carboxylic acid tert-butyl ester (3.45 g, 17.20 mmol, 1.2 equiv) in anhydrous DMF (40 mL) was heated to 60 0C for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3 x 50 mL). The combined organic phases were dried over MgStheta4 and the product purified with column chromatography on silica eluting with a gradient of heptane/ ethyl acetate (14:3 ? 1:1) providing 2.34 g (47%) of the title compound. 1H NMR (300 MHz, DMSO): delta 1.32-1.43 (m, 2H), 1.39 (s, 9H), 1.79-1.82 (m, 2H), 2.0 (quint, / = 7.5 Hz, 2H), 2.61 (t, / = 7.5 Hz, 2H), 2.70 (X, J = 7.5 Hz, 2H), 2.80-2.88 (m, 2H), 3.93-3.98 (m, 2H), 4.04-4.13 (m, IH), 7.07 (d, / = 8.0 Hz, IH). 13C NMR (75 MHz, DMSO): (521.12, 26.42, 28.04, 31.17, 33.19, 42.55, 47.12, 78.53, 114.87, 153.84, 157.95, 159.02, 172.18. MS (ISP): 353.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 160℃; for 0.333333h;Microwave irradiation; | Intermediate CI l; Piperidin-4-yl-(2,5,6-trichloro-pyrimidin-4-yl) -amine dihydrochloride; Step 1: 4-(2,5,6-Trichloro-pyrimidin-4-ylamino)-piperidine-l-carboxylic acid tert-butgammal ester; A solution of 2,4,5,6-<strong>[1780-40-1]tetrachloro-pyrimidine</strong> (1.67 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-l-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160 0C for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ ethyl acetate providing 0.85 g (29%) of the title compound. 1H NMR (400 MHz, DMSO): delta 1.41 (s, 9H), 1.49-1.60 (m, 2H), 1.73-1.77 (m, 2H), 2.81 (br s, 2H), 3.95-3.98 (m, 2H), 4.09-4.16 (m, IH), 7.88 (d, / = 8.0 Hz, IH). 13C NMR (100 MHz, DMSO): (528.07, 30.45, 43.33, 48.90, 78.65, 109.37, 153.80, 154.62, 155.66, 158.74. MS (ISP): 383.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Example AC; Example AC was prepared following the procedures for steps I-III (Scheme 20) for Example Z, with the exception that tert-butyl 4-amino-l- piperidinecarboxylate was used instead of tert-butyl 2-aminoethylcarbamate (Compound 62). After Combiflash purification, 60 mg (44%) of Example AC was obtained, m/z: 537.1 (M+H)+. 1H NMR (CDCk) delta 8.82 (s, IH); 7.87 (s, IH); 6.97 (s, IH); 5.82 (br s, IH); 5.30 (m, 3H); 4.80-4.40 (m, 5H); 4.03 (m, IH); 3.72 (br s, IH); 3.34 (m, IH); 3.18 (m, IH); 3.01 (s, 3H); 2.79 (m, IH); 2.20-1.90 (m, 4H); 1.40 (d, /=7 Hz, 6H); 0.97, 0.90 (d, /=7 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 80℃; for 6h; | A stirred suspension of <strong>[42521-09-5]2,6-dichloro-isonicotinic acid methyl ester</strong> (4.52 g, 21.9 mmol 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.39 g, 21.9 mmol, 1.0 equiv), palladium(II) acetate (0.50 g, 2.2 mmol, 0.1 equiv) and rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (1.39 g, 2.2 mmol, 0.1 equiv) in toluene (150 mL) was treated at rt with caesium carbonate (9.39 g, 28.5 mmol, 1.3 equiv) and then warmed to 80 C. After 6 h, the reaction mixture was poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 5.40 g (67%) of the title compound as a light yellow solid. MS (ISP): 370.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium phosphate; copper(l) iodide; N,N-diethylsalicylamide; In N,N-dimethyl-formamide; at 90℃; for 24h; | Step 2: 4-(Pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester A mixture of <strong>[38696-20-7]5-bromo-2-phenyl-pyrimidine</strong> (3.50 g, 14.89 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.48 g, 22.33 mmol, 1.5 equiv), copper(I) iodide (0.28 g, 1.49 mmol, 0.1 equiv), N,N-diethylsalicylamide (0.58 g, 2.98 mmol, 0.2 equiv) and K3PO4 (3.16 g, 14.89 mmol, 1.0 equiv) in degassed DMF (30 mL) was heated under Ar to 90° C. for 24 h. The solvent was removed under reduced pressure and the crude reaction product extracted from water (300 mL) and 25percent NH4OH (30 mL) with ethyl acetate (3*300 mL). The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluding with a gradient of heptane/ethyl acetate (4:1-->1:1) to provide 1.98 g (38percent) of the title compound. MS (ESI): 377.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 18h; | Add sodium triacetoxyborohydride (30. 50 g, 144 mmol) to a stirred solution of 4- amino-1-N Boc-piperidine (18.00 g, 89.9 mmol), <strong>[104146-17-0]4-chloro-thiazole-5-carbaldehyde</strong> (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1, 2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3 X 150 mL). Wash the ethyl acetate with brine (2 X 150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75percent ethyl acetate/hexanes then with 100 percent ethyl acetate to yield 21.78 g (74percent) of 4-f [ (4-chloro-thiazol-5-yl) methyl]-amino}- piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z = 332.1 (M+1) ; IH NMR (CDC13) : 8 = 8.67 (s, 1H), 4.10-4. 02 (m, 4H), 2.88-2. 82 (m, 2H), 2.74- 2.67 (m, 1H), 1.92-1. 89 (m, 2H), 1.49 (s, 9H), 1.37-1. 28 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 88a) tert-butyl 4-(((2,5-dimethyl-1H-imidazol-4-yl)methyl)amino)-1-piperidinecarboxylate N-(tert-butoxycarbonyl-4-piperidinyl)amine (4.8 g), <strong>[68282-52-0]2,5-dimethylimidazole-4-carbaldehyde</strong> (3.0 g) and acetic acid (1.7 ml) were dissolved in 1,2-dichloroethane (50 ml), under ice-cooling, sodium triacetoxyborohydride (7.7 g) was added thereto, and mixed at room temperature for 15 hours. The reaction solution was poured into an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified with silica gel column to obtain a pale yellow oily title compound (8.0 g, quantitative). NMR (CDCl3) delta:1.27-1.40 (2H, m), 1.45 (9H, s), 1.85-1.90 (2H, m), 2.15 (3H, s), 2.31 (3H, s), 2.66-2.80 (3H, m), 3.71 (2H, s), 4.00-4.18 (2H, m), 6.06 (2H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h; | 1 ,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 mL) was treated under argon at room temperature with 1 ,1-dimethylethyl 4-amino-1- piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70 (?80) 0C for 38h. The mixture was concentrated under vacuum, treated with water and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under vacuum to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether 6 CV) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H = 298.07, main fragment (molecule has lost its tert-butyl group) |
64% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h; | 1 ,4-Difluoro-2-methyl-5-nitrobenzene (D30, 1.5 mol, 260 mg) in dimethylformamide (10 ml.) was treated under argon at room temperature with 1 ,1-dimethylethyl 4-amino-1- piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70-80 0C for 38h. The mixture was concentrated under reduced pressure, treated with water and extracted twice with ether. Organics were combined, dried over MgSO4 and concentrated under reduced pressure to give a red- brown residue which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H-'Bu = 298.07, main fragment. |
64% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h; | Description 11; . 1,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1- piperidine-carboxylate (D11); .1 ,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 ml.) was treated under argon at room temperature with commercially available 1 ,1- dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70-80 0C for 38h. The mixture was concentrated under reduced pressure, treated with water and extracted twice with ether. The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H-'Bu = 298.07, main fragment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 75℃; | 1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (D22) (1.5 mmol, 284 mg) in dimethylformamide (5ml_) was treated under argon at room temperature with 1 ,1- dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 194 mg, 1 eq) then stirred at 75 C overnight. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous EPO <DP n="56"/>solution and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a clean orange solid (1.46 mmol, 539 mg, 97% yield). M-H = 368.16 |
88% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h; | Description 21. 1,1-Dimethylethyl 4-[(4-chloro-5-methyl-2-nitrophenyl)amino]-1- piperidinecarboxylate (D21).A solution of <strong>[170098-88-1]1-chloro-4-fluoro-2-methyl-5-nitrobenzene</strong> (D20, 473mg, 2.5mmol) in DMF (7ml) was treated with diisopropylethylamine (49OuI, 2.75mmol) followed by addition of 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (500mg, 2.5mmol), then heated at 60 0C under argon with stirring for 12 hours. The reaction mixture was concentrated under vacuum and the residue treated with NaHCO3 solution (50ml) and extracted with dichloromethane (2 x 50ml). The combined extract was concentrated under vacuum and the residue purified by chromatography on silica gel eluting with dichloromethane to afford the title compound (808mg, 88%). 1H NMR delta (CDCI3): 1.45-1.60 (13H, s + m), 2.02-2.08 (2H, m), 2.38 (3H, s), 3.02-3.12 (2H, m), 3.60-3.70 (1 H, m), 6.72 (1 H, s), 8.04 (1 H, br d), 8.18 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 17h; | A solution of <strong>[170098-98-3]1-bromo-4-fluoro-2-methyl-5-nitrobenzene</strong> (D33) (3 mmol, 702 mg) in dry dimethylformamide (20 ml.) was treated with 1-Boc-4-piperidinamine (3 mmol, 601 mg, 1eq) and diisopropylethylamine (3 mmol, 520 mul_, 1eq), and the mixture stirred under argon and heated to 80 0C for 17h. The reaction mixture was concentrated under reduced pressure, water added and the product extracted using ethyl acetate (chi2). The organic layers were combined, dried (MgSO4) and the solvent removed under reduced pressure to afford the product as an orange solid (2.3 mmol, 0.95 g, 77%). MH+=360.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; | 4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc- piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1- carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340). | |
With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; | 4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc- piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1- carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340). | |
Add 6.31 kg of raw material to a 100 L reactor, N,N-dimethylformamide (45 L), carbodiimide (6.59 kg), 1-hydroxybenzotriazole (4.65 kg), stirred for 0.5 h, The ice water bath was cooled to 0 to 10 C, and the starting material 1 (4.5 kg) was added in portions, and then the temperature was raised to 20-25 C, and the reaction was stirred for 16 hours. The reaction solution was added to 270 L of water, and a solid was precipitated, suction filtered, washed, and separated, and the organic phases were combined and dried |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; | Preparation of tert-butyl 4-[5-fluoro-4-(methoxycarbonyl)-2- nitrophenyl]amino}piperidine-1-carboxylate; <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (32.6 g, 150 mmol) was dissolved in 100 mL N, N- dimethylformamide, added 4-amino-1-Boc-piperidine (30.7 g, 153 mmol), washed sides of flask with 100 mL N,N-dimethylformamide, added N,N-diisopropylethylamine and stirred reaction at ambient temperature for 3 days. The solution was diluted with 500 mL diethyl