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CAS No. : | 5472-49-1 | MDL No. : | MFCD00012838 |
Formula : | C8H17Cl2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OBOBUDMMFXRNDO-UHFFFAOYSA-N |
M.W : | 198.13 | Pubchem ID : | 79624 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 57.03 |
TPSA : | 3.24 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) : | -5.48 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.86 |
Log Po/w (WLOGP) : | 2.52 |
Log Po/w (MLOGP) : | 2.45 |
Log Po/w (SILICOS-IT) : | 2.5 |
Consensus Log Po/w : | 2.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.67 |
Solubility : | 0.421 mg/ml ; 0.00213 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.59 |
Solubility : | 0.513 mg/ml ; 0.00259 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.42 |
Solubility : | 0.746 mg/ml ; 0.00377 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With sodium hydroxide; potassium carbonate In diethyl ether; water for 1 h; | N-(3-Chloropropyl)-piperidine hydrochloride (97percent purity from Aldrich Chemicals) (100 g) was dissolved in water (150 mL) and saturated aqueous potassium carbonate (250 mL) was slowly added to it. Also, ION sodium hydroxide (25 mL) and diethyl ether (250 mL) were added and the mixture was stirred for one hour. The layers were separated; the organic layer was dried over anhydrous potassium carbonate and concentrated on a Biichi Labortechnik AG Rotavapor.(R). evaporator to give the title compound (77.2 g, 94.4percent), which was used without purification for the next reactions |
94.4% | With potassium carbonate; sodium hydroxide In diethyl ether; water for 1 h; Inert atmosphere | N-(3-Chloropropyl)-piperidine hydrochloride (97percent purity from Aldrich Chemicals) (100 g) was dissolved in water (150 mL) and saturated aqueous potassium carbonate (250 mL) was slowly added to it. Also, 10N sodium hydroxide (25 mL) and diethyl ether (250 mL) were added and the mixture was stirred for one hour. The layers were separated; the organic layer was dried over anhydrous potassium carbonate and concentrated on a Büchi Labortechnik AG Rotavapor® evaporator to give the title compound (77.2 g, 94.4percent), which was used without purification for the next reactions. |
94.4% | With sodium hydroxide; potassium carbonate In diethyl ether; water for 1 h; | N-(3-Chloropropyl)-piperidine hydrochloride (97percent purity from Aldrich Chemicals) (100 g) was dissolved in water (150 mL) and saturated aqueous potassium carbonate (250 mL) was slowly added to it. Also, ION sodium hydroxide (25 mL) and diethyl ether (250 mL) were added and the mixture was stirred for one hour. The layers were separated; the organic layer was dried over anhydrous potassium carbonate and concentrated on a Biichi Labortechnik AG Rotavapor.(R). evaporator to give the title compound (77.2 g, 94.4percent), which was used without purification for the next reactions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In water; toluene at 40℃; for 3 h; Stage #2: With hydrogenchloride In methanol |
Reference Example 10 1-(3-Chloropropyl)piperidine Hydrochloride To a solution of piperidine (0.45 g, 5.3 mmol) and 1-bromo-3-chloropropane (5.2 g, 33 mmol) in toluene (17.5 mL) was added tetra-n-butylammonium hydrogensulfate (0.51 g, 1.5 mmol) and a 25percent aqueous sodium hydroxide (10 mL), and the resulting mixture was stirred at 40° C. for 3 hours. The reaction solution was cooled to room temperature, and the toluene layer was separated and was then washed with a saturated aqueous sodium chloride and was dried over anhydrous sodium sulfate. After sodium sulfate was filtered off, hydrochloric acid/methanol (2 mL) was added to the filtrate and themixture was concentrated. The resulting crude crystals were recrystallized from methanol/ether to afford the title compound (0.96 g, yield: 91percent) as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: for 4 h; Reflux Stage #2: With sodium hydroxide In toluene for 1 h; Reflux Stage #3: at 20℃; Cooling with ice |
1.72 g (20.3 mmol) of piperidine, 2 ml (24.3 mmol) of 3-chloropropanol and 10 ml toluene were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 4 h. Into the reaction mixture, 5percent NaOH 4 ml was added, and the mixture was refluxed for 1 h. After cooling to room temperature, the mixture was washed with 5percent NaOH solution. The organic layer was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtrated. 3 ml (40.6 mmol) thionyl chloride was added dropwise into the filtrate in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dry in a reduced pressure, and the residue was recrystallized with absolute ethyl alcohol to obtain 2.4 g of a khaki solid with the yield of 59percent. m.p. 218-220° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium hydroxide In methanol; isopropyl alcohol for 0.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; potassium iodide In water for 12h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; sodium iodide; In acetone; for 1.5h;Heating / reflux; | A mixture of 5.97 g of 4'-hydroxyacetophenone (43.8 mmol), 13.0 g of 1-(3-chloropropyl)-piperidine hydrochloride (65.8 mmol), 12.70 g of potassium carbonate (91.89 mmol), and 3.28 g of sodium iodide (21.9 mmol) in 100 mL dry acetone was stirred at reflux. After 1.5 h, the reaction was cooled to room temperature, filtered and concentrated. Ethyl acetate was added and the white solid that remained was filtered off. The filtrate was concentrated in vacuo and the crude residue was purified via silica gel chromatography using a gradient of ethyl acetate then 400:20:10 ethyl acetate: 7N ammonia in methanol:methanol to yield 583 mg of 1-[4-(3-piperidin-1-ylpropoxy)phenyl]ethanone as an oil. MS m/z 265 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | Reference Example 15: Production of 8-[4-(3-piperidin-1-ylpropoxy)phenyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one; 8-(4-Hydroxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decan-2-one (1.72 g, 6.92 mmol) obtained in Reference Example 14, <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (1.51 g, 7.62 mmol) produced according to the method described in a patent, WO03/101931 or according to a method similar to it, and potassium carbonate (2.87 g, 20.76 mmol) were mixed in DMF, and stirred overnight at 80C. The solvent was evaporated off under reduced pressure, and the residue was dissolved in chloroform, and washed with water and saturated saline in that order. The organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was suspended in mixed solvent of ethyl acetate/diethyl ether (1/1), and filtered under suction to obtain the entitled compound (1.45 g, 56 %) as a brown solid. 1H-NMR (400 MHz, CDCl3) delta: 1.47 (2H, s), 1.66 (4H, s), 1.89-1.96 (2H, m), 1.99-2.06 (2H, m), 2.11 (2H, d, J=13.2 Hz), 2.51-2.57 (6H, m), 3.20 (4H, dd, J=9.0, 3.7 Hz), 3.39 (2H, s), 3.97 (2H, t, J=6.1 Hz), 5.36 (1H, brs), 6.82 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In DMF (N,N-dimethyl-formamide); at 90℃; for 18h; | 1- (3-Chloropropyl) piperidine hydrochloride (9.9g, 50. [0MMOL),] potassium carbonate (17.6g, 127. [4MMOL)] and potassium iodide (1.1g, 6. [8MMOL)] were added to a solution of 4- iodophenol [(10G,] 45. [5MMOL)] in [DIMETHYLFORMAMIDE (150MI)] and the resulting mixture was heated at [90C] for 18 hours. The mixture was allowed to cool to ambient temperature, poured onto water/ice [(500MOI)] and stirred for 10 minutes. The solid was filtered and washed with ice water to give the title compound (13.5g). MS (ES+) m/e 346 [[M+H] +] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium iodide; In butanone; for 18.0h;Heating / reflux; | The product from step 1 was dissolved in 2-butanone (30ml), treated with [1- (3-] chloropropyl) piperidine hydrochloride (0.72g, 3. [63MOL),] potassium carbonate (1.17g, 8. [48MMOL)] and sodium iodide (0. [15G,] 0.91 [MMOL)] and heated under reflux for 18 hours. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate and washed with water. The organic layer was separated, dried under magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of. 880 ammonia: methanol : [DICHLOROMETHANE] (0.5 : 4.5 : 95) to give the title compound (0.76g). MS (ES+) m/e 367 [[M+H] +] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 80℃; for 24h; | A mixture [OF 4- (4-ACETYL-1-PIPERAZINYL)-3-BROMOPHENOL] (E226b) (1 g) in DMF (10 ml) and chloropropyl piperidine hydrochloride (0.72 g), [CS2CO3] (2.99 g), and Nal (75 mg) was heated at 80 [C] for 24 h. The mixture was cooled to room temperature and quenched with water (10 [ML),] then extracted with ethyl acetate and evaporated. The residue was treated with 5 mi of conc. HCI and 5 [ML] of water and heated to reflux. The reaction mixture was cooled to 20 C and diluted with water (10 [ML),] basified with solid potassium carbonate and extracted with DCM. The residue was purified by chromatography on biotage (40 g cartridge) eluting with DCM-EtOH-NH3 (45: 5: 1) to give the title compound (0.86 g) LCMS RT = 1.68 min, ES+ve m/z 382,384 (M+H) [+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | A solution of 1- (3-chloropropyl) piperidine hydrochloride (46 mg) in dry DMF was treated with a solution of [3- { [4- (8-QUINOLINYL)-L-PIPERAZINYL] METHYL} PHENOL] (E229c) (43 mg). The resultant solution was treated with sodium hydride (60% oil dispersion, 11 mg) and stirred at room temperature for 16 h. The reaction mixture was quenched with water (1 drop) and partitioned between water and DCM. The organic phase was concentrated in vacuo. The residue was purified by mass directed auto-preparative HPLC to give the title compound (5.7 mg). LCMS RT= 1.83 min, ES+ve [M/Z 445] (MH) [+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 3, 4-dinitrophenol (2g, 10.9mmol, LEQ) in dimethyl formamide (40ML), chloropropyl piperidine hydrochloride (2.8g, 14. 