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. : | 5570-77-4 | MDL No. : | MFCD00044489 |
Formula : | C6H12ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MYGXGCCFTPKWIH-UHFFFAOYSA-N |
M.W : | 133.62 | Pubchem ID : | 79342 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.45 |
TPSA : | 3.24 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.11 cm/s |
Log Po/w (iLOGP) : | 2.03 |
Log Po/w (XLOGP3) : | 1.41 |
Log Po/w (WLOGP) : | 0.94 |
Log Po/w (MLOGP) : | 1.49 |
Log Po/w (SILICOS-IT) : | 1.63 |
Consensus Log Po/w : | 1.5 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.56 |
Solubility : | 3.71 mg/ml ; 0.0277 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.08 |
Solubility : | 11.1 mg/ml ; 0.0827 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.34 |
Solubility : | 6.07 mg/ml ; 0.0454 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.31 |
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 |
---|---|---|
52% | With n-butyllithium; ammonia; diisopropylamine In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate | EXAMPLE 1 STR49 To a solution of diisopropylamine (1.078 mL) in anhydrous THF (7 mL) was added n-butyllithium (3.08 mL; 2.5M) dropwise at 0° C. The resulting solution was stirred at 0° C. for 40 minutes and then was cooled to -23° C. To this mixture was added N-methyl-2-piperidinone (0.80 mL) (1), the mixture was stirred at -23° C. for 0.5 hour, and then at -78° C. for 1 hour. To the above mixture was added dropwise a solution of 4-chloromethyl-N-trityl-imidazole (2.70 g) STR50 in anhydrous THF (14 mL). The mixture was stirred at -78° C. for 4 hours and then was allowed to warm up to room temperature slowly overnight (16 hours). Water and ethyl acetate were added to the mixture, the resulting mixture was shaken vigorously, the layers separated, and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash chromatography (1percent to 2percent of ammonia saturated methanol in CH2 Cl2) to give 2 (1.58 g; 52percent yield). |
52% | With n-butyllithium; ammonia; diisopropylamine In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate | EXAMPLE 1 STR49 To a solution of diisopropylamine (1.078 mL) in anhydrous THF (7 mL) was added n-butyllithium (3.08 mL; 2.5M) dropwise at 0° C. The resulting solution was stirred at 0° C. for 40 minutes and then was cooled to -23° C. To this mixture was added N-methyl-2-piperidinone (0.80 mL) (1.) the mixture was stirred at -23° C. for 0.5 hour, and then at -78° C. for 1 hour. To the above mixture was added dropwise a solution of 4-chloromethyl-N-trityl-imidazole (2.70 g) STR50 in anhydrous THF (14 mL). The mixture was stirred at -78° C. for 4 hours and then was allowed to warm up to room temperature slowly overnight (16 hours). Water and ethyl acetate were added to the mixture, the resulting mixture was shaken vigorously, the layers separated, and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash chromatography (1percent to 2percent of ammonia saturated methanol in CH2 Cl2) to give 2 (1.58 g; 52percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | To a suspension of Mg (5.57 [G,] 0.23 mol) in THF (25 mL) was added a few drops of bromoethane to initiate reaction. <strong>[5570-77-4]4-Chloro-1-methylpiperidine</strong> (24.5 g, 0.18 mol) in THF (80 mL) was then added dropwise. After addition the reaction was heated under reflux for 1 hour and then allowed to attain rt. The [AVAILABLE 2-FLUOROBENZONITRILE] (22.2 g, 0.18 mol) in THF (44 mL) was added and the mixture was heated under reflux for 3 hours and stirred at rt overnight. The reaction was treated with a ammonium chloride solution and water. After extraction with [ET20,] the organic layer was dried over [NA2SO4,] filtered and evaporated off. The crude oil was purified by distillation under vaccum [(T=110XB0;C)] to give the title compound as a yellow oil (10.0 g, 18 [MMOL)] in a 25% yield ; LC-MS: M+H [C13H, 7NFO] 222. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-chloro-succinimide; ammonium chloride; magnesium; In tetrahydrofuran; benzene; | Example 22 2-Chloro-11-(1-methyl-4-piperidyl)-11H-dibenz(b,f)-1,4-oxathiepin A solution of 7.05 g of 2-chloro-11H-dibenz (b,f)-1,4-oxathiepin (cf. Example 18) in 30 ml of benzene was treated with 3.85 g of N-chloro-succinimide. The mixture was stirred for 5hours while maintaining a maximum temperature of 25 C. by external cooling. After standing overnight, the mixture was added dropwise to a solution of a Grignard reagent prepared by reaction of 7.0 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> with 1.3 g of magnesium in 40 ml of tetrahydrofuran at 20-25 C. The mixture was stirred for another 5 hours at room temperature, allowed to stand for 48 hours and decomposed with a 20% ammonium chloride solution. It was extracted with benzene, the extract washed with water and the basic product reextracted by shaking with excessive dilute hydrochloric acid. The acid aqueous solution was made alkaline with aqueous ammonia and the base isolated by extraction with benzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1-Dibromoethane; In tetrahydrofuran; at 20 - 48℃; | N-methyl-piperidyl magnesium chloride, prepared by addition of N-methyl-4- chloropiperidine (136 gm, 1.02 mole) to A stirred solution of magnesium metal (33.4 gm, 1. 374 MOLE) 7 DIBROMOETHANE (72. 8 gm, 0. 386 mole) and dry TERAHYDROFURAN (TUF) (1.17 L) at 20 to 48C, is added slowly to a cooled (-85 TO-95C) solution of 8- chloro-6, 11-DIHYDRO-5H-BENZO [5,6] cyclohepta [1, 2-B]-11-ONE (100 gm, 0.41 mole) in dry THF (530ML). The reaction mixture is stirred for 2-3 hours at the same temperature. The reaction mixture is quenched with 10% NH4CL (600ML) and extracted twice with ethyl acetate (2X400 ml). The organic phase is washed with water and dried over anhydrous sodium sulfate, filtered and solvent removed. The crude material obtained (141 gm) is purified by ACETONITRILE to obtain desired carbinol compound (101 gm) in 71. 8 % yield with a purity of 94.35% (ODB, HPLC). | |
ethyl bromide; In tetrahydrofuran; | Example 1; 2,2-Dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol monofumarate; With cooling on ice, a THF solution of (1-methylpiperidin-4-yl)magnesium chloride (2 equivalents) that had been separately prepared from <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong>, Mg (2 equivalents) and EtBr (catalytic amount) was added to a THF (20 ml) solution of 2,2-dimethylindan-1-one (961 mg), followed by stirring for 2 hours at a temperature falling between that temperature and room temperature. An aqueous saturated ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol/aqueous saturated ammonia = 10/1/0.1) to obtain a colorless crystal (1.46 g). This was formed into its salt with 1 equivalent of fumaric acid, and washed with diethyl ether to obtain the compound of Example 1 as a colorless crystal.; Example 6; 2,2,6-Trimethyl-1-(1-methylpipendin-4-yl)indan-1-ol monofumarate; With cooling on ice, a THF solution of (1-methylpiperidin-4-yl)magnesium chloride (2 equivalents) that had been separately prepared from <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong>, Mg (2 equivalents) and EtBr (catalytic amount) was added to a THF (100 ml) solution of 2,2,6-trimethylindan-1-one (8.0 g), followed by stirring for 2 hours at a temperature falling between that temperature and room temperature. An aqueous saturated ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol/aqueous saturated ammonia = 10/1/0.1) to obtain a colorless crystal (9.2 g). This was formed into its salt with 1 equivalent of fumaric acid, and recrystallized from ethanol/ethyl acetate to obtain the compound of Example 6 as a colorless crystal. In Examples 7 to 12, the compounds shown in Tables 13 and 14 were produced in the same manner as in Example 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; magnesium; methyl iodide; In tetrahydrofuran; at 20℃; for 1h;Heating / reflux; | [2090] To a suspension of Mg (3.63 g) in anhydrous THF (95 mL) under nitrogen at room temperature was added 4-chloro-1-methyl piperidine (3 mL, 10% of the total amount) and one small crystal of iodine. The resulting solution was heated to reflux, followed by the addition of iodomethane (0.5 mL) and the remainder of the 4-chloro-1-methyl piperidine (27 mL). The reaction was stirred for one hour and then concentrated to dryness to give the crude Grignard reagent (0.8M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; | sample of 4-chloro-1-methyl-piperidine hydrochloride salt was basified with KOH and extracted with CH2CI2. The organic phase was dried over magnesium sulfate and concentrated under vacuum. The crude product was distilled from CaH2 at 50C at 1 mmHg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In tetrahydrofuran; hydrogenchloride; dichloromethane; toluene; | Preparative Example 34 To a stirred solution of alcohol (280) from Preparative Example 33, Step C (30.0 g, 104.5 mmol) in CH2Cl2 (500 mL) under nitrogen at -20 C. was added thionyl chloride (106.7 mL, 1,46 mmol). The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The crude mixtue was diluted with toluene (50 mL), followed by the addition of more SOCl2 (106.7 mL) at room temperature. The resulting solution was heated to reflux for 2 hours until the reaction went to completion. The reaction mixture was then cooled to room temperature and concentrated to dryness to give a light brown solid (292) (35.67 g, 100% yield, MBrCl=191). To a suspension of Mg (3.63 g) in anhydrous THF (95 mL) under nitrogen at room temperature was added 4-chloro-1-methyl piperidine (3 mL, 10% of the total amount) and one small crystal of iodine. The resulting solution was heated to reflux, followed by the addition of iodomethane (0.5 mL) and the remainder of the 4-chloro-1-methyl piperidine (27 mL). The reaction was stirred for one hour and then concentrated to dryness to give the crude Grignard reagent (0.8M). To a stirred solution of the chloro compound (292) from Preparative Example 34, Step A (35.67 g, 116.7 mmol) in anhydrous THF (200 mL) under nitrogen at room temperature, was added dropwise the Grignard reagent (as obtained above) (0.8M, 146 mL, 116.7 mmol).The resulting solution was stirred at room temperature for 3 hours, followed by the extraction with EtOAc-H2O. The combined organic layer was dried over MgSO4, filtered and evaporated to dryness to give the product (293) (49.25 g, 100% yield, MH+=368). To a stirred solution of Compound (293) from Step B above (42.9 g, 116.5 mmol) in toluene (400 mL) under nitrogen was added triethylamine (49 mL, 349.5 mmol). The resulting solution was heated to refux, followed by the dropwise addition of ethyl chloroformate (126 g, 1165 mmol). Continued to heat the solution at the reflux temperature for 2 hours. The reaction was then stirred at room temperature overnight, followed by extraction with an EtOAc-1N NaOH solution. The combined organic layer was dried over MgSO4, filtered, concentrated to dryness and the crude product purified by column chromatography on normal phase silica gel, eluding with 30% EtOAc/70% Hexane to give a light yellow solid (294) (2.99 g, 12% yield, MH+=426.3). A solution of the ester (294) from step C above (3.34 g, 7.83 mmol) in 6N HCl (20 mL) was heated to reflux overnight. The reaction was cooled to room temperature and basified with NH4OH solution, followed by extraction with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and evaporated to dryness to give a crude free piperidine (2.80 g, 100% yield, MH+=534) To the crude material (as obtained above) (2.77 g, 7.82 mmol) in 50% MeOH/1% H2O (200 mL) was added Di-tert-butyl dicarbonate (3.41 g, 15.64 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With n-butyllithium; ammonia; diisopropylamine; In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate; | EXAMPLE 1 STR49 To a solution of diisopropylamine (1.078 mL) in anhydrous THF (7 mL) was added n-butyllithium (3.08 mL; 2.5M) dropwise at 0 C. The resulting solution was stirred at 0 C. for 40 minutes and then was cooled to -23 C. To this mixture was added N-methyl-2-piperidinone (0.80 mL) (1), the mixture was stirred at -23 C. for 0.5 hour, and then at -78 C. for 1 hour. To the above mixture was added dropwise a solution of 4-chloromethyl-N-trityl-imidazole (2.70 g) STR50 in anhydrous THF (14 mL). The mixture was stirred at -78 C. for 4 hours and then was allowed to warm up to room temperature slowly overnight (16 hours). Water and ethyl acetate were added to the mixture, the resulting mixture was shaken vigorously, the layers separated, and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash chromatography (1% to 2% of ammonia saturated methanol in CH2 Cl2) to give 2 (1.58 g; 52% yield). |