ether, washed with water (2 x 250 mL), 0.5M hydrogen chloride (2 x 250 mL), brine (250 mL), dried with magnesium sulfate, filtered and concentrated to yield title compound slightly wet with diethyl ether. (62.4 g, quant yield) APCI" 396.2; Anal. HPLC Retention time = 20.2 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine; In methanol; at 20℃; | To a solution of <strong>[15365-25-0]2-bromomethyl-4-methoxy-benzoic acid methyl ester</strong> (1.28 g, 4.94 mmol, 1.0 equiv) in methanol (9 mL) and triethylamine (0.83 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 5.19 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice/diluted HCl, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaHCO3 and water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (3:7) yielding 0.84 g (49%) of the title compound as white crystals. MS (ISP): 347.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With caesium carbonate;palladium diacetate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 110℃; for 18h; | Description 1; 4-(6-Chloro-4-methoxy-pyridazin-3-ylamino)-piperidine-l-carboxylic acid tert- butyl ester (Dl); To a stirred solution of <strong>[70952-62-4]3,6-dichloro-4-methoxy-pyridazine</strong> (0.73 g, 4.08mmol) (prepared by a procedure similar to that described in Eichenberger, K.; Rometsch, R..; Druey, J. Australian Journal of Chemistry 1956, 9, 1755-1764), 4-amino-piperidine-l- carboxylic acid tert-bvXy ester (0.98 g, 4.90 mmol) and cesium carbonate (2.66 g, 8.16 mmol) in toluene (15 ml) in a sealed tube under nitrogen, were added (R)-(+)-2,T- bis(diphenylphosphino)-l,r-binaphthyl (0.38 g, 0.61 mmol) and palladium(II) acetate <n="20"/>(0.046 g, 0.20 mmol). The reactiom mixture was stirred at 110 C for 18 h.. After cooling to room temperature, the reaction mixture was filtered though Celite and the filtrate was evaporated. The crude product was purified by flash column chromatography (silica gel; 3 % ammonia in methanol (7M) / dichloromethane). The desired fractions were collected and evaporated in vacuo, to yield Dl (0.44 g, 32 %) as a yellow solid. Ci5H23ClN4O3 requires 342; Found 343 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In tetrahydrofuran; dichloromethane; at 0 - 25℃; | 3-[3-(1-benzylpiperidin-4-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenolExample 47Step 1, Preparation of 4-(2,6-Dichloro-5-nitro-pyrimidin-4-ylamino)-piperidine-1-carboxylic Acid Tert-Butyl EsterTo a solution of <strong>[4359-87-9]2,4,6-trichloronitropyrimidine</strong> (300 mg, 1.32 mmol) in CH2Cl2 (5 mL) at 0 C. was added a solution of 4-amino-1-BOC-piperidine (243 mg, 0.9 eq) and NEt3 (121 mg, 1.2 mmol, 0.9 eq) in THF (3 mL). The reaction mixture was stirred for another 1 hr at 25 C. to drive the reaction to completion. For purification silica gel (2 g) was added to the mixture and the solvent was removed so that product was absorbed on the silica gel. The silica gel plug was placed on a column and the product purified by flash chromatography with CH2Cl2 to give after removal of solvent the product as yellow solid (380 mg, 80% yield), MS (ESI) m/z 393.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; water; | Step 1: Synthesis of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester 4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2Cl2/DMF (99:1, 400 mL), treated cautiously with oxalyl chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (*3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-1-BOC-piperidine (25.0 g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 100 - 120℃; | Example 31. Preparation of 4-[4-(4-fluoro-benzenesulfonyl)- phenylamino]-piperidine-l-carboxylic acid tert-buty ester intermediate.A solution of 4-amino-piperidine-l-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), bis (4 -fluorophenyl) sulfone (493 mg; 1.94 mmol) and potassium carbonate (1.01 g; 7.76 mmol) in dimethylsulfoxide (5 mL) is heated over night at 1000C. The temperature is then increased to 1200C and the mixture is reacted at this temperature for 24 hours. The reaction is then diluted with dichloromethane (100 mL), filtered and the filtrate is washed with aq. IN hydrochloric acid (2 x 20 mL), and water (2 x 20 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane methanol 100:0 (200 mL) and then 98:2 (150 mL)) to afford the desired product (653 mg; 1.50 mmol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 90℃; for 18h; | Step 1. Preparation of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1-carboxylate; A mixture of <strong>[659731-48-3]5-chloro-2-fluoro-4-iodopyridine</strong> (517 mg, 2.008 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90 C. for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time=1.00 min. | |
With triethylamine; In dimethyl sulfoxide; at 90℃; for 18h; | A mixture of <strong>[659731-48-3]5-chloro-2-fluoro-4-iodopyridine</strong> (517 mg, 2.008 mmol), tert-butyl 4- aminopiperidine-1-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90 C for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time = 1.00 min | |
With triethylamine; In dimethyl sulfoxide; at 90℃; for 18h; | Example 5 (Compound 5)(5'-chloro-N6-(3-fluorobenzyl)-N2'-(piperidin-4-yl)-2,4'-bipyridine-2',6-diamine Step 1. Preparation of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1- carboxylate A mixture of <strong>[659731-48-3]5-chloro-2-fluoro-4-iodopyridine</strong> (517 mg, 2.008 mmol), tert-butyl 4- aminopiperidine-1-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90 C for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time = 1.00 min. |
