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CAS No. : | 7144-05-0 | MDL No. : | MFCD00006007 |
Formula : | C6H14N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LTEKQAPRXFBRNN-UHFFFAOYSA-N |
M.W : | 114.19 | Pubchem ID : | 23527 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 38.27 |
TPSA : | 38.05 Ų |
GI absorption : | High |
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) : | -7.28 cm/s |
Log Po/w (iLOGP) : | 1.6 |
Log Po/w (XLOGP3) : | -0.4 |
Log Po/w (WLOGP) : | -0.44 |
Log Po/w (MLOGP) : | 0.21 |
Log Po/w (SILICOS-IT) : | 0.72 |
Consensus Log Po/w : | 0.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.23 |
Solubility : | 67.2 mg/ml ; 0.589 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.06 |
Solubility : | 133.0 mg/ml ; 1.16 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.08 |
Solubility : | 9.54 mg/ml ; 0.0836 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3259 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
70% | at 25℃; | A solution of piperidinyl-4-methylamine (3.6 g) and N-tert-butoxycarbonylimidazole (5.3 g) in toluene (80 mL) was stirred at 25° C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 227-I (4.7 g) in a 70percent yield. Intermediate 227-I (4.7 g) and Et3N (2.7 mL) in 1-pentanol (20 mL) was reacted with 2,4-dichloro-6-aminopyrimidine (5.4 g) at 120° C. for 12 hours. After the solvent was removed, the residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 227-II (5.2 g) in a 70percent yield. A solution of Intermediate 227-II (1.0 g) treated with 1 M HCl (20 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 8 hours. After the solution was concentrated, the resultant residue was neutralization with NH4OH, and extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-III (636 mg) in a 90percent yield. Intermediate 222-III (790 mg) prepared from Example 222 was added to a solution of Intermediate 227-III (450 mg) in MeOH (20 mL). The mixture was stirred at 25° C. for 2 hours. NaBH(OAc)3 (2.0 g) was then added at 25° C. for 12 hours. After the solution was concentrated, a saturated aq. NaHCO3 solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-IV (539 mg) in a 60percent yield. N1-Morpholine-N1-piperazine ethane (240 mg) was added to a solution of Intermediate 227-IV (160 mg) in 1-pentanol (1 mL). The mixture was stirred at 120° C. for 8 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=5/1) to afford Intermediate 227-V (85 mg) in a 40percent yield. A solution of 20percent TFA/CH2Cl2 (1 mL) was added to a solution of Intermediate 227-V (85 mg) in CH2Cl2 (1 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21percent NH3 (aq)/MeOH=1/19) to afford Compound 227 (65 mg) in a 90percent yield. Compound 227 was then treated with 1 M HCl (1 mL) in CH2Cl2 (1 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 227. CI-MS (M++1): 544.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate; ethanethiol In dichloromethane for 16h; Ambient temperature; Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In ethanol at 120℃; for 0.25h; Microwave irradiation; | 3 (E)-N-benzylidene-1-(piperidin-4-yl)methanamine 10075] (E)-N-benzylidene-1 -(piperidin-4-yl)methanamine3. A mixture of piperidin-4-ylmethanamine (1.48 mE,12.3 mmol) and benzaldehvde (1.28 mE, 12.3 mmol) in ethanol (9.4 mE) was heated at 120° C. for 15 mm under microwave condition then solvent was removed in vacuo to give (E)-Nbenzylidene-l-(piperidin-4-yl)methanamine 3 as a yellow oil (2.71 g, 91%) and used without further purification. |
In toluene for 3h; Heating; | ||
In toluene at 120℃; for 4h; Dean-Stark trap; | 3.A 4-(Benzylidineaminomethyl)piperidine Step A 4-(Benzylidineaminomethyl)piperidine 4-Aminomethylpiperidine (11.4g) (1 equivalent) is dissolved in anhydrous toluene (125ml) and benzaldehyde (10.6g) (1 equivalent) is added. The mixture is heated at 120°C under reflux for 4h, using a Dean-Stark trap to remove water. The crude solution of the title compound is used directly in Step B below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium sulfate In chloroform at 20℃; for 24h; | |
84.7% | In ethanol at 120℃; for 0.25h; Microwave irradiation; | |
In tetrahydrofuran Ambient temperature; Yield given; |
In ethanol for 24h; Heating; | ||
In toluene at 5℃; Heating; | ||
In toluene Heating; | ||
In toluene for 12h; Heating; | ||
In toluene for 2h; Heating; | ||
In toluene Heating; | ||
In toluene at 20℃; for 3h; | 1.a EXAMPLE 1; 2- (4- AMINOMETHYL-PIPERIDYL)-N-PHENYLACETAMIDE DIHVDROCHLORIDE; (AF3R279); (Compound II : R3=R4=R5=R6=R7=R8=H, X=C (O) NH); a) N-HEXAHYDRO-4-PYRIDYLMETHYL-N-PHENYLMETHYLIDENEAMINE N-HEXAHYDRO-4-PYRIDYLMETHYL-N-PHENYLMETHYLIDENEAMINE Benzaldehyde (12.7 g; 0.12 mol) was added dropwise to a solution of 4-aminomethylpiperidine (13.7 g; 0.12 mol) in toluene (50 ml). The solution thus obtained was stirred at room temperature. After 3 hours, the solvent was removed by evaporation under reduced pressure and the residue was taken up twice with toluene (2 x 50 ML). N-HEXAHYDRO-4-PYRIDYLMETHYL-N-PHENYLMETHYLIDINEAMINE (25 g) was thus obtained, and was used without further purification. | |
In toluene at 20℃; for 3h; | 1.A.a BENZALDEHYDE (38.2 g, 0.36 moles) was added dropwise to a solution of 4-aminomethyl-piperidine (41.1 g, 0. 36 MOLES) in toluene (180 ML). The solution thus obtained was left at room temperature with stirring for 3 hrs. The solvent was then removed by evaporation under reduced pressure and the residue was taken up twice with toluene to give the desired product which was used without further purification. | |
In toluene at 20℃; for 3h; | 1c 1c) 1 -[1 -(2-Phenylethyl)-4-piperidinvNmethanamine (Compound Xl: R3 = R4 = H, R6+R7 = -CH2-CH2-, n = 1 , p = 2, m = 2). Benzaldehyde (28.0 g; 0.264 mol) was added, dropwise, to a solution of 4-aminomethylpiperidine (30.2 g; 0.264 mol) in toluene (100 ml). The solution thus obtained was kept stirred at room temperature. After 3 h, the solvent was removed by evaporation at reduced pressure and the residue was taken up twice in toluene. 53.4 g of N-hexahydro-4- pyridinylmethyl-N-phenylmethylidenamine was thus obtained, and was used in subsequent reaction without further purification.N-Hexahydro-4-pyridinylmethyl-N-phenylmethylidenamine (53.4 g; 0.264 mol) was dissolved in absolute ethanol (500 ml) containing anhydrous potassium carbonate (73.0 g; 0.528 mol) and phenethyl bromide (39.5 ml; 0.290 mol). The reaction mixture thus obtained was boiled under reflux for 24 h. After cooling to room temperature, the suspension was filtered and the solvent was evaporated at reduced pressure. The residue thus obtained was suspended in 3N HCI (200 ml) and stirred at room temperature for 2 h. The acidic aqueous phase was washed 4 times with ethyl acetate and then alkalized to pH approx. 13 with 6N NaOH and extracted with dichloromethane. The organic phase thus obtained was dried over anhydrous Na2SO4 and the solvent was removed by evaporation at reduced pressure.50.0 g of 1-[1-(2-phenylethyl)-4-piperidinyl]methanamine was thus obtained.1H-NMR (δ, CDCI3): 1.3-1.4 (m, 5H); 1.7-1.8 (m, 2H); 1.9-2.1 (m, 2H); 2.5-2.6 (m, 4H); 2.7-2.9 (m, 2H); 2.9-3.1 (m, 2H); 7.1-7.3 (m, 5H). | |
In toluene for 1.5h; Inert atmosphere; Reflux; | ||
In toluene at 25℃; for 3h; | ||
In toluene at 20℃; for 3h; | 1.a EXAMPLE 1; (N((4-nitrophenyl)ethyl)-4-piperidinyl)methyl)-1H-indazole-3-carboxamide hydrochloride (AF3R298) (I, Ra = Rb = Rd = H; Rc = 4-NO2; X = C(O)NHCH2); a) N-hexahydro-4-pyridinylmethyl-N-phenylmethylideneamine; Benzaldehyde (4.6 g; 0.044 mol) was added dropwise to a solution of 4-aminomethylpiperidine (5.0 g; 0.044 mol) in toluene (20 mL). The solution thus obtained was stirred for 3 h at room temperature. Then the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene to give the desired product that was used as such without further purification. | |
In ethanol for 24h; Reflux; | ||
In ethanol for 24h; Reflux; | ||