52% | With n-butyllithium; ammonia; diisopropylamine; In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate; | EXAMPLE 1 STR49 To a solution of diisopropylamine (1.078 mL) in anhydrous THF (7 mL) was added n-butyllithium (3.08 mL; 2.5M) dropwise at 0 C. The resulting solution was stirred at 0 C. for 40 minutes and then was cooled to -23 C. To this mixture was added N-methyl-2-piperidinone (0.80 mL) (1.) the mixture was stirred at -23 C. for 0.5 hour, and then at -78 C. for 1 hour. To the above mixture was added dropwise a solution of 4-chloromethyl-N-trityl-imidazole (2.70 g) STR50 in anhydrous THF (14 mL). The mixture was stirred at -78 C. for 4 hours and then was allowed to warm up to room temperature slowly overnight (16 hours). Water and ethyl acetate were added to the mixture, the resulting mixture was shaken vigorously, the layers separated, and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash chromatography (1% to 2% of ammonia saturated methanol in CH2 Cl2) to give 2 (1.58 g; 52% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N2;CeCl3; In tetrahydrofuran; | Step C [3-[(3-Chlorophenyl)thiomethyl]-2-pyridinyl][l -methyl-4-piperidinyl]methanone STR35 Anhydrous CeCl3 (1.1 g, 4.46 mmol) was placed in a 50 ml 2-necked flask and flamed out under vacuum. The vacuum was replaced with N2, and dry THF (20 ml) was added. The CeCl3/ THF solution was stirred at room temperature for 16 hours and then cooled to -40 C., and the Mg-Grignard reagent from <strong>[5570-77-4]4-chloro-1-methyl-piperidine</strong> (3 ml of an 0.8M stock solution in THF) was added. The resulting solution was stirred at -40 C. for 75 minutes, and then 3-[(3-chlorophenyl)thiomethyl]-N-methoxy-N-methyl-2-pyridinecarboxamide (345 mg, 1.07 mmol) was added dropwise. After 40 minutes, the mixture was poured into 5% HCI/EtOAc, stirred for 5 minutes, and then basified to pH ~8. The organic product was extracted with EtOAc (6*100 ml), the extracts were washed with brine, dried (Na2 SO4), filtered and concentrated. The product was chromatographed on silica and eluted with 5-10%MeOH/CH2 Cl2 to afford [3-[(3-chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone (251 mg, 64%); HRMS, FAB, calcd. 361.1141; found. 361.1141. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; water; | Stage A 4-(1-Hydroxy-7 methoxy-1,2,3,4-tetrahydronaphth-1-yl)-1-methylpiperidine A solution of 40 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> in 150 ml of tetrahydrofuran is added to a suspension of 6.9 g of magnesium in 50 ml of tetrahydrofuran. The formation of the magnesium compound is completed by refluxing for 2 hours. A solution of 32.2 g of 7-methoxy-1,2,3,4-tetrahydronaphth-1-one in 150 ml of tetrahydrofuran is then added at 10 C. Stirring of the reaction mixture is continued at ambient temperature for 15 hours and the mixture is then hydrolyzed at 0 C. using 15 g of ammonium chloride in solution in 80 ml of water. After evaporation of the solvent under vacuum, the residue is taken up in water, the mixture is acidified and washed with ethyl ether, the aqueous phase is then rendered alkaline and the product extracted with 400 ml of toluene is washed with 200 ml of water. After concentration under vacuum, the oil obtained crystallizes. Melting point: >60 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With ammonium chloride; magnesium; | REFERENTIAL EXAMPLE 2 8-Cyano-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol Into a tetrahydrofuran (THF) solution of a Grignard reagent prepared from 6.7 g of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> and 1.2 g of magnesium, 4.68 g of 8-cyano5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (the compound prepared in Referential Example 1) were added under ice cooling. After the resultant mixture was stirred for 3 hours at room temperature, a saturated aqueous solution of ammonium chloride was added, followed by stirring for 15 minutes. The reaction mixture was then extracted with chloroform. The Extract was dried over anhydrous Na2 SO4 and then filtered. The filtrate so obtained was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (50:1), 3.1 g of 8-cyano-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol were obtained (yield: 47%). 1 H-NMR delta ppm(CDCl3); 0.6-1.2(1H,m), 1.4-1.92(4H,m), 2.16(3H,s), 2.56-3.80(8H,m), 7.12-7.60(4H,m), 8.26(1H,d), 8.40(1H,dd). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; | C. 5-METHOXY-8-CHLORO-11-(1-METHYL-4-PIPERIDINYL)-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-OL STR98 Add a 1.5M Grignard solution of N-methyl 4-chloropiperidine (150 mL, 22.5 mmol) in THF dropwise over a 7 minute period to 5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00 g, 18.4 mmol) in THF (70 mL) at 0 C. and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH4 Cl (pH 8) and extract (3*) with CHCl3. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Purify via flash chromatography (5% CH3 OH in CH2 Cl2) to give the title compound (3.60 g, 53%) as a solid. The solid may be recrystallized from isopropyl ether to give a white powder (mp: 168-170 C.). | |
In tetrahydrofuran; dichloromethane; | C. 5-METHOXY-8-CHLORO-11-(1-METHYL-4-PIPERIDINYL)-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-OL STR75 Add a 1.5M Grignard solution of N-methyl 4-chloropiperidine (150 mL, 22.5 mmol) in THF dropwise over a 7 minute period to 5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00 g, 18.4 mmol) in THF (70 mL) at 0 C. and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH4 Cl (pH 8) and extract (3*) with CHCl3. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Purify via flash chromatography (5% CH3 OH in CH2 Cl2) to give the title compound (3.60 g, 53%) as a solid. The solid may be recrystallized from isopropyl ether to give a white powder (mp: 168-170 C). | |
In tetrahydrofuran; dichloromethane; | C. 5-METHOXY-8-CHLORO-11-(1-METHYL-4-PIPERIDINYL)-11H-BENZO [5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-OL STR101 Add a 1.5 M Grignard solution of N-methyl 4-chloropiperidine (150 mL, 22.5 mmol) in THF dropwise over a 7 minute period to 5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00 g, 18.4 mmol) in THF (70 mL) at 0 C. and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH4 Cl (pH 8) and extract (3*) with CHCl3. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Purify via flash chromatography (CH3 OH 5% in CH2 Cl2) to give the title compound (3.60 g, 53%) as a solid. The solid may be recrystallized from isopropyl ether to give a white powder (mp 168-170 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; | D. 1-METHYL-4-(8-CHLORO-11-HYDROXY5,11-DIHYDRO[1]-BENZOXEPINO[4,3-b]PYRIDINYL)PIPERIDINE STR158 Slowly add the Grignard reagent (11.9 mL, 1.2M) derived from <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> to a stirred solution of the title compound from part C above (3.47 g) in dry tetrahydrofuran (37 mL). Stir the solution for 30 minutes after the addition. Quench the reaction with ice and NH4 Cl. Extract the solution with CH2 Cl2 (2*), dry, filter and concentrate to obtain the title compound. Chromatograph the product on silica gel eluding with 5?7.5% CH3 OH/NH3 in CH2 Cl2 to obtain the title compound as a glass (2.56 g): MS (El) m/e 344 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; | C. 1-METHYL-4-(8-CHLORO-11-HYDROXY-5,11-DIHYDRO[1]BENZOTHIEPINO[4,3-b]PYRIDINYL)PIPERIDINE STR164 With cooling in an ice-water bath, add a suspension of the title ketone from Part B above (13.4 g, 51.2 mmol) in dry tetrahydrofuran (52 mL) to a stirred solution (55 mL of approximately 1M) in THF of the Grignard reagent derived from <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong>. Stir the resultant mixture for 1 h at room temperature. Quench the reaction by cooling the mixture to 10 C. in an ice-water bath and adding saturated aqueous ammonium chloride solution (50 mL). Add methylene chloride (100 mL), and stir the mixture for a few minutes. Filter the mixture through Celite, and wash the filter cake with methylene chloride. Combine the original filtrate and washes, separate the methylene chloride phase, and extract the aqueous phase (2*) with additional methylene chloride. Combine the organic extracts, wash with brine (2*75 mL), and dry over anhydrous sodium sulfate. Filter, strip the filtrate under reduced pressure, and chromatograph the residue on silica gel, eluding with methylene chloride-methanol-ammonium hydroxide (90:9:0.5), to obtain the title compound as an off-white to pale pink solid with m.p. 158.5-159.5 C. | |
