Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 56346-57-7 | MDL No. : | MFCD03411595 |
Formula : | C12H14FNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ABERUOJGWHYBJL-UHFFFAOYSA-N |
M.W : | 207.24 | Pubchem ID : | 2724440 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.42 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.43 |
TPSA : | 29.1 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.34 cm/s |
Log Po/w (iLOGP) : | 2.16 |
Log Po/w (XLOGP3) : | 1.73 |
Log Po/w (WLOGP) : | 2.05 |
Log Po/w (MLOGP) : | 2.06 |
Log Po/w (SILICOS-IT) : | 2.98 |
Consensus Log Po/w : | 2.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.38 |
Solubility : | 0.866 mg/ml ; 0.00418 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.96 |
Solubility : | 2.29 mg/ml ; 0.011 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.84 |
Solubility : | 0.03 mg/ml ; 0.000145 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.43 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With formic acid; at 55 - 60℃; for 3h; | 4-Fluorophenyl piperidin-4-yl methanone 1.79 g (8.66 mmol) was added to formic acid (1.5 ml) and formaldehyde 1.05 ml and the reaction mixture was stirred at 55-60 C. for 3 hours. After cooled down, water was added, basified with potassium hydroxide pellets to pH>10 and extracted with ethyl ether 3*50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.88 g of desired product in 98% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Intermediate 10: (4-fluoro-phenyl) -piperidin-4-yl-methanone (10)6.4g (49.5mmol) of isonipecotic acid are placed in the presence of 40ml of acetic anhydride. The reaction medium is heated to 1300C for 5h and then dry concentrated. After triturating with petroleum ether, the formed crystals are filtered. 7.79g of solid are obtained (92%) . 0.5g (2.92mmol) of the obtained solid are placed in ImL of 1,2- dichloroethane in the presence of 0.92mL (12.56mmol) of thionyl chloride, and this solution is then stirred for Ih at room temperature. The medium is dry concentrated and then the residue is taken up with 2mL of 1,2- dichloroethane . This solution is added to a mixture of 0.9Og (6.72 mmol) of AlCl3 and 1.29mL (13.73 mmol) of fluorobenzene in ImL of 1, 2-dichloroethane . The reaction medium is heated to 800C for 3h. After the solution has returned to room temperature, it is poured on ice water, then the medium is extracted with dichloromethane . After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH: 95-5) . 0.44 g of an oil are isolated(60%) . TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 95-5,Rf=O .38. The obtained oil is placed in 6mL of 6N hydrochloric acid and the mixture is heated to 1000C for18h. The medium is neutralized by adding a concentrated soda solution and extracted with ethyl acetate. After drying on MgSO4, the organic phases are dry concentrated. 0.23 g of intermediate 10 are obtained as an oil (62%) . TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 95-5, Rf=O.13. | |
In hydrogenchloride; | 4-(4-fluorobenzoyl)piperidine A solution of 1-acetyl-4-(4-fluorobenzoyl)piperidine in 6N hydrochloric acid is brought to reflux for 2 hours. The solution is cooled and then extracted twice with ether. The aqueous solution is made basic (NaOH) and then extracted with benzene. The extracts are dried (Na2 SO4) and filtered. The filtrate is concentrated under reduced pressure and the residual oil is converted to a hydrochloric acid salt. Melting point (hydrochloride): 222-224 C. | |
With hydrogenchloride; In water; for 10h;Reflux; | N-acetylpiperidine-4-carboxylic acid (1.3 g, 7.6 mmol) and 15 mL of 1,2-dichloroethane,Add to a 100mL three-necked flask and control the temperature at 40-50 C.Thionyl chloride (1 mL, 14 mmol) diluted with 3 mL of solvent was slowly added dropwise.After continuing to stir at this temperature for 2 hours,Add fluorobenzene (0.72mL, 7.6mmol) to the reaction systemAnd aluminum trichloride (2.0 g, 15 mmol), refluxed for 4 hours, cooled to room temperature, added ice water, stirred well, and allowed to stand for separation.The organic layer was washed with 20 mL × 2 of water, and concentrated under reduced pressure to obtain a brown oil (N-acetyl-4- (p-fluorobenzoyl) piperidine). N-acetyl-4- (p-fluorobenzoyl) piperidine,10 mL of water and 10 mL of concentrated hydrochloric acid were added to a 50 mL single-necked flask and refluxed for 10 hours.It was left to cool, washed with 20 mL of dichloromethane, washed with a 5% NaOH solution of the aqueous layer to adjust pH = 8-9, and extracted with 20 mL of dichloromethane, and the organic phases were combined and dried over anhydrous MgSO4.It was filtered and concentrated to give a white solid, which was directly used for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dichloromethane; ethyl acetate; acetonitrile; | 1-(3-Chloropropyl)-<strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> can be prepared as follows: a solution of 1-bromo-3-chloropropane (3.9 cc) and of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (2.4 g) in acetonitrile (20 cc) is stirred at 25 C. for 20 hours with potassium carbonate (8 g). The mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.06-0.2-mm particle size, 2-cm diameter, 20-cm height) and eluted with a mixture of dichloromethane and ethyl acetate (60-40 by volume), 15-cc fractions being collected. Fractions 9 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1-(3-Chloropropyl)-<strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (2.1 g) is obtained in the form of oil. 4-(4-Fluorobenzoyl)piperidine can be prepared according to the method described by R. L. Duncan et al., in J. Med. Chem., 13, 1 (1970). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1 (R)-[4-(4-Fluorobenzoyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine] A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (293 mg, 1.2 mmol) in EtOAc (5 ml) was added to a stirred mixture of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (207 mg, 1.0 mmol) and triethylamine (0.21 ml, 1.5 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (10 ml), treated with 1 M hydrochloric acid (2 ml) and the mixture stirred at ambient temperature for 1 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2*25 ml), the EtOAc extracts were washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 10% EtOA/DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (104 mg, 0.3 mmol). Mp: 78-79 C.; NMR: 1.7 (s, 3H), 1.8-2.0 (m, 4H), 3.2 (dd, 2H), 3.5 (m, 1H), 4.4 (dd, 2H), 5.25 (s, 1H), 7.15 (dd, 2H), 8.0 (dd, 2H); m/z 346. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In isopropyl alcohol; for 4h;Heating / reflux; | EXAMPLE 34 (4-Fluoro-phenyl)-{1-[2-methoxy-2-(4-nitro-phenyl)-ethyl]-piperidin-4-yl}-methanone; hydrochloride A mixture of 4-(4-fluorobenzoyl) piperidine(5 mmol) and 2-(4-nitro-phenyl) oxirane (5 mmol) was refluxed in 30 ml of isopropanol for 4 h. