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Structure of 41838-46-4 * Storage: {[proInfo.prStorage]}
* 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.
Step: 3A-1Synthesis of l-Methyl-piperidin-4-yIamineProcedure:Ammonium formate (2.226g, 0.035348mol) was added to a solution of 1 -Methyl- piperidin-4-one (lg, 0.008837mol) in MeOH and stirred for lOmins. 20percent Pd-C was added to this and the reaction mixture was heated at 60°C for 2hrs. The reaction was monitored by the TLC (10percent methanol in chloroform). The reaction mixture was filtered through celite bed, concentrated to afford lg (100percent yield) of l-Methyl-piperidin-4-ylamine.
1.4 g
With palladium 10% on activated carbon; ammonium formate In methanol; water at 20℃; for 24 h;
Ammonium formate (15.4 g; 240 mmol) and 10percent Pd/C (3.14 g; 29 mmol) are added to a solution of 1-methyl-4-piperidone (3.26 mL; 26.5 mmol) in aqueous methanol (80 mL, CH3OH/H2O 9:1); the mixture is stirred for 24 h. at r.t.;. catalyst removal by filtration over Celite and solvent evaporation to dryness at low pressure give a pale yellow residue of 1-methyl-4-aminopiperidine. Dropwise addition of 37percent HCl (4,6 mL) to a stirred solution of said amine in EtOH (50 mL) separates a white precipitate of 1-methyl-4-aminopiperidine hydrochloride that is filteted 18 hrs later, after cooling for 18 hrs at T = + 4°C. Finally, an aqueous solution of the hydrochloride treated with an excess of 0,1 N NaOH (≈ 10 mL) is extracted with CH2Cl2 (3x10 mL). After the usual work-up, solvent evaporation to dryness yields pure 1-methyl-4-aminopiperidine (1.4 g; 12.4 mmol). 1H-NMR (CDCl3): δ 2.85 (m, 2H); 2.58 (m, 1H); 2.25 (s, 3H); 2.01 (m, 2H); 1.85 (m, 2H); 1.63 (bs, 2H, NH2); 1.47 (m, 2H).
Reference：
[1] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 137
[2] Tetrahedron Letters, 2001, vol. 42, # 25, p. 4257 - 4259
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4390 - 4400
[4] Farmaco, 1998, vol. 53, # 3, p. 233 - 240
[5] Yakugaku Zasshi, 1951, vol. 71, p. 1053,1057[6] Chem.Abstr., 1952, p. 5044
[7] Patent: US2006/183769, 2006, A1, . Location in patent: Page/Page column 7
[8] Patent: EP1366018, 2016, B1, . Location in patent: Paragraph 0112
2
[ 359878-09-4 ]
[ 41838-46-4 ]
Yield
Reaction Conditions
Operation in experiment
51%
With formic acid In methanol for 24 h; Heating / reflux
N-((4-methoxyphenyl)methyl)-4-amino-l-methylpiperidine (1 g, 4.27 mmol) was dissolved in 4percent formic acid in methanol (60 mL). 10percent Pd/C (1 g) was added under argon and the reaction mixture was heated to reflux for 24 h. The mixture was filtered through celite and the filtrate was acidified with cone. HCl to pH~l. <n="128"/>Concentration yielded a yellow oil which was purified by flash chromatography (MeOH/CH2Cl2 3:7+3.5percent NH4 OH)to give 249 mg (51percent) of 4-amino-l-methylpiperidine (57-MBT36B) as a white solid. Rf 0.13 (10percent MeOH in CH2Cl2 +3.5percent NH4OH). HPLC- MS (method B) showed MH+ =115. UV/MS(percent)=-/100.
With hydrogenchloride; NaCNBH3 In methanol; diethyl ether
a) 4-Amino-1-methylpiperidine 1-Methylpiperidin-4-one (4.22 g, 37 mmol) and an ice cold soln of 1N HCl in Et2 O (37 mL, 37 mmol) were combined. Trituration followed by evaporation of the Et2 O at 23° under a stream of argon afforded the hydrochloride. MeOH (114 mL), anhydrous NH4 OAc (28.7, 373 mmol) and 3A molecular sieves were added. Stirred 10 min and then NaCNBH3 (2.33 g; 37 mmol) was added, and the mixture was stirred for 1 h. Acidified to 2 O. The resulting mixture was made basic with 50percent aq NaOH and extracted with EtOAc, dried (K2 CO3), and distilled (bp=55°-60°, 15 mm) to afford 3.88 g (88percent) of the title compound.
88%
With hydrogenchloride; NaCNBH3 In methanol; diethyl ether
a) 4-Amino-1-methylpiperidine 1-Methylpiperidin-4-one (4.22 g, 37 mmol) and an ice cold soln of 1N HCl in Et2 O (37 mL, 37 mmol) were combined. Trituration followed by evaporation of the Et2 O at 23° under a stream of argon afforded the hydrochloride. MeOH (114 mL), anhydrous NH4 OAc (28.7, 373 mmol) and 3A molecular sieves were added. Stirred 10 min and then NaCNBH3 (2.33 g, 37 mmol) was added, and the mixture was stirred for 1 h. Acidified to 2 O. The resulting mixture was made basic with 50percent aq NaOH and extracted with EtOAc, dried (K2 CO3), and distilled (bp=55°-60°, 15 mm) to afford 3.88 g (88percent) of the title compound.