2mmol, 1. 3eq) and potassium carbonate (3.2g, 22.9mmol, 2. 1eq) were added. The mixture was heated to 100C for 4 hours and the reaction was cooled to room temperature. The mixture was passed through a SCX column and eluted with 7N ammonia in methanol, the eluent was concentrated and the residue was subjected to chromatography on silica gel (100g) to yield 1- [3- (3, 4-dinitro-phenoxy)- PROPYLL-PIPERIDINE [3.45 g] as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Reference Example 10 1-(3-Chloropropyl)piperidine Hydrochloride To a solution of piperidine (0.45 g, 5.3 mmol) and 1-bromo-3-chloropropane (5.2 g, 33 mmol) in toluene (17.5 mL) was added tetra-n-butylammonium hydrogensulfate (0.51 g, 1.5 mmol) and a 25% aqueous sodium hydroxide (10 mL), and the resulting mixture was stirred at 40 C. for 3 hours. The reaction solution was cooled to room temperature, and the toluene layer was separated and was then washed with a saturated aqueous sodium chloride and was dried over anhydrous sodium sulfate. After sodium sulfate was filtered off, hydrochloric acid/methanol (2 mL) was added to the filtrate and themixture was concentrated. The resulting crude crystals were recrystallized from methanol/ether to afford the title compound (0.96 g, yield: 91%) as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Reference Example 19 1-(3-N-Benzyl-N-methylamino)propyl)piperidine Hydrochloride To a suspended solution of benzylmethylamine (0.61 g, 5.0 mmol) and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (1.5 g, 7.5 mmol) in acetonitrile (50 mL) was added potassium carbonate (1.03 g, 7.5 mmol), and the resulting mixture was refluxed for 5 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and methanol and subsequently hydrochloric acid/methanol were added to the resulting crude product. After concentrating the solution, the resulting crude crystal was recrystallized from methanol/ether to afford the title compound (0.82 g, yield: 51%) as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 10 ml of sieve-dried ethanol under N2 was added 0.025 g (0.63 mmol) of 60% NaH (in oil dispersion) with stirring followed by addition of 9 (0.081 g, 0.29 mmol, DE 2803870). Stirring was maintained until a homogeneous solution was attained and then <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (0.062 g, 0.31 mmol) was added. The mixture was heated under reflux for 18 h. TLC indicated the presence of starting material so additional phenol (21 mg) was added to the reaction mixture and the reaction was heated on a steam bath for 2 h. The reaction was concentrated in vacuo. The residue was treated with 0.5 N NaOH (50 ml) and extracted with ether. Combined extracts were washed with water, dried over anhydrous MgSO4 (Darco), and concentrated to give 0.022 g viscous residue which was converted to the hydrochloride salt by the addition of 1N HCl in ether. The title compound was obtained (0.038 g). Mass spec: m/z 408 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 78℃; for 24h; | B. 4-Imidazo[l,2-a]pyridin-7-yl-l-(3-piperidin-l-yl-propyl)-lH-pyridin-2-one; In a RBF under nitrogen, charge (850 mg, 4.0 mmols), l-(3- chlororpropyOpiperine HCl (1.18 g, 6 mmol), DMF (40 mL), and Cs2CO3 (2.8 g, 8.8 mmol), NaI (450 mg, 3 mmol) and heat to 78 0C for 24 hours. Filter the reaction and rinse the solids with DCM. Combine DCM and filtrate and strip off under reduced pressure then purify by passing through Varian SCX (10 g) column that is pre-washed with water and methanol, the product being eluted with (20%) 2 N NH3 in methanol/ (80%) DCM. Evaporate solvent from the product containing fractions under reduced pressure. Chromatograph using (40 g ISCO) SiO2 eluting with a gradient of 0% to10% 2 M NH3 in MeOH with the balance DCM Evaporate solvents to afford ivory solid 410 mg (30%) MS(ES), m/z 337 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate; at 80℃; for 2h; | 115 mg (0.58 mmol) of 1-(3-chlorophenyl)-piperidine hydrochloride and 158 mg (1.14 mmol) of potassium carbonate were added to 101 mg (0.38 mmol) of the obtained crude product of 4-(pyrido[3,2-d] [1,2,4]triazolo[4,3-b]pyridazin-6-yl)-phenol and 4-(pyrido[2,3-d][1,2,4]triazolo[4,3-b]pyridazin-6-yl)-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 5 mg (yield: 34 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.60 (br, 8H), 2.10 (m, 2H), 2.50 (m, 4H), 4.12 (t, 2H, J=6.4 Hz), 7.07 (d, 2H, J=8.8 Hz), 7.82 (m, 1H), 7.99 (m, 2H), 9.04 (d, 1H, J=8.4 Hz), 9.08 (s, 1H), 9.12 (m, 1H) ESI-MS(m/e): 389[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With potassium carbonate; at 80℃; for 2h; | 1-3-(Chlorophenyl)-piperidine hydrochloride and 53 mg (0.28 mmol) of potassium carbonate were added to 53 mg (0.25 mmol) of the obtained 4-pyrazolo[1,5-d][1,2,4]triazin-2-yl-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 12 mg (yield: 14 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.50 (m, 4H), 1.62 (m, 6H), 2.10 (m, 2H), 2.50 (m, 4H), 6.95 (m, 1H), 7.00 (dd, 2H, J=2.8, 8.8 Hz), 7.89 (dd, 2H, J=2.8 Hz, 8.8 Hz), 9.29 (d, 1H, J=5.6 Hz), 9.43 (s, 1H) ESI-MS(m/e): 338[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium carbonate; at 80℃; for 2h; | 95 mg (0.48 mmol) of 1-(3-chloropropyl)-piperidine hydrochloride and 66 mg (0.48 mmol) of potassium carbonate were added to 34 mg (0.16 mmol) of the obtained 4-[1,2,4]triazolo[4,3-b]pyridazin-6-yl-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 6 mg (yield: 10 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.60 (br, 6H), 2.00 (m, 2H), 2.42 (m, 6H), 4.10 (t, 2H, J=6.0 Hz), 7.05 (d, 2H, J=8.8 Hz), 7.56 (d, 1H, J=9.6 Hz), 7.92 (d, 2H, J=9.2 Hz), 8.14 (d, 1H, J=9.2 Hz), 9.11 (s, 1H) ESI-MS(m/e): 338[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; at 80℃; for 2h; | 89 mg (0.45 mmol) of 1-(3-chlorophenyl)-piperidine hydrochloride and 124 mg (0.90 mmol) of potassium carbonate were added to 68 mg (0.3 mmol) of the obtained 4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 79 mg (yield: 75 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.60 (br, 8H), 2.05 (m, 2H), 2.42 (s, 3H), 2.50 (m, 4H), 4.11 (t, 2H, J=6.0 Hz), 7.06 (d, 2H, J=8.8 Hz), 7.48 (m, 2H), 7.98 (s, 1H), 8.53 (d, 1H, J=8.4 Hz) ESI-MS(m/e): 352[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate; at 80℃; for 2h; | 30 mg (0.15 mmol) of 1-(3-chlorophenyl)-piperidine hydrochloride and 42 mg (0.30 mmol) of potassium carbonate were added to 35 mg (0.1 mmol) of the obtained 4-(3-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 10 mg (yield: 22 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.60 (br, 8H), 2.14 (m, 2H), 2.60 (m, 4H), 4.15 (t, 2H, J=6.4 Hz), 7.09 (d, 2H, J=8.4 Hz), 7.48 (m, 3H), 7.64 (d, 2H, J=8.8 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.94 (m, 2H), 8.49 (d, 2H, J=6.8 Hz), 8.80 (d, 1H, J=8.0 Hz) ESI-MS(m/e): 464[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; at 80℃; for 2h; | 96 mg (0.48 mol) of 1-(3-chlorophenyl)-piperidine hydrochloride and 66 mg (0.48 mmol) of potassium carbonate were added to 65 mg (0.24 mmol) of 6-(4-hydroxyphenyl)-N-methyl[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 61 mg (yield: 64 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.41-1.49 (2H, m), 1.58-1.63 (5H, m), 1.99-2.06 (2H, m), 2.42 (3H, s), 2.50 (2H, t, J=7.4 Hz), 3.16 (3H, d, J=5.1 Hz), 4.11 (2H, t, J=6.3 Hz), 7.06 (2H, d, J=9.0 Hz), 7.69 (1H, d, J=9.8 Hz), 7.83 (1H, br), 7.99 (2H, d, J=9.0 Hz), 8.23 (1H, d, J=9.8 Hz) ESI-MS(m/e): 395[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate; at 80℃; for 2h; | 115 mg (0.58 mmol) of <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> and 158 mg (1.14 mmol) of potassium carbonate were added to 101 mg (0.38 mmol) of 4-(pyrido[3,4-d][1,2,4]triazolo[4,3-b]pyridazin-6-yl)-phenol, and stirred at 80C for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 90 mg (yield: 59 %) of the entitled compound as a pale yellow solid. 1HNMR (CDCl3) delta: 1.47 (2H, d, J=5.1 Hz), 1.59-1.64 (4H, m), 2.02-2.09 (2H, m), 2.36-2.54 (6H, m), 4.14 (2H, t, J=6.5 Hz), 7.13 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.82 (1H, t, J=3.1 Hz), 9.02 (1H, d, J=5.5 Hz), 9.12 (1H, s), 10.11 (1H, s) ESI-MS(m/e): 389[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium carbonate; at 80℃; for 2h; | 38 mg (0.19 mmol) of 1-(3-chlorophenyl)-piperidin hydrochloride and 66 mg (0.48 mmol) of potassium carbonate were added to 56 mg (0.16 mmol) of 5-[1,2,4]triazolo[3,4-a]phthalazin-6-ylpyridin-2-ol, and stirred at 80C for 2 hours. The reaction liquid was concentrated and the resulting residue was purified through silica gel column chromatography (chloroform/methanol = 10/1) to obtain 20 mg (yield: 32 %) of the entitled compound as a white solid. 