2.71 g | In ethanol at 120℃; for 0.25h; Microwave irradiation; | 1-5 Example 1 Dissolve 4-aminomethylpiperidine (1.48mL, 12.3mmol) and benzaldehyde (1.28mL, 12.3mmol) in 9.5mL of ultra-dry absolute ethanol, then microwave at 120 for 15min, concentrate the solvent, and dry it to obtain 2.71g of the compound of formula II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide; In dichloromethane; at 0 - 20℃; for 24h; | A solution of 2-mesitylenesulfonyl chloride (19.49 g, 89.1 mmol) in CH2Cl2 (100 ml) was added to 4-(aminomethyl)piperidine (1) (5.15 g, 45.1 mmol) in 1 N NaOH (100 ml) at 0 C. After the addition was complete, the biphasic mixture was stirred for 24 hours (0 C. to room temperature). The layers were separated and the aqueous portion was extracted with CHCl3 (2×). The combined organic phase was washed with 0.5 N HCl (200 ml) and H2O (100 ml), dried with sodium sulfate and evaporated in vacuo. Recrystallization from aqueous ethanol produced 18.72 g (88%) of (2) as plates: mp 158.5-160 C.; NMR (CDCl3/TMS) delta0.8-2.0 (m, 5H), 2.25 (s, 6H), 2.46-2.93 (m+2s, 16H), 3.37-3.65 (m, 2H), 4.67 (t, 1H, J=6), 6.90 (s, 4H). Anal. calcd. for C24H34N2O4S2: C, 60.22, H, 7.16, N, 5.85. Found: C, 60.31, H, 7.19, N, 5.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In chloroform at 0 - 20℃; for 48h; | 5.a To a solution of 4-(aminomethyl)piperidine (100 g, 0.88 mol) in CHCI3 (550 ml_), cooled at 0 °C and under Ar-atmosphere, a solution of di-te/t-butyl dicarbonate (98 g, 0.45 mol) in CHCI3 (350 ml_) was added. The resulting mixture was stirred at room temperature for 48 h, washed with H2O and the aqueous phase extracted with CHCI3. The combined organic phases were dried over Na2SO4 and the solvents were removed to afford 84.5 g of the title compound (88 % yield). 1H NMR (80MHz, CDCI3) δ (TMS): 4.11 (broad d, J = 13.4 Hz, 2 H), 2.69 (m, 4 H), 1.45 (s, 9 H), 1.8-0.8 (complex signal, 7 H). |
86.5% | Stage #1: 4-Aminomethylpiperidine With benzaldehyde In toluene for 4h; Heating / reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate In toluene at 20℃; Stage #3: With potassium hydrogensulfate; water at 20℃; for 4h; | 28 Example 28 Preparation of intermediate 4-aminomethyl-1-(tert-butoxycarbonyl) piperidine Benzaldehyde (8.73 g, 82.3 mmol) was added all at once to a stirred solution of 4- aminomethylpiperidine (9.42 g, 82.3 mmol) in toluene (100 ml). The mixture was heated under reflux for 4 h with a Dean-Stark trap attached to collect the water. The reaction mixture was cooled to room temperature and di-tert-butyldicarbonate (19.75 g, 90.5 mmol) was added in divided portions under continuously stirring. The mixture was stirred overnight, evaporated in vacuo and the residue stirred vigorously with aqueous 1 N KHS04 (100 ml) at room temperature for 4 h. The mixture was extracted with Et20 (3 x 100 ml) and then the aqueous layer was made strongly basic with NaOH. The aqueous layer was extracted with CHzCIz (3 x 100 ml). The combined extracts were dried with Na2504, filtered and the solvent evaporated in vacuo to leave the product as an oil (15.4 g, 86.5 %). H-NMR (200 MHz, DMSO-d6) : 8 4.04-4. 01 (m, 2 H), 2,60 (t, 2 H), 2.50 (d, 2 H), 1.62 (d, 2 H), 1.32 (s, 9 H), 1.31-1. 28 (m, 1 H), 1.06 (br s, 2 H), 1.03-0. 93 (m, 2 H) |
36% | In chloroform at 20℃; for 18h; |
In chloroform for 18h; | ||
With sodium hydroxide; potassium hydrogensulfate; benzaldehyde; sodium chloride In toluene | 43 Preparation of 1-tert-butoxycarbonyl-4-aminomethylpiperidine (51) Example 43 Preparation of 1-tert-butoxycarbonyl-4-aminomethylpiperidine (51) 4-Aminomethylpiperidine (2.28 g; 20 mmol) is dissolved in dry toluene (25 mL) at ambient temperature. Benzaldehyde (2.03 mL; 20 mmol) is added in one portion and the solution is heated to azeotropic reflux for 135 minutes (with concommitant removal of water from the reaction medium). The reaction mixture is cooled to ambient temperature then di-tert-butyl dicarbonate (4.8 g; 22 mmol) is added portionwise and the resulting solution is stirred at ambient temperature for 64 hours. The solution is concentrated to dryness in vacuo at 40° C., then 1N KHSO4 (22 mL) is added to the residue and the resulting mixture is stirred rapidly at ambient temperature for 4 hours. The mixture is extracted with ether (3*20 mL), then the aqueous layer is basicified with 1N NaOH (30 mL). Solid NaCl is added to the alkaline aqueous layer, then it is extracted with dichloromethane (3*30 mL). The organic extracts are dried (MgSO4), filtered, and concentrated in vacuo affording the title compound (3.34 g) as a light colored liquid. ESMS: MH+ 215.4 | |
With triethylamine In chloroform | 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) EXAMPLE 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) A solution of C-piperidin-4-yl-methylamine (1) (5.0 g, 44 mmol) and triethylamine (12 ml 88 mmol) in 150 ml of chloroform was cooled to 0° C. To this solution was added dropwise ditertbutyldicarbonate (8.6 g, 40 mmol) in 100 ml of chloroform. After stirring at room temperature for 24 hours the solution was washed with water, dried over MgSO4, filtered and the solvents removed in vacuo to give the title compound 1 NMR (CDCl3, 400 MHz) 4.20-4.00 (br m, 2H), 2.75-2.62 (br t, 2H), 2.60 (d, 2H), 1.75-1.65 (br m, 2H), 1.50-1.30 (m, 3H), 1.63 (s, 9H), 1.20-1.00 (m, 2H). | |
In chloroform | R.1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine REFERENCE EXAMPLE 1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine To a cooled (0° C.) solution of 4-(aminomethyl)piperidine (40 g, 0.35 mol) in CHCl3 (300 mL) was added a solution of di-tert-butyl dicarbonate (39.2 g, 0.17 mol) in CHCl3 (300 mL) and the reaction mixture was stirred at room temperature for 48 h. The resulting solution was washed with H2 O and the aqueous phase was reextracted with CHCl3. The combined organic phases were dried over sodium sulphate and the solvent was removed to afford 54.1 of a crude product, which was directly used in the next step as obtained. 1 H NMR (80 MHz, CDCl3) δ(TMS): 4.11 (broad d, J=13.4 Hz, 2H), 2.69 (m, 4H), 1.45 (s, 9H), 1.8-0.8 (complex signal, 7H). | |
With sodium hydroxide; sodium monohydrogen sulfate; benzaldehyde In toluene | l 1-[(1,1-Dimethylethoxy)carbonyl]-4-aminomethyl piperidine 1-[(1,1-Dimethylethoxy)carbonyl]-4-aminomethyl piperidine A mixture of 4-aminomethyl piperidine (100 g, 0.88 mol) and benzaldehyde (102 g, 0.96 mmol) in toluene (1.5 L) was heated to reflux with a Dean-Stark trap for 1 hr, cooled to 5oC, and treated with a solution of di-t-butyl-dicarbonate (200 g, 0.92 mol) in toluene (700 mL). The mixture was stirred at room temperature overnight, treated with 1 M sodium hydrogen sulfate (1 L) and stirrred for 3 hr. The layers were separated, and the aqueous layer was washed with ether (3 X 250 mL), made basic with sodium hydroxide (50% solution) and extracted with ether (3 X 500 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 218.7 g of 1-[(1,1-dimethylethoxy)carbonyl]-4-aminomethyl piperidine as an oil. | |
In chloroform | R.1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine REFERENCE EXAMPLE 1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine To a cooled (0° C.) solution of 4-(aminomethyl)piperidine (40 g, 0.35 mol) in CHCl3 (300 mL) was added a solution of di-tert-butyl dicarbonate (39.2 g, 0.17 mol) in CHCl3 (300 mL) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was washed with H2 O and the aqueous phase was reextracted with CHCl3. The combined organic phases were dried and concentrated to a crude product (54.1 g), which was directly used in the next step as obtained. 1 H NMR (80 MHz, CDCl3) δ (TMS): 4.11 (broad d, J=13.4 Hz, 2H), 2.69 (m, 4H), 1.45 (s, 9H), 1.8-0.8 (complex signal, 7H). | |
In chloroform at 0 - 20℃; for 18h; | 4.3 Step 3 tert-Butyloxycarbonyl anhydride (6.69 g, 30.6 mmol) was added to a solution of 4-(aminomethyl)piperidine (7 g, 61.3 mmol) in chloroform (40 ml) at 0° C. The reaction mixture was allowed to warm to room temperature over 3 h and then stirred an additional 15 h.. The reaction mixture was washed with water, the organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide N-tert-butyloxy-carbonyl-4-(aminomethyl)piperidine (6.55 g) as a pale yellow oil. | |
In chloroform at 0 - 20℃; | 11.A Part AA solution of 4-(aminomethyl)piperidine (10 g, 87.6 mmol) in chloroform (60 mL) was chilled in an ice water bath. A dicarbonate (9.6 g, 43.8 mmol) in chloroform (37 mL) was added dropwise over a period of 30 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature over the weekend. The reaction was quenched with water (10O mL). The organic layer was dried EPO over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 9 g of (erf-butyl 4-(aminomethyl)piperidine-l-carboxylate. | |