Reference：
[1] Patent: US5593992, 1997, A,
[2] Patent: US5670527, 1997, A,
4
[ 359878-55-0 ]
[ 41838-46-4 ]
Yield
Reaction Conditions
Operation in experiment
51%
With formic acid; palladium 10% on activated carbon In methanol for 24 h; Inert atmosphere; Reflux
Example 88 N-((3-hydroxy-4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamide (57MBT54B) N-((4-methoxyphenyl)methyl)-4-amino-1-methylpiperidine (1 g, 4.27 mmol) was dissolved in 4percent formic acid in methanol (60 mL). 10percent Pd/C (1 g) was added under argon and the reaction mixture was heated to reflux for 24 h. The mixture was filtered through celite and the filtrate was acidified with conc. HCl to pH 1. Concentration yielded a yellow oil which was purified by flash chromatography (MeOH/CH2Cl2 3:7+3.5percent NH4OH) to give 249 mg (51percent) of 4-amino-1-methylpiperidine (57-MBT36B) as a white solid. Rf=0.13 (10percent MeOH in CH2Cl2+3.5percent NH4OH). HPLC-MS (method B) showed MH+=115. UV/MS (percent)=-/100.
With sodium cyanoborohydride; acetic acid; In methanol; at 0℃; for 3h;
4-Amino-1-methylpiperidine (57MBT36B) (26 mg, 0.231 mmol) was dissolved in methanol (1 mL) and <strong>[57295-30-4]3-hydroxy-4-methylbenzaldehyde</strong> (32 mg, 0.231 mmol) and acetic acid (33 muL) were added. The mixture was cooled to 0 C. NaBH3CN (29 mg, 0.462 mmol) was added and the cooling bath was removed. After 3 h the reaction mixture was evaporated and flash chromatography (0-30% MeOH in CH2Cl2) gave 27 mg (50%) of N-((3-hydroxy-4-methylphenyl)methyl)-4-amino-1-methylpiperidine (57MBT44C) as a white solid. Rf=0.27 (10% MeOH in CH2Cl2+3.5% NH4OH). HPLC-MS (method A) showed MH+=235. UV/MS (%)=99/99.
50%
With sodium cyanoborohydride; acetic acid; In methanol; at 0℃; for 3h;
4-Amino-l-methylpiperidine (57MBT36B) (26 mg, 0.231 mmol) was dissolved in methanol (1 mL) and <strong>[57295-30-4]3-hydroxy-4-methylbenzaldehyde</strong> (32 mg, 0.231 mmol) and acetic acid (33muL) were added. The mixture was cooled to 0 C. NaBH3 CN (29 mg, 0.462 mmol) was added and the cooling bath was removed. After 3 h the reaction mixture was evaporated and flash chromatography (0-30% MeOH in CH2Cl2) gave 27 mg (50%) of N-((3-hydroxy-4-methylphenyl)methyl)-4-amino-l-methylpiperidine (57MBT44C) as a white solid. Rf =0.27 (10% MeOH in CH2Cl2 +3.5% NH4 OH). HPLC-MS (method A) showed MH+ =235. UV/MS(%)=99/99.
With 10-chloro-2-cyclopentyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one; HATU; In N,N-dimethyl-formamide; at 18 - 25℃; for 18h;
1,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 1 g, 4.92 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 620 mg, 5.41 mmol), HAT (2.05 g, 5.41 mmol), DIPEA (2.57 mL, 14.76 mmol) and DMF (10 mL) were combined and stirred at room temperature for 18 hrs. Solvents were evaporated and the resultant material partitioned between DCM and water. Both phases were acidified with 2M aq HCl and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo and the resultant material taken up in DCM and purified on silica eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid. (635 mg, 43%)1H NMR (400.132 MHz, DMSO-D6) delta 1.53 (m, 2H), 1.80 (m, 2H), 1.98 (m, 2H), 2.16 (s, 3H), 2.73 (m, 2H), 3.70 (m, 1H), 7.79 (m, 1H), 8.21 (m, 1H), 8.59 (d, 1H); MS m/z 300 [M+H]+.
43%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 17 - 25℃; for 18h;
A mixture of l,5-difluoro-4-nitrobenzoic acid (1 g), 4-amino-l-methylpiperidine (0.62 g), HATU (2.05 g), DIPEA (2.57 mL) and DMF (10 mL) was stirred at r.t. for 18h and was then concentrated in vacuo. The resultant material partitioned between DCM and 2M aq HCl, both phases were loaded onto a SCX-2 column and washed with MeOH then eluted with 2M NH3 in MeOH. The material obtained was purified by FCC using a gradient of 0-5% (2M NH3 in MeOH) in DCM to afford the title compound (0.63 g, 43%) as a yellow solid; 1H NMR: 1.53 (m, 2H), 1.80 (m, 2H), 1.98 (m, 2H), 2.16 (s, 3H), 2.73 (m, 2H), 3.70 (m, IH), 7.79 (m, IH), 8.21 (m, IH), 8.59 (d, IH); m/z: MH+ 300.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 18 - 25℃; for 18h;
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0-10% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%)1H NMR (399.902 MHz, CDCl3) ?1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, 1H), 4.01 (s, 2H), 5.77 (d, 1H), 6.75 (m, 1H), 7.34 (m, 1H), 7.45 (m, 1H); MS m/z 252 [M+H]+.