1HNMR (CDCl3) delta: 1.40-1.55 (6H, m), 1.85 (1H, br), 2.00-2.07 (2H, m), 2.35-2.50 (5H, m), 4.15 (2H, t, J=6.7 Hz), 6.74 (1H, d, J=9.4 Hz), 7.66 (1H, dd, J=9.2, 2.5 Hz), 7.84 (1H, t, J=7.6 Hz), 8.02-7.96 (3H, m), 8.78 (1H, d, J=7.8 Hz), 9.01 (1H, s) ESI-MS(m/e): 389[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In ethanol; toluene; butanone; | EXAMPLE 3 (4S,5R)-4-(2-methylpropyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidine-2-one fumarate A mixture of (4S,5R)-4-(2-methylpropyl)-5-phenyl-1,3-oxazolidine-2-one (10.97 g, 50 mmol), <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (12.38 g, 62.5 mmol), anhydrous potassium carbonate powder (17.28 g, 125 mmol) and methyl ethyl ketone (100 ml) was heated under reflux with stirring for 24 hours. After completion of the reaction, the reaction mixture was cooled and insoluble matter was removed by filtration. The insoluble matter was washed with methyl ethyl ketone. The washing and filtrate were combined together and concentrated under reduce pressure. The residue was dissolved in toluene (70 ml). The toluene solution was washed three times with water (70 ml) and the toluene was then evaporated under reduced pressure. The residue was then dissolved in ethanol (50 ml), followed by addition of fumaric acid (5.80 g, 50 mmol). The resulting mixture was heated to dissolve the fumaric acid. The solution was allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration, washed three times with ethanol (30 ml) and then dried to give crude crystals (19.04 g). The crude crystals were recrystallized from water (70 ml) to obtain 16.73 g of the intended compound as white crystals (yield: 73%). m.p.: 174-176 C. (decomposed). [alpha]D:=+12.0 (c 1.00, MeOH). IR numaxKBr (cm-1): 3560, 3450, 2950, 2640, 2350, 1740 1725, 1690, 1635, 1540, 1450, 1405, 1240, 1200, 995, 975, 765, 745, 695. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 20 5-(Indol-3-ylmethyl)-3-(3-piperidylpropyl)hydantoin A mixture of 5-(indol-3-ylmethyl)hydantoin (10 g, 0.043 mole), N-(3-chloropropyl)piperidine hydrochloride (8.6 g, 0.043 mole), NaOC2 H5 (0.086 mole), 350 ml of anhydrous C2 H5 OH and 100 ml DMF was heated to reflux with stirring for 6 hours and poured into 1.5 l of H2 O. The solid was collected and recrystallized from aqueous methanol, yield 11.7 g, mp 185. ANALYSIS-- Calculated for C20 H26 N4 O2: C, 67.78; H, 7.39; N, 15.81. Found: C, 67.45; H, 7.32; N, 15.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; sodium chloride; In water; toluene; | EXAMPLE III 2,7-Bis(3-piperidinopropoxy) fluoren-9-one dihydrochloride A mixture of 63.6 g (0.30 mole) of <strong>[42523-29-5]2,7-dihydroxy-fluoren-9-one</strong>, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85percent potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis (3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., lambdamaxH2 O 270, and E1cm1percent 1370. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16h; | (trans) 1 -(1 H-benzimidazol-2-ylmethyl)-2,3,3a,4,5,9b-hexahydro-1 H-pyrrolo[3,2- /7]quinoline (0.032 g, 0.11 mmol), potassium carbonate (0.075 g, 0.55 mmol), 1-(3- chloropropyOpiperidine hydrochloride (0.025 g, 0.16 mmol), and potassium iodide (5 mg) in 3 mL of N,N-dimethylformamide were heated to 80 9C in a sealed tube for 16 hours. The mixture was allowed to cool to room temperature and quenched with 5 mL of water. The mixture was extracted 3 times with 5 mL of dichloromethane and the combined organic layers concentrated. The residue was purified by silica chromatography eluting with a 0% to 10% gradient of aqueous ammonia in acetonitrile to yield 33 mg (70%) of (trans) 1-({1-[3-(1-piperidinyl)propyl]-1 H- benzimidazol-2-yl}methyl)-2,3,3a,4,5,9b-hexahydro-1 H-pyrrolo[3,2-/7]quinoline. 1 H NMR (400 MHz, METHANOL-D4) delta ppm 1.4 (d, J=5.1 Hz, 2 H), 1.5 (m, 5 H), 1.6 (m, 3 H), 1.8 (m, 3 H), 2.1 (m, 1 H), 2.2 (m, 3 H), 2.4 (m, 2 H), 2.7 (m, 3 H), 2.9 (m, 1 H), 3.6 (d, J=8.6 Hz, 1 H), 3.6 (d, Lambda=13.5 Hz, 1 H), 3.7 (m, 1 H), 3.9 (dt, J=14.3, 7.2 Hz, 1 EPO <DP n="143"/>H), 4.7 (d, J=13.5 Hz, 1 H), 7.2 (m, 2 H), 7.3 (m, 1 H)1 7.4 (d, J=6.4 Hz, 1 H), 7.6 (m,1 H), 7.7 (d, J=7.7 Hz, 1 H), 8.4 (d, J=4.8 Hz, 1 H); MS m/z430 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16h; | To a solution of (cis) 1-(1 H-benzimidazol-2-ylmethyl)-1 ,2,3,4,4a,5,6,10b-octahydro- 1 ,10-phenanthroline (0.032 g, 0.10 mmol) in 5 mL of N,N-dimethylformamide was added potassium carbonate (0.14 g, 1.0 mmol), <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (0.050 g, 0.25 mmol), and potassium iodide (10 mg). The reaction mixture was heated to 80 QC in a sealed tube for 16 hours. After being allowed to cool, the mixture was diluted with 10 mL of water and extracted 3 times with 10 mL of dichloromethane. The combined organic layers were concentrated and the residue purified by silica chromatography eluting with a 0% to 10% gradient of 30% aqueous ammonium hydroxide in acetonitrile to yield 0.028 g (63%) of (cis) 1 -({1 -[3-(1 - piperidinyl)propyl]-1 H-benzimidazol-2-yl}methyl)-1 ,2l3l4>4a,5,6l10b-octahydro-1 l10- phenanthroline. 1 H NMR (400 MHz, METHANOL-D4) delta ppm 1.5 (m, 6 H), 1.6 (m, 4 H), 1.8 (m, 2 H), 1.9 (m, 2 H), 2.1 (m, 1 H), 2.3 (m, 5 H), 2.5 (m, 2 H), 2.8 (d, J=11.7Hz, 1 H), 2.9 (m, 1 H), 3.1 (ddd, J=17.5, 7.2, 2.7 Hz, 1 H), 3.4 (m, 1 H), 3.6 (m, 1 H), EPO <DP n="75"/>4.0 (ddd, J=14.3, 7.1 , 7.0 Hz, 1 H), 4.2 (m, 2 H)1 7.2 (m, 2 H), 7.3 (m, 1 H), 7.4 (d, J=7.0 Hz, 1 H), 7.5 (d, J=7.3 Hz, 1 H), 7.7 (d, J=I..5 Hz, 1 H), 8.4 (d, J=4.8 Hz, 1 H); MS m/z 444 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 90h; | To a solution of intermediate 6d) (468 mg) in DMF (8 ml) was added <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (373 mg) and Cs2CO3 (1710 mg). The reaction was stirred at room temperature for 18 h. An additional amount of <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (297 mg) and Cs2CO3 (489 mg) were added and stirring at room temperature was continued for 3 d. The reaction mixture was evaporated at 40 C in vacuo to dryness and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified using flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 90h; | To a solution of intermediate 23d) (468 mg) in DMF (8 mi) was added <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (373 mg) and CS2CO3 (1710 mg). The reaction was stirred at room temperature for 18 h. An additional amount of <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (297 mg) and Cs2CO3 (489 mg) were added and stirring at room temperature was continued for 3 d. The reaction mixture was evaporated at 40 C in vacuo to dryness and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified using flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 80℃; for 48h; | To 1-{3-[7-(6-Oxo-1 ,6-dihydro-pyridin-3-yl)-imidazo[1 ,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- trifluoro-ethyl)-urea (0.12g, 0.63mmol) in DMF (1.5ml) was added N-(3- chloropropyl)piperidine hydrochloride (0.125g, 0.63mmol) , Cs2CO3 (0.32g, 0.98mmol) and NaI (0.095g, 0.63mmol). The reaction was heated at 80 0C for 48 hours then partitioned between EtOAc and water , the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (16mg) MS: [M+H]+ 553 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With potassium carbonate; sodium hydroxide; In diethyl ether; water; for 1h;Inert atmosphere; | N-(3-Chloropropyl)-piperidine hydrochloride (97% purity from Aldrich Chemicals) (100 g) was dissolved in water (150 mL) and saturated aqueous potassium carbonate (250 mL) was slowly added to it. Also, 10N sodium hydroxide (25 mL) and diethyl ether (250 mL) were added and the mixture was stirred for one hour. The layers were separated; the organic layer was dried over anhydrous potassium carbonate and concentrated on a Buechi Labortechnik AG Rotavapor evaporator to give the title compound (77.2 g, 94.4%), which was used without purification for the next reactions. |
94.4% | With sodium hydroxide; potassium carbonate; In diethyl ether; water; for 1h; | N-(3-Chloropropyl)-piperidine hydrochloride (97% purity from Aldrich Chemicals) (100 g) was dissolved in water (150 mL) and saturated aqueous potassium carbonate (250 mL) was slowly added to it. Also, ION sodium hydroxide (25 mL) and diethyl ether (250 mL) were added and the mixture was stirred for one hour. The layers were separated; the organic layer was dried over anhydrous potassium carbonate and concentrated on a Biichi Labortechnik AG Rotavapor evaporator to give the title compound (77.2 g, 94.4%), which was used without purification for the next reactions |