With triethylamine In 1,4-dioxane; water | XIII 4-Aminomethyl-1-tert-butyloxycarbonylpiperidine EXAMPLE XIII 4-Aminomethyl-1-tert-butyloxycarbonylpiperidine 19 g of di-tert-butyl dicarbonate and 12 ml of triethylamine are added to 10 g of 4-aminomethylpiperidine in 120 ml of a dioxane/water (1:1) mixture at 0° C. and the mixture is stirred at room temperature for 12 hours. The dioxane is then distilled off in a rotary evaporator, and the aqueous phase is extracted six times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is purified by chromatography on an alumina column with methylene chloride/methanol=50:1. Yield: 7.4 g (39% of theory),; Rf: 0.48 (alumina; methylene chlorid/methanol=10:1) The following compound is obtained in analogy to Example XIII: | |
In tetrahydrofuran | 174.1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester Step 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester To a mixture of 15 g of 4-aminomethylpiperidine in 250 mL of anhydrous tetrahydrofuran cooled to -78° C. was added dropwise over 45 min a solution of 24 g of di-tert-butyl di-carbonate in 100 mL of anhydrous tetrahydrofuran. After stirring for 1 h at -78° C., the mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated to near dryness and diluted with 200 mL of 10% aqueous citric acid. The mixture was extracted with 3*100 mL of ether, then made basic with sodium hydroxide pellets and extracted with 3*200 mL of chloroform. The combined chloroform extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure. The resulting oil was homogeneous by TLC (development with 90:10 chloroform saturated with ammonia: methanol). 1H NMR (400 MHz, CDCl3): 4.1 (br s, 2 H), 2.7 (br m, 2H), 2.6 (d, 2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | at 170℃; for 1h; | |
Stage #1: phthalic anhydride; 4-Aminomethylpiperidine at 160℃; for 4h; Stage #2: With hydrogenchloride In ethanol | 5.4. Preparation of 2-(piperidin-4-ylmethyl)isoindoline-1,3-dione(21b) Phthalic anhydride (8.8 mmol, 1 eq) and 4-(aminomethyl)piperidine (8.8 mmol, 1 eq) were heated at 160 C for 4 h. Theresulting dark brown solid was dissolved in 1 N HCl in absoluteethanol (6 mL), then the solvent was removed under vacuum. Thecompound was obtained as a white hydrochloride salt via crystallizationwith absolute ethanol, yield 25%; m.p. 214 C dec. 1HNMR (300 MHz, DMSO-d6) d (ppm): 1.37e1.46, 1.73e2.01 and2.70e3.28 (m, 9H, piperidine), 3.47 (d, 2H, NCH2CH), 7.83e7.91 (m,4H aromatics). ESI-MS m/z: (IP: positive) 249 [MH]. | |
Stage #1: phthalic anhydride; 4-Aminomethylpiperidine at 160℃; for 4h; Stage #2: With hydrogenchloride In ethanol | 5.4. Preparation of 2-(piperidin-4-ylmethyl)isoindoline-1,3-dione(21b) Phthalic anhydride (8.8 mmol, 1 eq) and 4-(aminomethyl)piperidine (8.8 mmol, 1 eq) were heated at 160 C for 4 h. Theresulting dark brown solid was dissolved in 1 N HCl in absoluteethanol (6 mL), then the solvent was removed under vacuum. Thecompound was obtained as a white hydrochloride salt via crystallizationwith absolute ethanol, yield 25%; m.p. 214 C dec. 1HNMR (300 MHz, DMSO-d6) d (ppm): 1.37e1.46, 1.73e2.01 and2.70e3.28 (m, 9H, piperidine), 3.47 (d, 2H, NCH2CH), 7.83e7.91 (m,4H aromatics). ESI-MS m/z: (IP: positive) 249 [MH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h; | |
99% | In tetrahydrofuran at 20℃; for 12h; | 10 Example 10; 15: Neat 4-aminomethylpiperidine (1 mL, 7 mmol) was added to a clear solution of 14 (849 mg, 1.18 mmol) in THF (80 mL). The solution was stirred at RT for 12 h. The solvent was removed in vacuo, and then the residue was taken up in CH2Cl2 (100 mL). The solution was washed with water (3×150 mL), and then dried with MgSO4. Following filtration, the solvent was removed in vacuo to afford the product as a pure white foam. Yield: 940 mg (99%). 1H NMR (300 MHz, CDCl3) □: 5.77 (br, 2H, NH), 5.53 (br, 2H, NH), 4.68 (d, 2JH-H=13 Hz, 2H, amp-NCH2), 3.64 (br, 4H, Boc-NCH2), 3.55 (br, 4H, Boc-NCH2), 3.30 (br, 8H, CH2NHBoc), 2.76 (pseudo t, 2JH-H=13 Hz, 2H, amp-NCH2), 2.57 (d, 3JH-H=6 Hz, 2H, amp-CH2), 1.76 (br d, 2JH-H=11 Hz, 2H, amp-NCH2CH2), 1.4 (m, 1H, buried under tBu proton peaks, amp-CH), 1.40 (s, 18H, C(CH3)3), 1.38 (s, 18H, C(CH3)3), 1.11 (q of d, 2JH-H=11 Hz, 3JH-H=4 Hz, 2H, amp-NCH2CH2). 13C{1H} NMR (75.5 MHz, CDCl3) □: 165.8 (s, C3N3), 164.0 (s, C3N3), 156.1 (s, C(O)), 156.0 (s, C(O)), 78.8 (s, C(CH3)3), 78.6 (s, C(CH3)3), 47.7 (s, Boc-NCH2), 47.0 (s, Boc-NCH2), 46.2 (s, amp-NCH2), 43.0 (s, amp-CH2), 40.6 (s, CH2NHBoc), 39.7 (s, amp-CH), 38.1 (s, CH2NHBoc), 29.6 (s, amp-NCH2CH2), 28.2 (s, C(CH3)3). MS (MALDI): calcd 795.5331 (M+); found 796.5796 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.5% | In ethanol for 3h; Heating; | |
In chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In acetonitrile; at 60℃; | After dissolving 4-aminomethylpiperidine (5.754 ml, 50 mmol) in acetonitrile (200 ml), potassium carbonate (13.82 g, 100 mmol) and benzyl chloride (17.13 g, 150 mmol) were added and the mixture was stirred at 60C overnight. Upon completion of the reaction, the reaction mixture was filtered and the solvent was distilled off. A developing solvent (CH2Cl2/MeOH/NEt3 = 90/5/5) was used for purification by silica gel column chromatography to obtain (1-benzyl-4-piperidyl)methylamine. The compound was identified by LC-MS. Yield: 9.277 g (91%), M+1 = 205.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In acetonitrile at 60℃; | 1.1.1 Reference Example 1-1-1; Synthesis of C-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine After dissolving 4-aminomethyl-piperidine (10 g) in acetonitrile (250 ml), 3,4-dichlorobenzyl chloride (5.8 g) and potassium carbonate (5 g) were added at room temperature, and the mixture was stirred at 60°C overnight. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/triethylamine = 85/7/7) to obtain C-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine. The compound was identified by LC-MS. Yield: 6 g (75%), Purity: 100%, Found: ESI/MS m/e 273.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium carbonate; In acetonitrile; at 20℃; | 4-Piperidinemethanamine (0.65 mol) and potassium carbonate (96 g) were stirred inacetonitrile (1000 ml) and then a solution of 2-(methylsulfonyl)- 5-pyrimidinecarboxylic acid, ethyl ester (0.37 mol) in acetonitrile (500 ml) was addeddropwise at room temperature over 1 hour. The reaction mixture was stirred overnightat room temperature and the solvent was evaporated. The residue was stirred in waterand the mixture was extracted with DCM (2 x 500 ml). The organic layer wasseparated, washed with water, dried (MgSO4), filtered off and the solvent wasevaporated. The residue was purified by column chromatography over silica gel (eluent1 : EtOAc/Hexane 1/1; eluent 2: MeOH + small amount of NH4OH). The productfractions were collected, stirred with potassium carbonate slurry and the mixture wasextracted with DCM. The organic layer was separated, dried (MgSCU), filtered off andthe solvent was evaporated, yielding 31 g (32 percent) of intermediate 85. |
32% | With potassium carbonate; In acetonitrile; at 10 - 20℃; for 2h;Inert atmosphere; | A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.0434 mol) in acetonitrile (100 ml) was added dropwise at 10° c. to a solution of 4-piperidinemethanamine (0.0868 mol) and potassium carbonate (0.0434 mol) in acetonitrile (200 ml) under N2 flow. The mixture was stirred at room temperature for 2 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (14.18 g) was purified by column chromatography over silica gel (20-45 mum)(eluent: DCM/MeOH/NH4OH 90/10/1 to 80/20/2). The pure fractions were collected and the solvent was evaporated, yielding 3.7 g (32percent) of intermediate 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in DMA(80ml) was added dropwise to a solution of 4-piperidinemethanamine (0.116 mol) andjV-ethyldiisopropylamine (0.145 mol) in DMA (150ml) under NI flow. The mixture wasstirred at room temperature for 1 hour and 30 minutes, poured out into ice water andextracted with EtOAc, then with DCM. The organic layer was washed with water, dried(MgSOa), filtered and the solvent was evaporated. The residue was crystallized fromDIPE. The precipitate was filtered off and dried, yielding lOg (65%) of intermediate45. |
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in DMA (80ml) was added dropwise to a solution of 4-piperidinemethanamine (0.116 mol) and TV-ethyWV-(l-methylethyl)- 2-propanamine (0.145 mol) in DMA (150ml) under N2 flow. The mixture was stirred at room temperature for 1 hour and 30 minutes, poured into ice water and extracted with EtOAc, then with DCM. The organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 1Og (65%) of intermediate 31. |