100%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 18 - 25℃; for 18h;
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 5Og SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%) 1H NMR (399.902 MHz, CDC13) delta 1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, IH), 4.01 (s, 2H), 5.77 (d, IH), 6.75 (m, IH), 7.34 (m, IH), 7.45 (m, IH); MS m/z 252 [M+H]+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 18 - 25℃;
To a solution of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (Maybridge; 1.05 g, 4.75 mmol) in DMF (20 ml) was added 4-amino-1-methylpiperidine (Fluorochem; 604 mg, 5.29 mmol) followed by DIPEA (1.6 ml, 9.19 mmol) and HATU (2.06 g, 5.42 mmol). The reaction mixture was stirred at ambient temperature O/N. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (75 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The aqueous phase was re-extraced with DCM (50 ml) and the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as an amber gum (1.17 g, 78%)1H NMR (400.132 MHz, DMSO-D6) delta 1.75 (m, 2H), 1.93 (m, 2H), 2.64 (s, 3H), 2.87 (m, 2H), 3.93 (m, 1H), 5.93 (s, 2H), 6.80 (d, 1H), 7.64 (m, 2H), 8.08 (d, 1H); MS m/z 316.4 [M+H]+.
71%
Example 28; 4-Amino-N-(l-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide; <n="88"/>To a suspension of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (900 mg, 4 mmol) in dichloromethane (60 ml) TBTU (1.9 g, 6 mmol) and DIPEA (1.04 ml, 6 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then 1- methylpiperidin-4-amine (513 mg, 4.5 mmol) was added and the reaction was stirred for an additional 3 h. The solution was washed with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH/NH3aq, 9:1 :0.5), to give the title compound (900 mg, 71%), as an orange solid. 1H NMR (400 MHz, DMSO-J6) delta ppm 1.55 (dq, J= 3.90, 3.54 Hz, 2 H) 1.73 (d, J= 14.51 Hz, 2 H) 1.92 - 2.03 (m, 2 H) 2.19 (bs, 3 H) 2.79 (d, J= 10.73 Hz, 2 H) 3.69 (m, IH) 5.89 (bs, 1 H) 6.78 (d, J= 8.54 Hz, 1 H) 7.61 (dd, J= 1.95 Hz, 1 H) 7.64 (m, 1 H) 7.93 (d, J= 7.56 Hz, 1 H).
With 1-(1-pyrrolidinyl-1H-benzotriazol-1-ylmethylene)-pyrrolidinium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide To a solution of 0.5 g (2.3 mmole) of <strong>[175278-22-5]4-amino-3-trifluoromethoxy-benzoic acid</strong>, 0.31 g (2.8 mmole) of 4-amino-1-methyl-piperidine, 1.2 mL (69 mmole) of ethyldiisopropyl amine and 4 mL of dimethylformamide was added the solution of 1.2 g (2.8 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 2 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hour, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluding with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.7 g of 4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide as a white solid.
0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA are dissolved in 5 mL dichloromethane and stirred for 30 minutes at 25 C. Then 50 mg 1-methyl-4-aminopiperidine are added and the mixture is stirred for a further 2.5 hours at 25 C. stirred. The solution is then extracted with water and then evaporated down. The residue is dissolved in warm ethyl acetate and crystallised using ether and petroleum ether. Yield: 0.025 g white crystals.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 3h;Product distribution / selectivity;
0.15 g of the compound 23, 0.12 g TBTU, 0.12 mL DIPEA are dissolved in 5 mL dichloromethane and stirred for 30 minutes at 25C. Then 50 mg l-methyl-4- aminopiperidin are added and the mixture is stirred for a further 2.5 hours at 25C. The solution is then extracted with water and then evaporated down. The residue is dissolved in warm ethyl acetate and crystallised from ether and petroleum ether. Yield: 0.025 g of white crystals. M.p.: 203C as the base.; 0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA are dissolved in 5 mL dichloromethane and stirred for 30 minutes at 250C. Then 50 mg l-methyl-4- aminopiperidin are added and the mixture is stirred for a further 2.5 hours at 25C. The solution is then extracted with water and then evaporated down. The residue is dissolved in warm ethyl acetate and crystallised from, ether and petroleum ether. Yield: 0.025 g of white crystals.