With sodium hydroxide; In water; | A) 5-Oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester; A solution of 8.52 g (39.75 mmol) of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of N,N-dimethylacetamide was treated at 0 C. with 2.60 g (59.62 mmol) of NaH (55% in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in [49.6 g (250 mmol, 6.3 eq.) <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> were dissolved in 262 ml of 1 M aq. sodium hydroxide solution and extracted with toluene (200 ml). The organic phase was dried over Na2SO4]. The reaction was warmed up to room temperature and stirred over night. After 2 h at 50 C. and cooling to room temperature, the reaction was neutralized with water (50 ml), evaporated and then dissolved in sat. aq. sodium hydrogencarbonate solution/diethyl ether. After reextraction with diethyl ether, the organic phase was dried (Na2SO4), evaporated and crystallized from pentane to yield 12.08 g (90%) of the title compound as white crystals. MS: 340.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; | 3-{3-[2-(4-Fluoro-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-7-yl}-phenol (Ex. 1.102) (1 eq, 0.131 mmol, 50 mg), l-(3-chloropropyl)piperidine monohydrochloride (2.0 eq, 0.262 mmol, 53.7 mg) and potasium carbonate (3.0 eq, 0.394 mmol, 54.4 mg) are dissolved in DMF (4 ml) and heated at 60C for 16 h. The reaction mixture is diluted with CH2CI2 and washed with NaHCCh and brine. The organic phase is dried over MgStheta4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3 to yield 3-[2-(4-fluoro- phenyl)-pyridin-4-yl]-7-[3-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+ = 507 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 40 - 50℃; for 7h; | To a suspension of ethyl 3-hydroxy-I H-pyrazole-S-carboxylate (4.5 g, prepared with an analogous procedure to that described in P1 ) and K2CO3 (7.97 g) in CH3CN (100 ml) 1-(3- chloropropyl)piperidine HCI salt (5.71 g) and NaI (0.43 mg) were added and the mixture was stirred at 40-50 0C for 7 h. The mixture was diluted with EA (500 ml) and washed with water (3X40 ml). The organic layer was dried over Na2SO4, filtered and evaporated under vacuum; the residue was purified by column on silica gel (elunt MeOH:CH2CI2 with a gradient of MeOH from 0% to 5%) to the title compound (give 4.2 g).1H NMR (DMSO) delta: 13.05(1 H, s), 6.16(1 H, s), 4.25 (2H, q), 4.05 (2H, t), 2.30 (6H, m), 1.80 (2H, m), 1.44 (4H, m), 1.33 (2H, m), 1.27 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.5% | With potassium carbonate; potassium iodide; In acetone; at 65℃;Inert atmosphere of argon; Reflux; | Under argon atmosphere, a suspension of ethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}-5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (54.2 g, 150 mmol, P51 ) in Acetone (915 ml) was added dropwise (over 1 hour) to a suspension of 1-(3- chloropropyl)piperidine hydrochloride (59.6 g, 301 mmol), potassium carbonate (62.4 g, 451 mmol) and potassium iodide (74.9 g, 451 mmol) in Acetone (339 ml) previously heated at reflux; the reaction mixture was reacted at gentle reflux (650C of external temperature) for 15 hours after which it was cooled down to rt and taken up with ethyl acetate (1.5 L) and water (2 L). The aqueous phase was extracted with ethyl acetate (2 x 700 mL) and the combined organics were washed with brine (800 mL), dried on sodium sulphate, filtered and evaporated to dryness. 60 g of crude material were purified using a Biotage Amino Silica KP-NH column eluted with cycloexane/ethyl acetate from 9:1 to 1 :1 to obtain title compound (41.3 g, 85 mmol, 56.5 % yield) as yellow oil.1H NMR (400 MHz, CDCI3): delta 8.23 (m, 2 H) 7.37 (t, 1 H) 6.35 (s, 1 H) 5.83 (s, 2 H) 4.27 (q, 2 H) 4.18 (t, 2H) 2.43 (m, 6H) 1.98 (m, 2H) 1.60 (m, 4H) 1.45 (m, 2H) 1.33 (t, 3 H). UPLC/MS (m/z): 486 [MH]+ ; rt 0.63 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; | To a solution of 2-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-7-hydroxy-4-methyl-1- oxopyrrolo[1 ,2-a]pyrazin-2(1 H)-yl]-N-(1-methylethyl)acetamide (330 mg, P1 15) in dry DMF (3 mL), potassium carbonate (429 mg) and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (231 mg) were added at rt and the mixture was heated to 1000C and left stirring at that temperature overnight. The day after the mixture was diluted with AcOEt and washed with ice and brine. Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. Crude was purified first by sex cartridge eluting first with MeOH then with NH3 2M in MeOH, then by flash chromatography on SI column (eluent: DCM/(DCM:MeOH:NH3(acq) = 9:1 :0.1 ) from 100% to 0% of DCM) and at the end by flash chromatography on NH column (eluent: Cy/AcOEt from 0% to 100% of AcOEt) to give the title compound (186 mg).1H NMR (500 MHz, CDCI3) delta 7.58-7.68 (m, 2H), 7.31-7.40 (m, 1 H), 6.86-6.91 (d, 1 H), 6.79-6.85 (d, 1 H), 5.85-5.94 (m, 1 H), 4.11-4.33 (m, 2H), 4.06 (t, 2H), 3.91-4.02 (m, 1 H), 2.46-2.54 (m, 2H), 2.36-2.45 (m, 4H), 2.04 (s, 3H), 1.95-2.03 (m, 2H), 1.56-1.67 (m, 5H), 1.45-1.51 (m, 1 H), 1.12 (d, 6H). MS (m/z): 550 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; | A) 5-Oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic Acid tert-butyl ester; A solution of 8.52 g (39.75 mmol) of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of DMA was treated at 0 C. with 2.60 g (59.6 mmol) of NaH (55% dispersion in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in [49.62 g (250.42 mmol, 6.3 eq.) <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> were dissolved in 262 ml of 1 M aq. NaOH solution and extracted with toluene (200 ml). The organic phase was dried over Na2SO4]. The reaction was warmed up to RT and stirred overnight. After 2 h at 50 C. and cooling to RT, the reaction was neutralized with water (50 ml), evaporated and then dissolved in sat. aq. NaHCO3/Et2O. After reextraction with Et2O, the organic phase was dried (Na2SO4), evaporated and crystallized from pentane to yield 12.08 g (90%) of the title compound as white crystals. MS: 340.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Imidazo[1,2-b]pyridazin-7-yl-pyridin-2-ol (1 eq, 0.17 mmol, 36 mg), <strong>[5472-49-1]1-(3-chloropropyl)piperidine monohydrochloride</strong> (1.5 eq, 0.255 mmol, 52 mg) and sodium iodide (1.5 eq, 0.254 mmol, 37.9 mg) are dissolved in DMF (1 ml) and heated at 60 C. for 16 h to give a black solution. The reaction mixture is then poured into aq. sat. NaHCO3 and the organic phase is extracted with CH2Cl2. The organic phase is washed with brine, dried over MgSO4, filtered and evaporated to dryness to afford 4-imidazo[1,2-b]pyridazin-7-yl-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one; [M+H]+=338 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; potassium iodide In acetone for 16h; Reflux; | 4.2.3. General procedure of Williamson ether synthesis with Finkelstein exchange General procedure: Halogen alkane (1 eq.), alcohol (1.1 eq.), potassium carbonate (4 eq.)and potassium iodide (catalytic) was stirred in acetone under refluxconditions. The mixture was filtered and the filtrate was evaporated.Raw product was dissolved in dichloromethane and washed with 2 MNaOH solution. The organic phase was dried with MgSO4 and evaporated.The product was chromatograpically purified or used as obtained.4.2.4. (4-(3-(Piperidin-1-yl)propoxy)phenyl)methanol 348Synthesis from 4-(hydroxymethyl)phenol (4.966 g; 40.0 mmol) andcompound 2 according to general procedure of Williamson ether synthesis.Product did not need further purification. Yield: 90%APCI-MS (+): m/z: 250.2 [M + H+]+ 1H NMR (300 MHz, DMSO-d6) δ7.30 - 7.12 (m, 2H), 6.96 - 6.80 (m, 2H), 5.05 (s, 1H), 4.41 (s, 2H), 3.95(t, J = 6.4 Hz, 2H), 3.59 - 3.23 (m, 1H), 2.40 - 2.20 (m, 6H), 1.84 (dt, J= 7.7, 6.5 Hz, 2H), 1.49 (dq, J = 10.5, 5.0 Hz, 4H), 1.37 (q, J = 6.0 Hz,2H). |
With potassium carbonate; potassium iodide In acetone for 48h; Reflux; | ||
With potassium carbonate; potassium iodide In acetone for 48h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; potassium carbonate; In water; at 75℃; | General procedure: To a solution of corresponding reactant 6a-6j (4 mmol) in water (30 mL) was added K2CO3(1.656 g, 12 mmol) and sodium azide (0.390 g, 6 mmol). The reaction mixture was stirred at 75 C for10 h, then cooled to room temperature and extracted by dichloromethane (15 mL x 3). The organiclayer was partitioned, combined, washed with bine (15 mL), dried over magnesium sulfate andconcentrated to afford crude product 7a-7j. The crude residue 7a-7j was then dissolved in a mixturesolvent of t-BuOH/H2O (v:v = 1:1, 15 mL). Compound 5 (0.836 g, 2 mmol), sodium ascorbate (119 mg,0.6 mmol), and CuSO4*5H2O (5 mg, 0.02 mmol) were added into the mixture. The reaction mixturewas stirring at room temperature under N2 protection overnight. Then water (200 mL) was addedand the mixture was extracted by dichloromethane (15 mL x 3). The organic layer was partitioned, combined, washed with bine (15 mL), dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography (20:1 dichloromethane/methanol) to afford the products8a-8j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-(3-methoxyphenyl)prop-2-en-1-ol (365 mg) in dimethylsulfoxide (6 mL) are added successively powdered potassium hydroxide (278 mg 85%wt) and, portionwise, 1-(3-chloropropyl)piperidine, hydrochloride (400 mg). The mixture is stirred overnight at room temperature, then hydrolysed with water (80 mL). The solution is extracted twice with ethyl acetate (20 mL). The combined extracts are washed twice with water (10 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 98/2 to 90/10. Fractions containing the expected product are pooled, concentrated under reduced pressure, dissolved in 10 mL of dichloromethane, filtered over Millipore membrane and concentrated under reduced pressure. The base thus obtained is dissolved in 2 mL of ethanol and 100 muL of diethyl oxide. A solution of 88 mg of oxalic acid in 2 mL of ethanol is added. The precipitate that appears is filtered, washed with diethyl oxide and dried under reduced pressure at a temperature close to 40C to give 159 mg of trans-1-{3-[3-(3-methoxyphenyl)allyloxy]propyl}piperidine, oxalate as white crystals melting at 130C. 1H NMR oxalate (DMSO) 7.22 (m, 1 H, arom), 6.98 (m, 2H, arom), 6.80 (m, 1 H, arom), 6.55 (d, J=16 Hz, 1 H, ArCH=), 6.34 (dt, J=16 Hz, J=5.7 Hz, 1 H, CH=), 4.05 (d, J=5.7 Hz, 2H, OCH2), 3.73 (s, 3H, OCH3), 3.45 (t, J=5.9 Hz, 2H, OCH2), 3.00 (m, 6H, 3 CH2N), 1.88 (m, 2H, CH2), 1.67 (m, 4H, 2 CH2), 1.47 (m, 2H, CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate; potassium iodide; In methanol; at 85℃; for 0.25h;Microwave irradiation; | 3-(3-Methoxy-phenyl)-4-(3-piperidin-1-yl-propoxy)-2H-isoquinolin-1 -one (cmpd. 10)(I, L=CH2-CH2-CH2, R2=R3=H, R and Ri together = piperidino and R4=3-methoxyphenyl).To a suspension of 766 mg (2.86 mmol) of 4-hydroxy-3-(3-methoxy-phenyl)-2H-isoquinolin-1-one in methanol (29 ml_), 1.45 g (5.73 mmol) of 1-(3-Chloro-propyl)-piperidine hydrochloride, 1.58 g (11.5 mmol) of potassium carbonate and 47 mg (0.286 mmol) of potassium iodide were added and the mixture was submitted to microwaves at 85C with contemporary cooling for 15 min. The solvent was concentrated in vacuo and the mixture was worked-up with dichloromethane and sodium hydrogenocarbonate saturated solution. The organic layer was washed with brine and then evaporated to dryness. The crude was purified by flash chromatography (eluant: dichloromethane/methanol 96/4) to afford 456 mg of the title compound (41 %).1H NMR (DMSO- d6) delta (ppm): 11.19 (s, 1H), 8.23 (dd, J = 7.9, 0.