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was then washed with brine, the resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in dichloromethane (50 ml) and was added with methanesulfonyl chloride (2 eq.) and triethylamine (3 eq.) at 0 C. The reaction mixture was stirred at room temperature for 1 h. This solution was then concentrated on a rotary evaporator and dissolved in THF (50 ml), added triethylamine (3 eq.), followed by the addition of excess methanol (>10 eq.). After 12 hours stirring at 80 C., this solution is concentrated on a rotary evaporator and diluted with ethyl acetate. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexane=1:1). The resulting (4-fluoro-phenyl)-{1-[2-methoxy-2-(4-nitro-phenyl)-ethyl]-piperidin-4-yl}-methanone was dissolved in dichloromethane and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give (4-fluoro-phenyl)-{1-[2-methoxy-2-(4-nitro-phenyl)-ethyl]-piperidin-4-yl}-methanone; hydrochloride 1H-NMR (DMSO-d6, 200 MHz) delta11.1(br, 1H), 8.2(m, 2H), 8.0(m, 2H), 7.5(m, 2H), 7.2(m, 2H), 4.5(m, 1H), 3.4(s, 3H), 3.2(m, 2H), 2.9(m, 1H), 2.8(m, 1H), 2.5(m, 1H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In water; | B. N-[5-chloro-2-[2-[4-(4-fluorobenzoyl)-1 -piperidinyl]ethoxy]phenyl]urea(4-Fluorophenyl)-4-piperidinylmethanone (250 mg, 1.0 mmol) was treated with aqueous cesium carbonate (650 mg, 2.0 mmol), extracted into ether, dried and concentrated.The residue was dissolved in acetonitrile (10 ml_) and Intermediate 58a (200 mg, 0.6 mmol) was added. The mixture was stirred at ambient temperature for 5 days.Concentration and purification by reverse phase HPLC afforded Compound 58 (53 mg).1H NMR (400 MHz, DMSO-d6): delta/ppm = 1.82 (m, 1.7H), 2.01 (m, 2.3H), 3.20 (m, 2H),3.38 (m, 2H)1 3.65 (m, 3H), 4.18 (m, 2H), 6.90 (m, 1 H), 7.00 (d, 1 H), 7.30 (t, 2H), 7.95(s, 1 H), 8.04 (m, 2H), 8.10 (s, 1 H), 9.55 (br, 1 H).LRMS M+H 419 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h; | B. N-[5-chloro-2-[3-[4-(4-fluorobenzoyl)-1 -piperidinyl]-2- hydroxypropoxy]phenyl]urea and[1-[3-(2-amino-4-chlorophenoxy)-2-hydroxypropyl]-4-piperidinyl](4- fluorophenyl)methanoneTo a solution of Intermediate 56a (500 mg, 2.1 mmol) and (4-fluorophenyl)-4- piperidinylmethanone (540 mg, 2.2 mmol) in dimethylformamide (10 ml_) was added potassium carbonate (725 mg, 5.2 mmol). The mixture was heated at 110 C in a sealed tube for 2 days. After cooling to ambient temperature, the mixture was poured into ice water. Extraction and purification by reverse phase HPLC afforded Compounds 56 and 57 as yellow solids.Compound 56: 1H NMR (400 MHz, DMSO-Gf6 + TFA): delta/ppm = 1.50-1.85 (m, 4H), 2.80- 3.80 (m, 9H), 4.42 (m, 1 H), 6.60-6.74 (m, 2H), 7.04-7.14 (m, 2H), 7.68 (br, 1 H), 7.78- 7.86 (m, 2H), 7.90 (m, 1 H), 9.18 (br, 1 H).LRMS M+H: 450.2Compound 57: 1H NMR (400 MHz, DMSO-d6): delta/ppm = 1.8-2.1 (m, 4H), 3.05-3.90 (m, 9H), 4.30 (m, 1 H), 6.48 (dd, 1 H), 6.62 (m, 1 H), 6.74 (d, 1 H), 7.38 (dd, 2H), 8.10 (m, 2H).LRMS M+H: 407.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium perchlorate; In acetonitrile; at 80℃; for 24h; | Example 36. Mixture of (3R.4R; 3S.4SVf l-r4-(4-CMoro-phenoxy)-pyrrolidin-3-yl1- piperidin-4-yl )-(4-fluoro-phenylVmethanone bistrifluoroacetate; [00184] 3,4-Epoxypyrrolidine carbamate Wang resin (1.5 g, 1.8 mmol) was placed in a glass reaction vessel (50 mL). A solution of LiClO4 in acetonitrile (0.36 M, 10 mL, 3.6 mmol), 4-(4- fluorobenzoyl)piperidine (1.48 g, 7.2 mmol) and acetonitrile (5 mL) were added successively. The glass reactor was closed with a screw cap and the reaction mixture was heated at 8O0C for 24 h. The resin was transferred into syringes and washed with DMF (3x), isopropyl alcohol (3x), DMF (3x), isopropyl alcohol (5x) and dried under high vacuum. The aminoalcohol resin (1 g, 1 mmol) was placed into a glass reactor under N2. Dry tetrahydrofuran (5 mL) was added through a septum and the suspension was cooled to 5C. Triphenylphosphine (1.3 g, 5 mmol) and 4-chloro-phenol (494 mg, 5 mmol) were placed into a glass reactor and tetrahydrofuran (5 mL) was added through a septum under N2. Diazopropyl azodicarboxylate (970 uL, 5 mmol) was slowly added under N2. 3,3-Dimethyl- [l,2,5]thiadiazolidine 1,1-dioxide (751 mg, 5 mmol) was added as a solid under N2 and the reaction mixture was shaken for 5 min. The suspension was added to the resin at 5C under N2 and the suspension was shaken for 16 h at room temperature. The resin reactors were transferred into a syringe and washed with DMF (3x), methanol (3x), DMF (3x), toluene (3x), CH2Cl2 and dried. A solution of TFA : CH2Cl2 : H2O 50 : 50 : 5 (14 mL) was added and the suspension was shaken for 2 h. The solution and one subsequent wash with TFA : CH2Cl2 : H2O 70 : 30 : 2.5 (12 mL) were collected and combined. The solvent was removed to yield 452 mg of the title compound as the bistrifluoroacetate salt. ESEVIS ([MH-H]+): 403.1 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In tetrahydrofuran; dichloromethane; | Method B Preparation of {(R)-1-Benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester A solution of ((R)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.0 mmol), (4-fluoro-phenyl)-piperidin-4-yl-methanone (0.414 g, 2.0 mmol) and sodium triacetoxyborohydride (0.638 g, 3.0 mmol) in tetrahydrofuran (20 ml) is stirred at ambient temperature for 24 hours. The solvent is evaporated and the residue redissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The dichloromethane is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethylacetate:hexane, 3:1 elution) to afford {(R)-1-benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester. [MH]+ 441.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; In acetonitrile; | EXAMPLE 2 (COMPOUND NO. 28) 4-[2-[4-(4-fluorobenzoyl)-1-piperidyl]ethyl]-6-methoxy-2(1H)-quinolone hydrochloride (1:1) A mixture of 1.1 g (4.6 mmol) of 4-(2-chloroethyl)-6-methoxy-2(1H)-quinolone, 1.0 g (5.5 mmol) of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> and 0.38 g (4.6 mmol) of sodium hydrogen carbonate in 20 ml of acetonitrile is heated to reflux for 8.5 hours. The reaction medium is then evaporated to dryness and the crude product is purified by flash chromatography on silica, eluding with a methanol/dichloromethane (5:95) mixture containing traces of aqueous ammonia. 0.53 g of the expected product is obtained in base form. Yield=30% The hydrochloride is prepared in a methanol/hydrochloric acid mixture. Melting point=237 C. (decomposition) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In acetonitrile; | 3.6. 6-chloro-4-[2-[4-(4-fluorobenzoyl)-1-piperidyl]ethyl]-1-methyl-2(1H)-quinolone hydrochloride (1:1) A mixture of 0.90 g (3.5 mmol) of 6-chloro-4-(2-chloroethyl)-1-methyl-2(1H)-quinolone, 0.71 g (4.0 mmol) of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> and 0.60 g (7.0 mmol) of sodium bicarbonate in 15 ml of acetonitrile is heated to reflux for 11 hours. The reaction medium is then evaporated to dryness and the crude product is purified by flash chromatography on silica, eluding with a methanol/dichloromethane (4:96) mixture containing traces of aqueous ammonia. 