0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA were dissolved in 5 mL dichloromethane and stirred for 30 minutes at 25 C. Then 50 mg 1-methyl-4-aminopiperidin were added and the mixture was stirred for a further 2.5 hours at 25 C. The solution was then extracted with water and then evaporated down. The residue was dissolved in warm ethyl acetate and crystallised from ether and petroleum ether. Yield: 0.025 g of white crystals. M.p.: 203 C. as the base
Step (a) 5-fluoro-2-[(l-methylrhoiperidin-4-yl)amino]nicotinic acid <n="104"/>4-amino-N-methylpiperidine (0.2602 g, 2.28 mmoles), potassium carbonate (0.378 g, 2.74 mmoles), copper (0.015 g, 0.23 mmoles) and copper(I) bromide (0.033 g, 0.23 mmoles) were added to a stirred solution of <strong>[38186-88-8]2-chloro-5-fluoronicotinic acid</strong> (0.4 g, 4.56 mmoles) in l-methyl-2-pyrrolidinone (5 mL). The solution was heated to 120 0C for a period of 3 h then allowed to cool and stir for 48 h, before being applied directly to an SCX column. The column was washed with 200 mL methanol then eluted with 100 mL of 3.5N ammonia/methanol to give the crude product as a yellow oil. This material was dissolved in methanol (25 mL), loaded onto PE-AX resin (4 mL), washed with methanol and then eluted using 10percent acetic acid in methanol (50 mL). The acidic layer was concentrated to give the sub-title compound as a colourless solid (100 mg, 17percent). APCI (Multimode) m/z: 254 [M+H].
N-(1-methylpiperidin-4-yl)-5-nitropyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1-Methylpiperidin-4-amine (358 mg, 3.13 mmol) and NaH (60percent dispersion in mineral oil) (126 mg, 3.13 mmol) were taken up in THF (16 mL) under an atmosphere of dry N2. After stirring at rt for 10 min, <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> 15 (500 mg, 3.13 mmol) was added. The mixture was allowed to stir at rt for 1 h then quenched with 1 N HCl and concentrated to dryness.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 25℃; for 18h;
HATU (6.3 g) was added in portions to a cooled (ice-bath) mixture of 4-amino-3- chlorobenzoic acid (2.57 g), 4-amino-N-methyl-piperidine (1.88 g) and DIPEA (5.2 mL) in DMF (50 mL). The mixture was stirred at r.t. for 18h and was then concentrated in vacuo. The residue was diluted with sat. aq. NaHCO3 (100 mL), and extracted with EtOAc (4 x 50 mL).The combined organic portions were washed with brine (2 x 75 mL), dried (MgSO4) and concentrated in vacuo to afford a gum. Trituration with diethylether afforded the title compound (1.78g, 44% yield ) as a light brown solid; 1H NMR: 1.57-1.70 (2H, m), 1.77- 1.90 (2H, m), 2.40 (3H, s), 3.00-3.10 (2H, d), 3.15-3.50 (4H, m), 3.75-3.88 (IH, m), 5.85 (2H, s), 6.75-6.80 (IH, d), 7.55-7.60 (IH, dd), 7.75 (IH, s), 7.94-8.00 (IH, d); m/z: MH+ 268.
With 1-(1-pyrrolidinyl-1H-benzotriazol-1-ylmethylene)-pyrrolidinium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide To a solution of 1.0 g (5.9 mole) of <strong>[2486-71-7]4-amino-3-chlorobenzoic acid</strong>, 0.8 g (7.0 mole) of 4-amino-1-methyl-piperidine and 4.14 mL (23 mmole) of ethyldiisopropyl amine in 20 mL of dimethylformamide was added a solution of 2.4 g (6.4 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 5 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hours, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluding with dichloromethane-methanol (gradient, 100:0-60:40) gave 1.41 g of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide as a solid.
4~Amino-3-methoxy-N-(l-methyl-piperidin-4-yl)-benzamide; <n="64"/>To <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (1.064 g mg, 6.37 mmol) in dichloromethane (50 ml) was added DIPEA (2.22 ul, 12.74 mmol) and TBTU (2.25 g, 7.0 mmol) and the mixture stirred for 10 minutes. 4-amino-l-methylpiperidine (0.872 g, 7.65 mmol) was added and stirring continued for 16 hours. The resulting soild was filtered and dried under vacuum (1.04 g, 3.95 mmol, 62%).1H NMR (DMSO): 1.54 (2H, m, CH)5 1.68 (2H5 m5 CH), 1.90 (2H, m, CH), 2.15 (3H, s, N-CH3), 2.76 (2H5 d, J 11.5Hz, CH)5 3.66 (IH, m, CH), 3.77 (3H5 S5 OCH3), 6.56 (IH, m5 Ar-H)5 7.26 (IH5 m, Ar-H)5 7.75 (IH5 d, J 7.5Hz); MS (+ve) 264.4; tR = 7.45 min (Vydac 2).
59%
General procedure: Method c: To a mixture of benzoic acid (1.0 equiv.), TBTU (1.1 equiv.), and DCM was added DIPEA (2.0 equiv.). The solution was stirred at room temperature for 30 min followed by the addition of l-methylpiperidin-4-amine (1.2 equiv.). The reaction mixture was further stirred at room temperature overnight. Work-up and product isolation procedure are described below.
59%
General procedure: To a mixture of benzoic acid (1.0 equiv.), TBTU (1.1 equiv.), and DCM was added DIPEA (2.0 equiv.). The solution was stirred at room temperature for 30 min followed by the addition of 1- methylpiperidin-4-amine (1.2 equiv.). The reaction mixture was further stirred at room temperature overnight. Work-up and product isolation procedure are described below.
With benzotriazol-1-ol; triethylamine; In dichloromethane; N,N-dimethyl-formamide; for 20h;
Step 6: 4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide A mixture of <strong>[2486-69-3]4-amino-3-methoxybenzoic acid</strong> (0.334 g), resin supported N-[3-(benzyloxy) propyl]-N'-cyclohexylcarbodiimide (loading 1.2 mmol/g, 2.16 g), HOBT (88%, 0.399 g), triethylamine (0.280 ml) and 1-methylpiperidin-4-amine (0.250 g) in a mixture of dichloromethane (20 ml) and dimethylformamide (4 ml) was shaken for 20 hours. The polymer was filtered off, washed with dichloromethane, acetonitrile and again dichloro-methane. The solution was concentrated and the residue was dissolved in a mixture of ethyl acetate, 1M K2CO3 and a saturated solution of NaCl. The organic phase was separated, dried over Na2SO4 and concentrated to give the title compound as orange solid. 1H NMR (DMSO-d6) delta ppm): 7.75 (d, 1 H); 7.25 - 7.32 (m, 2 H); 6.59 (d, 1 H); 5.17 (s, 2 H); 3.80 (s, 3 H); 3.62 - 3.77 (m, 1 H); 2.76 (d, 2 H); 2.16 (s, 3 H); 1.92 (td, 2 H); 1.66 - 1.81 (m, 2 H); 1.55 (ddd, 2 H). MS (ESI Pos, 3.2 kV, 20 V, 400C): m/z 264,24 (MH+).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 16h;
2-Fluoro-5-methoxy-N-(l-methylpiperidin-4-yl)-4-nitrobenzamide: To a mixture of 2- fluoro-5-methoxy-4-nitrobenzoic acid (53.8 g, 250 mmol), l-methylpiperidin-4-amine (31.4 g, 275 mmol), DIEA (134 mL, 750 mmol) in 1 L of DCM at 0 0C was added HATU (114 g, 300 mmol) in four batches. The reaction mixture was stirred at room temp, for 16 h. After which, it was concentrated and diluted to IL of a mixture of MeOH in water (5%). The suspension was stirred vigorously for 2 h until seen a suspension of fine <n="415"/>powder. The solid was filtered, washed with more water and dried to give 55 g of light yellow product. The filtrate was extracted with EtOAc, concentrated and re-suspended in water (5% of MeOH) and repeating the same procedure as above, after which another batch of solid was obtained (total 67 g, 86%). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.53 (m, 2 H) 1.81 (m, 2 H) 2.04 (m, 2 H) 2.19 (s, 3 H) 2.77 (d, J= 8 Hz, 2 H) 3.73 (m, 1 H) 3.94 (s, 3 H) 7.42 (d, J= 5.6 Hz, 1 H) 7.98 (d, J= 8.8 Hz, 1 H) 8.51 (d, J= 7.6 Hz, 1 H). [M+H] calc'd for Ci4Hi8FN3O4, 312; found 312.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Product distribution / selectivity;
Compound 116: 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(l- methylpiperidin-4-yl)benzamide; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo- 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5- <n="360"/>methoxybenzoic acid and l-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1U NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J=13.8 Hz, 2 H) 4.81 (d, J=8.1 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J=13.4 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5- methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][l,4]diazepin-2-ylamino)-2-fluoro-5- methoxybenzoic acid (obtained above, 12 mg) as described in the general procedure for amide bond synthesis using HATU and l-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base (8 mg, 55percent). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J= 14 Hz, 2 H) 4.81 (d, J= 8 Hz, 1 H) 7.18 (d, J= 7 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J= 13 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
(I-176) To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-methylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluding with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-176).
To a solution of <strong>[367-80-6]ethyl 4-fluoro-3-nitrobenzoate</strong> (2.13 g) and 1-methylpiperidin-4-amine (1.14 g) in tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (5 mL). The mixture was then stirred at reflux overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (300 mL) and washed with aqueous NaHCO3, water and brine. After evaporation of the solvent, the residue was dissolved in tetrahydrofuran (20 mL), methanol (10 mL) and water (10 mL). Then, LiOH H2O (2 g) was added. The mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was neutralized with 5% aqueous HCl. The precipitate was filtered, washed with brine, and dried under vacuum to give the product.
Acetic acid was added to <strong>[202857-89-4]2-benzyloxy-4-fluorobenzaldehyde</strong> (150 mg, 0.65 mmol) and 4-amino-l-methylpiperidine (75 mg, 0.65 mmol) in methanol (10 mL), and the mixture was stirred for 2 h at room temperature. NaCNBH3 (82 mg, 1.3 mmol) was added under N2 atmosphere. The mixture was stirred for 2 h, quenched with aqueous NaOH and concentrated. Water was added and the aqueous solution was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 0.2 g of crude 4-(2-benzyloxy-4-fluorobenzyl)amino-l-methylpiperidine (NMR), which was used in the next step without further purification.
With triethylamine; In dichloromethane; at 20 - 25℃; for 0.5h;
Intermediate 14-Formyl-N-( 1 -methylpiperidin-4-yl)benzenesulfonamide1 step a.4-Formylbenzene-l-sulfonyl chloride (0.5 g, 2.44 mmol) was stirred with l-methyl-4- aminopiperidine (CAS RN 41838-46-4) (0.28 g, 2.47 mmol) and triethylamine (0.5 mL, 3.70 mmol) in DCM (10 mL) at rt for 30 min. When the sulfonyl chloride had been used up by tic the reaction mixture was concentrated to give an orange oil (1.1 g) and used without further purification in the next step.
With 4A molecular sieves; In ethanol; for 4h;Reflux;
59 B1 /-/-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1 -methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (1 OOmL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1 - -benzimidazol-2-ylmethylene)(1 -methylpiperidin-4-yl)amine as a beige solid.
In ethanol; for 4h;Molecular sieve; Reflux;
1 H-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1-methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (100mL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine as a beige solid.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;
EXAMPLE 13: 5-bromo-N-(l-methylpiperidin-4-yl)pyridine-4-amine17To a stirred solution of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (300mg, 1.562mmol) in DMF, DIPEA (400mg, 3.124mmol) was added followed by l-methylpiperidine-4-amine (0.193ml, 1.562mmol) and the reaction mixture was heated at 80 C overnight. TLC showed absence SM, and then reaction mixture was concentrated. The crude product was purified by flash column chromatography over 230-400 mesh silica gel and using a mixture of 30% EtO Ac/petroleum ether to afford the desired product 17, 180mg (Yield: 40 %) as yellow solid. The product was confirmed by 1FiNMR and MS spectrum analysis. 1H NMR (400 MHz, CDC13) delta: 8.4 (s, 1H), 8.35 (s, 1H), 6.81 (d, 1H), 4.95 (m, 1H), 2.78 (d, 2H), 2.17 (s, 3H), 1.95 (t, 2H), 1.6-1.8 (m, 4H); MS- 270 (M+l).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;
EXAMPLE 10: 6-chloro-N-(l-methylpiperidin-4-yl)pyrazin-2-amine11To a stirred solution of 2-bromo-6-chloro pyridine (500mg, 2.58mmol) in DMF, DIPEA was added followed by 4-amino-N-methylpiperidine and was heated at 80 C overnight. Reaction mixture was concentrated and the residue was diluted with water and extracted with ethyl acetate (50ml), the extract was washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. Purification was done by flash column using 230- 400 mesh silica gel eluting with 10% MeOH/DCM system to afford the desired product 11, 95mg (Yield: 14 %) as pale yellow solid. LCMS confirms the mixture of Br/CI isomers, majorly compound 11. 1H NMR (400 MHz, DMSO-d6) delta: 8.41 (s, 1H), 7.95 (s, 1H), 3.70 (s, 4H), 2.89 (s, 2H), 2.73 (bs, 2H), 2.01 (s, 1H), 1.98 (bs, 3H); MS: 226.8 (M+l).
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃;Inert atmosphere;
Add l-bromo-3-nitro-5-(trifluoromethyl)benzene (3 g, 11.11 mmol), CS2CO3 (9.5 g, 27.78 mmol), l-methylpiperidin-4-amine (1.9 g, 16.67 mmol) to 1,4-dioxane (25 mL), then under N2, add Pd(OAc)2 (50 mg, 0.22 mmol) and BINAP (207 mg, 0.33 mmol). Stir the reaction at 120C under N2 overnight. TLC (DCM:MeOH=10:l) shows the reaction is complete. Cool to room temperature and filter off the solid. Concentrate the filtrate to get the crude product. Purification by chromatography (silica gel, DCM:MeOH=10:l) affords the title compound (3.44 g, 99%). MS: (M+l): 304
99%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃;Inert atmosphere;
Add <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (3 g, 11.11 mmol), Cs2CO3 (9.5 g, 27.78 mmol), 1-methylpiperidin-4-amine (1.9 g, 16.67 mmol) to 1,4-dioxane (25 mL), then under N2, add Pd(OAc)2 (50 mg, 0.22 mmol) and BINAP (207 mg, 0.33 mmol). Stir the reaction at 120 C. under N2 overnight. TLC (DCM:MeOH=10:1) shows the reaction is complete. Cool to room temperature and filter off the solid. Concentrate the filtrate to get the crude product. Purification by chromatography (silica gel, DCM:MeOH-10:1) affords the title compound (3.44 g, 99%). MS: (M+1): 304.
A mixture of 1-fluoro-4-nitro-2-trifluoromethyl-benzene (0.3 g, 1.43 mmol) and 1-methyl-piperidin-4-ylamine (0. 73 ml,5.72 mmol) in THF (7 ml) was stirred at r.t. for 4 h. The reaction was poured in a saturated solution of NaHC03 and10 extracted with EtOAc (2 x15 ml). The organic phase was washed with brine, dried with anhydrous Na2S04 andevaporated under vacuum to obtain the title compound (0.41 g, 95percent) as yellow solid.1H NMR (600 MHz, DMSO-dG) o ppm 1.63- 1.75 (m, 2 H) 1.82 (d, J=11.17 Hz, 2 H) 2.01 - 2.07 (m, 2 H) 2.17 (s, 3 H)2.73 (d, J=11.54 Hz, 2 H) 3.52-3.64 (m, 1 H) 6.05 (d, J=7.88 Hz, 1 H) 7.09 (d, J=9.16 Hz, 1 H) 8.20-8.25 (m, 2 H).
With acetic acid; at 160℃;Inert atmosphere; Autoclave;
General procedure: To a pressure bottle containing <strong>[82437-64-7]methyl 3-amino-4-phenylthiophene-2-carboxylate</strong> (100 mg, 0.43 mmol), CH(OEt)3 (1 mL) was added, followed by allylamine hydrochloride (93 mg, 0.99 mmol) and AcOH (0.1 mL). The reaction mixture was stirred and refluxed at 160 C overnight. After the reaction, the mixture was evaporated then solidified with ether. The produced white crystals were filtered and dried in vacuo to give the title compound 4-1 (66 mg, 0.25 mmol, 58 % yield): 1HNMR (300 MHz, CDCl3) delta 8.11 (s, 1H), 7.84-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 6.08-5.95 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.67 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z: calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05
N-(1-methylpiperidin-4-yl)isoquinoline-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; for 24h;
192A. N-(l-Methylpiperidin-4-yl)isoquinoline-5-carboxamide: To isoquinoline- 5-carboxylic acid (0.22 g, 1.270 mmol) and l-methylpiperidin-4-amine (0.145 g, 1.270 mmol) in EtOAc (3 mL)/DMF(l mL) was added TEA (0.48 mL, 3.464 mmol) and a 50% EtOAc solution of T3P (0.306 mL, 1.082 mmol). After 24h, the reaction was partitioned with water (15 mL) and ethyl acetate (50 mL). The organic layer was washed with brine (10 mL) and dried (MgS04). MS (ESI) m/z: 270.1 (M+H)+.
6-chloro-2-(1-methyl-piperidin-4-ylamino)-nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; for 3h;
[0040 In a microwave vial containing 2,6-Dichloro-nicotinamide (200.00 mg; 1.05 mmol; 1.00 eq.) and 1-methyl-piperidin-4-ylamine (179.34 tl; 1.26 mmol; 1.20 eq.) in N,N-dimethylacetamide (2.00 ml; 21.76 mmol; 20.79 eq.) was added DIPEA (0.35 ml; 2.09 mmol; 2.00 eq.). The reaction was stirred at 85C for 3h before it was concentrated and caffied to the next step. MS: mlz = 269 [M+H]+.
N-((5-bromo-2-methoxypyridin-3-yl)methyl)-1-methylpiperidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 22h;
5-Bromo-2-methoxynicotinaldehyde (472 mg, 2.18 mmol) and 1-methylpiperidin-4- amine (249 mg, 2.18 mmol) were stirred in methanol (10 mL). Acetic acid (0.12 mL) and sodium cyanoborohydride (137 mg, 2.18 mmol) were then added and the mixturewas stirred at room temperature for 22 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a saturated aqueous sodium hydrogen carbonate solution. The phases were separated. The aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated under reducedpressure to give 647 mg (94% yield) of the title compound.LRMS (M+1): 314, 3161H NMR (400 MHz, Chloroform-d) 6 ppm 1.44 (2H, m), 1.88 (2H, m), 2.26 (3H, s), 2.43(1 H, m), 2.81 (2H, m), 3.73 (2H, s), 3.93 (3H, s), 7.69 (1 H, d, J = 2.4 Hz), 8.08 (1 H, d, J= 2.4 Hz)
3-chloro-5-[(1-methylpiperidin-4-yl)amino]methyl}phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18.5h;
A mixture of <strong>[1829-33-0]3-chloro-5-hydroxybenzaldehyde</strong> (0.540 g, 3.46 mmol) and 1-methyl piperidin-4-amine (0.434 mL, 3.46 mmol) in dichloromethane (20 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1 .46 g, 6.91 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueoussolution of sodium hydrogencarbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated todryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:1) to yield the title compound (0.85 g, 97%).LRMS (mlz): 255 (M+1).
N-{4-[(1-methylpiperidin-4-yl)amino]cyclohexyl}acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 14h;
In room temperature, to 772mg 4-amino-1-methylpiperidine (piperine) (CAS41838-46-4) and1g <strong>[27514-08-5]N-(4-oxo-cyclohexyl)acetamide</strong> (CAS27514-08-5) in 10ml 1,2-dichloroethane and 0.37ml of acetic acid was added in portions 2.05g sodium triacetoxyborohydride. Stirred for 14 hours, is then added to a 1N solution of sodium hydroxide. The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with a saturated solution of sodium chloride, dried over sodium sulfate, and the complete removal of the solvent in vacuo. The residue was re-dissolved in ethyl acetate, the resulting precipitate was suction filtered. To give 3.8g crude product as N-{4-[(1-methylpiperidin-4-yl)amino]cyclohexyl}acetamide cis / trans isomer mixture, which was used without further purification for subsequent reactions.UPLC-MS: Instrument: WatersAcquityUPLC-MSSQD; Column: AcquityUPLCBEHC181.750x2.1mm; Eluent A: Water + 0.2% by volume of ammonia (32%), Eluent B: acetonitrile; gradient: 0-1.6min1-99% B, 1.6-2.0min99% B; flow rate of 0.8ml / min; temperature: 60 ; Injection: 2mul; DADScan: 210-400nm.