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | Example A6; a).Preparatipn.of intermediate 32; A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in /V5TV- dimethyl- acetamide (80ml) was added dropwise to a solution of 4- piperidinemethanamine (0.116 mol) and TV-ethyl -TV-(I -methyl ethyl)- 2-propanamine (0.145 mol) in TV^N-dimethyl- acetamide (150ml) under N2 flow. The mixture was stirred at room temperature for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc, then with DCM. The organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 1Og (65%) of intermediate 32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; benzaldehyde; In tetrahydrofuran; dichloromethane; toluene; | Step 1 Preparation of Benzyl 4-(aminomethyl)piperidine-1-carboxylate 4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368 mmol) in toluene (600 mL) were heated to reflux under dean stark conditions for 2 h. The resulting reaction mixture was cooled to room temperature and 500 mL dichloromethane was added. The resulting solution was cooled to 5 C. and treated with N-(benzyloxycarbonyloxy)succinimide (91.7 g, 368 mmol). After 10 min, the cooling bath was removed and the reaction mixture stirred for 1 h. The solvents were evaporated and the resulting residue was stirred with 400 mL THF and 400 mL 2 M HCl for 1 h. The mixture was concentrated to remove organics and was then extracted with ether (3*300 mL). The aqueous phase was adjusted to pH14 with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give benzyl 4-(aminomethyl)piperidine-1-carboxylate as an oil. 1H-NMR 500 MHz (delta, CDCl3) delta7.4-7.2 (m, 5H); 5.12 (s, 2H); 4.20 (brs, 2H); 2.77 (brs, 2H); 2.58 (d, J=6.6 Hz, 2H) 1.9-1.7 (m, 2H); 1.0-1.5 (m, 5H). | |
With hydrogenchloride; benzaldehyde; In tetrahydrofuran; dichloromethane; toluene; | Step 1 Benzyl 4-(aminomethyl)piperidine-1-carboxylate 4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368 mmol) in toluene (600 mL) were heated to reflux under Dean Stark conditions for 2 h. The resulting reaction mixture was cooled to room temperature and 500 mL dichloromethane was added. The resulting solution was cooled to 5 C. and treated with N-(benzyloxycarbonyloxy)succinimide (91.7 g, 368 mmol). After 10 min, the cooling bath was removed and the resulting reaction mixture stirred for 1 h. The solvents were evaporated and the residue stirred with 400 mL THF and 400 mL 2M HCl for 1 h. The mixture was concentrated to remove organics and extracted with ether (3*300 mL). The aqueous phase was adjusted to pH14 with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give benzyl 4-(aminomethyl)piperidine-1-carboxylate as an oil. 1H NMR (500 MHz CDCl3) delta: 7.4-7.2 (m, 5H); 5.12 (s, 2H); 4.20 (brs, 2H); 2.77 (brs, 2H); 2.58 (d, J=6.6 Hz, 2H) 1.9-1.7 (m, 2H); 1.0-1.5 (m, 5H). | |
With hydrogenchloride; benzaldehyde; In tetrahydrofuran; dichloromethane; toluene; | Step 1 Benzyl 4-(aminomethyl)piperidine-1-carboxylate 4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368 mmol) in toluene (600 mL) were heated to reflux under dean stark conditions for 2 h. The reaction mixture was cooled to room temperature and 500 mL dichloromethane added. The solution was cooled to 5 C. and treated with N-(benzyloxycarbonyloxy)succinimide (91.7 g, 368 mmol). After 10 min., the cooling bath was removed and the reaction mixture stirred for 1 h. The solvents were evaporated and the residue stirred with 400 mL THF and 400 mL 2M HCl for 1 h. The mixture was concentrated to remove organics and extracted with ether (3*300 mL). The aqueous phase was adjusted to pH14 with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give benzyl 4-(aminomethyl)piperidine-1-carboxylate compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With ammonia In methanol; dichloromethane | 210 4-(N-(4-Chlorophenyl))aminomethylpiperidine (, entry 11) 4-(N-(4-Chlorophenyl))aminomethylpiperidine (, entry 11) Using the general procedure, 4-bromochlorobenzene (192 mg, 1.0 mmol) was coupled with 4-aminomethylpiperidine (171 mg, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using methanol/dichloromethane (saturated with ammonia) (1:20) as eluent afforded the desired product as a light yellow solid (138 mg, 62% yield). Rf=0.3 (methanol/dichloromethane (saturated with ammonia) (1:20)). |
60% | With ammonia In methanol; dichloromethane | 212 4-(N-(4-Chlorophenyl))aminomethylpiperidine (, entry 7) 4-(N-(4-Chlorophenyl))aminomethylpiperidine (, entry 7) Using the general procedure, 4-bromochlorobenzene (192 mg, 1.0 mmol) was coupled with 4-aminomethylpiperidine (171 mg, 1.5 mmol) at 100° C. for 20 h. Purification of the crude product by column chromatography on silica gel using methanol/dichloromethane (saturated with ammonia) (1:20) as eluent afforded the desired product as a light yellow solid (134 mg, 60% yield). Rf=0.3 (methanol/dichloromethane (saturated with ammonia)=1:20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
potassium carbonate; In water; toluene; | EXAMPLE 4 1-(1-methylbenzimidazol-2-yl)-4-aminomethyl-piperidine 27 g of 4-aminomethylpiperidine are placed in 300 ml of anhydrous toluene in the presence of 33 g of potassium carbonate and of 33 g of 1-methyl-2-chlorobenzimidazole. The mixture is subjected to reflux for 48 hours. After evaporation, the residue is taken up in ether and an excess of hydrochloric ether. The precipitate formed is spun down, washed with ether, and then taken up in 750 ml of water and 30% caustic soda is added to give a basic pH. The expected product is then extracted with dichloromethane. After drying, the organic phase is filtered and evaporated. The oil thus obtained is purified by chromatography on silica gel (eluding solvent: dichloromethane/methane/ammonia: 9/1/0.1). Melting point: 106 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With dmap In dichloromethane at 25℃; for 23h; | 5.A 4-(N-Benzyloxycarbonylaminomethyl)piperidine Step A 4-(N-Benzyloxycarbonylaminomethyl)piperidine 4- Aminomethylpiperidine (1 g; 1 equivalent) and DMAP (0.054g; 0.05 equivalents) are dissolved in anhydrous dichloromethane (40 ml). N-Benzyloxycarbonylimidazole (1.7709g; 1 equivalent) [prepared as described in: S. K. Sharma, M. J. Miller and S. M. Payne, J. Med. Chem., 32, 357-367 (1989)] is added and the mixture is stirred at 25°C for 23 h. The solution is diluted with dichloromethane and washed with 1.0N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a silica gel column (60X2.5cm) using 3% increasing to 7% (10% concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (1.0719g; 49% yield), FABMS: m/z 249.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine In water; butan-1-ol | 9 Example 9 Example 9 7-(4-aminomethylpiperidin-1-yl)-4-[2-(4-chlorophenyl)ethylamino]-6-nitroquinazoline (compound 9) 7-Chloro-4-[2-(4-chlorophenyl)ethylamino]-6-nitroquinazoline (100 mg, 0.275 mmol) obtained in Reference example 5 was suspended in n-butanol (5 ml). To this suspension, 4-(aminomethyl)piperidine (157 mg, 1.38 mmol) and N,N-diisopropylethylamine (240 μl, 1.38 mmol) were added, and the mixture was stirred at 120 °C for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added with water (20 ml), and the solution was stirred at room temperature for 30 minutes. The suspension was filtered to give 81 mg (yield 67%) of the title compound as yellow orange crystal. 1H-NMR(DMSO-d6) δ(ppm): 8.82(s,1H), 8.63-8.59(br.