In tetrahydrofuran; dichloromethane; | D. 1-Methyl-4-(8-chloro-11-hydroxy-5,11-dihydro[1]benzothiepino[4,3-b]pyridinyl)piperidine STR82 With cooling in an ice-water bath, add a suspension of the title ketone from Part C above (13.4 g, 51.2 mmol) in dry tetrahydrofuran (=THF; 52 mL) to a stirred solution (55 mL of approximately 1M) in THF of the Grignard reagent derived from <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong>. Stir the resultant mixture for 1 h at room temperature. Quench the reaction by cooling the mixture to 10 C. in an ice-water bath and adding saturated aqueous ammonium chloride solution (50 mL). Add methylene chloride (100 mL), and stir the mixture for a few minutes. Filter the mixture through Celite, and wash the filter cake with methylene chloride. Combine the original filtrate and washes, separate the methylene chloride phase, and extract the aqueous phase (2x) with additional methylene chloride. Combine the extracts, wash with brine (2*75 mL), and dry over anhydrous sodium sulfate. Filter, strip the filtrate under reduced pressure, and chromatographed the residue on silica gel, eluding with methylene chloride-methanol-ammonium hydroxide (90:9:0.5), to obtain the title compound as an off-white to pale pink solid with mp 158.5-159.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.53 g (17%) | With magnesium; In tetrahydrofuran; | 1,2-dibromoethane (few drops) was added to a stirring mixture of magnesium turnings (0.105 mol) in tetrahydrofuran (5 ml) under nitrogen. When the reaction was started, pure <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (few drops) was added, the remaining <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (0.115 mol) in tetrahydrofuran (50 ml) was added dropwise to maintain a temperature between 40 and 50 C. The mixture was diluted with tetrahydrofuran (50 ml) and refluxed for 2 hours. A suspension of intermediate (21) (0.049 mol) in tetrahydrofuran (200 ml) was added portionwise at 60 C. and the mixture was refluxed for 2 hours. The mixture was cooled, decomposed with a ammonium chloride solution and extracted with dichloromethane/methanol. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent 1: CH2 Cl2 /CH3 OH/NH4 OH 90/10/1 and eluent 2: CH2 Cl2 /CH3 OH/NH4 OH 50/50/1). The pure fractions were collected and evaporated, yielding 2.53 g (17%) of 10-(1-methyl-4-piperidinyl)-10H-thieno[3,2-d]-1,2,4-triazolo[1,5-a]azepin-10-ol (interm. 24). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; acetone; | a) A mixture of magnesium turnings (0.34 mol) and bromoethane (0.1 g) in tetrahydrofuran (180 ml) was stirred under N2. <strong>[5570-77-4]4-Chloro-1-methylpiperidine</strong> (0.34 mol) was added dropwise, the mixture was brought till reflux and it was stirred and refluxed for 2 hours. The mixture was cooled till 0 C. 3-Furancarboxaldehyde (0.26 mol) dissolved in tetrahydrofuran was added dropwise at a temperature<20 C. The mixture was brought to room temperature and stirred at room temperature for 1 hour. The mixture was decomposed with an ice/NH4 Cl solution and extracted with 4-methyl-2-pentanone. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2 Cl2 /(CH3 OH/NH3) 95/5). The pure fractions were collected and evaporated, yielding 38.7 g (76%) of product. A sample (1.2 g) was converted into the (Z)-2-butenedioic acid salt (1:1) in 2-propanone, yielding 1.66 g of alpha-3-furanyl-1-methyl-4-piperidinemethanol (Z)-2-butenedioate(1:1); mp. 150.3 C. (interm. 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With magnesium; In tetrahydrofuran; chloroform; | D. 9-Fluoro-11-(1-Methyl-4-Piperidinyl)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Ol STR88 Dissolve the title compound of Preparative Example 2C above (10.0 g, 44 mmol) in THF (100 mL) and add slowly to a cooled (-40 C.) solution of the Grignard reagent prepared from <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (57.9 mL, 88 mmol) and magnesium in THF (70 mL). Stir the mixture for about 1 hour while warming up to 0 C. Quench the reaction with NH4 Cl solution and extract with EtOAc (2*). Wash the organic phase with brine and dry over Na2 SO4, filter and remove the solvent. Purify the residue with flash chromatography and elute with MeOH (5%) in CHCl3 to give the title compound as white granular crystals. (10.1 g, Yield 70%, m.p. 126-127 C. after recrystallization from diisopropyl ether.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.4 g (20% overall) | With p-toluenesulfonic acid monohydrate; In tetrahydrofuran; ethyl vinyl ether; | A solution of 2-[(2-fluorophenyl)hydroxymethyl]-3-thiophenecarboxaldehyde in ethyl vinyl ether (70 ml) and p-toluenesulfonic acid hydrate (5 mg) was stirred at ambient temperature for 1 to 2 hrs. The reaction mixture was stirred over anhydrous potassium carbonate, filtered, and concentrated to 2-[(2-fluorophenyl)(1-(ethoxy)ethoxy)methyl]-3-thiophenecarboxaldehyde. To a stirred solution of the 2-[(2-fluorophenyl)(1-(ethoxy)ethoxy)methyl]-3-thiophenecarboxaldehyde and tetrahydrofuran (400 ml), cooled to -78 C. under nitrogen, was added, via syringe, N-methyl-4-piperidinylmagnesium chloride over 1.5 hrs. (the Grignard reagent was prepared from <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (29.4 g) according to the procedure of J. T. Strupczewski, et al., et al., J. Med. Chem., 28, 761 (1985), followed by dilution with tetrahydrofuran (45 ml)). The solution was allowed to warm slowly to -20 C. over 2.5 hrs, and dilute aqueous ammonium chloride solution and ether were added. The layers were separated and the organic layer washed with water. The combined aqueous layers were back-extracted with ether, and the combined organic layers washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-45% methanol/dichloromethane) to afford 6.4 g (20% overall) of alpha-[2-[2-fluorophenyl-(1-(ethoxy)ethoxy)methyl]-3-thienyl]-1-methyl-4-piperidinemethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With ammonium chloride; In tetrahydrofuran; water; | EXAMPLE 27 (RS)-3-[1-(Benzocyclobuten-1-ylmethyl)-4-piperidyl]-1,2-benzisoxazole hydrochloride STR25 STAGE A: 2-Fluorobenzoyl-1-methylpiperidine The magnesium compounds is prepared from 0.067 mole of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> and 0.055 gram-atom of magnesium in tetrahydrofuran. The reaction is initiated with a few drops of bromoethane. 0.07 mole of 2-fluorobenzonitrile is then introduced into the magnesium compounds. The mixture is brought to reflux for 2 hours and then left overnight at room temperature. It is hydrolyzed with a solution of 15.3 g of ammonium chloride, 45 g of ice and 50 ml of water. The mixture is brought to reflux for 3 hours. It is allowed to cool. It is extracted several times with ethyl ether. The oil obtained is dried. Yield: 50%. Proton nuclear magnetic resonance spectrum (solvent CDCl3): 1.7-2.15 ppm, m, 6H; 2.25 ppm, s, 3H; 2.85 ppm, m, 2H; 3.1 ppm, m, 1H; 7.0-7.3 ppm, m, 4H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.5 g (42%) | With ammonium chloride; magnesium; In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | EXAMPLE 1 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride To a suspension of 7.6 g of magnesium turnings in 25 ml of tetrahydrofuran was added a few drops of ethyl bromide, with stirring under nitrogen. After the reaction began approximately 50.0 g of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> in 125 ml of tetrahydrofuran was added dropwise at a rate such that moderate reflux was maintained. The reaction was heated under reflux for an additional hour. A solution of 37.2 g of o-fluorobenzonitrile in 30 ml of tetrahydrofuran was added dropwise. After completion of the addition the reaction mixture was heated under reflux for two hrs and stirred overnight at room temperature. The reaction mixture was poured into a solution of 85 g of ammonium chloride in 1200 ml of ice water and heated on a steam bath for 3 hrs. The mixture was cooled, extracted with benzene (3*, 250 ml) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave an oil. A 1.0 g-portion of the oil was dissolved in ether and a solution of ethereal hydrogen chloride was added. The precipitate was collected, dried and twice recrystallized from ethanol-ether to give 0.5 g (42%) of product, mp. 167-169 C. ANALYSIS: Calculated for C13 H17 ClFNO: 60.58%C, 6.65%H, 5.43%N, 7.37%F. Found: 60.30%C, 6.78%H, 5.43%N, 7.59%F. |
0.5 g (42%) | With ammonium chloride; magnesium; In tetrahydrofuran; | EXAMPLE 1 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride To a suspension of 7.6 g of magnesium turnings in 25 ml of tetrahydrofuran was added a few drops of ethyl bromide, with stirring under nitrogen. After the reaction began approximately 50.0 g of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> in 125 ml of tetrahydrofuran was added dropwise at a rate such that moderate reflux was maintained. The reaction mixture was heated under reflux for an additional hour. A solution of 37.2 g of 2-fluorobenzonitrile in 30 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was heated under reflux for two hrs and stirred overnight at room temperature. The reaction mixture was poured into a solution of 85 g of ammonium chloride in 1200 ml of ice waer and heated on a steam bath for 3 hrs. The mixture was cooled, extracted with benzene (3*250 ml) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave an oil. A 1.0 g-portion of the oil was dissolved in ether and a solution of ethereal hydrogen chloride was added. The precipitate was collected, dried and twice recrystallized from ethanol-ether to give 0.5 g (42%) of product as crystals, mp 167-169. Analysis: Calculated for C13 H17 ClFNO: 60.58%C; 6.65%H; 5.43%N; 7.37%F; Found: 60.30%C; 6.78%H; 5.43%N; 7.59%F. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; diethyl ether; Petroleum ether; | EXAMPLE 6 alpha-(1-Methyl-4-piperidinyl)-1-[(2-fluorophenyl)phenylmethyl]-1H-pyrrole-2-methanol To magnesium turnings (0.53 g) in 10 ml of 10% Et2 O/THF (tetrahydrofuran) solution, was added a few drops of 1,2-dibromoethane followed by a few drops of a 4-chloro-1-methyl piperidine solution (2.79 g in 15 ml of 10% Et2 O/THF). Reaction was initiated by heat and the rest of the <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> solution was added over 20 minutes. The mixture was stirred at reflux for one hour during which time the solution clouded up. The heat was removed and a solution of 1-[(2-fluorophenyl)phenylmethyl]pyrrole-2-carboxaldehyde (2.92 g) in 30 ml of 10% Et2 O/THF was added dropwise. The mixture cleared up and was refluxed for 1 hour. At this time, TLC showed completion of the reaction. The mixture was concentrated to about 1/2 volume and added to 150 ml of iced NH4 Cl solution. The mixture was stirred for 20 minutes and extracted with ether. The ether layer was washed (2*H2 O; 1*sat. NH4 Cl) and dried (sat. NaCl, anhydrous MgSO4). The mixture was filtered and concentrated to a yellow fibrous solid which yielded 3.76 g of a slightly yellowish solid upon tituration with ether/petroleum ether (1:3). Recrystallization from hexane/ethanol yielded slightly yellow crystals, m.p. 121.5-124 C. ANALYSIS: Calculated for C24 H27 FN2 O: 76.16%C, 7.19%H, 7.40%N. Found: 75.91%C, 7.02%H, 7.48%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.4 g (40%) | In tetrahydrofuran; | (a) 4-(2,5-difluorobenzoyl)-1-methylpiperidine To a stirred suspension of Mg (9.62 g, 0.40 moles) in tetrahydrofuran (THF) (45 ml) was added a few ml of bromoethane to initiate the reaction followed by dropwise addition of freshly distilled 4-chloro-N-methylpiperidine (42.3 g, 6.32 moles) in THF (140 ml). The reaction was initiated with a high intensity heat gun and controlled by the rate of addition of the piperidine. After the addition was complete, the reaction was refluxed for 1 hour. Next <strong>[64248-64-2]2,5-difluorobenzonitrile</strong> (48.2 g, 0.318 moles) in THF (20 ml) was added and the reaction was refluxed for an additional 3 hours. The reaction was allowed to stand for 65 hours and was then poured into a solution of NH4 Cl/H2 O (120 g/400 ml). The mixture was heated on a steam bath for 2 hours, cooled and extracted with ether (500 ml.). Concentration produced an oil (50.6 g) which the product was distilled from (112 C. a 0.5 mm) to yield 30.4 g (40%) of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; | (1) A mixture of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (110.1 g), 2-fluorothiophenol (117.3 g), and potassium carbonate (170.8 g) in N,N-dimethylformamide (1.0 l) was stirred at 90 C. for 2 hours and filtered. The filtrate was concentrated in vacuo to give an oily residue, which was diluted with brine and extracted three times with diethyl ether. The extracts were dried over magnesium sulfate, concentrated in vacuo, and distilled to give 4-[(2-fluorophenyl)thio]-1-methylpiperidine (111.1 g) as a yellow oil. bp: 119-123 C./0.4 mmHg. IR (film): 3060, 2930, 2840, 2780, 2720, 2670 