To a solution of N,N-di-CBZ-1H-pyrazole-1-carbamidine (3.0 g, 7.9 mmol) in THF (20 mL) was added 1-methylpiperidin-4-amine (1.1 g, 9.5 mmol) at 25 C. The reaction was stirred for 12 hrs at 25 C. The mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography to obtain compound 66 (2.0 g, 43% yield) as a white solid.
3-iodo-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; at 130℃;
Into a 50 mL round-bottom flask, a mixture of 4-chloro-3-iodo-1- (4-methoxybenzyl) -1H-pyrazolo [4, 3-c] pyridine (3.0 g, 7.5 mmol) , 1-methylpiperidin-4-amine (2.57 g, 22.5 mmol) and DIEA (3.87 g, 30 mmol) was stirred at 130 overnight. Then the reaction was concentrated in vacuo and the residue was purified with silica gel chromatography eluting with DCM/MeOH gradient to give the 3-iodo-1- (4-methoxybenzyl) -N- (1-methylpiperidin-4-yl) -1H-pyrazolo [4, 3-c] pyridin-4-amine (2.7 g, 75) as a brown solid. m/z (ESI)+: 478 [M+H]+.
With methanol; sodium cyanoborohydride; acetic acid; at 20℃; for 20h;pH 5;
Example 2 Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine Preparation (Option 2) Reacting 4-fluorobenzaldehyde (1.25 g; 10 mmol; 1.0 eq) and 1-methylpiperidin-4-amine (1.13 g; 10 mmol; 1.0 eq) in the presence of NaCNBH3 (0.83 g; 12.2 mmol) in methanol/acetic acid mixture (40 ml) at pH 5 during about 20 hours under ambient conditions leads to N-(4-fluorobenzyl)-1-methylpiperidin-4-amine formation. The reaction mixture is concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase is made basic by addition of Na2CO3. The aqueous phase is extracted twice with dichloromethane. The combined organic layers are collected and dried with Na2SO4. Concentration afforded N-(4-fluorobenzyl)-1-methylpiperidin-4-amine.
6-bromo-N-(1-methylpiperidin-4-yl)quinoline-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120 - 150℃; for 64h;Microwave irradiation;
General procedure: A solution of 4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline (Intermediate 4) (0.15 g, 0.35 mmol, 1.0 eq.), (S)-3-(Boc-amino)piperidine (0.14 g, 0.7 mmol, 2.0 eq.), DIPEA (0.09 g, 0.7 mmol, 2.0 eq.) in i-PrOH (3 mL) was heated at 140 C. under microwave irradiation for 1.5 h. After cooling to rt, solvent was evaporated and the crude reaction mixture was used in consecutive step without further purification (UPLC purity: 71%).
4-(chloromethyl)-N-(1-methylpiperidin-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6h;
General procedure: 4.1.1.1. 4-(Chloromethyl)-N-cyclopropylbenzamide (3a). A mixtureof 4-(chloromethyl)benzoic acid (2) (1.0 g, 5.9 mmol), cyclopropanamine(0.824 g/mL, 5.9 mmol), EDCI (7.1 mmol) and HOBt (7.1 mmol) was stirred in anhydrous DCM (20 mL) for 6 h at roomtemperature. After the reaction was finished, the mixture was filteredand filtrate was evaporated in vacuo, the crude productwas further purified by column chromatography on silica gel toyield compound 3a (92%) as a white solid.
methyl 3-fluoro-4-((1-methylpiperidin-4-yl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 12h;Inert atmosphere;
General procedure: To a stirring solution of methyl-5-bromopicolinate (0.5g, 2.31mmol) in anhydrous toluene (15mL) were added 1-methylpiperidin-4-amine (0.26g, 2.31mmol), Pd(OAc)2 (0.22g, 0.1mmol), BINAP (0.62g, 0.1mmol) and Cs2CO3 (1.37g, 2.2mmol) under an argon atmosphere. Reaction was stirred at 90C for 12h. Upon completion, the reaction mixture was filtered over Celite and rinsed with ethyl acetate. The mixture was extracted with ethyl acetate (40mL×3). Then, the combined organic phase was concentrated in vacuo and purified by silica gel column chromatography (EA: MeOH=20 : 1) to afford compound 22a as a white solid.
N-[(6-chloro-2-methoxypyridin-3-yl)methyl]-1-methylpiperidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
To a solution of <strong>[95652-81-6]6-chloro-2-methoxypyridine-3-carbaldehyde</strong> (95 mg, 0.55 mmol) in MeOH (2 mL) was added l-methylpiperidin-4-amine (63 mg, 0.55 mmol) at room temperature. The resulting solution was stirred for 30 min at room temperature and then was added by AcOH (0.03 mL, 0.50 mmol) and sodium boranecarbonitrile (35 mg, 0.56 mmol) in sequence at room temperature. The resulting mixture was stirred for 22 h at room temperature. When the reaction was done, the reaction mixture was quenched by sat. Na2C03 solution (10 mL). The resulting mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure to yield N-[(6- chloro-2-methoxypyridin-3-yl)methyl]- l-methylpiperidin-4-amine as colorless oil (131 mg, 87 %). MS: m/z = 270.1 [M + H]+.
4-(4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used
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