-t,1H), 8.45(s,1H), 7.36-7.29(m,4H), 7.18(s,1H), 3.73(dt,2H, J=7.2,5.7Hz), 3.28-3.26(m,2H), 2.94(t,2H,J=7.2Hz), 2.87-2.75(m,2H), 2.50-2.45(m,2H), 1.80-1.76 (m,2H), 1.59-1.15 (m,5H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; benzaldehyde; In isopropyl alcohol; toluene; acetonitrile; | Example 1 [[4-(Aminomethyl)-l-piperidinyl]iminomethyl]carbamic acid, phenylmethyl ester A 500-mL, round-bottomed flask equipped with Dean-Stark trap was sequentially charged with 4-aminomethylpiperidine (14.84 g, 129.96 mmole), toluene (250 mL), and benzaldehyde (14.98 g, 141.16 mmole). The mixture was heated to reflux under an argon atmosphere and stirred overnight (18 h). The reaction was cooled to room temperature and the toluene was removed in vacuo. Residual toluene was removed under high vaccuum to provide 28.14 g of the title compound as an orange oil (quantitative yield). The crude product was carried directly into the next step. A 500-mL, round-bottomed flask was sequentially charged with Part A Schiff base (21.20 g, 104.8 mmole), acetonitrile (200 mL), <strong>[152120-62-2][imino(1H-pyrazol-1-yl)methyl]carbamic acid, phenylmethyl ester</strong> (31.50 g, 128.96 mmole) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (18 mL, 120.36 mmole). After stirring for five minutes, the solution became clear yellow. The reaction was heated to 50 C and stirred under a nitrogen atmosphere for 16 h. After the reaction had cooled to room temperature, 12N hydrochloric acid (36 mL, 432 mmole, reaction mixture reached pH 1) was added over 20 minutes. The reaction was stirred for 2.5 h at room temperature. The mixture was concentrated in vacuoto a yellow oil and isopropanol (35 mL) was added. With stirring, acetonitrile (250 mL) was added resulting in the separation of an oil. The mixture was heated to 40 C providing a clear solution which was seeded. Within five minutes a white solid crystallized from solution. The slurry was stirred for an additional 40 minutes at 40C and then cooled to room temperature and stirred overnight. The product was collected by filtration and washed with 1:1 ethyl acetate/hexane (1 X 100 mL), 1:3 ethyl acetate/hexane (1 X 100 mL), and hexane (3 X 100 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In acetonitrile | [Reference Example 18] Synthesis of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine [Reference Example 18] Synthesis of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine K2CO3(3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol) were successively added to an acetonitrile (100 mL) solution of 4-(aminomethyl)piperidine (7.00 g, 61.3 mmol). The resulting reaction mixturewas stirred at 60 °C for 16 hours, cooled to 25 °C and concentrated. The obtained residue was fractionated between dichloromethane (75 mL) and water (50 mL) and then washed with water (50 mL*2) and brine (50 mL*1). The organic layer was dried (over MgSO4), concentrated and then purified by chromatography (SiO2, 4% H2O-iPrOH) to provide 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (3.58 g, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzaldehyde; In toluene; | Step A 1-Benzyloxycarbonyl-4-(aminomethyl)piperidine To a solution of 4-(aminomethyl)piperidine (200 mg, 1.75 mmol) in toluene (2.3 mL) was added benzaldehyde (178 muL, 1.75 mmol) and the reaction mixture was refluxed for 3 h with azeotropic removal of water. The reaction mixture was cooled and dibenzyl dicarbonate (471 muL, 1.92 mmol) was added dropwise. After stirring overnight, toluene was removed under reduced pressure and the residue was stirred in 1NKHSO4 (2 mL) for 5 h. The residue was washed with Et2O (discarded) then made strongly basic (>pH 12) with SN NaOH. The aqueous layer was extracted with CH2Cl2 (4 times), and the combined extracts were washed with brine. After drying (Na2SO4) and removal of the solvent under reduced pressure, 340 mg of the title compound was obtained. Partial 1H NMR (500 MHz, CDCl3): delta 7.38-7.27 (m, 5H); 5.1 (s, 2H); 4.19 (br s, 2H); 2.76 (br s, 2H); 2.57 (d, J=6.5 Hz 2H); 1.69 (brm, 2H); 1.44 (m, 1H); 1.09 (brm, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In toluene; at 25℃; | A solution of piperidinyl-4-methylamine (3.6 g) and N-tert-butoxycarbonylimidazole (5.3 g) in toluene (80 mL) was stirred at 25 C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 227-I (4.7 g) in a 70% yield. Intermediate 227-I (4.7 g) and Et3N (2.7 mL) in 1-pentanol (20 mL) was reacted with 2,4-dichloro-6-aminopyrimidine (5.4 g) at 120 C. for 12 hours. After the solvent was removed, the residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 227-II (5.2 g) in a 70% yield. A solution of Intermediate 227-II (1.0 g) treated with 1 M HCl (20 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 8 hours. After the solution was concentrated, the resultant residue was neutralization with NH4OH, and extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-III (636 mg) in a 90% yield. Intermediate 222-III (790 mg) prepared from Example 222 was added to a solution of Intermediate 227-III (450 mg) in MeOH (20 mL). The mixture was stirred at 25 C. for 2 hours. NaBH(OAc)3 (2.0 g) was then added at 25 C. for 12 hours. After the solution was concentrated, a saturated aq. NaHCO3 solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-IV (539 mg) in a 60% yield. N1-Morpholine-N1-piperazine ethane (240 mg) was added to a solution of Intermediate 227-IV (160 mg) in 1-pentanol (1 mL). The mixture was stirred at 120 C. for 8 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=5/1) to afford Intermediate 227-V (85 mg) in a 40% yield. A solution of 20% TFA/CH2Cl2 (1 mL) was added to a solution of Intermediate 227-V (85 mg) in CH2Cl2 (1 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Compound 227 (65 mg) in a 90% yield. Compound 227 was then treated with 1 M HCl (1 mL) in CH2Cl2 (1 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 227. CI-MS (M++1): 544.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS); | All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With LiHMDS at 20℃; for 17h; | |
84% | With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); sodium t-butanolate In 1,4-dioxane at 80℃; for 15h; Inert atmosphere; chemoselective reaction; | |
73% | With 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; sodium t-butanolate In toluene at 110℃; for 12h; Inert atmosphere; Glovebox; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In 2-dimethylamino-acetamide at 20℃; for 1.5h; | 11e Step 11e: Ethyl 2-(4-(aminomethyl)piperidin-1-yl)pyrimidine-5-carboxylate (Compound 0406) A mixture of 0405 (1.10 g, 5.9 mmol), piperidin-4-ylmethanamine (1.35 g, 11.8 mmol) in 2-(dimethylamino)acetamide (50 mL) was stirred at room temperature for 1.5 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (CH3OH in CH2Cl2 6% v/v) to give desired product 0406 (1.27 g, 81%): LCMS: 265 [M+1]+, 1H NMR (400 MHz, CDCl3): δ 1.16 (m, 2H), 1.22 (m, 5H), 1.36 (m, 1H), 1.64 (m, 1H), 1.85 (d, J=12 Hz, 2H), 2.62 (d, J=6.42 Hz, 2H), 2.94 (ds, J=12.8 Hz, J=2.4 Hz, 2H), 4.91 (d, J=11.2 Hz, 2H), 7.26 (s, 1H), 8.82 (s, 2H). |
81% | In N,N-dimethyl acetamide at 20℃; for 1.5h; | 11.11a Step 11a: Ethyl 2-(4-(aminomethyl)piperidin-l-yl)pyrimidine-5-carboxylate(Compound 0401)A mixture of 0405 (1.10 g, 5.9 mmol), piperidin-4-ylmethanamine (1.35 g, 11.8 mmol) in 2-(dimethylamino)acetamide ( 50 mL) was stirred at room temperature for 1.5 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (CH30H in CH2C12 6% v/v) to give desired product 0401 (1.27 g, 81%): LCMS: 265 [M+l]+, 1H NMR (400 MHz, CDC13): ^ 1.16 (m, 2H), 1.22(m, 5H), 1.36 (m, 1H), 1.64 (m, 7H), 1.85 (d, J= 12 Hz, 2H), 2.62 (d, J= 6.42 Hz, 2H), 2.94 (ds, J= 12.8 Hz, J= 2.4 Hz ,2H), 4.91 (d, J= 11.2 Hz, 2H), 7.26(s, 1H) , 8.82 (s, 2H). |
81% | In N,N-dimethyl acetamide at 20℃; for 1.5h; | 11.11a Step 11a: Ethyl 2-(4-(aminomethyl)piperidin-1-yl)pyrimidine-5-carboxylate (Compound 0401) Step 11a: Ethyl 2-(4-(aminomethyl)piperidin-1-yl)pyrimidine-5-carboxylate (Compound 0401)[0222]A mixture of 0405 (1.10 g, 5.9 mmol), piperidin-4-ylmethanamine (1.35 g, 11.8 mmol) in 2-(dimethylamino)acetamide (50 mL) was stirred at room temperature for 1.5 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (CH3OH in CH2Cl2 6% v/v) to give desired product 0401 (1.27 g, 81%): LCMS: 265 [M+1]+, 1H NMR (400 MHz, CDCl3): δ 1.16 (m, 2H), 1.22 (m, 5H), 1.36 (m, 1H), 1.64 (m, 1H), 1.85 (d, J=12 Hz, 2H), 2.62 (d, J=6.42 Hz, 2H), 2.94 (ds, J=12.8 Hz, J=2.4 Hz, 2H), 4.91 (d, J=11.2 Hz, 2H), 7.26 (s, 1H), 8.82 (s, 2H). |
81% | In N,N-dimethyl acetamide at 20℃; for 1.5h; | 11a Ethyl 2- (4- (aminomethyl) piperidin-1-yl) pyrimidine-5-carboxylate (Compound 0401) 2- (dimethylamino) acetamide (50mL) 0405 (1.10g, 5.9mmol), piperidine -4- A mixture of ylmethanamine (1.35g, 11.8mmol) and the mixture was stirred for 1.5 hours at room temperature. Removal of the solventAfter the residue was purified on silica gel by column chromatography (including CH3OH CH2C12 6% v / v), to give the desired product 0401 (1.27g, 81%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran at -5 - 0℃; for 2.5h; | 2; 3 4-aminomethyl piperidine (2) (6.365 g) is dissolved in tetrahydrofuran. The solution obtained is cooled to between -5°C and 00C, and a solution containing 10 g of Boc-D-Phe-OSu is added under stirring, in portions, in approx. 2.5 hours. 30 minutes after the end of the addition, when the disappearance of the Boc-D-Phe-OSu has been verified, the temperature is allowed to rise to ambient temperature and toluene is added, washing with 10% aq. Na2CO3 (2 x). A solvent change is then performed: at low pressure, part of the toluene is evaporated, cyclohexane is added (to a toluene: cyclohexane ratio of 2:3), and the mixture is cooled at 00C for 2 hours. The suspension obtained is filtered and washed with cyclohexane, and the solid is stove-dried under vacuum at 45°C to obtain 9.18 g of compound (17). Yield 92.0% HPLC purity: 95.2%1H-NMR (DMSO-d6, 200 MHz): δ (ppm) 0.84-0.98 (m, 2H),1.24 (bs, IH, NH), 1.30 (s, 9H,), 1.35-1.55(m, 3H), 2.28-2.41 (m, 2H), 2.70-2.78 (dd, IH), 2.80-3.00 (m, 5H), 4.07-4.17 (m, IH), 6.88 (d, IH), 7.1-7.3 (m, 5H), 7.82 (brt, IH) MS: m/z: 191 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | Example 7. Synthesis of N-[(piperidin-4-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were added to DMF (500mL) with stirring at about 0C and stirred for 1.5 hrs, then piperidin-4-yl-methylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mLx3), the combined organic phase was washed with saturated salt water (300mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 158.3g (602mmol) of N-[(piperidin-4-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 60.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | In dichloromethane at 0 - 20℃; | 33 2-Chloroacetic chloride (4.5g, 40mmol) was added drop by drop to a solution of 4-aminomethylpiperidine (4.56g, 40mmol) in dichloromethane (50mL) with stirring at about 0°C. Afterwards, the reaction was warmed to room temperature and stirred until completion was indicated by thin layer chromatography (TLC). The solvent was distilled off to give 6.74g (35.68mmol) of an oily residue. Yield 89.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 25% 2: 48% | With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; | B53 Preparation of compound 84 and intermediate 75 A mixture of intermediate 5b (700 mg; 1.48 mmol), 4-(aminomethyl)piperidine (337 mg; 2.95 mmol) and Cs2C03 (962 mg; 2.95 mmol) in DMF (28 mL) was heated at 100°C for 3 h. The r.m. was cooled to r.t., poured onto iced water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude residue was purified by chromatography over silica gel (Irregular SiOH 15-40μιη 300g; mobile phase: gradient from 1 % NH4OH, 90% DCM, 10% MeOH to 1.5% NH4OH, 85% DCM, 15% MeOH). The pure fractions were collected and evaporated to dryness to give respectively 365 mg (48%) of intermediate 75 and 200 mg (31 %) of an oily residue which was crystallized from ACN. The precipitate was filtered off and dried, yielding 160 mg (25%) of compound 84 (MP: 159X DSC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran at -5 - 0℃; for 2.5h; | 3 (R)-tert-butyl 1-oxo-3-phenyl-1-(piperidin-4-ylmethylamine)propan-2-ylcarbamate (17) 4-aminomethyl piperidine (2) (6.365 g) is dissolved in tetrahydrofuran.The solution obtained is cooled to between -5° C. and 0° C., and a solution containing 10 g of Boc-D-Phe-OSu is added under stirring, in portions, in approx. 2.5 hours. 30 minutes after the end of the addition, when the disappearance of the Boc-D-Phe-OSu has been verified, the temperature is allowed to rise to ambient temperature and toluene is added, washing with 10% aq. Na2CO3 (2*). A solvent change is then performed: at low pressure, part of the toluene is evaporated, cyclohexane is added (to a toluene:cyclohexane ratio of 2:3), and the mixture is cooled at 0° C. for 2 hours.The suspension obtained is filtered and washed with cyclohexane, and the solid is stove-dried under vacuum at 45°C. to obtain 9.18 g of compound (17). Yield 92.0% HPLC purity: 95.2% 1H-NMR (DMSO-d6, 200 MHz): δ (ppm) 0.84-0.98 (m, 2H), 1.24 (bs, 1H, NH), 1.30 (s, 9H,), 1.35-1.55 (m, 3H), 2.28-2.41 (m, 2H), 2.70-2.78 (dd, 1H), 2.80-3.00 (m, 5H), 4.07-4.17 (m, 1H), 6.88 (d, 1H), 7.1-7.3 (m, 5H), 7.82 (brt, 1H) MS: m/z: 191 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 2-chlorotrityl chloride resin (0.05 mmol, 75 mg, 0.67 mmol/g) was swelled by stirring in CH2Cl2 (5 mL) at 25 C for 30 min. Next, a pre-mixed solution of Fmoc-Lys-OAllyl·HCl salt (0.5 mmol, 222.4 mg) and N,N?-diisopropylethylamine (DIPEA, 0.5mmol, 88 muL) pre-dissolved in anhydrous CH2Cl2 (5 mL) was added to the resin and allowed to react at 25 C, 30 min. Unreacted reagents and solvent were removed by filtration and the resin washed with DMF (15 x 3 mL) and CH2Cl2 (15 x 3 mL) followed by DMF (15 x 3 mL). Next, 20% piperidine in DMF (v/v, 5 mL) was added to the resin. The mixture was subjected to microwave irradiation while stirring at60C for 10 min. Unreacted reagents and solvent were removed by filtration and theresin washed with DMF (15 x 3 mL) and followed by CH2Cl2 (15 x 3 mL). Next, a premixed solution of Ac-Lys(Boc)-OH (0.5 mmol, 144 mg), DIC (0.25 mmol, 27 muL) and HOBt (0.25 mmol, 33.8 mg) dissolved in 90% CH2Cl2 in DMF (v/v, 5 mL) wasadded to the resin and the mixture was subjected to microwave irradiation while stirring at 60 C for 10 min. Unreacted reagents and solvent were removed by filtration and the resin washed with DMF (15 x 3 mL) and CH2Cl2 (15 mL) followed by CHCl3 (15 x 3 mL). The -OAllyl protecting group was removed by adding a premixed solution of Pd0[P(Ph3)4] (5 mol %, 3 mg), phenylsilane (0.05 mmol, 7 muL) in 5mL anhydrous CHCl3 and microwaved at 40C for 30 min. This step was repeated. Excess reagents and solvent were drained and the resin was washed with CHCl3 (15 x 3 mL) followed by CH2Cl2 (15 x 3 mL). In the next step, a pre-mixed solution of theappropriate diamine (0.5 mmol), DIC (0.25 mmol, 27 muL) and HOBt (0.25 mmol,33.8 mg) dissolved in 90% CH2Cl2 in DMF (v/v, 5 mL) was added to the resin. The reaction mixture was subjected to microwave irradiation while stirring at 60 C for 10 min. Unreacted reagents and solvent were removed by filtration and the resin washedwith CH2Cl2 (15 x 3 mL), DMF (15 x 3 mL) followed by CH2Cl2 (15 x 3 mL). Next, guanidinylation was conducted using a pre-mixed solution of N,N?-bis(tertbutoxycarbonyl)thiourea (0.5 mmol, 146 mg), DIPEA (0.5 mmol, 88 muL) and DMF (5 mL) was added to the resin and the reaction mixture subjected to microwave irradiation while stirring at 60 C for 10 min. Unreacted reagents were removed by filtration and the resin washed with DMF (15 x 3 mL) and CH2Cl2 (15 x 3 mL). The target was cleaved from the resin using 95% TFA in CH2Cl2 (v/v, 1.5 mL) at 25 C over 30 min. Excess TFA was removed by a stream of N2 (g) to yield a colorless oil which was dissolved in MeOH (1 mL) and purified by HPLC (C18 column, H2O and CH3CN solvent). Target compounds were lyophilized in vacuo to give white powders (10-20 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium sulfate In chloroform at 0℃; | Synthesis of (E)-N-ethylidene-1-(piperidin-4-yl)methanamine intermediate. To a mixture of 4-(aminomethyl)piperidine (1.00 g, 8.76 mmol) and anhydrous Na2SO4 (1.56 g, 11,0 mmol) in CHCl3 (50 mL) at 0°C, were slowly added 0.39 g (8.76 mmol) of acethaldehyde previously dissolved in a small amount of chloroform. The reaction was allowed to perform overnight and monitored by TLC. The inorganic salt was removed by filtration and the residue was concentrated in vacuum to afford 1.17 g (8.34 mmol) of the corresponding Shiff base as a light-yellow oil. Oil. Yield: 95%. 1H NMR (CDCl3/TMS) ppm (δ): 1.06 (d, 3H,CH3), 1.45 (broad s. 1H, NH disappearing on deuteration), 1.50-3.20 (m, 9H, pip.), 7.60 (m, 1H, =CH). MS: m/z 141 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere; | General Procedure for the synthesis diadamantyl biureas 1a-f from adamantyl isocyanate and diamines General procedure: To a solution of 1-isocyanatemethyl adamantane (1mmol) in DMF (10 mL) was added corresponding diamine (0.45 equiv) at 0°C. The reaction mixtures were allowed to slowly warm to room temperature overnight.The reaction mixtures were poured into water, and the resulting precipitates were collected and washed with 1 N HCl solution followed by water. The crude product was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In dichloromethane at 20℃; for 16h; | General procedure D: Synthesis of PMP-protected N-substituted pantothenamides to generate 55a-d, f-j, l,) General procedure: NHS ester 54 (143 mg, 0.33 mmol) was dissolved in DCM (5 ml). The appropriate amine (0.66 mmol) was added and the reaction mixture was stirred at room temperature for 6-16 h depending on the amine. Evaporation of the solvent under vacuum and purification of the crude product on silica gel yielded the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With methanol at 20℃; for 12h; diastereoselective reaction; | General synthetic procedure and characterization data for selected heterocyclicaminoparthenolide compounds: General procedure: To a stirred solution of parthenolide (50 mg,0.201 mmol) in methanol (2 mL), was added the appropriate heterocyclicamino compound (16.53 mg, 0.201 mmol). The reaction mixture was stirred at ambient temperature for 15 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the crude compound, water (5 mL) was added to the crude compound and extracted with dichloromethane (2 5 mL). The organic layer was dried over Na2SO4 and concentrated to afford pure compound (6b) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With water In 1,4-dioxane at 120℃; for 12h; Sealed tube; | S1.2.6. N'-Substituted ethyl 1,2-diaminoethylphosphonates (11, Alk = Et) General procedure: To the aziridinephosphonate 5 (0.2 mmol, 36 mg), dissolved in 3 mL of H2O/dioxan (5:1), 200μL (5-15 molar excess) of an amine NH2R1 (for the structure of R1 see Scheme 1 and Table 1)was added. The reaction mixture was stirred in a sealed reactor, heated in an oil bath at 120°Cfor 12 h. Volatile components were evaporated under reduced pressure. An excess of highlyvolatile amines was extracted by appropriate organic solvent. The obtained crude ammoniumsalts of ethyl 1,2-diaminoethylphosphonates (water phase) were purified by HPLC (WatersSpherisorb S10ODS2 column, flow 10 mL/min, gradient A:B 100:025:75 in 30 min), tR: 22.5min (11c), 19.5 min (11d), 25.2 min (11g), 20.9 min (11h), 24.5 min (11i), 27.8 min (11j), 24.5min (11k), 19.5 min (11l), 18.2 min (11m), 25.3 min (11n), 26.2 min (11p), 27.2 min (11q),22.5 min (11r), 22.5 min (11s), 23.6 min (11t) and 25.6 min (11u). For the yields see Table S1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 2-bromo-5-(4-chlorophenyl)-1,3,4-oxadiazole; 4-Aminomethylpiperidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 3h; Stage #2: With hydrogenchloride In diethyl ether; ethyl acetate at 0 - 20℃; | 30 30. 5-(4-Chlorophenyl)-N-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-amine (E-30) 2-Bromo-5-(4-chlorophenyl)-1,3,4-oxadiazole (0.150 g, 0.578 mmol), 4-(aminomethyl)piperidine (0.176 mL, 1.734 mmol) and DIPEA (0.3 mL, 1.734 mmol) in DMF (3 mL) were heated to 70 °C for 3 h in which time the solution changed from yellow to orange. On reaction completion, the mixture was diluted in EtOAc (50 mL) and washed with H20 (30 mL). The organic layer was collected and washed with H20 (2 x 30 mL) and brine (1 x 30 mL) before being collected, dried (MgSO4), filtered and concentrated to a yellow semi-solid (0.177 g). Crude material was then triturated in Et20 and filtered to produce an orange solid (0.143 g). To remove impurities, this solid was further dissolved in EtOAc (4 mL), and 2.0M HC1 in diethyl ether (1 mL) was added at 0 °C. The mixture was left to stir at rt overnight before being filtered and washed with EtOAc, forming a light brown solid (0.054 g, 43% yield). Mp = 191 °C. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H, NH), 8.90 (d, = 6.7 Hz, 2H, CH), 8.08 (d, = 6.6 Hz, 2H, CH), 7.82 (d, = 8.7 Hz, 2H, CH), 7.62 (d, = 8.7 Hz, 2H, CH), 4.81 (s, 2H, CH2). 13C NMR (101 MHz, DMSO) δ 163.35 (C), 159.92 (C), 157.82 (C), 141.45 (CH), 135.75 (C), 129.78 (CH), 127.42 (CH), 125.45 (CH), 123.03 (C), 45.61 (CH2). LCMS Rf (min) = 3.185 MS m/z 287.1 (M + H). HR-ESI calcd for C14H16ClN302+ (M + H) 287.0694, found 287.0706. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With toluene-4-sulfonic acid In toluene at 150℃; for 12h; Microwave irradiation; | General Procedure1: Procedure for the synthesis ofcompounds 4-10, 13-18, 20, 25-30 and 32-52 and 66. General procedure: Spirothiazamenthane 3 (1.0 eq) was dissolved in toluene (0.1 M concentration) in a microwave vial and the solution was treated with amine (10 eq) and PTSA (20 mol %). This mixture was heated at 150 °C using microwaves for 4 h. After cooling, the solvents were removed by evaporation and the resulting residue was taken up in 1:1 Et2O/2M NaOH. The layers were separated and the aqueous layer was extracted 2 × with Et2O. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude products were purified as described below. Variations in reaction conditions are also noted below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 72h; | Preparation of Triazine Compound (Curing agent 2) 15.0 g of cyanuric chloride was dissolved in solvent tetrahydrofuran (150 ml) to which N, N- diisopropylethylamine 21.1g and methoxy ethylamine 12.2g were added and the mixture was stirred at room temperature for 72 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. After the extract was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure to give compound 6-chloro-N2, N4- bis (2-methoxyethyl)-1,3,5-triazine-2,4-diamine 10.8g (51% yield). This compound 10.0g was dissolved in 150ml of tetrahydrofuran, 9.9g diisopropylethylamine, 4- (aminomethyl) piperidine 8.75g and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, added water and extracted with ethyl acetate. After the extract was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1 containing 2% triethylamine) to give compound 6-(4-(aminomethyl)piperidin-1-yl)-N2, N4- bis(2-methoxyethyl)-1,3,5-triazine-2,4-diamine 7.94g (61% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 24h; | Preparation of Triazine Compound (Curing agent 3) 4.21g of cyanuric chloride was dissolved in the solventtetrahydrofuran (50ml), to this 5.9g of N, N- diisopropylethylamine, and 3-methylthiopropylamine 4.8g were added and the mixture was stirred at room temperature for4 days. Water was added to the reaction mixture, after the precipitation of thetarget substanceby suction filtration, to obtain compound 6-chloro-N2, N4- bis (3-(methylthio) propyl)1,3,5-triazine-2,4-diamine6.54g (89% yield). This compound was dissolved in tetrahydrofuran50ml, diisopropylethylamine 6.57g and 4- (aminomethyl) piperidine 5.8g wereadded and the mixture was stirred at room temperature for 24 hours. After concentratingthe reaction solution,water was added and extracted with ethyl acetate.After the extract was washed with a saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, the solvent was removed bydistillation under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate: methanol = 1: 1 containing 2%triethylamine) to give compound6-(4-(aminomethyl)piperidin-1-yl)-N2,N4- bis(3-(methylthio)propyl)-1,3,5-triazine-2,4-diamine 6.67g (82% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (CyPFCy)Ni(o-tol)Cl; sodium t-butanolate In 1,4-dioxane at 25℃; for 16h; Inert atmosphere; Sealed tube; | Procedures for Scope of Cross-Coupling Using C1Ammonia General procedure: In a nitrogen-filled glovebox, pre-catalyst C1 (5-7.5 mol%), (hetero)aryl pseudohalide (1.0 equiv), base (2.2 equiv), and NH3 (0.5M solution in 1,4-dioxane, 0.96 mL, 0.48 mmol, 4 equiv) wereadded to a screw-capped vial containing a magnetic stir bar. Thevial was sealed with a cap containing a PTFE septum, removedfrom the glovebox, and placed in a temperature-controlled aluminumheating block set to 80 °C, at which point magnetic stirringwas initiated. After 16 h, the vial was then removed fromthe heating block and was allowed to cool to ambient temperature.The crude product was purified by flash-column chromatographyto afford the purified product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogen In ethanol at 88℃; for 1h; | 5 In the 1L hydrogenation kettle, add 100 g of 4-piperidine carbonitrile and 3 g of Raney-Ni, 400 mL of ethanol, and continuously charged with H2, so that the pressure of the system during the reaction was always maintained at 6 MPa. After reaction at a reaction temperature of 88 ° C for 1 h, then the temperature was lowered. When the temperature in the reaction vessel was lowered to room temperature, the gas was vented, and 4-piperidine methyl amine (purity: 99% or more) was obtained by filtration and recrystallization in a yield of 92 wt%. |