0.86 g of the expected product are obtained in base form. Yield=62% The hydrochloride is prepared in a methanol/hydrochloric acid/ether mixture. Melting point=244 C. (decomposition) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.89 g (77.6%) | With sodium hydrogencarbonate; In acetonitrile; | PREPARATION 17 (4-Fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone A mixture of 34.16 g (0.165 mol) of the <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong>, 33.80 g (0.199 mol) of isopropyl iodide and excessive sodium bicarbonate in 600 mL of acetonitrile was heated at reflux for 14 h. The solvent was removed in vacuo, and the residue was partitioned between CH2 Cl2 and dilute NaOH. The CH2 Cl2 solution was dried (Na2 SO4), and the solvent was removed in vacuo to give a solid. This was recrystallized from CH2 Cl2 /hexane to give 31.89 g (77.6%) of crystalline solid, mp 120-121 C. Analysis calculated for: C15 H20 NOF: C, 72.26; H, 8.09; N, 5.62. Found: C, 72.21; H, 8.16; N, 5.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 32 5-[2-(4-(4-Fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one salicylate To a solution consisting of 5-(2-chloroethyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (2.5 g) and DMF (85 ml) was added anhydrous potassium carbonate (0.6 g), diisopropylethyl amine (2.2 ml), <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (2.3 g) and potassium iodide (70 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80 C. for 19 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 1.5 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorphenyl)-6,7-dihydro-1,2-benzisoxazol-4-(5H)-one, as an oil. | |
With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 32 5-[2-(4-(4-Fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorphenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one salicylate To a solution consisting of 5-(2-chloroethyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (2.5 g) and DMF (85 ml) was added anhydrous potassium carbonate (0.6 g), diisopropylethyl amine (2.2 ml), <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (2.3 g) and potassium iodide (70 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80 C. for 19 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 1.5 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorphenyl)-6,7-dihydro-1,2-benzisoxazol-4-(5H)-one, as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; | b. 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one (0.85 g) and DMF (20 ml) was added anhydrous potassium carbonate (0.52 g) diisopropylethyl amine (0.33 ml), <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (0.92 g) and potassium iodide (62 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80 C. for 24 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine. The organic phase was then dried (MgSO4), filtered, and concentrated to give the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 0.70 g of 6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The product was dissolved and flushed through alumina with dichloromethane. Recrystallization with ether/hexane gave the product as a solid, m.p. 81-83 C. Analysis: Calculated for C23 H27 FN2 O3: 69.33% C; 6.83% H; 7.03% N; Found: 69.51% C; 6.65% H; 7.01% N. | |
With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; | b. 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one (0.85 g) and DMF (20 ml) was added anhydrous potassium carbonate (0.52 g) diisopropylethyl amine (0.33 ml), <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (0.92 g) and potassium iodide (62 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80 C. for 24 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine. The organic phase was then dried (MgSO4), filtered, and concentrated to give the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 0.70 g of 6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The product was dissolved and flushed through alumina with dichloromethane. Recrystallization with ether/hexane gave the product as a solid, m.p. 81-83 C. Analysis: Calculated for C23 H27 FN2 O3: 69.33% C, 6.83% H, 7.03% N. Found: 69.51% C, 6.65% H, 7.01% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; triethylamine; In tetrahydrofuran; ethanol; chloroform; | EXAMPLE 52 Synthesis of 2-[2-[4-(4-Fluorobenzoyl)piperidin-1-yl]propyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]-pyridin-3(2H)-one 2-(3-Chloropopyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]-pyridin-3(2H)-one (1.4 g) and 3 g of sodium iodie were refluxed in 100 mlambda of tetrahydrofuran for 20 minutes. to the reaction mixture were added 2.1 g of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> and 2 mlambda of triethylamine, followed by refluxing for 8 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was applied to a column contained with 30 g of silica gel and eluted with a 20:1 (by volume) mixture of chloroform and ethanol. The resulting oily substance was crystallized from isopropyl ether to obtain 1.2 g of the entitled compound as pale yellow crystals. Melting Point: 136-137 C. NMR Spectrum (CDCllambda3) delta: 1.6-2.3 (12H, m), 2.34-2.59 (2H, m), 2.59-2.8 (2H, m), 2.8-3.18 (2H, m), 3.18-3.4 (1H, m), 3.4-3.7 (2H, m), 3.7-3.94 (2H, t), 7.20 (2H, t), 8.03 (2H, dd) IR Spectrum nu (KBr) cm-1: 1695, 1670, 1595, 1590, 1500, 1450, 1410 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; | EXAMPLE 76 Synthesis of 3-[2-[4-(4-Fluorobenzoyl)-piperidin-1-yl)ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione A solution of 3.3 g of 3-(2-methanesulfonyloxyethyl)-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Reference Example 33, 1.01 g of triethylamine and 2.27 g of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> in 25 ml of acetonitrile was refluxed for 4 hours. After concentration of the reaction mixture, the residue was extracted with chloroform. The chloroform solution was concentrated to dryness, and the residue was purified by column chromatography (silica gel, eluent: methanol-chloroform) to give 2.17 g of the entitled compound as yellow crystals. Melting point: 170-172 C. NMR Spectrum (CDCl3) delta: 1.8-2.2 (10H, m), 2.26 (2H, t), 2.81 (2H, t), 3.0-3.3 (3H, m), 3.84 (2H, t), 4.06 (2H, t), 7.13 (2H, t), 7.95 (2H, dd) IR Spectrum nu (KBr) cm-1: 1730, 1670, 1600, 1490, 1450, 1410 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; | EXAMPLE 58 Synthesis of 2-[2-[4-(4-Fluorobenzoyl)piperidin-1-yl]ethyl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c]-1,2,4-triazol-3-one Hydrochloride In the manner described in Example 52, the entitled compound was obtained as an oily substance from 2-(2-chloroethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c]-1,24-triazol-3-one and <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong>. The product was dissolved in 50 mlambda of ethanol, and 1 mlambda of concentrated hydrochloric acid was added thereto. The mixture was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixture of ethanol and isopropyl ether to obtain 0.65 g of the entitled compound as a colorless powder Melting