cm-1. NMR (CDCl3, delta): 1.3-2.2 (6H, m), 2.25 (3H, s), 2.65-3.35 (3H, m), 6.85-7.65 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran; chloroform; | D. 9-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-OL A solution of the product of previous Step C above (10.0 g, 44 mmol) in THF (100 mL) is added slowly to a cooled (-40 C.) solution of the Grignard reagent prepared from N-methyl-4-chloro-piperidine (57.9 mL, 88 mmol) in THF (70 mL). This is allowed to stir for about 1 hour while warming up to 0 C. The reaction is then quenched with NH4 Cl solution and then extracted twice with ethyl acetate. The organic phase is washed with brine, dried over Na2 SO4, filtered and solvent removed. The residue is flash chromatographed and eluted with 5% methanol in CHCl3 to give the desired compound (10.1 g) in 70% yield as white granular crystals, m.p. 126-127 C. after recrystallization from diisopropyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; water; benzene; | EXAMPLE XV 4-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine, equatorial isomer A Grignard solution prepared from 13.4 grams (0.1 mole) of <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong>, 2.43 grams (0.1 gram atom) of magnesium and 100 milliliters of tetrahydrofuran is added dropwise with stirring to a cooled solution of 17.0 grams (0.075 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 100 milliliters of tetrahydrofuran. After completion of the addition, stirring is continued for several hours at ambient temperature. The solvent is then vaporized under reduced pressure to obtain a residue which is dissolved in a biphasic mixture of benzene and water. The benzene solution is washed, dried filtered and the solvent vaporized as previously described to obtain the desired 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine, equational isomer as residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethereal hydrochloric acid; ammonium chloride; magnesium; In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | EXAMPLE 59 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride To a suspension of 7.6 g of magnesium turnings in 25 ml of tetrahydrofuran was added a few drops of ethyl bromide, with stirring under nitrogen. After the reaction began, approximately 50.0 g of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> in 125 ml of tetrahydrofuran was added dropwise at a rate such as to maintain moderate reflux. The reaction mixture was heated under reflux an additional hr, and 37.2 g of 2-fluorobenzonitrile in 50 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was refluxed for two hrs, and stirred overnight at room temperature. The reaction mixture was poured into a solution of 85 g of ammonium chloride in 1200 ml of ice water and heated on a steam bath for 3 hrs. The mixture was cooled, extracted with benzene (3*250 ml), dried over anhydrous sodium sulfate, and the excess solvent was removed under reduced pressure to give 62.72 g (91%) of 4-(2-fluorobenzoyl)-1-methyl piperidine as an oil. A small amount of 4-(2-fluorobenzoyl)-1-methyl piperidine (1.0 g) was removed, dissolved in ether and a solution of ethereal hydrochloric acid was added. The precipitate was collected, dried and recrystallized from ethanol-ether (2*) to give 0.5 g of 4-(2-fluorobenzoyl)-1-methylpiperidine hydrochloride, mp, 167-169. ANALYSIS: Calculated for C13 H17 ClFNO: 60.58%C; 6.65%H; 5.43%N; 7.37%F; Found: 60.30%C; 6.78%H; 5.43%N; 7.59%F. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; water; | EXAMPLE I To 5 parts of magnesium are added 2.18 parts of 1,2-dibromoethane and a small amount of iodine to initiate the reaction. Then there is added dropwise a solution of 28 parts of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> in 180 parts of tetrahydrofuran while the mixture is heated to 70 C. After cooling, there is added dropwise a solution of 14 parts of 3-methylbenzonitrile in 90 parts of tetrahydrofuran. Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled and poured onto a solution of 75 parts of ammonium chloride in water. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 35 parts of (3-methylphenyl) (1-methyl-4-piperidinyl)methanone as an oily residue. Following the same procedure and using equivalent amounts of the appropriately substituted benzonitriles and <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> there are also prepared: | |
With ammonium chloride; magnesium; In tetrahydrofuran; water; | Example V To 5 parts of magnesium are added 2.18 parts of 1,2-dibromoethane and a small amount of iodine to initiate the reaction. Then there is added dropwise a solution of 28 parts of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> in 180 parts of tetrahydrofuran while the mixture is heated to 70 C. After cooling, there is added dropwise a solution of 14 parts of 3-methylbenzonitrile in 90 parts of tetrahydrofuran. Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled and poured onto a solution of 75 parts of ammonium chloride in water. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 35 parts of (3-methylphenyl) (1-methyl-4-piperidinyl)methanone as an oily residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; methanol; water; | EXAMPLE VII To a stirred and cooled (10-15 C.) Grignard-complex, previously prepared starting from 13.5 parts of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> and 2.4 parts of magnesium in 68 parts of tetrahydrofuran, is added dropwise a solution of 10 parts of 4-bromobenzonitrile in 22 parts of tetrahydrofuran. Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is decomposed by pouring onto a mixture of 50 parts of ammonium chloride in 250 parts of water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 10 parts of (4-bromophenyl)-(1-methyl-4-piperidinyl)methanone as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; iodine; magnesium; In tetrahydrofuran; water; acetonitrile; | EXAMPLE 1 1-Methyl-4-(2-chloro-5-methylbenzoyl)piperidine fumarate To a suspension of 10.8 g of magnesium in 30 ml of anhydrous tetrahydrofuran was added a crystal of iodine followed by a few mls of 4-chloro-N-methylpiperidine. The reaction was initiated with a hot air gun and 54.3 g of 4-chloro-N-methylpiperidine in 100 ml of anhydrous tetrahydrofuran was added dropwise at a rate maintaining reflux. Upon completion of the addition, the reaction mixture was refluxed for 3 hrs and then 50 g of <strong>[4387-32-0]2-chloro-5-methylbenzonitrile</strong> in 225 ml of tetrahydrofuran was added dropwise. Upon completion of the addition, the reaction mixture was heated under reflux for an additional 2 hrs and stirred overnight at room temperature. The reaction mixture was poured into a solution of 100 g of ammonium chloride in 1 l of water, heated on a steam bath for 2 hrs, cooled, extracted with ether and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was distilled (0.2 mm, 115-125) to give 54 g (56%) of product. The fumarate salt was made by dissolving 1 g of product in approximately 5 ml of acetonitrile and adding 0.5 g of fumaric acid. The suspension was stirred for 1 hr, filtered and the filter cake was recrystallized twice from ethanol-ether to give the salt, mp, 148-150. ANALYSIS: Calculated for C14 H18 ClNOC4 H4 O4: 58.77%C; 6.03%H; 3.81%N; Found: 58.57%C; 5.89%H; 3.82%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; oxalic acid; magnesium; In tetrahydrofuran; methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetone; | EXAMPLE 14 1-Methyl-4-(2,6-difluorobenzoyl)piperidine A 6.60 g sample of magnesium was added to a 3-neck, round-bottom flask equipped with a condenser, mechanical stirrer and addition funnel. The apparatus was flame dried and cooled under a stream of nitrogen. About 1 ml of ethyl bromide was dissolved in 30 ml of tetrahydrofuran and added to the magnesium. The mixture was heated to reflux and 30.0 g of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong>, dissolved in 75 ml of tetrahydrofuran, was added. The addition was made at such a rate to achieve a moderate reflux. After the addition was complete, the reaction mixture was heated under reflux for 1 hr. The reaction mixture was cooled to 0 and 31.4 g of 2,6-difluorobenzonitrile, dissolved in 100 ml of tetrahydrofuran, was added dropwise through the addition funnel. After the addition was complete, the mixture was warmed to 40 for 3 hrs. The mixture was poured into 1000 ml of ice-water, containing 65 g of ammonium chloride. The mixture was heated on a steam bath for 2 hrs and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by high pressure liquid chromatography (7% methanol in acetone) to yield the desired ketone (9.00 g, 17%) as an oil. The oil was dissolved in ether and a dilute solution of oxalic acid/ether was added. The salt was collected, washed with ether and recrystallized two times from ethyl acetate to yield product as the oxalate, mp, 160-162. ANALYSIS: Calculated for C13 H15 F2 NOHO2 CCO2 H: 54.68%C; 4.86%H; 4.25%N; Found: 55.06%C; 5.12%H; 4.60%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | (a) A Grignard reagent is prepared from 14.0 g <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> and 2.6 g magnesium in 200 ml boiling tetrahydrofuran. After cooling, a solution of 10.0 g 6-chloro-2,2-dimethyl-indanone in 50 ml tetrahydrofuran is added dropwise at 5-10, and the reaction mixture is refluxed for 6 hours. After cooling, a 10% aqueous solution of ammonium chloride is added and the mixture is extracted with toluene. The toluene phase is dried and evaporated, to give 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol (m.p. 181-182). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | A solution of the Grignard reagent is prepared by a reaction of 12.0 g <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> with 2.3 g of magnesium in 70 ml of tetrahydrofuran and is treated for 10 minutes with a solution of 17.4 g 2-(2-fluorophenylthio)-5-trifluoromethylbenzaldehyde in 40 ml of tetrahydrofuran added dropwise. The mixture is refluxed for 4 hours and after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is dried with potassium carbonate and evaporated. There are obtained 23.2 g (100%) crude oily alpha-(1-methyl-4-piperidyl)-2-(2-fluorophenylthio)-5-trifluoromethylbenzyl alcohol which is used in this state for the final reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | There are obtained 13.3 g (52%) of 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde boiling at 163-165 C./40 Pa. The product is crystallized from cyclohexane and melts in a pure state at 67-68 C. A solution of a Grignard reagent is prepared by a reaction of 6.7 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> with 1.25 g of magnesium in 40 ml of tetrahydrofuran and is treated while stirring for 10 minutes with a solution of 9.35 g 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde in 20 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 3 hours and, after cooling, it is decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 12.6 g (100%) of crude oily alpha-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-methoxybenzyl alcohol which is used in this state for the next reaction. For characterization the crystalline hydrogen oxalate may be prepared by neutralization of a sample with oxalic acid; it is purified by crystallization from acetone and melts at 160-163 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | A solution of a Grignard reagent is prepared by a reaction of 12.0 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> with 2.4 g of magnesium in 70 ml of tetrahydrofuran and is treated dropwise for 10 minutes with a solution of 21.2 g of 2-(2,5-difluorophenylthio)-5(trifluoromethylthio)benzaldehyde in 40 ml of tetrahydrofuran. The mixture is refluxed for 5 hours and, after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 26.9 g of crude oily alpha-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-(trifluoromethylthio)benzyl alcohol which is used in this state for further reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | A solution of the Grignard reagent is obtained by reaction of 2.7 g of magnesium with 13.7 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (reference above) in 80 ml of tetrahydrofuran and is treated for 10 minutes with a solution of 20 g of 2-(2-fluorophenylthio)-5-chlorobenzaldehyde in 40 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 4.5 hours and after standing overnight it is decomposed by the addition of 20% of ammonium chloride solution and extracted with benzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 parts (95%) | With magnesium; In tetrahydrofuran; acetonitrile; | EXAMPLE IX To a stirred and cooled Grignard-complex previously prepared starting from a mixture of 134 parts of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong>, 25 parts of magnesium and 652.5 parts of tetrahydrofuran was added dropwise a solution of 170 parts of (4-fluorophenyl)(3-pyridinyl)methanone in 405 parts of tetrahydrofuran at a temperature between 10-20 C. Upon completion, stirring was continued for 1 hour at room temperature and for 30 minutes at minutes at reflux. After cooling, the whole was decomposed by pouring onto a mixture of crushed ice and ammonium chloride. 270 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was boiled in acetonitrile with activated charcoal. The latter was filtered off over Hyflo and the filtrate was evaporated, yielding 240 parts (95%) of alpha-(4-fluorophenyl)-alpha-(1-methyl-4-piperidinyl)-3-pyridinemethanol as a residue (intermediate 18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; In tetrahydrofuran; dichloromethane; | EXAMPLE 4 4,9-Dibromo-6-(1-methylpiperidin-4-yl)-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine 1,2-Dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (6 gm) in tetrahydrofuran (70 ml) to initiate a Grignard reaction. A solution of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (35 ml) in tetrahydrofuran (100 ml) was added rapidly. The reaction mixture was refluxed for 2 hours, during which a white precipitate formed. The mixture was cooled to room temperature and transferred to a flask containing 4,9-dibromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (20 gm) in tetrahydrofuran (200 ml) in one portion at ice-temperature. After 1 hour of stirring, the mixture was poured into ice-water/concentrated hydrochloric acid (600 ml:35 ml), and stirred for 15 minutes. The acid solution was slowly added to a stirred mixture prepared from dichloromethane (1 L) and an ammonium hydroxide solution (40 ml). The organic solution was separated, washed with water (500 ml) and brine (2*500 ml) and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to an oil (26 gm). The crude product was purified on a silica gel column (400 gm, eluted with 4% methanol/dichloromethane). The resultant product (14.8 gm) was recrystallized from ethanol (450 ml) to yield 9.5 gm of crystals, m.p. 237-238 C. ANALYSIS: Calculated for C21 H23 Br2 N3: 52.85%C, 4.86%H, 8.80%N, Found: 52.52%C, 4.72%H, 8.86%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66 parts (44%) | With hydrogenchloride; ammonium hydroxide; ammonium chloride; magnesium; In tetrahydrofuran; di-isopropyl ether; water; toluene; acetonitrile; | EXAMPLE XIII To a stirred and refluxing Grignard complex previously prepared starting from 80.2 parts of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong>, 14.6 parts of magnesium and 270 parts of tetrahydrofuran, was added dropwise a solution of 101 parts of (2-fluorophenyl)phenylmethanone in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 18 hours at reflux temperature. The reaction mixture was cooled in an ice-bath and decomposed with a solution of 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product was filtered off and washed with tetrahydrofuran. The filtrate was evaporated, the residue was taken up in methylbenzene and the latter was evaporated again in a boiling water-bath. The residue was dissolved in 700 parts of 2,2'-oxybispropane. The turbid solution was filtered and gaseous hydrogen chloride was bubbled through the filtrate. The solid product was filtered off and suspended in 1000 parts of water. The suspension was treated with ammonium hydroxide and extracted twice with 280 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The oily residue was crystallized from 240 parts of acetonitrile. After cooling to 0 C., the product was filtered off and dried, yielding 66 parts (44%) of alpha-(2-fluorophenyl)-1-methyl-alpha-phenyl-4-piperidinemethanol (intermediate 33). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In tetrahydrofuran; | EXAMPLE 5 10,11-Dihydro-5-methyl-10-[(1-methyl)piperidin-4-yl]-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine To a warm Grignard reagent prepared from 7.2 g of 4-chloro-1-methyl piperidine and 1.4 g of magnesium metal in 50 ml of tetrahydrofuran was added a solution of 5.3 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 15 minutes, added to an iced ammonium chloride solution and extracted with ethyl acetate (3*). The combined organics were washed with water (2*) followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% methanol/dichloromethane). Recrystallization from ethyl acetate:methanol (20:1) afforded 1.65 g of 10,11-dihydro-5-methyl-10-[(1-methyl)piperidin-4-yl]-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp: 235-238 C. (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | EXAMPLE 9 In a reaction vessel, 1.95 g (0.08 mole) of magnesium chips under dry nitrogen is covered with 12 ml of abs. tetrahydrofuran, and corroded with a trace of iodine and 0.1 ml of ethylbromide. While stirring is maintained, 10.7 g (0.08 mole) of <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong>, dissolved in 30 ml of abs. tetrahydrofuran, is added dropwise at 60 in such a manner that the reaction mixture remains boiling. Refluxing is performed for a further 30 minutes until all the magnesium is dissolved. To this Grignard solution cooled to 5 is then added dropwise at 5-10 in the course of 30 minutes, with stirring, 4.46 g (0.02 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one dissolved in 20 ml of abs. tetrahydrofuran. The reaction mixture is subsequently heated to ca. 20 and then stirred into 350 ml of a 3% ammonium chloride solution. The reaction product precipitated in crystalline form is filtered off with suction, washed with water and dried in a water-jet vacuum at ca. 50 to obtain 4-(11-hydroxy-1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-yl)-1-methyl-piperidine; M.P. 239-242. The hydrochloride prepared therefrom in chloroform solution with ethereal hydrochloric acid is recrystallized from methanol/ether; M.P. 285-286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; | EXAMPLE 10 To 1.2 l g. (0.05 mol) of magnesium turnings covered by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> (from 8.5 g., 0.025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is initiated, the remainder of the chloro compound in about 20 ml. of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-Bromothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours, and then stirred at room temperature 3 days. The reaction mixture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9(1-methyl-4-piperidyl)thioxanthene-9-ol, m.p. 225.5-226 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | To the Grignard reagent obtained from <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> (0.70 mol) and magnesium (0.54 mol) in tetrahydrofuran is added 0.38 mol of the above oxepinone in 750 ml. of tetrahydrofuran at a rate sufficient to maintain a gentle reflux. The mixture is refluxed for about 90 minutes and stirred at room temperature overnight. the reaction mixture is poured over ice, treated with ammonium chloride and extracted several times with ether. The combined ether fractions are dried and concentrated to give 9-chloro-11-(1-methyl-4-piperidyl)-6,11-dihydrodibenzo[b,e]oxepine-11-ol, hydrochloride salt, m.p. 150-160 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; | EXAMPLE 17 4-Chloro-1-ethyl-1,5,6,11-tetrahydro-11-(1-methyl-4-piperidinyl)-benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol, hydrochloride (1:2) A Grignard reagent is prepared from 7.2 g. of magnesium turnings (0.3 mol.), 230 ml. of dry tetrahydrofuran and 40 g. of <strong>[5570-77-4]4-chloro-1-methyl-piperidine</strong> (0.3 mol.). To this Grignard solution 31 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.1 mol.), from example 1(e), dissolved in 230 ml. of dry tetrahydrofuran is added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; In tetrahydrofuran; ice-water; | EXAMPLE 8 To a stirred suspension of 2.43 g. (0.1 g.-atom) of magnesium turnings in 5 ml. of tetrahydrofuran under nitrogen is added several drops of ethyl bromide. After the reaction is started, 13.4 g. (0.1 mole) of 4-chloro-1-methylpiperidine in 50 ml. of tetrahydrofuran is added at a rate sufficient to cause reflux. The mixture is stirred and refluxed for one hour, then it is cooled to 0 C. and 20.6 g. (0.075 mole) of <strong>[56341-31-2]2-bromoxanthone</strong> is added in portions. The stirred mixture is refluxed for four hours and then it is poured into a solution of 26.5 g. (0.5 mole) of ammonium chloride in 500 ml. of ice-water. The crystalline alcohol, 2-bromo-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 201-202, is filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; magnesium; In tetrahydrofuran; | The Grignard reagent prepared from 0.62 g. of magnesium turnings and 3.5 g. of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> in tetrahydrofuran is treated with a solution of 3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydrofuran. The mixture is refluxed for four hours, cooled, treated with saturated ammonium chloride solution and extracted with ether. The ether extract is washed with water, dried and concentrated to give 3-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 120-130 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; | Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is reacted with the Grignard reagent derived from 1.06 g. of magnesium turnings and 5.85 g. of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> in tetrahydrofuran as described above to give the corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 189-190 C. The latter is dehydrated by the same procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperidine as the maleate salt, m.p. 175-179 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; | The Grignard reagent prepared from 2.7 g. (0.02 mol) of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> and 0.5 g. (0.02 mol) of magnesium turnings in tetrahydrofuran is treated with 2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate to maintain slow reflux. The mixture is refluxed for six hours, hydrolyzed with saturated ammonium chloride solution and extracted with ether to yield 2,6-difluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 207-209 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; magnesium; In tetrahydrofuran; ice-salt; acetic acid; acetone; | To a Grignard-solution prepared from 130 grams of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> and 24 grams of magnesium turnings in 500 milliliters of dry tetrahydrofuran was added 174 grams of 2-methylthio-6-fluoro-thioxanthene-9-one in portions while stirring and cooling in an ice-salt mixture. The reaction temperature was kept below 10 degrees Centigrade. The cooling bath was then removed and the reaction mixture was stirred at 35-40 degrees Centigrade for 1.5 hours. The reaction mixture was then poured into a mixture of ice, water and ammonium chloride. The crystalline precipitate which was obtained upon cooling was sucked off, washed with water and dissolved in 10% aqueous acetic acid. The solution was treated with charcoal, extracted three times with 100 milliliters of ether and then made alkaline with 10 N sodium hydroxide solution. After cooling the precipitated base was sucked off, washed with water, suspended in 100 milliliters of acetone, filtered, again suspended in 100 milliliters of acetone, and then filtered and dried to yield 142 grams of 2-methylthio-6-fluoro-9-(1-methyl-4-piperidyl)-thioxanthen-9-ol which melted at 180-189 degrees Centigrade. The analytically pure compound melts at 192-195 degrees Centigrade after recrystallization from diethylether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; In tetrahydrofuran; | (e) 4.8 g of iodine-activated magnesium are covered with a layer of 60 cc of anhydrous tetrahydrofuran and cauterized with a few drops of ethylene bromide. A solution of 25.0 g of <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> in 160 cc of anhydrous tetrahydrofuran is then added dropwise at such a rate that the solvent boils continually, and stirring is subsequently effected at the boil for 2 hours. The reaction mixture is cooled to 10, and a solution of 20.0 g of 9,10-dihydro-10-methyl-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-one in 100 cc of anhydrous tetrahydrofuran is added dropwise at this temperature. After stirring at room temperature for 11/2 hours and at the boil for 30 minutes, the reaction mixture is cooled, poured on 300 cc of a 20% ammonium chloride solution, and the organic phase is separated. The aqueous solution is extracted with methylene chloride, the combined organic solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The 9,10-dihydro-10-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-ol, obtained as residue, is recrystallized twice from isopropanol. M.P. 177-178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; magnesium; In tetrahydrofuran; | 1.1. 10,11-Dihydro-3-fluoro-5-(1-methyl-4-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-ol Tetrahydrofuran (THF) is introduced into a 4 l reactor containing finely ground magnesium (40 g; 1.65 mol) until the magnesium is just covered, and a crystal of iodine is introduced, followed by pure <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (2-3 ml). When a brisk reaction occurs, stirring is begun, and <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong>, dissolved in THF (210 g; 1.57 mol; 200 ml of THF) is added at a rate such that refluxing of the THF is maintained. When the addition is complete, 500 ml of THF are added and refluxing is continued for 2 hours. The reaction mixture is then cooled to 5 C. A solution of 10,11-dihydro-3-fluoro-5H-dibenzo[a,d]cyclohepten-5-one (175 g; 0.775 mol; 750 ml of THF) (British Patent Application 2,132,618) is then added dropwise, after which the mixture is allowed to return slowly to room temperatue and stirring is continued at room temperature for 2 hours. The reactor is then placed in a cooling mixture (-10 C.) and the magnesium derivative is hydrolyzed by the slow addition of saturated aqueous ammonium chloride solution (190 ml); the mixture is stirred for 1 hour at room temperature, filtered and washed with THF, and the filtrate is evaporated to dryness. The oil obtained is taken up with methylene chloride, the mixture is washed with water, dried and evaporated, the oil is redissolved in ether (500 ml) and ethereal hydrogen chloride (500 ml; 4 mol/l) is added dropwise, the mixture is stirred for 1 h at room temperature and the precipitated product is filtered off, washed with ether, then with water and then again with ether. The hydrochloride thereby obtained is added to aqueous sodium hydroxide solution (1,000 ml; 2.5 mol/l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N2;CeCl3; In tetrahydrofuran; | Step C: [3-[(3-Chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone Anhydrous CeCl3 (1.1 g, 4.46 mmol) was placed in a 50 ml 2-necked flask and flamed out under vacuum. The vacuum was replaced with N2, and dry THF (20 ml) was added, The CeCl3/THF solution was stirred at room temperature for 16 hours and then cooled to -40C, and the Mg-Grignard reagent from <strong>[5570-77-4]4-chloro-1-methyl-piperidine</strong> (3 ml of an 0.8M stock solution in THF) was added. The resulting solution was stirred at -40C for 75 minutes, and then 3-[(3-chlorophenyl)thiomethyl]-N-methoxy-N-methyl-2-pyridinecarboxamide (345 mg, 1.07 mmol) was added dropwise. After 40 minutes, the mixture was poured into 5% HCl/EtOAc, stirred for 5 minutes, and then basified to pH ~8. The organic product was extracted with EtOAc (6 x 100 ml), the extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica and eluted with 5-10%MeOH/CH2Cl2 to afford [3-[(3-chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone (251 mg, 64%); HRMS, FAB, calcd. 361.1141; found. 361.1141. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; iodine; magnesium; In tetrahydrofuran; | iv: alpha-(4-fluorophenyl)-alpha-(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol A suspension of magnesium turnings (36.7 g) in tetrahydrofuran (470 ml) was heated to 55 C. under nitrogen gas and an aliquot (20.0 ml) of a solution of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (221.6 g) in tetrahydrofuran (1400 ml), followed by 1 crystal of iodine and then ethylbromide (14.0 ml were added. Almost immediately initiation occurred as the temperature rose to 64 C. accompanied by the loss of the iodine coloration and onset of reflux. The rest of the N-methyl 4-chloropiperidine solution (containing 14.0 ml of ethylbromide) was then added over 75 min, maintaining a gentle reflux. Once addition was complete the mixture was stirred at 64 C. for a further 90 min, after which only a few grains of magnesium remained. The solution was cooled in an ice/water bath to 20 C., and was then pumped via positive nitrogen pressure, into a solution of 4-chloro-2-(4-fluorobenzoyl)thiophene (140.0 g) in tetrahydrofuran (1.4 l) which had been precoled to 0 C. in an ice/salt bath, over a period of 60 min, keeping the internal temperature below 8 C. The solution was added, over about 40 min, to a cold (5 C.) saturated solution of ammonium chloride (4.6 l), maintaining the temperature below 15 C. The mixture was extracted with ethyl acetate and the extract was washed with water, dried (Na2 SO4) and evaporated to dryness to give a brown gum (202 g). The gum was crystallized from dichloromethanemethyl tertbutyl ether to give a solid which was filtered and washed with cold methyl tert.butyl ether. The solid was filtered and dried and the product (79.2 g) was recrystallized from dichloromethane/methyl tert.butyl ether to give alpha-(4-fluorophenyl)-alpha-(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol (61.6 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.90 gm (47%) | With iodine; magnesium; In tetrahydrofuran; methanol; | 1-methyl-4-(2-(4-acetamidophenoxy)acetyl)piperidine A crystal of iodine was added to 0.45 gm (18.7 mMol) magnesium turnings covered with 6 mL tetrahydrofuran. To this mixture were added 5-6 drops of dibromoethane and the mixture was heated with a heat gun to initiate the reaction. Once the iodine color disappeared, 2 mL (15 mMol) <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong> were added and heating continued for an additional 30 seconds. After the exothermic reaction no longer maintained reflux temperature, the reaction mixture was heated at reflux for 30 minutes and was then cooled to 0C. To the cold mixture was added the previously prepared N-methyl-N-methoxy 2-(4-acetamidophenoxy)acetamide and the resulting mixture stirred for 30 minutes at 0C and then an additional hour after warming to room temperature. The reaction was quenched by the addition of water and the resulting mixture extracted well with ethyl acetate. The combined organic extracts were washed saturated aqueous ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluding with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.90 gm (47%) of the desired ketone. MS: m/e = 291(M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium;iodine; In tetrahydrofuran; for 1h;Heating / reflux; | A dried, three-necked flash equipped with argon inlet, a dropping funnel and a thermometer was charged with magnesium turnings (2.52 g, 0.10 mol), which before use had been washed with 0.01 M H2SO4 (aq.) and dried. A small amount of dry THF was added to cover the magnesium. A crystal of iodine was added followed by dibromoethane. When the vigorous reaction had subsided, a solution of distilled 4-chloro-l-methylpiperidine (9.20 g, 0.07 mol) in THF (70 mL) was added dropwise. When the addition was complete, the reaction mixture was heated to refluxing with stirring for 1 h. The reaction mixture was EPO <DP n="49"/>then allowed to cool to room temperature. Full conversion was confirmed by hydrolysis (GC) and generation of Grignard reagent by iodolysis (GC). | |
With magnesium; ethylene dibromide; In tetrahydrofuran; at 20℃; for 2h;Reflux; | Step 2: Chloro(1-methylpiperidin-4-yl)magnesium Magnesium turnings (14.5 g, 600 mmol) were mixed with THF (700 mL) at room temperature and 1,2-dibromoethane (2.59 mL, 30.0 mmol) was added drop wise. After the gas evolution was finished, freshly distilled <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (80 g, 600 mmol) was added drop wise to magnesium (14.58 g, 600 mmol) at a pace to maintain gentle reflux. The mixture was refluxed for 2 h once the addition was completed and it was then cooled down. This Grignard reagent was used as such in the following reaction. | |