With triethylamine; In dimethyl sulfoxide; at 90℃; for 18h; | Example 5 (Compound 5) (5'-chloro-N6-(3-fluorobenzyl)-N2'-(piperidin-4-yl)-2,4'-bipyridine-26-diarnineStep 1. Preparation of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1- carboxylateA mixture of <strong>[659731-48-3]5-chloro-2-fluoro-4-iodopyridine</strong> (517 mg, 2.008 mmol), tert-butyl 4- aminopiperidine-1 -carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90 C for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2x), water (3x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time = 1.00 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tert-butyl methyl ether; for 2.5h; | tert-Butyl 4-[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) Pyrimidine-4-carbaldehyde (C12) (23.00 g, 212.8 mmol) was added to a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (42.61 g, 212.8 mmol) in tert-butyl methyl ether (1.52 L). After 2.5 hours, the reaction was filtered, and the filtrate was concentrated in vacuo to provide an amber oil, which was generally taken directly to the following step. Yield: 56.30 g, 193.9 mmol, 91%. 1H NMR (400 MHz, CDCl3) partial spectrum, characteristic peaks: delta 1.49 (s, 9H), 7.95 (dd, J=5.2, 1.5 Hz, 1H), 8.36 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 9.28 (d, J=1.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 2h;Reflux; Inert atmosphere; | A mixture of Methyl 3-formyl-2-nitrobenzoate 1 (l .Oeq.) and 4-Amino-piperidine-l- carboxylic acid tert-butyl ester 2 (1.05eq.) in EtOH (0.2M) was stirred at reflux under N2 atmosphere for 2 hr until TLC revealed completation of the reaction (Hexane/EtOAc=75:25). Evaporation of the solvent gave Compound 3 as a white solid which was used in the next step without further purification. 1H NMR (400MHz, CDC13, 300K): delta 8.51 (IH, d, J=7.3 Hz), 8.41 (IH, s), 8.11 (IH, d, J=7.8 Hz), 7.67 (IH, t, J=7.8 Hz), 7.43 (2H, t, J=7.8 Hz), 7.31 (IH, t, J=7.3 Hz), 7.16 (2H, d, J=7.8 Hz), 3.94 (3H, s). | |
In ethanol; for 2h;Inert atmosphere; Reflux; | 1)3-aldehyde group-2-nitrobenzoatewith4-Amino-piperidine-1-carboxylic acid tert-butyl esterThe mixture was dissolved in ethanol,Stirred under nitrogen for 2 hours under reflux,Until TLC showed the reaction was complete (hexane / EtOAc = 75:25).The solvent was removed by evaporation,A white solid was obtained,which is4 - [(3-methoxycarbonyl-2-nitro-benzylidene) -amino] -Piperidine-1-carboxylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium tetrahydroborate; magnesium sulfate; In ethanol; at 80℃; for 8h;Inert atmosphere; | General procedure: Carbamate (1.0 equiv) or carboxylate (1.0 equiv), the corresponding aldehyde (1.0 equiv) and anhydrous MgSO4 (1.5 equiv) were filled into a Pyrex pressure flask, suspended in absolute EtOH and flushed with argon for 5 min. The mixture was heated to 80 C for 8 h. After filtration of the cooled mixture, the filtrate was flushed again with argon and NaBH4 (6.5 equiv) was added. The reaction was stirred at rt for 14 h (TLC control) and quenched with satd NaHCO3 solution. After extraction with CH2Cl2 (three times) and washing with satd NaCl solution, the combined organic layers were dried over MgSO4, concentrated and the obtained residue was purified by column chromatography using a sufficient mixture of CH2Cl2/MeOH (v/v) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | <strong>[1570-05-4]3,4-bis(benzyloxy)benzoic acid</strong> (12) (50.0 mg, 0.14 mmol) was dissolved in dry DMF (2 mL), and then treated with 4-amino-1-Boc-piperidine (34.0 mg, 0.17 mmol), HOBT (22.9 mg, 0.17 mmol), EDC (0.030 mL, 0.17 mmol), TEA (0.058 mL, 0.42 mmol), and DMAP (1.2 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 16 h under an argon atmosphere and the solvent was removed. The crude compound was purified by column chromatography on silica gel using hexane/AcOEt 40:60 as eluent. Yield 55percent. Mp 158?160 °C. 1H NMR (CDCl3), (delta) 1.46?1.58 (m, 2H), 1.50 (s, 9H, CH3), 1.94?1.99 (d, 2H, CH2, J = 10.63), 2.82?2.94 (t, 2H, J = 11.91), 4.02?4.08 (d, 3H, J = 11.90), 5.18 (s, 4H, CH2O) 5.78?5.82 (br s, NH), 6.86?7.46 (m, 13H, ArH). 13C NMR (CDCl3), 166.2, 154.7, 151.6, 148.7, 136.8, 136.6, 128.6, 128.0, 127.6, 127.5, 127.2, 119.9, 114.0, 113.6, 79.7, 71.3, 71.0, 47.2, 42.7, 32.2,28.5; Anal. C31H36N2O5 (C, H, N). HPLC-GS 100percent. MS m/z 517 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | tert-But l 4-aminopiperidine-l-carboxylate (1.4 g, 7.1 mraol, Aldrich) was dissolved in methylene chloride (10. mL) and to this solution was added N,N- diisopropylethylamine (2.5 mL, 14 mmol) and 4,6-dichloro-2- (trifluoromethyl)pyrimidine (1.7 g, 7.8 mmol, Synchem). The reaction was stirred overnight. The mixture was diluted with water and the product was extracted with EtOAc. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification in Step 2. LCMS ( +H)+: 381.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20 - 50℃; for 19h;Inert atmosphere; | 4-(3,6-Dichloro-pyridazin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester 3,4,6-Trichloropyridazin (10.5 g; 57.25 mmol) was dissolved in 10 ml of dry NMP. Afterwards were added DIPEA (28.4 ml; 171.73 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.04 g; 60.11 mmol) and all let stir at ambient temperature for 16 hours and 3 hours at 50 C. The reaction mixture was purified by using reversed phase chromatography under basic conditions. Yield: 49% (9.73 g; 28.03 mmol) HPLC-MS: (M+H)+=347/349; tRet=1.82 min; method FECBM3ESI |
49% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20 - 50℃; for 19h;Inert atmosphere; | 3,4,6-Trichloropyridazin (10.5 g; 57.25 mmol) was dissolved in 10 ml of dry NMP. Afterwards were added DIPEA (28.4 ml; 171.73 mmol) and 4- amino-piperidine-1- carboxylic acid tert-butyl ester (12.04 g; 60.11 mmol) and all let stir at ambient temperature for 16 hours and 3 hours at 50 C. The reaction mixture was purified by using reversed phase chromatography under basic conditions. Yield: 49 % (9.73 g; 28.03 mmol) HPLC-MS: (M+H)+ = 347/349; tRet = 1.82 min; method FECBM3ESI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | To a stirred solution of 4-amino-piperidine-l-carboxylic acid tert -butyl ester (0.3g,1.8mmol) and <strong>[31680-07-6]4-methyl-3-nitro-benzaldehyde</strong> (0.363g, 1.8mmol) in ethanol (6ml) was added titanium isopropoxide (0.3ml) at 0C and stirred. The reaction was gradually brought to RT and stirred for 16h. Then sodium borohydride (0.068g,l .8mmol) was added followed by catalytic amount of acetic acid and stirred for 3h at ambient temperature. Upon completion, the solvents in the reaction were distilled out. The crude was diluted with 10%MeOH-CH2Cl2 solution and washed with water. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The obtained crude was taken was purified by (100-200mesh) silicagel column chromatography eluting the required compound with 80% EtOAc-Petether as a off-white solid (0.370g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | To a stirred solution of 4-amino-piperidine-l -carboxylic acid tert-butyl ester (0.35g,1.75mmol) and <strong>[35969-75-6]5-nitro-pyridine-2-carbaldehyde</strong> (0.27g,1.75mmol) in ethanol(6ml) was added titanium isopropoxide(0.35ml) at 0C and stirred. The reaction was gradually brought to RT and stirred for 16h. Then sodium borohydride(0.066g,1.75mmol) was added followed by catalytic amount of acetic acid and stirred for 3h at ambient temperature. Upon completion, the solvents in the reaction were distilled out. The crude was diluted with 10%MuepsilonOmicronEta-Omicrontheta2 solution and washed with water. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The obtained crude was taken was purified by (100-200mesh) silicagel column chromatography eluting the required compound with 7% MeOH-CH2Cl2 as a brown solid (0.35g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 4-amino-piperidine-l-carboxylic acid tert -butyl ester (0.35g, 1.75mmol) and <strong>[27613-36-1]5-formyl-2-methyl-benzonitrile</strong> (0.327g, 1.97mmol) in ethanol(6ml) was added titanium isopropoxide (0.35ml) at 0°C and stirred. The reaction is gradually brought to RT and stirred for 16h. Then sodium borohydride (0.078g, 1.97mmol) was added followed by catalytic amount of acetic acid and stirred for 3h at ambient temperature. Upon completion, the solvents in the reaction were distilled out. The crude was diluted with 10percent MeOH-CI^C solution and washed with water. The organic layer was then dried over Sodium sulfate and concentrated under reduced pressure. The obtained crude was purified by (100-200mesh) silicagel column chromatography to afford the required compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine; In dimethyl sulfoxide; at 150℃; for 15h; | tert-Butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidne-l-carboxylate (10). Et3 (4.52 mL, 74.578 mmol) was added to a stirred solution of 9 (4.29 g, 24.859 mmol), 2 (5.0 g, 24.859 mmol) in anhydrous DMSO (45 mL) at rt. The resulting reaction mixture was stirred at 150 for 15 hr. After the reaction was complete, it was cooled to rt and ice-cold 0 was added. The resulting mixture was extracted with EtOAc (2 x 50 mL).The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo in order to afford crude compound as a thick brown liquid. This was washed with n- hexane to give 4.50 g (54% yield) of 10 as a yellow solid. LCMS m/z 281 [M - 56 + H], 237 [M - 100 + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃;Inert atmosphere; Schlenk technique; | A Schlenk tube was charged with tert-butyl 4-aminopiperidine-1-carboxylate (0.249 g,1.24 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.193 g, 1.04 mmol), potassium tertbutoxide (0.290 g, 2.58 mmol) and toluene (5 mL). The Schlenk tube was subjected tothree cycles of evacuation-backfilling with argon and then tris(dibenzylideneacetone) dipalladium (76 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2?,4?,6?-triisopropyl biphenyl (10 mg, 0.02 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schienk tube was sealed and the mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth Celite® and the filtrate was concentrated to dryness. The crude residue was purified by reverse phase chromatography (gradientfrom water to methanol) to yield the title compound (188 mg, 60percent). LRMS (mlz): 306 (M+1).1H-NMR (300 MHz, CDCI3): 1.34 (td, 2H), 1.47 (s, 9H), 2.01 (dd, 2H), 2.39 (s, 6H), 2.93 (t, 2H), 3.39-3.54 (m, 1H), 3.92 (d, 1H), 4.06 (d, 2H), 6.15 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | A mixture of <strong>[23688-89-3]<strong>[23688-89-3]6-chloropyrazine-2-carboxylic</strong> acid</strong> [CAS-RN: 23688-89-3] (1.00 g,6.31 mmol, 1.0 eq), tert-butyl 4-aminopiperidine-1-carboxylate [CAS-RN: 87120-72-7] (1.39 g, 6.94 mmol, 1.1 eq), HATU (2.64 g, 6.94 mmol, 1.1 eq) and DIPEA(2.33 mL, 12.6 mmol, 2.0 eq) was dissolved in 38 mL DMF and stirred at rt overnight. The reaction mixture was partitioned between ethyl. acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 