Point: 215-217 C. NMR Spectrum (DMSO-d6) delta: 1.8-2.2 (4H, m), 2.3-2.5 (2H, m), 2.66 (2H, t-like), 3.0-3.7 (7H, m), 3.64 (2H, t), 4.10 (2H, t), 7.38 (2H, t), 8.10 (2H, dd) IR Spectrum nu (KBr) cm-1: 3450, 2450, 1700, 1600 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.2 g (26%) | With potassium iodide; potassium carbonate; In dichloromethane; isopropyl alcohol; acetonitrile; | EXAMPLE 1 7-[3-(4-p-fluorobenzoyl-1-piperidinyl)propoxy]chromen-4-one hydrochloride To a solution of 3.9 g (18.8 mmole) of 4-p-fluorobenzoyl-piperidine and 4.5 g (18.8 mmole) of 7-(3-chloropropoxy) chromen-4-one in 250 ml of acetonitrile, 2.7 g (18.8 mmole) of anhydrous potassium carbonate and 0.2 g of potassium iodide were added. The resulting suspension was refluxed for 24 hours, then cooled, filtered, and the filtrate was evaporated to dryness. The oil obtained was dissolved in dichloromethane, washed with NaCl saturated solution, dried over sodium sulfate and evaporated. The residue was dissolved in isopropanol and precipitated by addition of HCL solution in isopropanol to provide 2.2 g (26%) of product. Elemental analysis for C24 H24 FNO4.HCl: (calculated) C 64.64, H 5.65, N 3.14, Cl 7.95; (found) C 64.34, H 5.77, N 2.93, Cl 8.13. Melting point: 235-238 C. (i-PrOH). IR (KBr): 3200-3600, 2930, 2300-2800, 2680. 1650, 1630, 1595, 1445, 1270, 1230 cm-1. 1 H-NMR (d6 -DMSO): 2.01 (m, 4H, piper-3H and -5H), 2.30 (m, 2H, O--CH2 --CH2), 3.13 (m, 2H, piper-2Hax and -6Hax), 3.24 (t a, J=6Hz, 2H, N--CH2 --CH2 --CH2 --O), 3.61 (d a, J=10.2Hz, 2H, piper-2Heq and -6Heq), 3.75 (m, 1H, 4-H), 4.25 (t a, J=6Hz, 2H, O--CH2), 6.29 (d, J=6.3Hz, 1H, 3-H), 7.08 (dd, J=9 and 2 Hz, 1H, 6-H), 7.16 (d, J=2Hz, 1H, 8-H), 7.40 (t, J=9Hz, 2H, Ph-3H and -5H), 7.96 (d, J=9Hz, 1H, 5-H), 8.11 (dd, J=9 and 6Hz, 2H, Ph-2H and -6H), 8.25 (d, J=6Hz, 1H, 2-H). 13 C-NMR (d6 -DMSO): 22.93 (O--CH2 --CH2), 25.46 (piper-3C and 5C), 40.03 (piper-4C), 50.85 (piper-2C and -6C), 53.18 (O--CH2 --CH2 --CH2 --N), 65.77 (O--CH2), 101.77 (8-C), 111.91 (3-C), 114.62 (6-C), 115.65 (d, J=21.7Hz, Ph-3C and -5C), 117.90 (4a-C), 126.13 (5-C), 131.04 (d, J=9.2Hz, Ph-2C and -6C), 131.52 (d, J=3.5Hz, Ph-1C), 156.16 (2-C), 157.34 (8a-C), 162.31 (7-C), 164.78 (d, J=250.4Hz, Ph-4C), 175.25 (4-C), 199.09 (Ph-C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81 mg (25.0%) | With triethylamine; In dichloromethane; | REFERENCE EXAMPLE 62 1-(2,2-Diethoxyethyl)-<strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> 4-(4-Fluorobenzoyl)piperidine (207 mg, 1.0 mmol) was dissolved in methylene chloride (5 ml) to which were subsequently added bromoacetoaldehyde diethylacetal (305 mg, 1.5 mmol) and triethylamine (0.5 ml). After 12 hours of heating under reflux, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether) to obtain 81 mg (25.0%) of the title compound in the form of orange oil. IR (neat): 2976, 2944, 1682, 1598, 1278, 1230, 1206 1156, 1120, 1062, 976, 852 cm-1 NMR (CDCl3) delta: 1.21 (6H, t, J=7 Hz), 1.50-1.98 (4H, m), 2.02-2.44 (2H, m), 2.56 (2H, d, J=5.6 Hz), 2.85-3.30 (3H, m), 3.58, 3.66 (each 2H, q, J=7 Hz), 4.65 (1H, t, J=5.6 Hz), 7.12 (2H, dd, J=9 Hz, 9 Hz), 7.95 (2H, dd, J=9 Hz, 6 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
107 mg (46.1%) | With hydrogenchloride; sodium cyanoborohydride; potassium carbonate;molecular sieve; In methanol; water; acetone; | INVENTIVE EXAMPLE 1 N-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-3-methoxy-N-(2-methoxyphenyl)benzamide N-Formylmethyl-3-methoxy-N-(2-methoxyphenyl)-benzamide (141 mg, 0.473 mmol), and <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (125 mg, 0.60 mmol) were dissolved in methanol (4.5 ml) to which was subsequently added molecular sieve 4A (300 mg) at room temperature. After 1 hour of stirring at the same temperature, sodium cyanoborohydride (12 mg, 0.191 mmol) was added to the above mixture, followed by 45 minutes of stirring and subsequent addition of acetone (2 ml). The reaction solution was diluted with ether (15 ml) and filtered through cerite, and the solvent was removed by evaporation. The thus obtained colorless oily residue was dissolved in ether (7 ml), mixed with saturated hydrogen chloride/ether solution (7 ml) and stirred for 5 minutes. After removing the ether layer, the reaction solution was mixed with water (7 ml) and potassium carbonate (1.5 g) and extracted with ether and dried on potassium carbonate, and then the solvent was removed by evaporation. Thereafter, the resulting colorless oily residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:2) to obtain 107 mg (46.1%) of the title compound in the form of light yellow oil. IR (neat): 2944, 1678, 1638, 1596, 1500, 1458, 1390, 1278, 1248, 1156, 1046, 748 cm-1 NMR (CDCl3) delta: 1.58-1.93 (4H, m), 2.00-2.36 (2H, m), 2.63 (2H, t, J=7.5 Hz), 2.80-3.30 (3H, m), 3.64, 3.70 (each 3H, s), 3.90-4.40 (2H, m), 6.55-7.30 (10H, m), 7.95 (2H, dd, J=9 Hz, 6 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In acetonitrile;Heating / reflux; | EXAMPLE 8; SYNTHESIS OF 6-[4-(4-FLUOROBENZOYL)PIPERIDIN-I-YL]PYRIDAZINE-S- CARBOXYLIC ACID (2-CYCLOPROPYLETHYL)AMIDE; A mixture of delta-chloropyridazine-S-carboxylic acid (2-cyclopropylethyl)amide (0.500 g, 2.22 mmol), (4-fluorophenyl)piperidin-4-ylmethanone (0.620 g, 2.55 mmol) and triethylamine (0.7 mL, 5 mmol) in acetonitrile (20 mL) was heated to reflux overnight. The solvent was removed in vacuo. The residue was diluted with water, then extracted with ethyl acetate. The residue obtained upon the evaporation of solvent was purified by column chromatography. The title compound was obtained as a white solid in 85% yield (0.270 g). 1H NMR (300 MHz, CDCI3) delta 8.26 (d, J = 9.0 Hz, 1 H), 8.02-7.93 (m, 2H), 7.65 (d, J = 9.0 Hz, 1H), 7.2-7.11 (m, 2H), 6.98 (d, J = 9.0 Hz, 1 H), 4.55-4.44 (m, 2H), 3.63-3.49 (m, 3H), 3.32-3.19 (m, 2H), 2.5-1.8 (m, 2H), 1.7-1.44 (m, 4H), 0.8-0.67 (m, 1 H), 0.52-0.41 (m, 2H), 0.15-0.07 (m, 2H). 13C NMR (75 MHz, CDCI3) 5 200.1 , 167.5, 164.1 , 163.2, 161.4, 159.9, 158.9, 151.8, 144.6, 132.0, 131.0, 130.9, 129.4, 128.0, 126.9, 116.1 , 115.8, 112.2, 44.5, 43.1 , 40.0, 39.6, 34.5, 34.3, 27.9, 8.64, 8.6, 4.2. MS (ES+) m/z 397 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; ethyl acetate; | EXAMPLE 8 4-(4-p-Fluorobenzoyl)piperidinyl-6,7-dimethoxyisoquinoline hydrochloride STR19 70 mg of 4-chloromethyl-6,7-dimethoxyisoquinoline was dissolved in 10 ml of dimethyl sulfoxide. 