With magnesium; ethylene dibromide; In tetrahydrofuran; | Example 10. Production of 4-(6-Bromo-10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)-1-methylpiperidine 6-Bromo-10H-9-oxa-3-thiabenzo[f]azulen-4-one (21.6 g, 100 mmol) was added to a Grignard reagent prepared from <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> (20 mL, 150 mmol), a metal magnesium (3.6 g, 150 mmol), dibromoethane (0.1 mL), and THF (200 mL). The reaction mixture was stirred at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the solution to stop the reaction, and a product was then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, the resulting residue was dissolved in dichloromethane (300 mL), trifluoroacetic acid (77 mL, 1.0 mol) was added thereto, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the resulting residue was then purified by column chromatography (hexane-ethyl acetate = 3:2), to give 16.2 g (81 %) of the captioned compound. MS (EI): m/z 378.0 [M++1]. 1H-NMR (DMSO-d6) delta: 2.09-2.77 (m, 11H), 4.85 (d, J = 15.5 Hz, 1H), 5.42 (d, J = 15.5 Hz, 1H), 6.81-7.45 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; thionyl chloride; iodine; magnesium; In tetrahydrofuran; water; | g) Synthesis of 2,5-dimethyl-3-(1-methylpiperidin-4-yl)-2-phenyl-2,3-dihydrobenzothiophen-3-ol 7 For the synthesis of 2,5-dimethyl-3-(1-methylpiperidin-4-yl)-2-phenyl-2,3-dihydrobenzothiophen-3-ol, 0.42 g of magnesium turnings in 5 ml of dried THF are initially introduced, and the Grignard reaction is initiated by addition of iodine and ethyl bromide. 2.3 g (17.2 mmol, 1.5 equiv.) of <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (obtained from N-methylpiperidinol by reaction with thionyl chloride), dissolved in 5 ml of THF, are added with stirring, and the mixture is refluxed for one hour. After cooling to 10 C., 2.66 g (11.0 mmol) of 6, dissolved in 10 ml of THF, are added dropwise, and the mixture is stirred overnight. After addition of 2 ml of water, the precipitate is filtered off, the liquid phase is evaporated, and 1 N HCl is added, and the mixture is extracted with ethyl acetate. The separated-off aqueous phase is adjusted to pH 12 using NaOH solution, and the precipitated reaction product is filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) To a mixture of 975 mg of magnesium, 100 muL of bromoethane, and 20 mL of tetrahydrofuran, a catalyst amount of iodine was added, and the mixture was stirred for about 10 minutes until the brown color from iodine disappears. Thereto, 20 mL of a tetrahydrofuran solution containing 5.9 g of 4-chloro-l-methylpiperidine was added, and heated for 2.5 hours under reflux. Thus produced white suspension was cooled to 00C, and 10 mL of a tetrahydrofuran solution containing 2 g of the compound [39] was added thereto (See REFERENCE 1). After the overnight stirring under gradually heating back to room temperature, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 100/0 - 90/10), to obtain 2.27 g of tert-butyl((lS)-l-{4- [hydroxy(l-methylpiperidin-4-yl)methyl]phenyl}ethyl)carbamate [7-1] (hereinafter, referred to as the compound [7-1]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
l-(3'-Hydroxybenzenesulfonyl) indole, (0.36 mmol, 0.1 grams) (obtained from preparation 1), was dissolved in dimethyl sulfoxide (2 mL). Potassium carbonate (0.074 grams) was added and the resulting reaction mixture was stirred 40 - 45 0C for a period of one hour. In another round bottom flask, <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> (0.54 mmol, 0.072 grams) was dissolved in dimethyl sulfoxide (1.5 mL). The content of the first flask were added to the second flask at 40 - 45 0C. The resulting reaction mass was further heated to 140 -145 0C and maintained there for a period of 5 hours while monitoring the reaction by thin layer chromatography. Cooled the reaction mass to room temperature, poured it onto water (25 mL) and extracted the product with ethyl acetate (30 mL x 3). Combined organic extracts were dried over sodium sulfate and the volatiles were removed under the reduced pressure to obtain 0.110 grams crude compound. The compound was purified by column chromatography using silica gel (100-200 mesh), eluent being ethyl acetate and 1% triethylamine to obtain 50 mg of pure compound. IR (cm-'): 2933, 1595, 1445, 1372, 1 173;IH-NMR (ppm): 1.73 - 1.79 (2H, m), 1.90 - 2.05 (2H, m), 2.17 (2H, m), 2.31 (3H, s), 2.64 - 2.66 (2H, m), 4.32 (I H, m), 6.66 - 6.67 (IH, d, J = 3.72 Hz), 7.01 - 7.03 (IH, dd, J = 8.24, 2.36 Hz), 7.23 - 7.29 (IH, m), 7.29 - 7.33 (4H, m), 7 52 - 7.54 (2H, m), 7.99 - 8.01 (IH, d, J = 8.28 Hz); Mass (m/z): 371.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of magnesium (0.426 g, 17.51 mmol) in THF (50 mL) was added 1,2-dibromoethane (0.058 mL, 0.674 mmol) and stirred for 10 min and then <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (1.8 g, 13.47 mmol) in THF (4 mL) was added and the mixture was refluxed under nitrogen overnight. Cooled solution of the (1-methylpiperidin-4-yl)magnesium chloride was canulated into a cold (-78 C.) solution of sulfuryl chloride (1.3 mL, 16 mmol) in THF (10 mL). The mixture was stirred at 0 C. for 1.5 h and cooled to -78 C. and bubbled ammonia gas for 10 min and stirred at -78 C. for 10 min and allowed to warm to r.t. maintained under balloon pressure of NH3 for 2 h. Diluted with 100 mL ether, filtered off the solids and the filtrate was concentrated to afford a brown solid. Brown solid in THF was stirred with K2CO3 for 1h and filtered and concentrated to afford 1-methylpiperidine-4-sulfonamide as a beige solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 1.59 (2 H, m), 1.84 (2 H, m), 1.93 (2 H, m), 2.15 (3 H, s), 2.71 (1 H, ddd, J=12.13, 8.32, 3.66 Hz), 2.84 (2 H, m), 6.69 (2 H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | 11-(1-Methylpiperidin-4-yl)-6,11-dihydrodibenzo[b,e]oxepine-2-11-diol 2-Hydroxy-6H-dibenzo[b,e]oxepin-11-one (1.0 g, 4.42 mmol) in THF (30 mL) was treated at 0 C. with a solution of 1-methypiperidine-4-magnesium chloride* (0.79 M, 11.8 mL, 9.3 mmol). The resulting orange solution was stirred at 0 C. for 1 hour when deemed complete by TLC analysis [hexane/EtOAc (1:1)]. [The Grignard solution was prepared from <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (1.0 equivalent, free base only) and fresh Mg turnings (1.1 equivalents) in THF (1 mL/g). This mixture was treated with an iodine crystal and heated at reflux for 12-24 hours when a milky suspension had formed.] The reaction mixture was quenched by addition of saturated aqueous NH4Cl (10 mL) and partitioned between EtOAc (50 mL) and water (30 mL). The aqueous phase was further extracted with EtOAc (3*50 mL) and the combined organic extracts were dried over Na2SO4 and concentrated to an orange oil. This oil was triturated with EtOAc to provide 11-(1-Methylpiperidin-4-yl)-6,11-dihydrodibenzo[b,e]oxepine-2-11-diol (715 mg, 50%) as a brown solid, which was homogenous by TLC and NMR analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | Step 8: Preparation of ll-[N-Methyl-4-piperidinyl]-8-chloro-6, ll-dihydro-5H-benzo[5,6]cycIohepta[l,2 -b]pyridine (XI)(a) N-Methyl piperidyl magnesium chloride prepared by addition of N-methyl -4-chloropiperidine (136 gm , 1.02 mole) to a stirred solution of magnesium metal (33.4gm,l,374 mole ), dibromoethane (72.8 gm, 0.386 mole) and dry tetrahydrofuran(1.17L)at 20- 48C is added slowly to a cooled (-70 to 80C) solution of 8-chloro-6, 11-dihydro-5H-benzo [5,6] cyclohepta [l,2-b]-ll- one, X (100gm,0.41 mole ) in dry THF(530ml). The reaction mixture is stirred for 2-3 hrs at the same temperature. Thereaction mixture is quenched with 10% NH4CI (600ml) and extracted twice with ethylacetate (2x 400ml). The organic phase is washed with water and dried over anhydroussodium sulfate, filtered and solvent removed to get crude material (150 g),The crude material obtained is purified by dissolving in methanol (560ml) andcrystallized with caustic solution (140 ml) at refluxing temperature. The material isfiltered after cooling to 10-15C and washed with water (560 ml) to obtain desiredcarbinol of formula XI in 73.6% yield with purity of 97.3% (ODB, HPLC); (b); The experiment is conducted as described in example 10 except that methanol isreplaced by ethanol to get purified carbinol of formula XI with an yield of 70.0% andpurity of 96% (ODB.HPLC) (c) The experiment is conducted as described in example 10, except that methanol is replaced by isopropanol to get purified carbinol of Formula XI with an yield of 70% and purity of 95% (ODB, HPLC).(d) The experiment is conducted as described in example 10, except that the purification is effected as given below :Crude product (lOOg) is dissolved in acetonitrile (240 ml) at reflux temperature. Ammonia solution (20-25%, 180ml) is slowly added and the mass is cooled to 0-5C. Purified product (65g, 69.15%) is obtained after filtration and drying having 98.35% (HPLC, ODB).(e) The experiment is conducted as described in example 10, except that the purification is effected as given below :Crude product (lOOg) is dissolved in acetonitrile (240ml) at reflux temperature. Triethylamine (2-10 g) is added and mass is stirred for 30 min followed by cooling to 0-5C. Purified product (69g, 73.4%) is obtained after filtration and drying having assay 99.2% (HPLC, ODB).(f) The experiment is conducted as described in example 10, except that the purification is effected as given below :Crude product (lOOg) is dissolved in acetonitrile (240 ml) at reflux temperature.Sodium hydroxide solution (5-15%, 480 ml) was added slowly. Mass was cooled to 5-10C. Purified product (64 g, 68.1%) is obtained after filtration and drying havingassay 98% (HPLC.ODB). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1) Add 1.96kg of freshly polished magnesium dust into a 300L reaction bottle, fill with nitrogen protection, add 30kg of tetrahydrofuran, heat to 60-65 C, and then add 7.5kg of tetrahydrofuran containing <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong> The solution was 70 kg. The reaction was slightly boiled during the dropwise addition. After the dropwise addition, the reaction was refluxed for 1 h to obtain a <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong> magnesium solution;2) After cooling the <strong>[5570-77-4]1-methyl-4-chloropiperidine</strong> magnesium solution to 5 C, slowly add 10.2 kg of dibenzo [a, e] cycloheptatrien-5-one, and react at room temperature for 1 h to obtain 1- Methyl 4- (5-hydroxy-5-dibenzo [a, e] cycloheptatrienyl) piperidine solution;3) The 1-methyl 4- (5-hydroxy-5-dibenzo [a, e] cycloheptatrienyl) piperidine solution was distilled off under reduced pressure at 40-50 C, and then cooled to 2 with stirring. , slowly add 80L of distilled water, the speed of adding distilled water should be controlled so that the temperature of the mixed solution does not exceed 1 2 / min. It is advisable to adjust to neutral with dilute hydrochloric acid, leave it to precipitate overnight, filter the precipitate and centrifuge to dry , To obtain crude 1-methyl 4- (5-hydroxy-5-dibenzo [a, e] cycloheptatrienyl) piperidine 16.4 kg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: Chlorof 1 -methylpiperidin-4-yl)magnesium; Magnesium turnings (14.5 g, 600 mmol) were mixed with THF (700 mL) at room temperature and 1 ,2-dibromoethane (2.59 mL, 30.0 mmol) was added drop wise. After the gas evolution was finished, freshly distilled 4-chloro-l-methylpiperidine (80 g, 600 mmol) was added drop wise to magnesium (14.58 g, 600 mmol) at a pace to maintain gentle reflux. The mixture was refluxed for 2 h once the addition was completed and it was then cooled down. This Grignard reagent was used as such in the following reaction.; Step 3: (2-Bromo-5-fluorophenyl)( 1 -methylpiperidin-4-yl)methanone; To a suspension of 2-bromo-5-fluorobenzoic acid (5.0 g, 22.8 mmol) in 1,2- dichloroethane (30 mL) stirred at room temperature was added oxalyl chloride (4.0 mL, 45.7 mmol) in one portion. The reaction mixture was stirred at 70 0C for 6 h and the solvent was evaporated under vacuum. The residue was dissolved in THF (60 mL) and cooled to -78 0C. Then, chloro(l-methylpiperidin-4-yl)magnesium (28.5 mL, 22.8 mmol) was added drop wise. The mixture was stirred at -78 0C for 10 min and was allowed to warm up to rt. The reaction mixture was cooled in an ice bath, water (200 mL) was added and the mixture was extracted with ethyl acetate (2x 100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Isolute Flash Si; 100 g prepacked), eluting with 0- 15%CH2Cl2/Me0H to give (2-bromo-5-fluorophenyl)(l-methylpiperidin-4-yl)methanone as a yellowish solid. 