50 g SNAPcartridge: hexane-> hexane/ethyl acetate 2/3) to give 2.1 g (94% yield of theory) of the title compound.UPLC-MS (Method 2): R = 1.14 mm; MS (Elneg) m/z = 339 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0202j meta-Fluoro-4-(trifluoromethoxy)aniline (500 mg, 2.56 mmol) and triethylamine (388 mg, 3.84 mmol) were dissolved in CH2C12 (4 mL) and was added dropwisely into a solution of triphosgene (341 mg, 1.15 mmol) dissolved in CH2C12 (5 mL) at -78 C. The reaction mixture was stirred at 0 C for lh and was then cooled to -78 C. 4-amino-1-Boc- piperidine (769 mg, 3.84 mmol) and triethylamine (388 mg, 3.84 mmol) were dissolved in CH2C12 (4 mL) and the suspension was added dropwisely to the reaction mixture at -78 C. The reaction mixture was stirred at rt for 2h. The reaction was quenched by addition of water. The organic layer was isolated and the organic layer was further washed by HC1 solution (1M) for 4 times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo yielding final crude product (1.05 g, 86% pure, 2.13 mmol, 83.4% yield). The impurities 38 were purified by column chromatography using EtOAc:Hex (1:1).[0203j ?H NMR (d6-DMSO, 300 Mhz): A: 8.77 (s, 1H), 7.66 (dd, J 13.5, 2.4 Hz, 1H), 7.38 (t, J 8.1 Hz, 1H), 7.10 (d, J 9Hz, 1H), 6.33 (d, J 7.5 Hz, 1H), 3.81 (d, J= 12.9 Hz, 2H), 3.6-3.8 (m, 1H), 2.8-3.0 (m, 2H), 1.78 (dd,J= 12.3Hz, 3.3Hz, 2H), 1.40 (s, 9H), 1.2-1.4 (m, 2H); 38: 9.28 (s, 1H), 7.69 (dd, J= 14.9, 2.4 Hz, 1H), 7.46 (t, J 9Hz, 1H), 7.2-7.3 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In tetrahydrofuran; at 25℃; for 15h;Inert atmosphere; | To a magnetically stirred solution of 2,4-dichloro-pyrido[2,3-d]pyrimidine (450 mg) in THF (30 mL) under an atmosphere of nitrogen was added 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (470 mg) and TEA (500 mg). The mixture was stirred at 25 C. for 15 h and then quenched with aqueous NH4Cl (50 mL, 2 M). The mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated. The residue thus obtained was purified by recrystallization from n-hexane/ethyl acetate to give compound 121-I (610 mg, 75% yield) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Example 35A tert-Butyl 4-[(4-bromo-3-methylphenyl)sulphonyl]amino}piperidine-1-carboxylate 4-Bromo-3-methylbenzenesulphonyl chloride (1 g, 3.7 mmol) was dissolved in dichloromethane (20 ml), the mixture was cooled to 0 C. and tert-butyl 4-aminopiperidine-1-carboxylate (1.11 g, 5.6 mmol) and N,N-diisopropylethylamine (1.62 ml, 9.3 mmol) were added. The reaction mixture was stirred at RT overnight and concentrated, and the residue was purified chromatographically by HPLC (Method 9). This gave 1.2 g (74% of theory) of the title compound. 1H NMR (300 MHz, DMSO-d6): delta=ppm 1.09-1.23 (m, 2H), 1.32 (s, 9H), 1.50 (dd, 2H), 2.39 (s, 3H), 2.64-2.82 (m, 2H), 3.06-3.21 (m, 1H), 3.67 (d, 2H), 7.51 (dd, 1H), 7.72-7.84 (m, 3H). LC-MS (Method 4): Rt=1.37 min; MS (ESIpos): m/z=435.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Example 36A tert-Butyl 4-[(5-bromopyridin-3-yl) sulphonyl]amino}piperidine-1-carboxylate 5-Bromopyridine-3-sulphonyl chloride (1 g, 3.9 mmol) was dissolved in dichloromethane (20 ml), the mixture was cooled to 0 C. and tert-butyl 4-aminopiperidine-1-carboxylate (1.18 g, 5.8 mmol) and N,N-diisopropylethylamine (1.7 ml, 9.7 mmol) were added. The reaction mixture was stirred at RT overnight and concentrated, and the residue was purified chromatographically by HPLC (Method 9). This gave 1.0 g (62% of theory) of the title compound. 1H NMR (300 MHz, DMSO-d6): delta=ppm 1.09-1.24 (m, 2H), 1.33 (s, 9H), 1.47-1.59 (m, 2H), 2.66-2.83 (m, 2H), 3.19-3.25 (m, 1H), 3.63-3.75 (m, 2H), 8.09 (br. s, 1H), 8.36 (t, 1H), 8.91 (d, 1H), 8.95 (d, 1H). LC-MS (Method 4): Rt=1.19 min; MS (ESIneg): m/z=420.3 [M-H]-. |
62% | With diisopropylamine; In dichloromethane; at 20℃; for 2h; | Example 25A tert-Butyl 4-[(5-bromopyridin-3-yl)sulphonyl]amino}piperidine-1-carboxylate 5-Bromopyridine-3-sulphonyl chloride (1.0 g, 3.9 mmol) was dissolved in 20 ml of dichloromethane, the mixture was cooled to 0 C. and N,N-diisopropylamine (1.7 ml, 9.7 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.2 g, 5.8 mmol) were added. The reaction mixture was allowed to warm to RT and was stirred for another 2 h. Subsequently, the mixture was concentrated and purified by HPLC (Method 9). This gave 1.0 g (62% of theory) of the title compound. 1H-NMR (300 MHz, DMSO-d6): delta=ppm 1.09-1.25 (m, 2H), 1.33 (s, 9H), 1.47-1.58 (m, 2H), 2.71-2.83 (m, 2H), 3.20-3.27 (m, 1H), 3.63-3.74 (m, 2H), 8.07-8.12 (m, 1H), 8.36 (t, 1H), 8.91 (d, 1H), 8.95 (d, 1H). LC-MS (Method 1): Rt=1.19 min; MS (ESIneg): m/z=420 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | A solution of 4 '- (trifluoromethyl) - [1,1' biphenyl] -2-carboxylic acid (20.0 g, 83 mmol) was successively added under nitrogen at 0 C in a three-neck flask equipped with a thermometer and a dropping funnel. (200 ml), oxalyl chloride (12.7 g, 100 mmol) and DMF (5 drops) at room temperature for 3 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 ml)(16.6 g, 83 mmol) and triethylamine (34.0 mL, 249 mmol) were added dropwise to a solution of 4-(200 ml x 3) and saturated brine (200 ml x 3). The organic phase was dried over anhydrous Na2SO4. The organic layer was dried over anhydrous magnesium sulfate, Evaporation of the solvent gave the title compound as an intermediate (9) (33.5 g, 90.5%) as a white solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: 1,2-Dichloro-4-fluoro-5-nitrobenzene (0.43 mL, 3.3 mmol) was added to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (655 mg, 3.3 mmol) and K2CO3 (497 mg, 3.6 mmol, 1.1 equiv.) in DMSO (5 mL) and the solution was stirred at room temperature under argon overnight. Reaction progress was monitored by LCMS and upon completion, water (20 mL) was added and the organic layer extracted with ethyl acetate (3 x 15 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification was achieved by flash column chromatography on silica gel using a gradient of ethyl acetate:hexanes as the eluent. (0060) Fractions containing the desired product were pooled and concentrated under reduced pressure to give the product as an orange solid. 