1 ml of triethylamine and 140 mg of 4-(p-fluorobenzoyl) piperidine were added to the solution and the mixture was heated to 80 C. for 1 h. The reaction mixture was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. The product was purified according to silica gel column chromatography and converted into its hydrochloride. Yield: 80 mg Melting point: 185 to 190 C. Elementary analysis for C24 H25 N2 O3 F.2HCl: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; water; | EXAMPLE 4 1-{4-[4-(4-Fluorobenzoyl)piperidino]butyl}-4-(2-fluorobenzyl) piperazine 2,6-dione hydrochloride 2.61 g of 4-(2-fluorobenzyl)-l-(4-bromobutyl)piperazine 2,6-dione, dissolved in 40 ml of dimethylformamide, are added dropwise at 20 C. to a mixture of 1.4 g of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> and 0.84 g of triethylamine in 50 ml of dimethylformamide. After 15 hours, stirring at 20 C., the solvent is concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane. The oil obtained is purified by chromatography on 210 g of 230-400 mesh silica, eluding with a mixture of dichloromethane and methanol (95:5 V/V). The base thereby obtained is then salified with ethanolic hydrogen chloride in a mixture of ethanol and ethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrachloromethane; ethyl acetate; | EXAMPLE 3 7-[3-[4-(p-fluorobenzoyl)-piperidino]-propyl]-theophylline (Sgd 144-80) STR8 10.2 g 4-(p-fluorobenzoyl)-piperidine and 16.5 g 7-(chloropropyl)-theophylline are carefully mixed in the solid state and heated to 100 C. in a round flask in an oil bath. The mixture at first results in a clear melt, subsequently begins to crystallize and then changes into a solid mass. It is allowed to cool after 10 minutes, dissolved in ethyl acetate and 2n hydrochloric acid is added, whereby a dark oil separates in the organic phase, crystallizing on standing overnight. By recrystallizaing with 100 ml carbon tetrachloride, an intially oily then crystallizing substance is obtained, 7.4 g of the product with an mp of 114 to 119 C. (yield: 43.5%) C22 H26 FN5 O3: 427.5; calc. C 61.81; H 6.13; N 16.38; F 4.45; fd. C 61.90; H 6.01; N 16.40; F 4.29 The 7-(3-chloropropyl)-theophylline, used as a starting material, may be obtained in a known manner, for instance by the reaction of theophylline with 1,3-bromo-chloropropane. | |
With hydrogenchloride; In tetrachloromethane; ethyl acetate; | EXAMPLE 2 7-[3-[4-(p-fluorobenzoyl)-piperidino]-propyl]-theophylline (Sgd 144-80) STR6 10.2 g 4-(p-fluorobenzoyl)-piperidine and 16.5 g 7-(chloropropyl)-theophylline are carefully mixed in the solid state and heated to 100 C. in a round flask in an oil bath. The mixture at first results in a clear melt, subsequently begins to crystallize and then changes into a solid mass. It is allowed to cool after 10 minutes, dissolved in ethyl acetate and 2n hydrochloric acid is added, whereby a dark oil separates in the organic phase, crystallizing on standing overnight. By recrystallizing with 100 ml carbon tetrachloride, an initially oily then crystallizing substance is obtained, 7.4 g of the product with an mp of 114 to 119 C. (yield: 43.5%) The 7-(3-chloropropyl)-theophylline, used as a starting material, may be obtained in a known manner, for instance by the reaction of theophylline with 1,3-bromo-chloropropane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
aluminium chloride; In fluorobenzene; water; | Step B 4-(4-fluorobenzoyl) piperidine A mixture of 3000 g of fluorobenzene and 1680 g aluminium chloride is kept under stirring while 1300 g N-acetyl isonipecotic acid chloride is portionwise added. Once this addition is achieved the whole mixture is heated to reflux then let to revert to room temperature. The reagent in excess is destroyed with water and the aqueous suspension is extracted with ethyl acetate. 1475 g of row 4-(fluoro benzoyl)N-acetyl piperidine is thus obtained as an oily residue. The (4-fluorobenzoyl) N-acetyl piperidine is thereafter hydrolyzed with 1050 g hydrochloric acid and 1300 ml water. The solvent is evaporated off and taken up with isopropanol. 1064 g 4-(4-fluorobenzoyl) piperidine are recovered as the hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.0 g (48%) | With sodium hydrogencarbonate; In N-methyl-acetamide; water; | EXAMPLE 24 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-<strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> hydrochloride To 30 ml of dry dimethylformamide was added 3.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 3.1 g of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong>, 8.0 g of sodium bicarbonate, and a crystal of potassium iodide. After stirring at 100 C. for two hrs, the mixture was filtered and the filtrate was evaporated. The residue was stirred with 100 ml of water and then extracted into ether. The ether extract was washed with water (2*), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the ether solution was acidified with ethereal hydrogen chloride and the precipitate was collected and dried. The precipitate was recrystallized from ethyl acetate/methanol/ether to yield 3.0 g (48%) of product, mp 240-243 C. Recrystallization from ethyl acetate/methanol/ether gave the analytical sample, mp 247-248 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; hexane; ethyl acetate; | EXAMPLE 4 A mixture of 16.4 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-chloropropyl ester and 16.6 g of 4-(p-fluorobenzoyl)-piperidine is kept for 1 hour under argon in a bath heated to 145. After cooling, 100 ml of ethyl acetate and 50 ml of 2N hydrochloric acid are added and the mixture is stirred until the reaction mass has completely dissolved. The partly oily aqueous-acidic phase is adjusted to pH 10 with 50% potassium carbonate solution; methylene chloride is added and the whole is filtered with suction. The methylene chloride phase of the filtrate is separated off and concentrated by evaporation and the residue is dissolved in ethyl acetate; the solution is dried over sodium sulphate and filtered. Filtration is then carried out over 1 kg of silica gel Merck 9385 using a hexane/ethyl acetate/methanol mixture (4:2:0.5) as eluant. The 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-[4-(p-fluorobenzoyl)-piperidino]-propyl ester obtained after working up is converted by means of ethereal hydrogen chloride solution into the hydrochloride which, after recrystallisation from isopropanol, melts at 198-205 with the evolution of gas. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.10 g (55%) | With sodium iodide; In chloroform; acetone; benzene; | EXAMPLE 4 3-Acetyl-2-[2-[3-[4-(4-fluorobenzoyl)-1-piperidyl]propoxy]-5-nitrophenyl]benzothiazoline (compound 8) To a solution of 3-acetyl-2-[2-(3-chloropropoxy)-5-nitrophenyl]benzothiazoline (3.93 g) in acetone (20 ml), sodium iodide (1.50 g) is added and the mixture is refluxed for 2 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo to remove acetone. To the residue, benzene (20 ml) and <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (4.20 g) are added and the mixture is refluxed for 9 hours. After cooling to room temperature, chloroform (100 ml) is added to the reaction mixture. The mixture is washed with N hydrochloric acid, N sodium hydroxide solution and then saturated sodium chloride solution. The solution is dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography to give 3.10 g (55%) of the titled compound. mp 169-172 C. IR (KBr, cm-1): 1665, 1588, 1508, 1489, 1460, 1449, 1376, 1330, 1262 NMR (DMSO-d6, delta): 1.57-3.53 STR30 2.33 (3H, m, --COCH3), 4.25 (2H, t, J=6.0 Hz, --OCH2 --), 6.83-8.30 (12H, m, C2 -H and aromatic H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; ethanol; | EXAMPLE 1 41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine are dissolved in 120 ml of dioxan, and 28.3 g (0.1 mol) of N-(2-bromoethyl)-5-cyano-2-methoxybenzamide are added and the whole is then stirred at room temperature for 60 hours. A solution of potassium carbonate is then added to the reaction mixture and the whole is then extracted with methylene chloride. The methylene chloride solution is washed neutral with water and concentrated in a water-jet vacuum. A light yellow crystalline product remains behind which is suspended in 200 ml of ethanol and stirred for 2 hours. The solid product is then filtered with suction and subsequently washed with 20 ml of ice-cold ethanol. 