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.80 (ddd, J =8.2, 7.0, 1.3 Hz, 1H), 7.56 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.9, 1.1 Hz, 1H), 7.23(dd, J = 2.5, 1.5 Hz, 1H), 7.02 (ddd, J = 8.2, 2.6, 0.7 Hz, 1H), 3.83 (s, 3H), 3.55 (t, J = 6.2 Hz, 2H), 2.22 (br. s., 6H),1.68 (br. s., 2H), 1.45 (br. s., 4H), 1.37 (br. s., 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 12h; | Intermediate 38EEthyl 2-((4-methoxyphenyl)amino)-1-(3-(piperidin-1-yl)propyl)-1 H-imidazo[4,5-c]pyridine-6- carboxylate To a stirred suspension of ethyl 2-((4-methoxyphenyl)amino)-1 H-imidazo[4,5-c]pyridine-6- carboxylate (0.5g, 1.6 mmol) and K2C03 (0.7g, 4.8 mmol) in DMF (10 mL) was added 1 -(3- chloropropyl)piperidine hydrochloride (0.28g, 1.9 mmol). The suspension was stirred at 65C for 12h. The mixture was poured into ethyl acetate (50 mL), washed with water (3 x 10 mL) and brine (10 mL). The organic layer was dried over Na2S04, filtered and concentrated to an oil. The residue was purified by reverse-phase preparative HPLC (Solvent A: MeOH:H20:TFA (5:95:0.05).Solvent B: MeOH:H20:TFA (95:5:0.05). Gradient 20 to 70% B in 15 min. Column: Zorbax SB-C18 PrepHT, 5 microns, 21.2 x 100 mm. Wavelength 220 nm) to afford the title compounds as a yellow solid (0.35g, 33%). LCMS m/z 438.3 (M + H)+, ret. time= 1.60 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 45A/,/V-dibutyl-2-((4-methoxyphenyl)amino)-1-(3-(piperidin-1-yl)propyl)-1 /-/-imidazo[4,5-6]pyridine-6-carboxamideTo a stirred suspension of /V,/V-dibutyl-2-((4-methoxyphenyl)amino)-1 W-imidazo[4,5-b]pyridine- 6-carboxamide (120 mg, 0.3 mmol) in DMF (1.0 mL),was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (0.31 mL, 0.31 mmol). The resulting mixture was stirred at room temperature for 30 minutes and a solution of 1 -(3-chloropropyl)piperid ine hydrochloride (60 mg, 0.30 mmol) and lithium bis(trimethylsilyl)amide (0.31 mL, 0.31 mmol). in DMF (1.0 mL) was added. The resulting mixture was stirred at 60 C.for 14 hours. The mixture was allowed to cool to room temperature and trifluoroacetic acid was added. The mixture was filtered and purified by reverse-phase preparative HPLC (Solvent A: MeOH:H20:TFA (5:95:0.05). Solvent B: MeOH:H20:TFA (95:5:0.05). Gradient 30 to 100% B in 12 min. Column: Zorbax SB-C18 PrepHT, 5 microns, 21.2 x 100 mm. Wavelength 220 nm). LCMS m/z 521.4 (M + H)+, ret. time= 2.15 min. |
Yield | Reaction Conditions | Operation in experiment |
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21% | With triethylamine; In ethanol; at 50℃; | Example 4General Procedure for the Syntheses of Compounds 5a, 5b and 5cThe crude base of compound 4, (+/-)-2-phenylbicyclo [2.2.1] heptan-2-amine or 2-(4-fluoro-phenyl)-bicyclo[2.2.1]hept-2-ylamine (5.4 mmol) and appropriate alkyl halogen derivatives (5.6 mmol) dissolved in ethanol (30 mL) and triethylamine (1 ml, 7.1 mmol), to form a mixture that was heated at 50 C. for 20-48 h. After cooling, the solvent was removed under reduced pressure and the residue was treated with water. The mixture was extracted with ethyl acetate (3×20 mL). Organic phase was separated, dried over sodium sulfate, and purified by column chromatography. Hydrochloride salt of the compound was obtained by bubbling hydrogen chloride gas in the ethyl ether solution of the compound. Fumarate salt was obtained using equal molar amounts of fumaric acid and compound in methanol. The solvent used for crystallization was the mixture of methanol and ethyl ether at 0 C.Example 5 (±)-2-Phenyl-N-(3-(piperidin-1-yl)propyl)bicyclo[2.2.1]heptan-2-amine (5a) The compound was prepared from 4a (1.63 g, 6.2 mmol) and 1-(3-chloroethyl)piperidine hydrochloride (1.43 g, 7.2 mmol) according to general procedure and was purified by column chromatography (EtOAc/i-prOH/TEA 8:2:0.2) to give 5a (0.58 g, 21% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta ppm 7.37-7.25 (m, 4H), 7.20 (tt, J=6.22, 1.71 Hz, 1H), 2.47 (s, 1H), 2.39-2.14 (m, 8H), 2.14-2.01 (m, 2H), 1.89 (dd, J=12.62 Hz, 1H), 1.78-1.68 (m, 1H), 1.61-1.51 (m, 4H), 1.51-1.25 (m, 8H),1.05 (dd, J=7.45 Hz, 2H); MS (ESI+) m/z: 313 (100%), [M+H]. Fumarate salt was prepared to give colorless crystals, m.p. 190-192 C. Anal. Calcd. for fumarate salt; C29H40N2O8.0.4H2O: C, 63.12; H, 7.45; N, 5.08. Found: C, 63.18; H, 7.42; N, 5.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Compound 2a (0.200 g, 0.71 mmol) was added to dry dichloromethane (25 mL) with stirring under nitrogen atmosphere. To this solution NaH (0.290 g, 7.25 mmol) 60% dispersion in mineral oil was added and the reaction heated at reflux for 1 h. The reaction mixture was then cooled in an ice-bath and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrogen chloride salt</strong> (0.238 g, 1.2 mmol), potassium carbonate (0.660 g, 4.8 mmol), tetrabutylammoniumbromide (0.090 g, 0.279 mmol) and potassium iodide (0.357 g, 2.15 mmol) added with stirring. The reaction mixture was then heated at reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (10 ml * 2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.168 g (58%) of KSCM-11 as a brown paste. 1H NMR (300 MHz, CDCl3) delta 1.39-1.57 (m, 6H), 1.82-1.92 (qt, J = 7.14 Hz, 2H), 2.33-2.37 (m, 6H), 2.35 (s, 3H), 3.74 (s, 3H), 3.90-3.95 (t, J = 7.57 Hz, 2H), 6.52 (s, 1H), 6.78-6.80 (d, J = 8.61 Hz, 1H), 7.12-7.33 (m, 6H). 13C NMR (300 MHz, CDCl3) delta 9.2, 24.5, 25.3, 26.0, 49.0, 54.6, 55.6, 56.6, 95.3, 112.3, 120.6, 122.1, 122.4, 126.6, 127.0, 129.0, 143.1, 143.6, 154.6, 159.6, 161.4. MS(ESI)+ calcd for C25H31N2O3 [M+H]+: 407.2335, found: 407.2339. | |
58% | F. 6-Methoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-11). [0067] Compound 2a (0.200 g, 0.71 mmol) was added to dry dichloromethane (25 mL) with stirring under nitrogen atmosphere. To this solution NaH (0.290 g, 7.25 mmol) 60% dispersion in mineral oil was added and the reaction heated at reflux for 1 h. The reaction mixture was then cooled in an ice-bath and 1-(3-chloropropyl) piperidine hydrogen chloride salt (0.238 g, 1.2 mmol), potassium carbonate (0.660 g, 4.8 mmol), tetrabutylammoniumbromide (0.090 g, 0.279 mmol) and potassium iodide (0.357 g, 2.15 mmol) added with stirring. The reaction mixture was then heated at reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (10 ml×2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.168 g (58%) of KSCM-11 as a brown paste. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Compound 2b (0.100 g, 0.321 mmol) was added to dry dichloromethane (15 mL) with stirring under nitrogen atmosphere. To this solution NaH (0.130 g, 3.25 mmol) 60% dispersion in mineral oil was added and the reaction heated at reflux for 1 h. The reaction mixture was then cooled in an ice-bath and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrogen chloride salt</strong> (0.110 g, 0.555 mmol), potassium carbonate (0.380 g, 2.75 mmol), tetrabutylammoniumbromide (0.046 g, 0.143 mmol) and potassium iodide (0.292 g, 1.76 mmol) added with stirring. The reaction mixture was then heated at reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (5 ml * 2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.0841 g (60%) of KSCM-1 as a light brown paste. 1H NMR (300 MHz, CDCl3) delta 1.38-1.56 (m, 6H), 1.81-1.91 (qt, J = 7.58 Hz, 2H), 2.31-2.36 (m, 6H), 2.34 (s, 3H), 3.80 (s, 3H), 3.87 (s, 3H), 3.86-3.93 (m, 2H), 6.52 (s, 1H), 6.81 (s, 1H), 7.10-7.30 (m, 5H). 13 C NMR (300 MHz, CDCl3) delta 9.9, 10.1, 24.5, 25.3, 26.0, 29.7, 49.0, 54.6, 56.2, 56.3, 56.6 94.7, 100.8, 120.8, 122.4, 126.5, 126.9, 128.9, 143.2, 143.6, 146.7, 148.4, 149.9, 161.4. MS(ESI)+ calcd for C26H33N2O4 [M+H]+: 437.2440, found: 437.2440. | |
60% | D. 5,6-Dimethoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-1). [0063] Compound 2b (0.100 g, 0.321 mmol) was added to dry dichloromethane (15 mL) with stirring under nitrogen atmosphere. To this solution NaH (0.130 g, 3.25 mmol) 60% dispersion in mineral oil was added and the reaction heated at reflux for 1 h. The reaction mixture was then cooled in an ice-bath and 1-(3-chloropropyl) piperidine hydrogen chloride salt (0.110 g, 0.555 mmol), potassium carbonate (0.380 g, 2.75 mmol), tetrabutylammoniumbromide (0.046 g, 0.143 mmol) and potassium iodide (0.292 g, 1.76 mmol) added with stirring. The reaction mixture was then heated at reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (5 ml×2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.0841 g (60%) of KSCM-1 as a light brown paste. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Compound 2c (0.200 g, 0.80 mmol) was added to dry dichloromethane (25 ml) with stirring under nitrogen atmosphere. To this solution NaH (290 mg, 7.25 mmol) 60% dispersion in mineral oil was added and at reflux for 1 h. The reaction mixture was cooled in an ice-bath and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrogen chloride salt</strong> (0.238 g, 1.2 mmol), potassium carbonate (0.660 g, 4.8 mmol), tetrabutylammoniumbromide (0.100 g, 0.310 mmol) and potassium iodide (0.299 g, 1.8 mmol) added with stirring. The reaction mixture was reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (10 ml * 2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.189 g (63%) of KSCM-5 as a light brown paste. 1H NMR (300 MHz, CDCl3) delta 1.36-1.56 (m, 6H), 1.82-1.92 (qt, J = 7.58 Hz, 2H), 2.31-2.36 (m, 6H), 2.34 (s, 3H), 3.90-3.95 (t, J = 7.64 Hz, 2H), 7.03-7.05 (d, J = 8.03 Hz, 1H), 7.11-7.26 (m, 7H), 7.43-7.45 (d, J = 6.85 Hz, 1H). 13 C NMR (300 MHz, CDCl3) delta 9.1, 24.5, 25.3, 26.0, 49.0, 54.6, 56.6, 111.4, 120.3, 121.2, 122.6, 126.2, 126.7, 127.0, 128.9, 129.0, 142.8, 144.4, 153.4, 161.5. MS(ESI)+ calculated for C24H29N2O2 [M+H]+: 377.2229, found: 377.2227. | |