788 mg of the product tert-butyl 4-((4,5- dichloro-2-nitrophenyl)amino)piperidine-1-carboxylate was obtained (62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With trifluoroacetic acid; In isopropyl alcohol; at 90℃; for 16h; | Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4- amine (150 mg, 1.04 mmol, 1 equiv), trifluoroacetic acid (480 mg, 4.25 mmol, 4.00 equiv), IPA (5 mL), tert-butyl 4-aminopiperi dine- 1-carboxy late (250 mg, 1.25 mmol, 1.19 equiv). The resulting solution was stirred for 16 h at 90 C in an oil bath. The crude product was purified by Prep-HPLC C NH4HC03. This resulted in 42.2 mg (19%) of N4-methyl-N2- (piperidin-4-yl)pyrimidine-2,4-diamine as light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.499 g | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 120℃; | To <strong>[92992-85-3]2-bromo-3,5-dimethylpyridine</strong> (1 g) were added 4-amino-1-(tert-butoxycarbonyl)piperidine (1.29 g),tris(dibenzylideneacetone)dipalladium(0)(250 mg),2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (330 mg),sodium tert-butoxide (770 mg) and toluene (8 mL) and the mixture was stirred at 120c overnight. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (hexane:ethyl acetate)to give 4-(3,5-dimethylpyridin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (1.499 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12.3333h; | General procedure: To a stirred solution of phenol 6a or 2-chloropyridine 11a(1.1 mmol), ethyl 4fluorobenzoate 7 of ethyl 4hydroxybenzoate 12 (1.0 mmol) in N, N-dimethylformamide wasadded K2CO3 or CsCO3 (2.0 mmol) at 130 C for12 h. Thereaction mixture was extracted with EtOAc. The organiclayers dried over anhydrous MgSO4 and concentrated.Then the residue was dissolved in ethanol, a little NaOH(1.5 mmol) was added. The reaction mixture was stirred at80 C for 1 h and then concentrated in vacuo to give of thecrude acid 8a-r and 13a-d, which was directly used for thenext step (48-89% for 2 steps).To a solution of acids 3a-j, 8a-r and 13a-d (0.8 mmol)and tertbutyl 4aminopiperidine1carboxylate (1.0 mmol)in dichloromethane (3 mL) at 0 C were added 1-hydroxybenzotriazoleHOBt (0.9 mmol), 1-(3-dimethylaminopropyl)3ethylcarbodiimide hydrochloride EDCI(0.9 mmol). The reaction mixture was stirred at 0 C and atroom temperature for a further 12 h. Then washed with10% aqueous HCl, 5% aqueous NaOH, H2O and brine,dried over MgSO4, and concentrated in vacuo. The residuewas dissolved in AcOEt and 4 N HCl in dichloromethanewas added dropwise. The reaction was stirred at rt for 2 hand then evaporated to dryness. The resdiue was dilutedwith dichloromethane and washed with 2 N NaOH. Theorganic layer was dried over MgSO4, and concentrated invacuo. The residue was purified by crystallization fromdichloromethane to afford as a white solid (66-90% for 2steps).To a solution of intermediate 4a-j, 9a-r and 14a-d (0.3 mmol) and 2-(bromomethyl)-1,3-difluorobenzene(0.3 mmol) in DMF (3 mL) was added. K2CO3(0.6 mmol). The reaction was stirred at rt for 20 h was thenadded some water. The aqueous mixture was extracted withAcOEt. The organic phase was combined and washed withbrine, dried over anhydrous MgSO4, filtered, and concentratedin vacuo. The residue was purified by columnchromatography (ethyl acetate/hexane) to provide the titlecompound (54-91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
420 mg | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; | j003201 A flask was charged with t-butyl 4-aminopiperidine-1-carboxylate (416 mg, 2.06 mmol, 2.00 equiv), <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (250 mg, 1.03 mmol, 1.00 equiv), DIPEA (403 mg, 3.09 mmol, 3.00 equiv), and dimethyl sulfoxide (10 mL), as described in Example 1, Step 5. The residue was chromatographed on a silica gel column to provide 420 mg (96% yield) of t-butyl 4-((2-bromo-4-(trifluoromethyl)phenyl)amino)piperidine- 1 -carb oxylate as a yell ow oil. LCMS (ESI, m/z): 423 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium phosphate; copper(I) bromide; 1,1'-bi-2-naphthol; In N,N-dimethyl-formamide; at 85℃; for 3h;Sealed tube; Inert atmosphere; | A dry 20 mL reaction vial is charged with <strong>[233770-01-9]3-bromo-5-iodopyridine</strong> (2.0 g, 6.9 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol), copper(I) bromide (0.2 g, 1.4 mmol), l,l '-bi-2-naphthol (0.4 g, 1.4 mmol), K3PO4 (2.9 g, 13.8 mmol), and DMF (6.5 g, 6.9 mL). Dry nitrogen is bubbled subsurface for 5 minutes. The vial is sealed and heated to 85 C for a total of 3 h and then cooled to RT. The mixture is diluted with EtOAc and the mixture filtered over diatomaceous earth and a pad of silica gel. The filtrate is washed with saturated aqueous NaCl, dried over MgS04, and concentrated under reduced pressure. The resulting residue is purified by silica gel flash column chromatography, using a gradient of 40 to 100% EtOac in hexanes, to yield the title compound (1.6 g, 65% yield). ES/MS m/z (79Br/81Br) 356.0/358.