5-Cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxybenzamide is obtained in the filtration residue in the form of white powder of melting point 167-169. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate; | 27 (+-)2-[4-(p-Fluoro-benzoyl)-piperidin-1-yl]-1-(3-methoxy-isoxazol-5-yl)-ethan-1-ol A solution of 3.5 g of 1-(3-methoxy-isoxazol-5-yl)-2-bromoethanol and 4.9 g of 4-(4'-fluorobenzoyl)piperidine and 5.4 ml of N-ethyldiisopropylamine in 160 ml of absolute ethanol was refluxed for 2 hours. The solvent was removed in vacuo and ethyl acetate was added to remove N-ethyldiisopropylamine hydrochloride. The reaction mixture was chromatographed on silica gel eluding with ethyl acetate/cyclohexane 3/7. The fraction containing the compound were pooled, the solvent removed and after crystallization from di-isopropyl ether, 1.6 g of the title compound as brown crystals were obtained in 29% yield, m.p. 125-128 C. 1 H-NMR (DMSO-d6): delta 8.05 (m, 2 H, arom.), delta 7.35 (m, 2 H, arom.), delta 6.08 (s, 1 H, CH isox.), delta 5.61 (d, 1 H, OH), delta 4.7 (q, 1 H, CHOH), delta 3.82 (s, 3 H, OCH3), delta 3.3 (m, 1 H4'), delta 2.9 (m, 2 H eq.2'/6'), delta 2.6 (d, 2 H, CH2N), delta 2.2 (m, 2 H ax., 2'/6'), delta 1.7 (m, 2 H eq., 3'/5'), delta 1.55 (m, 2 H ax., 3'/5'). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 4-methyl-2-pentanone; at 100℃; | A mixture of (4-fluorophenyl)-4-piperidinyImethanone (0.01 mol), l,4-dichloro-2-butyne (0J.05 mol) and sodium carbonate (1 g) in MIK (20 ml) was stirred overnight at 100C. The reaction mixture was washed with water, and the organic solvent was evaporated. The residue was purified by HPLC over Kromasil silica gel (200 g, 100 A, 5 urn) (eluent: C^C^CHaCVCHsOH 90/10)/CH3OH (Ornin) 100/0/0, (34 min) 0/100/0, (40 min) 50/0/50, (43 min) 0/0/100, (46.6-60 min) 100/0/0). The pure fractions were collected and the solvent was evaporated, yielding 0.75g of product. This fraction was dried, yielding 0.558g of of compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | Intermediate E Trans-(4-{2-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (0.850 g, 3.4 mmol), Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in 1, 2 dichloroethane (10 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Intermediate N {Trans-2-[4-(4-Fluoro-benzoyl)-piperidin-1-ylmethyl]-cyclopropylmethyl}-carbamic acid tert-butyl ester A mixture of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (0.300 g, 1.2 mmol), Trans-(2-Formyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (0.294 g, 1.2 mmol), in 1, 2 dichloroethane (2 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (0.470 g, 2.2 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 0.288 g (0.74 mmol, 60% yield) of a white solid. MS (m/e): 391.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a stirred suspension [OF 4- (2-PYRIDYL)] aniline (172mg, [L.] [OLMMOL)] and PS-DIEA (2 mmol) in DCM (5 ml) was added trichloroacetyl chloride (134 [GL,] 1.2 mmol). The solutions were stirred for 72 hours. The reaction was filtered and the filtrate evaporated in vacuo. The residue was dissolved in DMSO (3 ml), and treated with sodium carbonate (424 mg, 4 mmol) and [4-FLUOROBENZOYLPIPERIDINE] (approx [LMMOL] dissolved in [2ML] DMSO) at [80C] for 6 hours. The reaction mixture was cooled to room temperature, and evaporated under high vacuum. The resultant gum was triturated with EtOAc [(10ML)] and filtration afforded the product as an off-white solid (135mg, [33%).] NMR (DMSO-d6): 1.41-1. 61 (m, 2H), 1.73-1. 88 (br d, 2H), 3.01 (t, 2H), 3.59-3. 77 (m, 1H), 4.08-4. 25 (br d, 2H), 7.18-7. 28 (app t, 1H), 7.36 (t, 2H), 7.57 (d, 2H), 7.73-7. 90 (m, 2H), 7.96 (d, 2H), 8.03-8. 15 (m, 2H), 8.59 (d, 1H), 8.66 (s, 1H); [M/Z] 371.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The following general procedure was used to make Examples 346-351. To the Acid, R3-C [(O)-OH,] (1.83 mmol) in a 4-dram glass vial was added sequentially [PS-DIEA] (880mg) and a solution of HATU (1.83 mmol) in DMF (6ml). The mixture was agitated and allowed to stand for 5-10 minutes prior to the addition of a solution of benzoyl piperidine, [(R1-PH] C (O) -piperidine), (1.83 mmol) and DIEA (2.01 mmol) in DMF [(6ML).] The mixture was shaken, (sonicated if required to effect dissolution) and left to stand, without agitation for 16 hours. The reaction mixture was poured onto an Isolute SCX-2 column [(LOG)] transferred with DCM (2ml) and eluted with DCM (2.5 column volumes), the filtrate was then passed through and Isolute-NH2 column (20g) and eluted with DCM. The eluents were then evaporated in vacuo taken up in EtOAc and evaporated again in vacuo to give the piperidine amide. The amides (0.29 mmol) were dissolved in THF (2.5 ml) and [LHMDS] (0.46 ml of a 1.6 M solution in THF) added, alkylating agent [(R2-BR)] [(1.] [18MMOL)] was then added. The reactions were stirred at room temperature, under argon for 19 hours and then quenched with water. The reactions mixtures were concentrated in vacuo, diluted with DCM and passed through a phase separation cartridge. The crude materials were purified using a Biotage Quad3+ flash chromatography system eluting with 25% EtOAc/isohexane to afford the final compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium carbonate; In acetonitrile; for 15h;Reflux; | General procedure: To a solution of 6 hydrochloride salt (250 mg, 1.09 mmol) and 1-chloromethyl-5-methoxybenzimidazole (253.6 mg, 1.09 mmol) in anhydrous acetonitrile (6 mL) was added Na2CO3 (576.7 mg, 5.45 mmol). The reaction mixture was refluxed for 15 h, cooled down to room temperature, quenched with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel with CH2Cl2/MeOH/NH4OH (98:2:0.1) to afford 7a (225 mg, 59%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.08h; | Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0 C.) solution of (4-fluorophenyl)(piperidin-4-yl)methanone (5.00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4 (100 mL), H2O, and DCM was added. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers was dried (Na2SO4), filtered, concentrated under reduced pressure and chromatographed (CH2Cl2/EtOAc) to provide the title compound as a clear oil. | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.08h; | Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0 C.) solution of (4-fluorophenyl)(piperidin-4-yl)methanone (5.00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4 (100 mL), H2O, and DCM. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, concentrated under reduced pressure and chromatographed (DCM/EtOAc) to provide the title compound as a clear oil. | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.08333h; | Intermediate 44: 1-(4-(4-fluorobenzoyl)piperidin-1-yl)ethanone Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0 C) solution of (4- fluorophenyl)(piperidin-4-yl)methanone (5,00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room, temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4(100 mL), H20, and DCM. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers were dried (Na2S04), filtered, concentrated under reduced pressure and chromatographed (DCM/EtOAc) to provide the title compound as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; | 10343] Referring to Scheme 3, a pyridinedicarboxylic acid monomethyl ester (v), for example, is coupled with an amine (here a substituted 1-benzylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinecarboxamide (vi). The ester is saponified to form the corresponding carboxylic acid (vii), which is then coupled with a suitable amine (in this case, a substituted 4-benzoylpiperidine) to form Compound 160 of Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In ethanol; for 120h;Heating; | General procedure: The cis epoxide precursor (±)-2 was synthesized as already described [27]. In brief, elimination of water from cyclohexane-1,4-diol gave cyclohex-3-enol [40] which was epoxidized diasterioselectively by using tert-butyl hydroperoxide and Mo(CO)6 [41] to obtain the racemic epoxy alcohol. Subsequent O-p-fluorobenzylation resulted in the cis-epoxide (±)-2. To synthesize the 4-O-p-fluorobenzyl ether vesamicol derivatives (±)-3a -(±)-3m, the amine (1.41 mmol) and (±)-2 (1.12 mmol) were dissolved in 5 mL EtOH and stirred at 65-70 C for 5 days. The crude product was purified by column chromatography (silica gel 60) or by crystallization (details described for each compound). To synthesize the 5-O-p-fluorobenzyl ether vesamicol derivatives (±)-4a -(±)-4m, the cis-epoxide (±)-2 (1.12 mmol) and LiClO4 (1.97 mmol) were dissolved in 3 mL CH3CN and stirred for 10 min. Subsequently, the amine (1.41 mmol) was added and the reaction mixture was stirred at rt for 24 h. Products were purifiedby column chromatography (silica gel 60) or by crystallization (details described for each compound). The regioisomeric purity was checked by HPLC. (±)-3k (±)-(1-(5-(4-fluorobenzyloxy)-2-hydroxycyclohexyl)piperidin-4-yl) (4-fluorophenyl)methanone: The crude product was purified by column chromatography using EtOAc/n-hexane/NH3 (1/1/0.01). Removal of the solvent led to 197 mg (41%) of a slightly yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: The cis epoxide precursor (±)-2 was synthesized as already described [27]. In brief, elimination of water from cyclohexane-1,4-diol gave cyclohex-3-enol [40] which was epoxidized diasterioselectively by using tert-butyl hydroperoxide and Mo(CO)6 [41] to obtain the racemic epoxy alcohol. Subsequent O-p-fluorobenzylation resulted in the cis-epoxide (±)-2. To synthesize the 4-O-p-fluorobenzyl ether vesamicol derivatives (±)-3a -(±)-3m, the amine (1.41 mmol) and (±)-2 (1.12 mmol) were dissolved in 5 mL EtOH and stirred at 65-70 C for 5 days. The crude product was purified by column chromatography (silica gel 60) or by crystallization (details described for each compound). To synthesize the 5-O-p-fluorobenzyl ether vesamicol derivatives (±)-4a -(±)-4m, the cis-epoxide (±)-2 (1.12 mmol) and LiClO4 (1.97 mmol) were dissolved in 3 mL CH3CN and stirred for 10 min. Subsequently, the amine (1.41 mmol) was added and the reaction mixture was stirred at rt for 24 h. Products were purifiedby column chromatography (silica gel 60) or by crystallization (details described for each compound). The regioisomeric purity was checked by HPLC. (±)-4k (±)-(1-(4-(4-fluorobenzyloxy)-2-hydroxycyclohexyl)piperidin-4-yl) (4-fluorophenyl)methanone: The crude product was purified by column chromatography using CHCl3/MeOH/NH3(10/1/0.1). Adding of n-hexane to a concentrated CHCl3 solution of(±)-4k and keeping a few days at 4 C resulted in the formation of 323 mg (67%) of a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25%; 27% | With triethylamine; In ethanol; at 60℃; for 48h; | Compound 15 (200 mg, 1.2 mmol), (4-fluorophenyl)(piperidin-4-yl)methanone 16 (585 mg, 2.4 mmol) and triethylamine (1 mL) were mixed in ethanol (5 mL) and heated at 60 C for 2 d. Ethyl acetate (50 mL) was used to dilute the solution and then washed with brine (2 * 10 mL). After concentration, the residue was loaded onto silica gel column and eluted using CH2Cl2/methanol (20/1, v/v). Compound 17a was obtained as the first component, a white solid (109 mg, 25%). Mp 229-230 C. 1H NMR (300 MHz, CDCl3) delta 8.00-7.94 (m, 2H), 7.15-7.11 (m, 2H), 7.02 (t, J = 7.8 Hz, 1H), 6.66 (dd, J = 25.2 Hz, 7.8 Hz, 2H), 5.01 (br, 1H), 3.92-3.83 (m, 1H), 3.32-3.23 (m, 2H), 3.07-2.97 (m, 2H), 2.89-2.77 (m, 4H), 2.64-2.45 (m, 2H), 1.97-1.89 (m, 3H), 1.88-1.76 (m, 1H). 13C NMR (75.5 MHz, CDCl3) delta 201.1, 166.2 (d, J = 301.0 Hz), 153.6, 135.8, 130.9, 130.8, 126.9, 121.8, 121.4, 115.8 (d, J = 21.7 Hz), 112.1, 66.5, 65.3, 51.9, 43.8, 37.8, 29.5, 29.2, 28.5, 20.0. HRMS (ESI) Calcd for C22H25FNO3 (M+H)+ 370.1818, found: 370.1817. Compound 17b was obtained as the second component, a white solid (120 mg, 27%). Mp 208-210 C. 1H NMR (400 MHz, CDCl3) d1.76-1.93 (m, 4H), 2.46-2.64 (m, 2H), 2.76-2.89 (m, 4H), 2.97-3.07 (m, 2H), 3.25-3.32 (m, 2H), 3.88 (s, 1H), 6.61 (d, J = 8.4 Hz,2H), 6.72 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 8.1 Hz, 2H), 7.98 (t,J = 8.4 Hz, 2H). 13C NMR (75.5 MHz, CD3SOCD3) d 201.5, 165.4 (d,J = 251.6 Hz), 155.2, 137.1, 132.8, 131.6 (d, J = 9.3 Hz), 126.6,121.6, 119.7, 116.2 (d, J = 21.7 Hz), 112.1, 66.5, 65.7, 50.3, 46.6,43.6, 32.9, 29.6, 29.4, 27.8. HRMS (ESI) Calcd for C22H25FNO3(M+H)+ 370.1818, found: 370.1833. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.4% | With potassium carbonate; potassium iodide; In acetonitrile;Reflux; | General procedure: To a suspension of compounds 5 (0.32 mmol) and K2CO3 (1.22 mmol) in acetonitrile (5.0 mL), arylpiperazine (piperidine) (0.32 mmol) and a catalytic amount of KI were added and the resulting mixture was refluxed for 7-9 h. After filtering, the resulting filtrate was evaporated to dryness under reduced pressure. The residue was suspended in water (10.0 mL) and extracted with dichloromethane (25 mL × 3). The combined organic layers were evaporated under reduced pressure, and the crude product was purified by means of chromatography (10% MeOH/CHCl3) to yield compounds 6-26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In ethanol; at 78℃; | To a solution of 7a (94 mg, 0.25 mmol) in EtOH (5 mL) was added TEA (0.10 mL, 3 equiv) and <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (64 mg, 1.25equiv). The mixture was stirred at 78 C overnight, concentrated and then chromatographed on a 4 g silica gel column using a 0-100%EtOAc/hexanes gradient, thus providing 128 mg (94%) of a solid, mp183-184 C. 1H NMR (300 MHz, CDCl3) delta 8.40 (s, 1H), 8.01 (dd,J=5.4, 8.8 Hz, 2H), 7.46-7.57 (m, 1H), 7.29-7.42 (m, 5H), 7.19-7.25(m, 2H), 7.16 (t, J=8.6 Hz, 2H), 5.56 (br s, 2H), 3.53-3.70 (m, 1H),3.39 (t, J=11.6 Hz, 2H), 1.81-2.03 (m, 4H). 