1H NMR (400 MHz, DMSOd6): delta 7.75 (dd, IH), 7.53 (dd, IH), 7.32 (td, IH),2.97 (tt, IH), 2.76 (d, 2H), 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.76 (d, 2H), 1.60-1.48 (m, 2H). MS (ESI, Q+) m/z 300 (M+ 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1 Step 1 To a reaction vessel where the atmosphere was replaced with argon, <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (100 g), magnesium (22 g) and THF (50 mL) were added, and the resultant mixture was heated under reflux using an oil bath. Once an exothermic reaction was observed, the oil bath was removed, and vigorous stirring was continued until the exothermic reaction was completely terminated. After the reaction system was brought to room temperature (over a period of about one hour), 3-chlorobenzonitrile (100 g) was added and the resultant mixture was heated under reflux for 2 hours. After the reaction system was cooled to 0C using an ice bath, 100 ml of water was gradually added and subsequently 12N hydrochloric acid solution (1 L) was gradually added to the mixture. Then, the reaction solvent was eliminated under reduced pressure. With the addition of a solution prepared by mixing water (500 mL) and sodium hydroxide (500 g), the reaction mixture was thoroughly stirred and the reaction solvent was again eliminated under reduced pressure. With the addition of ethyl acetate (500 mL), the reaction mixture was sufficiently stirred, and thereafter the target ethyl acetate solution was separated by repeating the procedure for decantation 10 times. The whole ethyl acetate solution thus obtained was concentrated to obtain the desired compound as a crude product. The product was purified by silica gel chromatography, thereby obtaining 53 g of the desired compound. Step 2 In a reaction vessel where the atmosphere was replaced with argon, 2-methoxybromobenzene (10 g) was added to a mixture of magnesium (23 g) and THF (400 mL) with vigorously stirring. Stirring was continued until an exothermic reaction was initiated. Thereafter, 2-methoxybromobenzene (140 g) was further added with due attention to the use of an ice bath and the rate of addition of 2-methoxybromobenzene. After the reaction system was brought to room temperature, the compound (34 g) synthesized in the Step 1 of Example 1 was added and the resultant mixture was stirred for 3 hours. After water (100 mL) was gradually added, 12N hydrochloric acid solution (500 mL) was gradually added to the mixture. Then, the reaction solvent was eliminated under reduced pressure. The reaction mixture was thoroughly stirred with the addition of a solution prepared by mixing water (500 mL) and sodium hydroxide (500 g), and the reaction solvent was again eliminated under reduced pressure. With the addition of ethyl acetate (500 mL), the reaction mixture was sufficiently stirred, and thereafter the ethyl acetate solution was separated by repeating the procedure for decantation 10 times. The whole ethyl acetate solution thus obtained was concentrated to obtain the desired compound. Step 3 The compound obtained in the Step 2 of Example 1 was dissolved in a solution previously obtained by mixing concentrated sulfuric acid (24 mL) and methanol (60 mL). The resultant mixture was heated to 50C for 3 hours. The above-mentioned concentrated sulfuric acid solution containing the target compound was brought to room temperature and then gradually added to a solution prepared by mixing water (50 mL) and sodium hydroxide (40 g) and cooled using an ice bath. The mixture was extracted with two 300 mL portions of ethyl acetate, and thereafter the resultant solution was concentrated to obtain the desired compound as a crude product. Further, the product was purified by silica gel chromatography, thereby obtaining 17 g of the compound shown in Table. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5 Step 1 To a reaction vessel where the atmosphere was replaced with argon, <strong>[5570-77-4]N-methyl-4-chloropiperidine</strong> (15 g), magnesium (3.3 g) and THF (50 mL) were added and the resultant mixture was heated under reflux using an oil bath. Once an exothermic reaction was observed, the oil bath was removed, and vigorous stirring was continued until the exothermic reaction was completely terminated. After the reaction system was brought to room temperature (over a period of about one hour), 2-methoxybenzonitrile (100 g) was added and the resultant mixture was heated overnight under reflux. After the reaction system was cooled to 0C using an ice bath, 10 ml of water was gradually added and subsequently 12N hydrochloric acid solution (100 mL) was gradually added to the mixture. Then, the reaction solvent was removed under reduced pressure. The reaction mixture was thoroughly stirred with the addition of a solution prepared by mixing water (50 mL) and sodium hydroxide (50 g), and the reaction solvent was again removed under reduced pressure. With the addition of ethyl acetate (50 mL), the reaction mixture was sufficiently stirred, and thereafter the target ethyl acetate solution was separated by repeating the procedure for decantation 10 times. The whole ethyl acetate solution thus obtained was concentrated to obtain the desired compound as a crude product. The product was purified by silica gel chromatography, thereby obtaining 4 g of the desired compound. Step 2 In a reaction vessel where the atmosphere was replaced with argon, the compound (1.2 g) obtained in the Step 1 of Example 5 was added to a Grignard reagent in THF (50 mL), the Grignard reagent being prepared by vigorously stirring 2-bromothiophene and magnesium (1 g). The resultant mixture was stirred for 3 hours. Water (10 ml) was gradually added and subsequently 12N hydrochloric acid solution (50 mL) was gradually added to the reaction mixture. Then, the reaction solvent was removed under reduced pressure. The reaction mixture was thoroughly stirred with the addition of a solution prepared by mixing water (50 mL) and sodium hydroxide (50 g), and the reaction solvent was again removed under reduced pressure. With the addition of ethyl acetate (50 mL), the reaction mixture was sufficiently stirred, and thereafter the ethyl acetate solution was separated by repeating the procedure for decantation 10 times. The whole ethyl acetate solution thus obtained was concentrated to obtain the desired compound. Step 3 The compound obtained in the Step 2 of Example 4 was dissolved in a solution previously obtained by mixing concentrated sulfuric acid (8 mL) and methanol (20 mL), and the resultant mixture was heated to 50C for 3 hours. The concentrated sulfuric acid solution was brought to room temperature, and then gradually added to a solution prepared by mixing water (20 mL) and sodium hydroxide (20 g) and cooled using an ice bath. The mixture was extracted with two 150 mL portions of ethyl acetate, and thereafter the resultant solution was concentrated to obtain the desired compound as a crude product. Further, the product was purified by silica gel chromatography, thereby obtaining 1 g of the compound shown in Table. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Magnesium (36 mg) and 1,2-dibromoethane (4.3 muL) was added to tetrahydrofuran (1 mL), followed by stirring at room temperature until forming occurs no longer, and 4-chloro-1-methyl piperidine (133 mg) was added thereto, and the resultant product was stirred at room temperature for 0.5 hours, stirred at 50 C. for 10 minutes, and stirred for 10 minutes while refluxing. This reaction mixture was added to a solution (1 mL) of (R,E)-2-methyl-N-((5-methyl pyridin-2-yl)methylene)propane-2-sulfinamide obtained in Reference Example 23-2-1 (1) in tetrahydrofuran at -78 C., followed by stirring at room temperature for 10 minutes. A saturated sodium chloride aqueous solution was added thereto, then, the resultant product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby (R)-2-methyl-N-((1-methylpiperidin-4-yl)(5-methylpyridin-2-yl)methyl)propane-2-sulfinamide (optically active substance A) was obtained. (1591) MS(ESI m/z): 324 (M+H) (1592) RT(min): 0.53 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a 1000-mL oven-dried 3-necked round-bottom flask purged and maintained under nitrogen, were added a solution of Mg (8.8 g, 366.7 mmol) in tetrahydrofuran (100 mL), <strong>[5570-77-4]4-chloro-1-methylpiperidine</strong> (40.7 g, 304.8 mmol). After the reaction solution was refluxed for 2 h, a solution of 5-bromo-2-fluoro- N-methoxy-N-methylbenzamide (40 g, 152.6 mmol) in tetrahydrofuran (400 mL) was added, and the resulting solution was stirred overnight at room temperature, and then saturated sodium bicarbonate solution (200 mL) was carefully added, and extracted with ethyi acetate (3x 200 mL). The combined organic extract was dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20:1) to yield 4-[(5-bromo-2-fluorophenyl)carbonyl]-1-methylpiperidine as a yellow solid. LC/MS (ES, m/z); 300 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
224 g | Under N2 protection, 800 ml of a THF solution of <strong>[5570-77-4]4-chloro-N-methylpiperidine</strong> (245 g, 1.8 mol) was slowly added dropwise to 250 ml of tetrahydrofuran to which Mg powder (55.7 g, 2.3 mol) and a small amount of ethyl bromide had been added, After refluxing for 1 hour, 440 ml of THF solution of 2-fluorobenzonitrile (222 g, 1.8 mol) was added dropwise to the reaction solution, and after completion of the dropwise addition, the mixture was refluxed for 3 hours and reacted at room temperature for 13 hours to obtain 700 g Of NH 4 Cl, refluxed for 2 hours, extracted with diethyl ether after cooling, the extracts were combined, evaporated to dryness, fractionated and fractions at 124 C. were collected and collected 224 g of product are obtained. |
Tags: 5570-77-4 synthesis path| 5570-77-4 SDS| 5570-77-4 COA| 5570-77-4 purity| 5570-77-4 application| 5570-77-4 NMR| 5570-77-4 COA| 5570-77-4 structure
A443389[ 5382-23-0 ]
1-Methyl-4-chloropiperidine hydrochloride
Reason: Free-salt
[ 5382-19-4 ]
4-Chloropiperidine hydrochloride
Similarity: 0.92
[ 5472-49-1 ]
1-(3-Chloropropyl)piperidine hydrochloride
Similarity: 0.92
[ 57616-69-0 ]
1-(3-Chloropropyl)pyrrolidine hydrochloride
Similarity: 0.80
[ 5382-19-4 ]
4-Chloropiperidine hydrochloride
Similarity: 0.92
[ 5472-49-1 ]
1-(3-Chloropropyl)piperidine hydrochloride
Similarity: 0.92
[ 57616-69-0 ]
1-(3-Chloropropyl)pyrrolidine hydrochloride
Similarity: 0.80
[ 207852-63-9 ]
1-(4-Chloropiperidin-1-yl)ethanone
Similarity: 0.73
[ 100911-49-7 ]
2-(Piperidin-1-yl)ethanamine dihydrochloride
Similarity: 0.69
[ 5382-19-4 ]
4-Chloropiperidine hydrochloride
Similarity: 0.92
[ 5472-49-1 ]
1-(3-Chloropropyl)piperidine hydrochloride
Similarity: 0.92
[ 2008-75-5 ]
1-(2-Chloroethyl)piperidine hydrochloride
Similarity: 0.77
[ 207852-63-9 ]
1-(4-Chloropiperidin-1-yl)ethanone
Similarity: 0.73
[ 100911-49-7 ]
2-(Piperidin-1-yl)ethanamine dihydrochloride
Similarity: 0.69
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 :