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.49% | 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 120℃;Inert atmosphere; | Example 68 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-3-(piperidin-4-ylamino)isonicotinamide Compound 118a. To a stirred solution of <strong>[59786-31-1]methyl 3-bromoisonicotinate</strong> (0.500 gm, 2.3148 mmol, 1 equiv) & tert-butyl 4-aminopiperidine-1-carboxylate (0.463 gm, 2.3148 mmol, 1 equiv) and CS2CO3 (1.5 gm, 4.6296 mmol, 2 equiv) in dioxane (15 mL). The resulting mixture was purged with nitrogen for 10 min followed by addition of Pd2(dba)3 (0.106 gm, 0.1157 mmol, 0.05 equiv) and xantphos (0.134 gm, 0.2314 mmol, 0.1 equiv), again purged with nitrogen for 10 min. The reaction mixture was heated at 120 C. for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (2*50 mL). The combined organic layers were washed with water (30 mL), with brine (30 mL), dried over Na2SO4, concentrated to afford the crude which was purified by flash chromatography to obtain methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinate (400 mg, 51.49%) as a white solid. LCMS: 336.3 [M+H]+ 1H NMR: (400 MHz, DMSO-d6) delta 8.41 (s, 1H), 7.60-7.51 (m, 2H), 7.27 (d, J=7.9 Hz, 1H), 3.00 (m., 4H), 2.04-1.88 (s, 3H), 1.44-1.35 (s, 9H), 1.31-1.12 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 2h;Microwave irradiation; | To a solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (350 mg, 1.97 mmol) in NMP (3 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (415 mg, 1.97 mmol) and triethyl- amine (0.82 mL, 5.9 mmol). The reaction mixture was heated under focussed microwave irradiation for 1 h at 90C. Further aliquots of tert-butyl 4-aminopiperidine-1-carboxylate (2 x 450 mg) were added and, after each addition, the mixture was heated for a further 1 h at 90C. The reaction mixture was cooled, then partitioned between EtOAc and water. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (686 mg, 98%) as a solid. LCMS (Method 5):[M+H]+ m/z 355, RT 1.37 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | To a stirred solution of tert-butyl 4-aminopiperazine-l-carboxylate (315 mg, 1.5 mmol, 1.0 equiv) in DMF (05 mL) was added HATU (1140 mg, 3.0 mmol, 2.0 equiv) at RT and stirred for 10 minutes. Then 5~(trifuorome?hyl)picolinic acid (300 mg, 1 .5 mmol, 1.0 equiv) was added followed by the addition of DIPEA (0.8 mL, 4.5 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL c 2). The combined organic layer was washed with water (30mL), brine solution (30 mL c 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain tert-butyl 4-(5- (trifluoromethyl)picolinamido)piperazine-l-carboxylate (100 mg, 17 % Yield) as a brown solid. LCMS 375.1 [M+Hf; 'H NMR (400 MHz, DMSO-rfe) d 10.04 (s, 1 H), 9.00 (br s , 1 H), 8.93 (s, 1 H), 8.41 (d, .7=7.89 Hz, 1 H), 8.19 (d, .7=8.33 Hz, 1 H), 3.42 (br. s., 4 H), 2.87 - 2.94 (m, 4 H), 1.41 (d, .7=3.51 Hz, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | To a stirred solution of tert-butyl 4-aminopiperidine-l-carboxylate (1.02 g, 5.10 mmol, 1.0 equiv) in DMF (10 mL) was added 5-chlorobenzofuran-2 -carboxylic acid (1 .0 g, 5.1 mmol, 1.0 equiv) and HATU (3.800 g, 10.02 mmol, 2.0 equiv) at RT. The resulting reaction mixture was stirred for 10 minutes and DIPEA (2.5 mL, 15.00 mmol, 3.00 equiv) was added. The reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL c 2). Combined organic extracts were washed with water (20 mL *4), dried over anhydrous NaaSOr and concentrated. The crude product obtained was treated w ith ether- hexane (50:50) to obtain tert-butyl 4-(5-chlorobenzofuran-2-carboxaniido)piperidine-1 - carboxylate (0.800 g, 43% yield) as an off-white solid. LCMS: 379.2 [M+H] 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72 mg | With [(2-di-cyclohexylphosphino-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; caesium carbonate; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation; Inert atmosphere; | To a flask was added <strong>[448906-60-3](4-bromo-6-methyl-2-pyridyl)methanol</strong> (compound 5a, CAS: 448906-60-3, Vendor: BePharm, 150 mg, 742 m mol), tert-butyl 4-aminopiperidine-1-carboxylate (compound 5b, CAS: 87120-72-7, Vendor: BePharm, 223 mg, 1.11 mmol), CS2CO3 (726 mg, 2.23 mmol) and 1,4-dioxane (5 mL), the suspension was bubbled with N2 for 5 mins and BrettPhos Pd-G3 (20 mg, 22 m mol) was added. The mixture was heated to 100 C under microwave for 2 hrs. After being cooled down, the mixture was diluted with 10 mL EA and filtered through celite, the filtrate was concentrated to give a brown oil, which was purified by flash column (MeOH/DCM = 0 to 15%) to give compound 5c (72 mg) as a yellow oil. MS: calc'd 322 (MH+), measured 322 (MH+). |
Tags: 87120-72-7 synthesis path| 87120-72-7 SDS| 87120-72-7 COA| 87120-72-7 purity| 87120-72-7 application| 87120-72-7 NMR| 87120-72-7 COA| 87120-72-7 structure
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P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
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. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
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. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
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: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
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 |
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