13C NMR (75 MHz,CDCl3) delta 200.3, 167.4, 164.1, 153.9, 153.2, 152.3, 145.7, 134.2, 134.2,133.1, 132.5, 132.3, 132.3, 131.4, 131.0, 130.9, 130.0, 129.7, 129.4,128.0, 126.9, 119.8, 116.0, 115.7, 45.0, 43.6, 28.6. MS (m/z) 546.3(M+1). HPLC=99% at 21.85 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium iodide; potassium hydroxide; In ethanol; for 24.1h;Reflux; | <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (1.1 g, 5.3 mmol),1-(2-Bromoethoxy)naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and ethanol 30mL were added to a 100mL eggplant-shaped flask and heated to reflux, and 5mL of a 20% KOH solution was added dropwise The addition was completed in 10 minutes. Reflux for 24 hours, evaporate the solvent and dissolve in 30 mL of dichloromethane.The organic layer was washed three times with 20 mL of water, and the organic layer was concentrated.Using ethyl acetate and petroleum ether as the eluent,Gradient elution. Column chromatography gave 1.31 g of brown solid with a yield of 65.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.3% | With potassium iodide; potassium hydroxide; In ethanol; for 24.1h;Reflux; | 4- (4-fluorobenzoyl) piperidine (1.1 g, 5.3 mmol),1-(2-bromoethoxy)-4-methoxybenzene (1.6 g, 6.9 mmol), KI (1.6g, 10mmol) and 30mL ethanol were added to a 100mL eggplant-shaped flask and heated under reflux. 5 mL of 20% KOH solution was added dropwise, and the addition was completed in 10 minutes. Reflux for 24 hours, Evaporate the solvent, add 30mL of dichloromethane to dissolve, and wash with 20mL of water three times. The organic layer was concentrated to obtain a brown oil. A mixture of ethyl acetate and petroleum ether was used as the eluent. Gradient elution. Column chromatography gave 0.83 g of pale yellow solid with a yield of 42.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium iodide; potassium hydroxide; In ethanol; for 24.1h;Reflux; | <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (1.1 g, 5.3 mmol),1-(2-methylethoxy)-4-methylbenzene (1.5 g, 6.9 mmol), KI (1.6g, 10mmol) and 30mL ethanol will be added to a 100mL eggplant-shaped flask and heated to reflux5 mL of 20% KOH solution was added dropwise, and the addition was completed in 10 minutes. Reflux for 24 hours, evaporate the solvent,It was dissolved in 30 mL of dichloromethane, the organic layer was washed three times with 20 mL of water, and the organic layer was concentrated.A mixture of ethyl acetate and petroleum ether was used as the eluent.Column chromatography yielded 0.45 g of brown solid with a yield of 25.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.4% | With potassium iodide; potassium hydroxide; In ethanol; for 24.1h;Reflux; | 4- (4-fluorobenzoyl)piperidine (1.1 g, 5.3 mmol),1-(2-bromoethoxy)-4-methoxybenzene (1.5 g, 6.9 mmol),KI (1.6g, 10mmol) and 30mL ethanol were added to a 100mL eggplant-shaped flask and heated under reflux.5 mL of a 20% KOH solution was added dropwise, and the addition was completed in 10 minutes. Reflux for 24 hours, evaporate the solvent, dissolve in 30 mL of dichloromethane, wash the organic layer three times with 20 mL of water, and concentrate the organic layer. A mixture of ethyl acetate and petroleum ether was used as the eluent.Column chromatography gave 1.45 g of brown solid with a yield of 79.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.8% | With potassium iodide; potassium hydroxide; In ethanol; for 22.1h;Reflux; | 4-(4-fluorobenzoyl) piperidine (1.1 g, 5.3 mmol),1-(2-bromoethoxy)-4-chlorobenzene (1.6 g, 6.9 mmol), KI (1.6g, 10mmol) and 30mL ethanol were added to a 100mL eggplant-shaped flask and heated under reflux.5 mL of 20% KOH solution was added dropwise, and the addition was completed in 10 minutes. Reflux for 22 hours, evaporate the solvent, add 30mL of dichloromethane to dissolve, and wash with 20mL of water three times.The organic layer was concentrated to obtain a brown oil. A mixture of ethyl acetate and petroleum ether was used as the eluent.Gradient elution. Column chromatography gave 0.71 g of a light brown solid with a yield of 36.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.7% | With potassium iodide; potassium hydroxide; In ethanol; for 22.1h;Reflux; | <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (1.1 g, 5.3 mmol),1-(2-bromoethoxy)-4-bromobenzene (1.9 g, 6.9 mmol), KI (1.6g, 10mmol) and 30mL ethanol were added to a 100mL eggplant-shaped flask and heated under reflux. 5 mL of 20% KOH solution was added dropwise, and the addition was completed in 10 minutes. Reflux for 22 hours,Evaporate the solvent, add 30mL of dichloromethane to dissolve, and wash with 20mL of water three times. The organic layer was concentrated to obtain a brown oil. A mixture of ethyl acetate and petroleum ether was used as the eluent.Gradient elution. Column chromatography gave 1.37 g of a light brown solid with a yield of 63.7%. |
Tags: 56346-57-7 synthesis path| 56346-57-7 SDS| 56346-57-7 COA| 56346-57-7 purity| 56346-57-7 application| 56346-57-7 NMR| 56346-57-7 COA| 56346-57-7 structure
[ 25519-78-2 ]
(4-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.98
[ 639468-63-6 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.98
[ 1558734-88-5 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.96
[ 118412-66-1 ]
3-[(4-Fluorophenyl)carbonyl]piperidine hydrochloride
Similarity: 0.94
[ 149452-43-7 ]
(3,4-Difluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.94
[ 25519-78-2 ]
(4-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.98
[ 639468-63-6 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.98
[ 1558734-88-5 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.96
[ 118412-66-1 ]
3-[(4-Fluorophenyl)carbonyl]piperidine hydrochloride
Similarity: 0.94
[ 149452-43-7 ]
(3,4-Difluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.94
[ 25519-78-2 ]
(4-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.98
[ 639468-63-6 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.98
[ 1558734-88-5 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.96
[ 118412-66-1 ]
3-[(4-Fluorophenyl)carbonyl]piperidine hydrochloride
Similarity: 0.94
[ 149452-43-7 ]
(3,4-Difluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.94
[ 25519-78-2 ]
(4-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.98
[ 639468-63-6 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.98
[ 1558734-88-5 ]
(3-Fluorophenyl)(piperidin-4-yl)methanone hydrochloride
Similarity: 0.96
[ 118412-66-1 ]
3-[(4-Fluorophenyl)carbonyl]piperidine hydrochloride
Similarity: 0.94
[ 149452-43-7 ]
(3,4-Difluorophenyl)(piperidin-4-yl)methanone
Similarity: 0.94
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :