* 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.
Load isonipicotic acid (1 kg, 7.74 mol), water (10 L), formaldehyde (37percent solution in water, 720 g, 8.87 mol, 1.15 eq. ) and wet Pd/C catalyst (10percent; 55percent paste, 100 g) into a stainless steel hydrogenation reactor. Pressurize the reactor with H2 (3 bar) and stir the reaction mixture overnight at 200-300 rpm at 16-25°C. Stop the reaction and filter off the catalyst. Wash the filtrate with water (500 ml) and concentrate under vacuum. Distill off the remaining water from the residue using ethanol (2x 1 L). Dry the solid overnight under vacuum at 50°C to obtain the title product as an off-white solid (1087 g, 98. 1percent yield).
76%
With hydrogen In water at 20℃; for 18 h;
Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37percent formaldehyde (125 ml). 10percent Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours. [00375] The catalyst was filtered, washed with water, and the filtrate was concentrated under reduced pressure. The residue was slurried in water and concentrated in vacuo. The residue was slurried in ethanol and concentrated in vacuo to give a white solid. Drying under vacuum at ambient temperature for 18 h gave 42.2 g (76percent) of a white solid, [00376] mp 173-5° C. MS(m/e): 143 (M+). [00377] Analysis for C7H13NO2: [00378] Calcd: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.24; H, 9.59; N. 9.71.
18%
for 20 h; Heating / reflux
Reference Example 249: l-MethvI-piperidine-4-carboxylic acid . A solution of 4-piperidine carboxylic acid (1.0 g, 7.75 mmol) in a mixture of90percent formic acid (3 mL) and 37percent formaldehyde solution (2 mL) was heated at reflux for 20 h. The volatiles were removed in vacuo and cone. HCl added to the residue. The reaction mixture was extracted with dichloromethane and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and dried to afford 1-methyl- piperidine-4-carboxylic acid (0.20 g, 18 percent).
Reference：
[1] Patent: WO2003/84949, 2003, A1, . Location in patent: Page/Page column 45; 46
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
[3] Patent: US6777428, 2004, B1, . Location in patent: Page column 24
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 4, p. 449 - 459
[5] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 161-162
[6] Journal of the American Chemical Society, 1949, vol. 71, p. 2825
[7] Patent: US2833775, 1955, ,
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 1995, vol. 36, # 2, p. 193 - 204
[9] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 21
2
[ 24252-37-7 ]
[ 68947-43-3 ]
Yield
Reaction Conditions
Operation in experiment
1.79 g
With sodium hydroxide In water at 20℃;
(0550) A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid. (0551) 1H-NMR (CD3OD): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m), 2.78 (3H, s), 2.88-3.04 (2H, m), 3.32-3.44 (2H, m).
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 25, p. 7212 - 7217[2] Angew. Chem., 2016, vol. 128, # 25, p. 7328 - 7333,6
6
[ 5746-18-9 ]
[ 68947-43-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 1201
7
[ 55-22-1 ]
[ 68947-43-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 1201
[2] Patent: US2833775, 1955, ,
8
[ 824-77-1 ]
[ 68947-43-3 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1954, vol. 19, p. 949,951
9
[ 1126-09-6 ]
[ 68947-43-3 ]
Reference：
[1] Patent: US2016/128945, 2016, A1,
10
[ 1690-75-1 ]
[ 68947-43-3 ]
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
11
[ 2459-09-8 ]
[ 68947-43-3 ]
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
12
[ 7630-02-6 ]
[ 68947-43-3 ]
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
13
[ 64-18-6 ]
[ 590-29-4 ]
[ 824-77-1 ]
[ 68947-43-3 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1954, vol. 19, p. 949,951
14
[ 68947-43-3 ]
[ 24252-37-7 ]
Yield
Reaction Conditions
Operation in experiment
50%
With hydrogenchloride; sodium hydrogencarbonate In 1,4-dioxane; dichloromethane
a) A solution of 2N hydrochloric acid in dioxane (2.8 ml, 11.13 mmol) was added to 1-methyl-4-piperdine carboxylic acid (20 g, 111.33 mmol) and the mixture heated at reflux for 18 hours. The reaction was concentrated to dryness and the resultant solid dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate, dried (magnesium sulphate) and concentrated to afford 1-methyl-4-piperdine carboxylic acid ethyl ester as a white solid (9.52 g, 50percent yield).
Reference：
[1] Patent: US7235559, 2007, B1,
[2] Collection of Czechoslovak Chemical Communications, 1954, vol. 19, p. 949,951
[3] Helvetica Chimica Acta, 1954, vol. 37, p. 1762,1765
15
[ 68947-43-3 ]
[ 6638-79-5 ]
[ 215950-19-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 63 h; Stage #2: With sodium hydroxide In water
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80percent) of product as a light yellow liquid. [00381] MS (m/e): 186(M+). [00382] Analysis for C9H18N2O2:
1-Methyl-piperidine-4-carboxylic acid [(S)-1-[(S)-1-((1S,2R,3S)-1-cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide[ No CAS ]
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4- carboxylic acid (1.79 g) as a colorless solid. H-NMR (CD30D) : 1.80-1. 98 (2H, m), 2.00-2. 14 (2H, m), 2.28- 2.42 (lH, m), 2.78 (3H, s), 2.88-3. 04 (2H. m), 3.32-3. 44 (2H. m). A mixture of 1-methylpiperidine-4-carboxylic acid (1.72 g) obtained above, tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1, [1-ETHYL-3- [3-] (dimethylamino) propyl] carbodiimide hydrochloride (2.30 g), 4- dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 [ML).] The ethyl acetate layer was washed with saturated brine (50 [ML),] dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: [HEXANE=50] : 50, then 80: 20). IN Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid. [H-NMR] [(DMSO-D6)] : 1.70-2. 20 (4H, m), 2.40-3. 50 [(13H,] m), 4. 31 (2H, m), 9.25 (2H, br), 10.77 (lH, br).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 20℃; for 16h;
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4- carboxylic acid (1.79 g) as a colorless solid. H-NMR (CD30D) : 1.80-1. 98 (2H, m), 2.00-2. 14 (2H, m), 2.28- 2.42 (lH, m), 2.78 (3H, s), 2.88-3. 04 (2H. m), 3.32-3. 44 (2H. m). A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1, [1-ETHYL-3- [3-] (dimethylamino) propyl] carbodiimide hydrochloride (2.30 g), 4- dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 [ML).] The ethyl acetate layer was washed with saturated brine (50 [ML),] dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: [HEXANE=50] : 50, then 80: 20). IN Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid. [H-NMR] [(DMSO-D6)] : 1.70-2. 20 (4H, m), 2.40-3. 50 [(13H,] m), 4. 31 (2H, m), 9.25 (2H, br), 10.77 (lH, br).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 15 - 30℃; for 16h;
A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added saturated aqueous solution of sodium bicarbonate (50 mL), and extracted with ethyl acetate (100 mL). The ethyl acetate layeer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate, followed by concentrating under reduced pressure. The residue was purified with basic silica gel column chromatography (eluted with methanol : ethyl acetate = 50 : 50, then 80 : 20). To the purified material (2.73 g) was added 1 N hydrochloric acid (25 mL), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and isopropanol was added, then, concentrated again under reduced pressure. The precipitated crystals were collected by filtration to give title compound as colorless solid (1.72 g).1H-NMR (DMSO-d6) : 1.70-2.20(4H,m), 2.40-3.50 (13H,m), 4.31(2H,m), 9.25(2H,br), 10.77 (1H,br).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 20℃; for 16h;
A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=50:50, then 80:20). 1N Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid.1H-NMR(DMSO-d6) : 1.70-2.20 (4H,m), 2.40-3.50 (13H,m), 4.31 (2H,m), 9.25 (2H,br), 10.77 (1H,br).
1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Preparation of 3:0.1 mol of I was stirred with 0.11 mol of CDI in 200 ml of chloroform at room temperature for 2 hours. Then 2 (0.1 mol) was added and reaction mixture was stirred at room temperature overnight. 200 ml of water were added, after that organic layer was separated and solvent removed under reduced pressure.
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80percent) of product as a light yellow liquid. [00381] MS (m/e): 186(M+). [00382] Analysis for C9H18N2O2:
With hydrogenchloride; sodium hydroxide; In ethanol;
1-Methyl-4-piperidinecarboxylic acid may be prepared in the following manner: 12.5 cm3 of a 4 N aqueous sodium hydroxide solution are added, at 20° C., to 7.60 g of ethyl 1-methyl-4-piperidinecarboxylate in solution in 35 cm3 of ethanol. After stirring for 20 hours, the reaction mixture is concentrated to a reduced volume and then neutralized with 12.5 cm3 of a 4 N aqueous hydrochloric acid solution and finally concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 60 cm3 of anhydrous ethanol, and then filtered. The filtrate is concentrated to dryness under reduced pressure (2.7 Kpa) at 20° C., to give 6.3 g of 1-methyl-4-piperidinecarboxylic acid in the form of a white solid. 1H NMR spectrum (300 MHz, (CD3)2SO d6, delta in ppm): 1.56 (mt: 2H); 1.78 (mt: 2H); 1.98 (dt, J=11.5 and 2.5 Hz: 2H); 2.13 (mt: 1H); 2.18 (s: 3H); 2.74 (broad d, J=11.5 Hz: 2H).
With sodium hydroxide; water; at 15 - 30℃;
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and water (150 mL) was added thereto, followed by extracting with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. To the residue (2.64 g) was added 1 N aqueous solution of sodium hydroxide (20 mL), and stirred at room temperature overnight. To the reaction solution was added 1 N hydrochloric acid (20 mL) to neutralize, and concentrated under reduced pressure. To the residue was added ethanol, and the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. After repeating this operation again, to the residue were added ethanol and ethyl acetate to crystallize, which gave 1-methylpiperidine-4-carboxylic acid as colorless solid (1.79 g). 1H-NMR (CD3OD) : 1. 80-1.98 (2H,m), 2.00-2.14 (2H,m), 2.28-2.42 (1H,m), 2.78(3H,s), 2.88-3.04(2H.m), 3.32-3.44(2H.m).
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.1H-NMR (CD3OD) : 1.80-1.98 (2H,m), 2.00-2.14 (2H,m), 2.28-2.42 (1H,m), 2.78(3H,s), 2.88-3.04(2H.m), 3.32-3.44(2H.m).
1.79 g
With sodium hydroxide; In water; at 20℃;
(0550) A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid. (0551) 1H-NMR (CD3OD): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m), 2.78 (3H, s), 2.88-3.04 (2H, m), 3.32-3.44 (2H, m).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;Heating / reflux;
Suspend N-methylisonipicotic acid (365 g, 2.55 mol) in CH2CI2 (3500 ml) and add a catalytic quantity of DMF (2 ml). Add oxalyl chloride (435 g, 3.42 mol, 1.35 eq.) to the reaction mixture maintaining the temperature at 20°C. Heat the suspension under reflux for 2 hrs. Cool the reaction mixture and concentrate on a rotary evaporator. Resuspend the residue in toluene (1000 ml), evaporate and dry under vacuum to yield the title product (489 g, 96percent) as an off-white solid residue, which is used without further purification in the next reaction step.
With thionyl chloride; for 4h;Reflux;
EXAMPLE 25: N-(6-chloropyrazine-2-yl)- 1 -methylpiperidine-4-carboxamide37A solution of l-methylpiperidine-4-carboxylic acid (500mg, 3.1mmol) in thionyl chloride (8ml) was refluxed for 4h. All volatiles are removed under nitrogen. To the crude acid chloride, pyridine (6ml) was added followed by 2,6-Dichloropyrazine and the mixture was heated at 100°C overnight. Reaction was completed as shown by TLC. Pyridine was removed under vacuum and the obtained crude product was purified by flash column over neutral alumina using 5percent methanol/DCM as eluent. Compound 37 was obtained as dark brown solid, 130mg (40percent) and confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDC13) delta: 11.06 (s, 1H), 9.30 (s, 1H), 8.46 (s, 1H), 2.77 (d, 2H), 2.58 (d, 2H), 2.15 (s, 3H), 1.86 (m, 4H), 1.8-1.74 (m. 2H); MS- 254, (M+l), LCMS- 98percent.
Methyl-phenyl-carbamic Acid 4-{2-[(1-methyl-piperidine-4-carbonyl)-amino]-ethyl}-phenyl Ester A solution of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 5percent yield as an oil. HPLC-MS: m/z=396.4 (M+1); Rt=2.03 min.
1-N-(N-(N-methyl piperidine-4-carbonyl)-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 256 Preparation of 1-N-(N-(N-methyl piperidine-4-carbonyl)-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "N-methyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid" and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+H+ =557.
With EDAC; benzotriazol-1-ol; In N,N-dimethyl-formamide;
Example 5 [7-(1-Methylpiperidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl]-(4-methoxyphenyl)-methanone STR18 2-(3-Thienyl)ethanamine (3 g) was treated with <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (4.24 g), HOBT (3.18 g), and EDAC (6.78 g) in DMF (180 ml). Procedure exactly as described in example 4. Yield 1.22 g crystals of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (2-thiophen-3-yl-ethyl)-amide, identified by NMR and MS: M+252.
EXAMPLE 1 3-(4-Fluorobenzyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-b] pyridine fumarate Grams 3.3 of 2,3-diaminopyridine and 5.4 g of N-methylisonipecotic acid hydrocloride are heated at 190° C. for 24 hours. The reaction mixture is cooled and diluted with a small amount of water then made alkaline to pH 10 by addition of NaOH then extracted several times with methylene chloride. The organic extracts are collected together and evaporated to dryness. The residue, crystallized from acetonitrile, gives 2 g (31percent of the theoretical value) 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine melting at 224°-226° C.
With sodium hydroxide;
Example 1 3-(4-Fluorobenzyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-b] pyridine fumarate. Grams 3.3 of 2,3-diaminopyridine and 5.4 g of N- methylisonipecotic acid hydrocloride are heated at 190°C for 24 hours. The reaction mixture is cooled and diluted with a small amount of water then made alkaline to pH 10 by addition of NaOH then extracted several times with methylene chloride. The organic extracts are collected together and evaporated to dryness. The residue, crystallized from acetonitrile, gives 2 g (31percent of the theoretical value) 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine melting at 224-226°C.
N-(4'-methyl-2-[5-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}-4,5'-bi-1,3-thiazol-2'-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
N-{2-[(2E)-2-amino-2-(hydroxyimino)ethyl]-4'-methyl-4,5'-bi-1,3-thiazol-2'yl}acetamide, obtained in step I as describe above (45 mg; 0.14 mmol; 1 eq.), is dissolved in DMF (3 ml) at RT. N-Methyl-4-piperidine carboxylic acid (102 mg; 0.72 mmol; 5 eq.), pre-activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138.5 mg; 0.72 mmol; 5 eq.) in DCM (3 ml), is added into the reaction mixture. It is stirred for 3 hours at RT. Upon completion of the reaction, water (1 ml) is added and solvents are concentrated to dryness. The residue is taken up in EtOAc and washed several times with water (3x5mL). The organic phases are dried over MgSO4, filtrated and evaporated. Residue is directly taken up in pyridine (3 mL) and heated up at 900C for 12 hours. Reaction mixture is cooled down and pyridine is evaporated to dryness. The crude material is purified by flash chromatography on silica gel (cyclohexane/ethylacetate, 10/90), affording Compound (83) as an oil (30 mg; 66percent).1H NMR (DMSO-d6, 300 MHz) delta 1.90 (m, 2H), 2.10 (s, 3H), 2.30 (m, 2H), 2.40 (s, 3H), 2.75 (s, 3H), 3.10 (m, 2H), 3.40 (m, 1H), 3.50 (m, 2H), 4.60 (s, 2H), 7.66 (s, 1H), 9.50 (m, 1H), 12.10 (m, 1H). M (ESI): 417.5; M+(ESI): 419.5. HPLC (method A), Rt: 1.96 min (purity: 86.9percent).
Reference Example 262: 2-Bromo-l-(l-methyI-piperidin-4-vI)-ethanone hydrobromide. A mixture of l-methyl-piperidine-4-carboxylic acid (0.40 g, 2.79 mmol) and thionyl chloride (0.32 mL, 4.44 mmol) in dichloromethane (10 mL) was heated to reflux for 6 h. The reaction mixture was distilled under reduced pressure and the residue dissolved in dry acetonitrile (4 mL). Trimethylsilyl diazomethane (4 mL, 8.08 mmol) was added and the mixture stirred for 2 h at ambient temperature. The reaction was cooled to 0 °C and 30percent HBr in acetic acid (2 mL) added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The precipitate was filtered and washed with ether to afford 2-bromo-l-(l-methyl-piperidin-4-yl)-ethanone hydrobromide (200 mg, 33 percent).
2-((1S)-1-[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-4-phenylpyridinium bis(trifluoroacetate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of the amine (O3) (1 eq.) and DIPEA (2.2 eq.) in DMF was added a solution of EDC.HCl (1.3 eq), HOBt (1.3 eq) and <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.2 eq) in DMF. The mixture was stirred at RT for 3 h and the desired material was isolated by preparative RP-HPLC, using H2O (+0.1percent TFA) and MeCN (+0.1percent TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the imidazole as a colourless oil.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
A mixture of 4-[(4-methyl-1H-indol-5-yl)amino]-1l,2f,3',6'-tetrahydro-3,4'-bipyridine-5- carbonitrile (100mg, 0.23 mmol), i-methylpiperidine-4-carboxylic acid (54 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyI) carbodiimide hydrochloride (88 mg, 0.46 mmol), and triethylamine (69.7 mg; 0.69 mmol) in 2 mL of DMF was stirred at room temperature for 1 h. The reaction was filtered and the filtrate was purified by HPLC to give 4-[(4-methyl-1H-indol-5- yOaminol-i'^i-pifiethylpiperidin-^-ylJcarbonyll-i'^'.S'.e'-tetrahydro-S^'-bipyridine-delta-carbonitrile as its TFA salt; MS 455.4 (M+H); HPLC: rt = 4.2 min [a].
N-(3-((2R)-2-(((2R)-2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yl)-1-methylpiperazine-4-carboxamide trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
A solution of (5R)-3-((1R)-2-(7-amino-1H-indol-3-yl)-1-methylethyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (30 mg, 0.08 mmol), N-methylpiperidine-4-carboxylic acid (34 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole (32 mg, 0.24 mmol) and triethylamine (67 muL, 0.48 mmol) in tetrahydrofuran (2 mL) is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform: methanol = 100:1 --> 20: 1). A solution of the purified residue and potassium hydroxide (0.5 g) in ethanol (2 mL)/water (1 mL) is stirred at 80°C for 3.5 hours. The reaction solution is acidified with hydrochloric acid, and purified by preparative HPLC (trifluoroacetic acid-acetonitrile-water) and preparative thin layer chromatography (silica gel, a saturated ammonia solution in chloroform:methanol = 10:1) to give the title compound (5 mg, yield: 13 percent). 1H-NMR (CDCl3) delta: 1.12 (3H, d, J=6.2Hz), 1.90-2.07 (6H, m), 2.32 (3H, s), 2.36 (1H, m), 2.61 (1H, dd, J=9.2, 12.1Hz), 2.81-2.88 (3H, m), 2.96-3.05 (3H, m), 4.49 (1H, dd, J=3.6, 9.2Hz), 6.75 (1H, d, J=7.4Hz), 7.01 (1H, dd, J=7.8, 7.8Hz), 7.05 (1H, d, J=2.1Hz), 7.15-7.18 (1H, m), 7.19-7.23 (2H, m), 7.33 (1H, s), 7.42 (1H, d, J=7.9Hz), 7.57 (1H, s), 9.88 (1H, brs).
4-(3-hydroxymethylphenyl)-2-[3-(1-methylpiperidin-4-ylcarbonylamino)phenyl]-6-morpholinopyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Diisopropylethylamine (0.054 ml) was added to a stirred mixture ofl-methylpiperidin-4-ylcarboxylic acid (0.02 g), 2-(7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.053 g) and DMF (0.35 ml) and theresultant mixture was stirred for approximately 1 minute under an atmosphere of nitrogen. Asolution of 2-(3-aminophenyl)-4-(3-hydroxymethylphenyl)-6-rnorpholinopyrimidine (0.044 g)in DMF (0.3 ml) was added and the mixture was stirred for 5 hours. The DMF wasevaporated and the residue was purified by HPLC using a Waters 'Xterra' preparativereversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasinglypolar mixtures of water and acetonitrile (containing 1percent acetic acid) as eluent. There was thusobtained the title compound as a solid (0.03 g); NMR Spectrum: (DMSOde) 1.61-1.96 (m, 5H)2.18 (s, 3H), 3.74-3.87 (m, 8H), 4.63 (d, 2H), 5.27 (t, 1H), 7.27 (s, 1H), 7.41 (t, 2H), 7.48-7.53(m, 2H), 7.93-7.99 (m, 1H), 8.11-8.23 (m, 3H), 8.52 (t, 1H), 9.99 (s, 1H); Mass Spectrum:M+H1" 488; Analytical HPLC: method Al, Retention Time 2.87 minutes.
With triethylamine; isobutyl chloroformate; for 1h;
-Methylisonipecotic acid sodium salt (1.5 g) in DMF (14 ml) was treated with 1 N hydrochloric acid (9.1 ml) and dried to give a white solid. This solid was dissolved in isobutyl chloroformate (1.24 g) and triethylamine (1.0 g), followed by stirring for 1 hour. To the reaction mixture, CVAU (1.3 g) and triethylamine (2.7 g) were added and stirred overnight. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, followed by evaporation to dryness under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform:methanol=7:1) to give a crude product. The crude product was immediately treated with a large excess of a 10percent hydrochloric acid/methanol solution to give a crude hydrochloride salt. This crude product was suspended in ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and evaporated to dryness under reduced pressure. The resulting residue was purified again by NH silica gel column chromatography (chloroform:methanol=7:1), treated with about 2 molar equivalents of a 10percent hydrochloric acid/methanol solution, and then lyophilized to give Compound 5 (182 mg). 1H-NMR (DMSO-d6) delta 11.60 (s, 1H), 7.63 (s, 1H), 7.20 (d, 1H, J=13.3 Hz), 6.64 (d, 1H, J=13.3 Hz), 6.04 (d, 1H, J=4.3 Hz), 5.72, 5.66 (each d, each 1H J=4.3, 3.6 Hz), 4.54 (dd, 1H, J=11.5 Hz, J=7.6 Hz), 4.19 (dd, 1H, J=11.4 Hz, J=3.0 Hz), 3.97 (m, 3H), 3.33-1.71 (m, 9H), 2.46 (s, 3H)MS (FAB): m/z 430
Example 14; 1-Methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14); A mixture of 0.120 g (0.26 mmole) of 2-[6-(4-amino-piperidin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.13), 5 mL of dimethylformamide, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.105 g (0.39 mmole) of triethylamine was stirred for 15 minutes, then 0.056 g (0.39 mmole) of 1-methyl-piperidine-4-carboxylic acid was added. After 3 hours, the mixture was taken up in 100 mL of ethyl acetate, washed twice with 100 mL of water, and then once with 100 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-(methanol-ammonium hydroxide, (92.8:0.3)) (gradient 100:0-0:100) to give 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14). This material was taken up in 20 mL of dichloromethane, washed with 20 mL of 1M sodium hydroxide solution. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.065 g of 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14) as a solid. MH+/Z=592
To a solution of l-methylpiperidine-4-carboxylic acid (25.9 mg, 0.181 mmol) in DMF (0.5 mL), were successively added N,N'-diisopropylethylamine (0.053 mL, 0.302 mmol), EDC (23.14 mg, 0.121 mmol) and HOBt (18.49 mg, 0.121 mmol). After stirring at room temperature for 5 min, 7-amino-3-(3-methoxyphenyl)- 9H-carbazole-l -carboxamide (20 mg, 0.060 mmol, Example 138) was added. After stirring for 16h, the reaction was diluted with MeOH, and the product was isolated by preparative HPLC (100 x 30 mm Luna Cl 8 column, flow rate 42 ml permin, gradient elution starting with A:B =90: 10 and ending with A:B =30:70 [A = 10 mM NH4OAc in 5percent aqueous acetonitrile; B = IO mM NH4OAc in 95percent aqueous acetonitrile] over 20 min). The HPLC fractions that contained the product were applied onto a PHENOMENEX.(R). Strata-X-C 33 um cation mixed-mode polymer cartridge. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents gave 18.9 mg of 3-(3-methoxyphenyl)-7-(l- methylpiperidine-4-carboxamido)-9H-carbazole-1-carboxamide as a white solid. MS (ESI) m/z 457.2 (M+H). 1H NMR (MeOD) delta ppm 8.43 (1 H, s), 8.13 (1 H, d, J=1.22 Hz), 8.08 (1 H, d, J=8.55 Hz), 8.04 (1 H, s), 7.30 - 7.43 (3 H, m), 7.27 (1 H, dd, J=8.39, 1.68 Hz), 6.92 (1 H, dd, J=5.49, 2.14 Hz), 3.90 (3 H, s), 3.00 (2 H, d, J=11.60 Hz), 2.38 - 2.51 (1 H, m), 2.33 (3 H, s), 2.06 - 2.20 (2 H, m), 1.85 - 2.04 (4 H, m).
With hydrogenchloride; In water; N,N-dimethyl-formamide;
-Methylisonipecotic acid sodium salt (1.5 g) in DMF (14 ml) was treated with 1 N hydrochloric acid (9.1 ml) and dried to give a white solid. This solid was dissolved in isobutyl chloroformate (1.24 g) and triethylamine (1.0 g), followed by stirring for 1 hour. To the reaction mixture, CVAU (1.3 g) and triethylamine (2.7 g) were added and stirred overnight. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, followed by evaporation to dryness under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform:methanol=7:1) to give a crude product. The crude product was immediately treated with a large excess of a 10percent hydrochloric acid/methanol solution to give a crude hydrochloride salt. This crude product was suspended in ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and evaporated to dryness under reduced pressure. The resulting residue was purified again by NH silica gel column chromatography (chloroform:methanol=7:1), treated with about 2 molar equivalents of a 10percent hydrochloric acid/methanol solution, and then lyophilized to give Compound 5 (182 mg). 1H-NMR (DMSO-d6) delta 11.60 (s, 1H), 7.63 (s, 1H), 7.20 (d, 1H, J=13.3 Hz), 6.64 (d, 1H, J=13.3 Hz), 6.04 (d, 1H, J=4.3 Hz), 5.72, 5.66 (each d, each 1H J=4.3, 3.6 Hz), 4.54 (dd, 1H, J=11.5 Hz, J=7.6 Hz), 4.19 (dd, 1H, J=11.4 Hz, J=3.0 Hz), 3.97 (m, 3H), 3.33-1.71 (m, 9H), 2.46 (s, 3H)MS (FAB): m/z 430
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