63% | E. 3-Methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-5). [0065] Compound 2c (0.200 g, 0.80 mmol) was added to dry dichloromethane (25 ml) with stirring under nitrogen atmosphere. To this solution NaH (290 mg, 7.25 mmol) 60% dispersion in mineral oil was added and at reflux for 1 h. The reaction mixture was cooled in an ice-bath and <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrogen chloride salt</strong> (0.238 g, 1.2 mmol), potassium carbonate (0.660 g, 4.8 mmol), tetrabutylammoniumbromide (0.100 g, 0.310 mmol) and potassium iodide (0.299 g, 1.8 mmol) added with stirring. The reaction mixture was reflux for 24 h. The reaction mixture was then cooled and slowly quenched with ethanol. The reaction mixture was washed with water (10 ml×2) and the organic layer dried over magnesium sulfate. The crude product was purified by high performance flash purification using a Biotage Isolera 4 system, SNAP (SiO2) KP-NH column, solvent dichloromethane/methanol (9:1) as eluent to give 0.189 g (63%) of KSCM-5 as a light brown paste. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; sodium iodide; In acetone; for 24h;Reflux; | General procedure: A mixture of 3,4-dihydroquinazolin-4-one (0.5 mmol), sodium iodide (0.05 mmol), potassium carbonate (2.5 mmol), and an appropriate alkylating agent (0.5 mmol) in acetone (5 mL) was heated under reflux for 24 h. The resultant mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL) and organic phase was dried with sodium sulfate. Crude products were purified by column chromatography (hexane/ethyl acetate 8:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | 1.72 g (20.3 mmol) of piperidine, 2 ml (24.3 mmol) of 3-chloropropanol and 10 ml toluene were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 4 h. Into the reaction mixture, 5% NaOH 4 ml was added, and the mixture was refluxed for 1 h. After cooling to room temperature, the mixture was washed with 5% NaOH solution. The organic layer was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtrated. 3 ml (40.6 mmol) thionyl chloride was added dropwise into the filtrate in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dry in a reduced pressure, and the residue was recrystallized with absolute ethyl alcohol to obtain 2.4 g of a khaki solid with the yield of 59%. m.p. 218-220 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In acetone; for 12h;Reflux; | 0.19 g (0.56 mmol) of Compound VIa, 0.3 g (2.24 mmol) of potassium carbonate, 0.17 g (0.84 mmol) of Compound VIIb and 30 ml acetone were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 12 h, then filtrated while it is still hot. The filtrate was concentrated to dry in a reduced pressure. The residue was dissolved with 20 ml dichloromethane, and the substance undissolved was filtered off. The filtrate was concentrated to dry in a reduced pressure and the residue was purified by column chromatography to obtain 0.08 g red solid with the yield of 31%. m.p. 132-138 C. 1H-NMR (CDCl3): 5.66-8.74 (12H, m, Ar-H), 4.20 (2H, t, J=6.3 Hz, OCH2), 2.76 (6H, m, NCH2), 2.70 (2H, brs, CH2), 1.85 (4H, brs, 3, 5-piperidyl), 1.59 (2H, brs, 4-piperidyl). EI-MS m/z: 464[M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydroxide; In 1,4-dioxane; for 3h;Reflux; | General procedure: A mixture of 6H-quinobenzothiazine 3a (0.13 g, 0.5 mmol) [or 9-chloro-6H-quinobenzothiazine 3c (0.14 g, 0.5 mmol) or 9-methylthio-6H-quinobenzothiazine 3f (0.15 g, 0.5 mmol)], sodium hydroxide (0.30 g, 7.5 mmol) and hydrochloride of dialkylaminoalkylchloride (1.5 mmol, 2-diethylaminoethyl - 0.26 g, 3-dimethylaminopropyl - 0.24 g, 3-dimethylamino-2-methylpropyl - 0.26 g, 2-(1-pyrrolidyl)ethyl - 0.26 g, 2-(1-piperidyl)ethyl - 0.28 g, 2-(1-methyl-2-piperydinyl)ethyl - 0.30 g) in dry dioxane (5 mL) was refluxed for 3 h. After cooling the reaction mixture was poured into water (25 mL) and extracted with chloroform (3 x 10 mL). The combined extracts were washed with water to pH = 7 and dried over Na2SO4. Chloroform was evaporated in vacuo and the residue was purified by column chromatography (Al2O3, CHCl3) to give compounds 6-11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydroxide; In 1,4-dioxane; for 3h;Reflux; | General procedure: A mixture of 6H-quinobenzothiazine 3a (0.13 g, 0.5 mmol) [or 9-chloro-6H-quinobenzothiazine 3c (0.14 g, 0.5 mmol) or 9-methylthio-6H-quinobenzothiazine 3f (0.15 g, 0.5 mmol)], sodium hydroxide (0.30 g, 7.5 mmol) and hydrochloride of dialkylaminoalkylchloride (1.5 mmol, 2-diethylaminoethyl - 0.26 g, 3-dimethylaminopropyl - 0.24 g, 3-dimethylamino-2-methylpropyl - 0.26 g, 2-(1-pyrrolidyl)ethyl - 0.26 g, 2-(1-piperidyl)ethyl - 0.28 g, 2-(1-methyl-2-piperydinyl)ethyl - 0.30 g) in dry dioxane (5 mL) was refluxed for 3 h. After cooling the reaction mixture was poured into water (25 mL) and extracted with chloroform (3 x 10 mL). The combined extracts were washed with water to pH = 7 and dried over Na2SO4. Chloroform was evaporated in vacuo and the residue was purified by column chromatography (Al2O3, CHCl3) to give compounds 6-11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydroxide; In 1,4-dioxane; for 3h;Reflux; | General procedure: A mixture of 6H-quinobenzothiazine 3a (0.13 g, 0.5 mmol) [or 9-chloro-6H-quinobenzothiazine 3c (0.14 g, 0.5 mmol) or 9-methylthio-6H-quinobenzothiazine 3f (0.15 g, 0.5 mmol)], sodium hydroxide (0.30 g, 7.5 mmol) and hydrochloride of dialkylaminoalkylchloride (1.5 mmol, 2-diethylaminoethyl - 0.26 g, 3-dimethylaminopropyl - 0.24 g, 3-dimethylamino-2-methylpropyl - 0.26 g, 2-(1-pyrrolidyl)ethyl - 0.26 g, 2-(1-piperidyl)ethyl - 0.28 g, 2-(1-methyl-2-piperydinyl)ethyl - 0.30 g) in dry dioxane (5 mL) was refluxed for 3 h. After cooling the reaction mixture was poured into water (25 mL) and extracted with chloroform (3 x 10 mL). The combined extracts were washed with water to pH = 7 and dried over Na2SO4. Chloroform was evaporated in vacuo and the residue was purified by column chromatography (Al2O3, CHCl3) to give compounds 6-11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate; potassium iodide; In acetone; for 12h;Reflux; | General procedure: Potassium carbonate (0.49g, 3.54mmol) and catalytic amount of potassium iodide were added to the solution of compound 5 (0.30g, 0.80mmol) and 2-chloro-N, N-dimethylethanamine hydrochloride (0.22g, 1.55mmol) in acetone. The mixture was stirred and heated to reflux for 12 h. The hot solution was immediately filtered and filtrate was evaporated under reduced pressure to remove solvent. The rude product was purified by column chromatography on silica to yield compound 6a as light yellow solid (0.12g, 30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
136 mg | General procedure: To a solution of 9a (200 mg, 0.7 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (239 mg, 1.3 mmol) in acetone (30 mL) was added K2CO3 (700 mg, 5.0 mmol). The reaction mixture was refluxed until the reaction was completed from TLC monitoring. The mixture was concentrated in vacuo and partitioned between H2O and CH2Cl2. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give free amine form of 10a. To a solution of the free amine compound in EtOH was added acetyl chloride (370 mg, 4.7 mmol) at 0 C. The reaction mixture was stirred in rt until the salt formation was completed. The solvent was removed and the residue was precipitated in diethyl ether to afford 10a (154 mg, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38 mg | General procedure: To a solution of 9a (200 mg, 0.7 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (239 mg, 1.3 mmol) in acetone (30 mL) was added K2CO3 (700 mg, 5.0 mmol). The reaction mixture was refluxed until the reaction was completed from TLC monitoring. The mixture was concentrated in vacuo and partitioned between H2O and CH2Cl2. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give free amine form of 10a. To a solution of the free amine compound in EtOH was added acetyl chloride (370 mg, 4.7 mmol) at 0 C. The reaction mixture was stirred in rt until the salt formation was completed. The solvent was removed and the residue was precipitated in diethyl ether to afford 10a (154 mg, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; sodium iodide; In acetone;Reflux; | 4-Hydroxybenzaldehyde (1 g, 8.19 mmol), NaT (0.61 g, 4.09 mmol), K2C03 (3.51 g,25.4 mmol) and N-3?-chloropropylpiperidine.HCl (2.43 g, 12.3 mmol) were suspended in acetone (30 mL). The mixture was heated at refiux temperature overnight. The mixture was filtered over Celite and the filter cake was rinsed with acetone. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solids formed were removed by filtration. The filtrate was concentrated in vacuo yielding a yellow oil(2.4 g, 9.6 mmol, 100%). The product was used as such in the next step. |
99% | General procedure: To a solution of 2- or 4-hydroxy-benzaldehyde (1.64mmol) in anhydrous acetone (25mL) was added cesium carbonate (4.92mmol) and the solution was stirred at room temperature for 10min under an argon atmosphere. Chloropropylpiperidine hydrochloride (2.46mmol) and sodium iodide (0.82mmol) was added to the solution and the mixture was heated at reflux overnight. The resulting solution was filtered and evaporated to dryness. The crude compound was diluted with EtOAc, the solution was washed successively with a saturated sodium carbonate solution and water, dried over MgSO4, filtered, and evaporated under reduce pressure. Purification by flash chromatography (hexanes/acetone/TEA, 80:19:1 to 70:29:1) yielded the desired compound 1 (360mg, 89%) or 2 (400mg, 99%). 1H NMR (400MHz, CDCl3) delta: 1.45 (m, 2H), 1.59 (q, J=5.6Hz, 4H), 2.00 (m, 2H), 2.40 (broad s, 4H), 2.47 (t, J=7.4Hz, 2H), 4.10 (t, J=6.4Hz, 2H), 7.00 (d, J=8.7Hz, 2H), 7.82 (d, J=8.7Hz, 2H), 9.88 (s, 1H). APCI-MS for C15H22O2N [M+H]+: 248.3m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 50℃; for 18.5h; | To a suspension of 1 -(3-chloropropyl)piperidine hydrochloride (0.500 g, 2.52 mmol) in THF (14.83 ml, 181 mmol) was added triisopropylsilanethiol (1 .092 ml, 5.05 mmol) and tetrabutylammonium iodide (0.093 g, 0.252 mmol). Sodium hydride 60%wt. in Mineral Oil (0.252 g, 6.31 mmol) was added portionwise. The resulting white suspension was heated to 50 C and stirred for 18.5 hours. Cooled to 20 C and diluted the reaction mixture with Water (15 mL). The mixture was extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with Water (2 x 15 mL) then with Brine (15 mL). The organic layer was dried over anh. MgS04, filtered and concentrated to give 1 .51 g as an orange oil. The residue was purified by flash chromatography to give Intermediate 2A, 1 -(3-((triisopropylsilyl)thio)propyl)piperidine (714 mg, 90 % yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 1 .06 (d, J=7.0 Hz, 18 H) 1 .14 - 1 .29 (m, 3 H) 1 .36 (m, J=5.1 Hz, 2 H) 1 .46 (quin, J=5.4 Hz, 4 H) 1 .65 (quin, J=7.0 Hz, 2 H) 2.29 (m, J=6.7 Hz, 6 H) 2.53 (t, J=7.3 Hz, 2 H); MS m/z 316.2 (M+H)+; HPLC >95%, RT = 2.19 minutes. |
0.71g | With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 50℃; for 19h;Inert atmosphere; | To a mixture of 1-(3-chloropropyl)piperidine.HCI (0.500 g, 2.52 mmol) in THE (14.8 ml, 18 mmol) under N2 was added triisopropylsilanethiol (1.09 ml, 5.0 mmol) and tetrabutylammoniun iodide (0.093 g, 0.25 mmol). Then NaH (0.252 g, 6.3 mmol; 60% weight) was added portion-wise and the mixture was heated at 5000 for 19h. The reaction was cooled to rt, diluted with water (15 ml) and extracted with EtOAc (4 x 15 mL). The organic phases were combined and washed with water (2 x 15 ml) then with brine (15 ml). The organic layer was dried over MgSO4, filtered and the solvent removed under vacuum. Purification on ISCO using a RediSep column (CH2CI2-MeOH) from 20 to 100% afforded 0.71g of the title compound. 1H NMR (400 MHz, DMSO-d6) oe ppm 1.06 (d, J=7.0 Hz, 18 H) 1.14 - 1.29 (m, 3 H) 1.36 (m, J=5.1 Hz, 2 H) 1.46 (quin, J=5.4 Hz, 4 H) 1.65 (quin, J=7.0 Hz, 2 H) 2.29 (m, J=6.7 Hz, 6 H) 2.53 (t, J=7.3 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Example 4: 8-chloro-N-(3 -(piperidin- 1 -yl)propyl)-_V-(4- (trifluoromethoxy)phenyl)quinolin-2 -amine ; compound (30) <strong>[1258453-75-6]8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine</strong>, i.e. compound (24), was synthesised as in WO2010/143169, in example 5. A reaction mixture of 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2- amine (24) (500 mg, 1.47 mmole, 1 eq.) and NaH (177 mg, 4.43 mmoles, 3 eq.) in anhydrous DMF (2 mL) was stirred at room temperature for 30 minutes. A reaction mixture of 1 -(3 -chloropropyl)piperidine hydrochloride (292 mg, 1.47 mmole, 1 eq.), KI (245 mg, 1.47 mmole, 1 eq.) and Et3N (205 iL, 1.47 mmole, 1 eq.) in anhydrous DMF (5 mL) was stirred at room temperature for 30 minutes under an inert atmosphere of argon. The activated quinoline was then added to the piperidine chain and the resulting reaction mixture was stirred at 90C for 4 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO-t, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-iV-(3-(piperidin- 1 -yl)propyl)-jV-{4- (trifluoromethoxy)phenyl)quinolin-2-amine (30) (472 mg, 69%). 1H NMR (300 MHz, CDC13) delta 7.73 - 7.63 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.39 - 7.26 (m, 4H), 7.13 (t, J = 7.9 Hz, 1H), 6.67 (d, J = 9.1 Hz, 1 H), 4.26 - 4.14 (m, 2H), 2.52 - 2.33 (m, 6H), 2.1 1 - 1 .97 (m, 2H), 1.64 - 1.52 (m, 4H), 1.45 (s, 2H). 13C NMR (75 MHz, CDCl3) delta 156.5, 147.3, 144.1, 143.5, 137.1 , 130.8, 129.7, 129.1 , 126.4, 124.7, 122.7, 122.4, 118.9 (t, J= 222 Hz), 1 12.5, 56.9, 54.5, 49.6, 25.6, 24.6, 24.3. MS (ESI) [M+H]+ - 464.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: To a solution of 2- or 4-hydroxy-benzaldehyde (1.64mmol) in anhydrous acetone (25mL) was added cesium carbonate (4.92mmol) and the solution was stirred at room temperature for 10min under an argon atmosphere. Chloropropylpiperidine hydrochloride (2.46mmol) and sodium iodide (0.82mmol) was added to the solution and the mixture was heated at reflux overnight. The resulting solution was filtered and evaporated to dryness. The crude compound was diluted with EtOAc, the solution was washed successively with a saturated sodium carbonate solution and water, dried over MgSO4, filtered, and evaporated under reduce pressure. Purification by flash chromatography (hexanes/acetone/TEA, 80:19:1 to 70:29:1) yielded the desired compound 1 (360mg, 89%) or 2 (400mg, 99%). 1H NMR (400MHz, CDCl3) delta: 1.45 (q, J=6.0Hz, 2H), 1.59 (p, J=5.6Hz, 4H), 2.05 (m, 2H), 2.40 (broad s, 4H), 2.50 (t, J=7.4Hz, 2H), 4.14 (t, J=6.3Hz, 2H), 7.01 (t, J=8.1Hz, 2H), 7.53 (m, 1H), 7.83 (dd, J=1.8, 7.8Hz, 1H), 10.51 (s, 1H). APCI-MS for C15H22O2N [M+H]+: 248.3m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: A suspension of compound 18 (0.4g, 1mmol), alkyl chlorides (2.5mmol), TBAB (0.1mmol) in THF (5mL) was stirred at room temperature. A solution of NaOH (0.2g, 5mmol) in water (1mL) was added. The mixture was heated to reflux for 4h under nitrogen. The reaction mixture was poured into ice water (25mL). The precipitated product was collected by filtration, and further purified by silica gel column chromatography to afford the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In acetonitrile; for 12h;Reflux; | Oxadiazole-2-thiol 17 (0.2g, 0.75mmol), <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (0.148g, 0.75mmol) and Et3N (0.15g, 0.2mL, 1.5mmol) were dissolved in MeCN (10mL), and the reaction mixture was refluxed for 12h. Upon completion, the solvent was evaporated, and the residue was partitioned between EtOAc (20mL) and 10% aq. K2CO3 (20mL). The aqueous phase was then extracted with EtOAc (2×20mL), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated. The product was purified using column chromatography (mobile phase: Hexane/EtOAc/Et3N, 75:25:1). Yield: 65% asa yellow oil. 1H NMR (500MHz, Acetone-d6) delta 9.12 (s, 3H), 3.48 (t, J=7.1Hz, 2H), 2.50 (t, J=6.6Hz, 2H), 2.42 (br s, 4H), 2.09 - 2.04 (m, 2H), 1.60 - 1.54 (m, 4H), 1.48-1.40 (m, 2H). 13C NMR (126MHz, Acetone-d6) delta 167.55, 163.41, 150.10, 127.76, 126.87, 121.48, 57.73, 55.14, 31.43, 27.24, 26.68, 25.13. HRMS (ESI+): m/z [M+H]+ calcd for C16H20N5O5S+: 394.1180; found: 394.1178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | General procedure: Sodium hydride (0.75 g, 60%, 18.72 mmol) was added toa stirred suspension of diphenol 5 (0.5 g, 1.56 mmol) in dryDMF (30 ml) and the resulting reaction mixture stirred for30 min under an argon atmosphere at ambient temperature.Dialkylaminoalkyl chloride hydrochloride (6.24 mmol) wasthen added into the reaction mixture, which was heated underan argon atmosphere. The reaction was quenched withwater and the mixture was extracted with ethyl acetate. Theorganic phase was washed with water, dried over Na2SO4and evaporated in vacuo to give a residue, which was furtherpurified by column chromatography using as eluent a mixtureof methanol in DCM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: Sodium hydride (0.75 g, 60%, 18.72 mmol) was added toa stirred suspension of diphenol 6 (0.5 g, 1.56 mmol) in dryDMF (10 ml) and the resulting reaction mixture stirred for30 min under an argon atmosphere at room temperature.Then, dialkylaminoalkylchloride hydrochloride (6.24 mmol)was added into the reaction mixture, which was heated underan argon atmosphere. The reaction was quenched with waterand the mixture was extracted with ethyl acetate. The organicphase was washed with water, dried over Na2SO4 andevaporated under vacuum to give a residue, which was furtherpurified by column chromatography using a mixture ofmethanol in DCM as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: Sodium hydride (0.7 g, 60%, 17.6 mmol) was added to astirred suspension of diphenol 7 (0.5 g, 2.2 mmol) in dryDMF (15 ml) and the resulting reaction mixture stirred for30 min under an argon atmosphere at room temperature.Then, dialkylaminoalkylchloride hydrochloride (8.8 mmol)was added into the reaction mixture, which was heated underan argon atmosphere. The reaction was quenched with waterand the mixture was extracted with ethyl acetate. The organicphase was washed with water, dried over Na2SO4 andevaporated under vacuum to give a residue, which was furtherpurified by column chromatography usinga mixture ofmethanol in DCM as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 15h; | Example 2 A mixture of the Compound 1 (110 mg), the Compound 2 (34 mg), diisopropylethylamine (105 muL), and acetonitrile (2 mL) was stirred at 80 C. for 15 hours. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate, water, and chloroform were added thereto, and the resulting mixture was stirred, and then the resulting organic layers were separated, and concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (chloroform:methanol=98:2 to 85:15) and NH silica gel column chromatography (chloroform:methanol=100:0 to 97:3) to give ethyl 1-[2-({2-[({(3S,4R)-4-(2,4-difluorophenyl)-1-[3-(piperidin-1-yl)propyl]pyrrolidin-3-yl}carbonyl)amino]-1H-imidazol-1-yl}methyl)-5-methylphenyl]piperidine-4-carboxylate 3 (83 mg) as a colorless powder. MS (APCI): m/z 677 [M+H]+ |
83 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 15h; | Compound 1 (110 mg) and Compound 2 (34 mg),Diisopropylethylamine (105 muL),And acetonitrile (2 mL) was stirred at 80 C. for 15 hours.After allowing the reaction mixture to cool to room temperature, a saturated aqueous solution of sodium hydrogencarbonate, water and chloroform were added and stirred, then the organic layer was separated and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 to 85: 15) and NH silica gel column chromatography (chloroform: methanol = 100: 0 to 97: 3)Ethyl 1 - [2 - ({2 - [({(3S, 4R) -4- (2,4- difluorophenyl) -1- [3- (piperidin- 1 - yl) propyl] pyrrolidin- Carbonyl) amino] -1 H-imidazol-1-yl} methyl) -5-methylphenyl] piperidine-4-carboxylate3 (83 mg)As a colorless powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 mg | The mixture of 5 -(4-hydroxy-1 ,6-naphthyridin-2-yl)- 1 -methyl-N-( 1 -methylpiperidin-4-yl)- 1H- indole-2-carboxamide (140 mg, 0.336 mmol) and Cs2CO3 (325 mg, 1 mmol) in DMF (2 mL) was heated to 70C and held for 2hrs, then the mixture was cooled to 0C, <strong>[5472-49-1]1-(3-chloropropyl)piperidine hydrochloride</strong> (80 mg, 0.404 mmol) was added in one portion, then the resulting reaction mixture was heated to 70C and held for lhrs. The reaction mixture was poured into water (20 mL), extracted with EA (10 mL x3), the combined organic layers were washed by water and brine, dried over Na2SO4. The drying agent was filtered off and the filtrate was concentrated under the reduced pressure to get the residue which was purified with Prep-TLC (silica gel, DCM/Methanol/NH3.H20=10/1/0.1) to afford 1-methyl-N-(1- methylpiperidin-4-yl)-5 -(4-(3-(piperidin-1 -yl)propoxy)-1 ,6-naphthyridin-2-yl)- 1H-indole-2-carboxamide (5 mg, 3%), HPLC/UV purity:95 %; LC-MS (ESI): 541 (M + 1). ?H NMR (CD3OD) 5 9.51 (s, 1H), 8.67 (d, J 6.1 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J 8.9 Hz, 1H), 7.92 (d, J= 6.1 Hz, 1H), 7.60 -7.70 (m, 2H), 7.25 (s, 1H), 4.60 (t, J 5.6 Hz, 2H), 4.16 (m, 1H), 4.07 (s, 3H), 3.36 - 3.56 (m, 6H), 3.12 (d, J= 11.3 Hz, 2H), 2.83 (s, 3H), 2.48 (dd, J= 9.9, 6.0 Hz, 2H), 2.14 -2.29 (m, 2H), 1.75 -2.05 (m, 1OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; potassium iodide; In butanone; for 48h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; potassium iodide; In butanone; for 72h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; potassium iodide; In butanone; for 72h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate; potassium iodide; In butanone; for 48h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; potassium iodide; In butanone; for 72h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium carbonate; potassium iodide; In butanone; for 24h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine; In acetonitrile; for 48h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With triethylamine; In acetonitrile; for 48h;Reflux; | General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | N-(3-(lH-pyrazol-5-yl)phenyl)-4-(3-(piperidin-l-yl)propoxy)benzamide (0533) (LLM41). To a solution of compound 5 (0.28 mmol) in 3 ml DMF was added potassium carbonate (0.84 mmol). The mixture was heated to 90 C and l-(3- chloropropyl)piperidine hydrochloride (0.31 mmol) was added. Then the reaction mixture was stirred at 90 C for two hours. After reaction was completed, the mixture was poured into 50 ml water and then extracted with dichloromethane (50 ml x 3).(0534) The organic layer was dried with anhydrous Na2S04 and evaporated to dryness under reduced pressure to give a light yellow paste. Then the paste was dissolved in 3 ml 1.25 M hydrogen chloride methanol solution and heated to 50 C and maintained at that temperature for 30 min. 30 ml water was added to reaction mixture and the pH of solution was adjusted to 7 by adding 2 M sodium bicarbonate drop-wise. The aqueous solution was extracted with dichloromethane (30 ml x 3), and then the organic layer was dried with Na2S04 and evaporated to dryness under reduced pressure to give crude product, which was future purified by flash silica gel column chromatography (methanol : dichloromethane = 1:20) and preparative layer chromatography (methanol : dichloromethane = 1:8) to give a light yellow paste (yield 25%). MS (ESI)w 405 (M + H+). 1H NMR (CDCb) d 8.05 (1H, d, J = 2.1 Hz), 7.82 (2H, m), 7.75 (1H, d, J = 9.3 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.49 (1H, d, J = 7.8 Hz). 7.28 (1H, t, J = 7.8 Hz), 6.93 (2H, m), 6.62 (1H, d, J = 2.1 Hz), 4.05 (2H, t, J = 6.3 Hz), 2.52 (2H, m), 2.44 (4H, m), 2.03 (2H, m), 1.60 (4H, m), 1.46 (2H, m). 13C NMR (CDCb) d 165.47, 162.30, 138.63, 133.207, 129.67, 129.63, 128.56, 121.89, 118.98, 117.53, 114,78, 102.85, 66.81, 55.72, 54,92, 29.34, 25.81, 24.31 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate; sodium iodide; In dimethyl sulfoxide; at 90℃; for 18h; | A mixture of N-(5-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide (0.015 g, 0.027 mmol), l -(3- chloropropyl)piperidine hydrochloride (0.007 g, 0.032 mmol), K2CO3 (0.011 g, 0.08 mmol), and Nal (0.001 g) in DMSO (0.5 ml) was stirred at 90 C for 18 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by chromatography (dichloromethane/MeOH = 10/1.5) to provide N-(5-((6-methoxy-7-(3-(piperidin-l- yl)propoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2- d]pyrimidine-2-carboxamide as a off-white solid (0.01 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | With caesium carbonate; sodium iodide; In acetone; at 50℃; for 8h; | A mixture of tert- butyl 4-hydroxyphenethylcarbamate (474 mg, 2 mol), cesium carbonate (1.95 g, 6 mmol), Nal (4.8 mg, 0.2 mmol) and l-(3-chloropropyl)piperidine hydrochloride (396 mg, 2 mmol) in acetone (10 mL) was stirred at 50 C for 8 h. The reaction mixture was filtrated. The filtrate was concentrated and purified by column chromatography to afford the title compound as gray solid (443 mg, 61.2% yield). 'HNMR (500 MHz, DMSO-r/d) S: 7.07 (d, 2H), 6.82 (d, 3H), 3.94 (t, 2H), 3.09 (q, 2H), 2.62 (t, 2H), 2.50 (m, 6H), 1.50 (t, 6H), 1.36 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 100℃; for 24h; | To solution of 4-bromoaniline (1.34 mL, 12 mmol) in DMF (50 mL), K2C03 (3.2 g, 23 mmol), Nal (8.7 g, 58 mmol) and 3-chioropropylpiperidine hydrochloride (3.4 g, 18 mmol) were added. The reaction mixture was stirred at 100C for 24 h. DMF was removed under reduced pressure and the residue was taken up in 20 mL of water. The aqueous layer wasextracted with DCM (3 x 60 mL). The combined organic layers were dried over MgSO4 and evaporated. The residue was purified by column chromatography (EtOAc/MeOH, 8.5:1.5 (v:v)) to afford 42 as a brown oil (779 mg, 23 %). 1H NMR (300 MHz), (5(ppm, CDC13): 7.23 (d, J= 8.8 Hz, 2H), 6.47 (d, J= 8.8 Hz, 1H), 3.15 (t, J= 6.2 Hz, 2H), 2.67 - 2.41 (m, 6H), 1.97 - 1.76 (m, 2H), 1.77 - 1.44 (m, 6H). 13C NMR (75 MHz), (5 (ppm,CDC13): 147.7, 131.9, 114.1, 108.4, 57.7, 54.5, 43.4, 29.7, 25.5, 24. LCMS m/z calc for [M+H]: 283.1, 285.1 found: 283.1, 285.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | 6-Nitro-3H-1,3-benzoxazol-2-one (45) (6.30 g, 35 mmol) was suspended in ACN (150 mL) and K2C03 (6.91 g, 50 mmol) was added. The reaction mixture was stirred at 80C for 30 mi 3-Chloropropylpiperidine hydrochloride (3.96 g, 20 mmol) was added and the reaction mixture was stirred at 80C for another 5 h. The inorganics were removed by filtration and the solvent was evaporated. The residue was purified by flashchromatography (DCM/MeOH(NH3), 9.8:0.2 (v/v)) to give compound 46a as a beige solid(5 g, 98%). Mp 8 1C. 1H NMR (300 MHz), 5 (ppm, CDC13): 8.21 (dd, J= 8.7 Hz, J= 2.1Hz, 1H), 8.10 (d, J= 2.1 Hz, 1H), 7.25 (d, J 8.5 Hz, 1H), 4.00 (t, J 6.5 Hz, 2H), 2.38 -2.28 (m, 6H), 2.02- 1.98 (m, 2H), 1.56- 1.53 (m, 4H), 1.45 - 1.41 (m, 2H). 13C NMR (75MHz), 5 (ppm, CDC13): 154.1, 143.0, 141.9, 137.3, 120.7, 108.0, 106.1, 55.4, 54.4, 41.1,25.9, 24.4, 24.3. LCMS m/z calc for [M+H]: 306.2, found: 306.2. |
Tags: 5472-49-1 synthesis path| 5472-49-1 SDS| 5472-49-1 COA| 5472-49-1 purity| 5472-49-1 application| 5472-49-1 NMR| 5472-49-1 COA| 5472-49-1 structure
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
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 |
Sorry,this product has been discontinued.
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