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 16h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide at 50℃; for 6h; | 9 The preparation of N- (4-methylpiperidine) -2,3-dihydrobenzo [b] [1,4] -dicyclohexane-5-carboxamide is prepared as follows: Preparation process:In a reaction flask equipped with a stirrer2-diazo-1,3-bis (2,3-dihydrobenzo [b] [1,4] dioxane) propane-1,3-dione(408 mg, 1.2 mmol)) and DMF (1 mL)Then 4-aminomethylpiperidine (1 mmol, 114 mg) was added to the system,The reaction was carried out at 50 ° C for 6 hours, the reaction was terminated, the water quenching reaction was added to the system,And the mixture was extracted three times with methylene chloride. The organic phases were combined, dried and the solvent was removed and chromatographed to give N- (4-methylpiperidine) -2,3-dihydrobenzo [b] [1,4] -dicyclohexane-5-carboxamide (235 mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 4-toluenesulfonyl azide In N,N-dimethyl-formamide at 50℃; for 8h; | 10 The preparation of 3,5-dichloro-N- (4-methylpiperidine) benzamide is as follows: Preparation process:In a reaction flask equipped with a stirrer1,3-bis (3,5-dichlorophenyl) propane-1,3-dione(543 mg, 1.5 mmol)And DMF (1 mL),Then, 4-aminomethylpiperidine (1 mmol, 114 mg) was added to the system,And TsN3 (1 mmol, 197 mg) were reacted at 50 ° C for 8 hours. The reaction was terminated,The reaction was quenched by adding water to the system and extracted three times with dichloromethane. The organic phases were combined, dried, the solvent was removed, and subjected to column chromatography,To give 3,5-dichloro-N- (4-methylpiperidine) benzamide (258 mg, 90%) having a purity of 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With caesium carbonate; XPhos In toluene at 100℃; for 26h; | 6 Example 61 ‘-((2-(4-Aminomethyl)piperidin-l-yl)-4-(isobutylamino)pyrimidin-5-yl)methyl)-6’- Jluorospiro[cyclopropane-1, 3 ‘-indolin]-2 ‘-one A solution of 1 ‘-((2-chloro-4-(isobutylamino)pyrimidin-5-yl)rnethyl)-6’-fluorospiro[cyclopropane-1,Y-indolin]-2’-one from Preparatory Example 9 (75 mg, 0.2 mmol) and 4-(aminomethyl)piperidine (17 iii, 0.2 mmol) in toluene (8 ml), was treated with cesium carbonate (130 mg, 2 eq.) . Dicyclohexylphosphino-2’,4’,6’- triisopropylbiphenyl (GD2) (23.7 mg, 15 mol%) was added and the mixture heated at 100 °C for 26 hours. The mixture was allowed to cool, toluene removed under reducedpressure and purified by column chromatography (200:8:1 DCM:EtOH:NH3) affording the title compound as an off white solid (21 mg, 23%).‘I-I NMR (400 MHz, CDC13) 7.96 (s, IH), 6.81 (dd, J= 8.8, 2.0 Hz, 1H), 6.76-6.67 (m, 211), 6.48 (d, J= 5.0 Hz, 111), 4.76 -4.70 (m, 2H), 4.63 (s, 2H), 3.20 (dd, J 6.7, 5.4 Hz, 2H), 2.78 (td, J= 13.1, 2.6 Hz, 2H), 2.58 (d, J 6.5 Hz, 2H), 1.93 - 1.83 (m,1H), 1.80-1.75 (m, 111), 1.77-1.73 (m,2H), 1.61-1.45 (m, 8H), 1.19-1.07 (m,2H), 0.91 (d, J= 6.7 Hz, 6H); MS CI 453.0 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-[(1''r,3''r,5''R,7''R)-dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6',2''-tricyclo[3.3.1.13,7]decan]-4-yl]benzoic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: 4-Aminomethylpiperidine In dichloromethane at 0 - 20℃; for 2h; | 9 3.3.6. General procedure for the amide formation (7a-j) General procedure: To a solution of the acid 6b (2.33 mmol) in dry DCM (30 mL)was added triethylamine (0.7 mmol, 1.5 eq) and ethylchloroformate(2.33 mmol, 1.0 eq). The reaction was allowed to stir for 60min at 0 C. (2.33 mmol, 1.0 eq) of the required amine was added,and after stirring for 30 min, the reaction mixture was allowed towarm to room temperature and and then allowed to stir for a further90 min. The reaction mixture was then diluted with water andextracted with DCM (3 x 30 mL). The combined organic extractswere washed with brine, dried over anhydrous Na2SO4 and concentrated.Purification by flash column chromatography affordedthe required amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | at 50℃; | General procedure for the synthesis of nitrogen-containingpyridoxal derivatives. General procedure: An equimolar amounts (2.99 mmol) of pyridoxal (or 2.0 mmol of pyridoxal-5-phosphate) and the corresponding amine were heated with stirring (50°C) for 3-12 h (in the case of compound 3b, no heating was performed). The precipitate was separated, washed with ethanol and diethyl ether, then dried in a vacuum. Compounds 3b and 7 were isolated after removal of the solvent from the reaction mixture by recrystallization of a solid residue from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 5-(4-bromo-2-chlorophenyl)furan-2-carbaldehyde; 4-Aminomethylpiperidine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol for 4h; Stage #3: With hydrogenchloride In diethyl ether | 5.1.1. 2. 1-[5- (4-Bromo-2-chlorophenyl )-2-furyl ]-N-(4-piperidinylmethyl)methanamine dihydrochloride (12) [53] To a solutionof 16 in CH2Cl2 were added 4-(aminomethyl)piperidine (1.2equiv) and Na2SO4 (6 equiv.). The reaction was kept at room temperatureovernight and then filtered, the solvent removed underreduced pressure and replaced by a 3:1 mixture of THF/methanol,followed by addition of NaBH4 (2 equiv.) in an ice bath. The reactionwas magnetically stirred at room temperature for 4 h while beingmonitored by TLC and then quenched with a 1M NaOH solution.After extraction with CH2Cl2, the organic layer was dried overNa2SO4, filtered, and concentrated under reduced pressure followedby separation by column chromatography with neutralalumina (eluent: CH2Cl2/methanol 0.5% + NH4OH 0.5%). After purification,the product was solubilized in diethyl ether and precipitatedas its dihydrochloride salt by adding an ethereal HCl solution.After solvent evaporation 12 was obtained as a pale-yellow solid inan average 30% yield. mp: 208-210 °C. IR (neat, cm-1): 3378, 2951,1611, 1582, 1465, 1207, 1087. 1H NMR (400 MHz, MeOH-d4): δ 7.89(d, J 8.4 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.19(d, J = 3.2 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H), 4.43 (s, 2H), 3.44 (d,J = 12.8 Hz, 2H), 3.11-3.00 (m, 4H), 2.19 (br s, 1H), 2.07 (d,J = 14.0 Hz, 2H), 1.65-1.51 (m, 2H). 13C NMR (101 MHz, MeOH-d4) δ 152.3, 146.3, 134.2, 132.2, 131.7, 130.7, 128.8, 122.8, 116.1, 113.6,52.7, 44.8, 44.4 (2C), 32.4, 27.5 (2C). HRMS (ESI): (m/z) 383.0521[MH], calcd 383.0520C17H20N2OBrCl (free base). The 1H NMR forthis compound, together with the assignment of each peak isshown as Fig. S6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 70℃; for 24h; Sealed tube; | 2.2.2. Intermediate 2 Intermediate 1 (5.14 g, 16.0 mmol) was dissolved in 70 mL THF, followed by addition of DIPEA (3.10 g, 24.0 mmol) and 4- aminomethylpiperdine (2.18 g, 19.1 mmol) in the flask. The flask was sealed and heated to 70 °C for 24 h. Upon cooling, the solvent was removed by rotary evaporation and the residue was purified by silica gel chromatography using DCM:MeOH (9:1-8:2) with 1% NH4OH. The Intermediate 2 was obtained as a light-yellow oil (5.56 g, yield: 87%). TOFMS: calculated for [M+H]+: 400.2672; found [M+H]+: 400.2667. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In butan-1-ol at 200℃; for 0.333333h; Microwave irradiation; | General procedure for the synthesis of 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidines 1-7. General procedure: The proper amine 14-16 [1], 18-21 (3mmol) was added to a solution of the 5-chloro-2-(2-furanyl)thiazolo[5,4-d]pyrimidin-7-amine derivative13 [2] (1 mmol) in n-BuOH (2 mL). The reaction mixture was microwaveirradiated at 200 °C for 20 minutes, then cooled at rt. Addition of water (100mL) afforded a solid which was collected by filtration and washed with Et2O.The crude material was purified by crystallization or by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: phthalic anhydride; 4-Aminomethylpiperidine for 4h; Stage #2: benzyl bromide With potassium carbonate; triethylamine In acetonitrile at 50℃; | 3.2.1.1. Synthesis of the N-benzyl Compounds with Isoindoline-1,3-Dione Protection (1-4a, 10-12a): General Procedure General procedure: Phthalic acid anhydride (1 eq) and the aminoalkyl-piperidines or -piperazine derivatives (i-(aminomethyl)piperidine (i = 2,3,4) or 1-(2-aminoethyl)piperazine (1 eq) were heated at 160°C for 4 h. The resulting dark brown solid (1 eq) was mixed with K2CO3 (6.6 eq), triethylamine (1.4 eq), and benzyl bromide derivatives or 2-(bromomethyl)pyridine (2.3 eq), and refluxed in acetonitrile for 24 h. Then, the mixture was cooled at rt, filtered and to the organic phase was added water, and then extracted with ethyl acetate (three times). The organic layers were collected, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude material was purified through chromatography column (with eluent: DCM/MeOH/TEA (98:2:0.1) or ACN/H2O (7:1)) or recrystallization. 2-((1-Benzylpiperidine-4-yl)methyl)isoindoline-1,3-dione (1a). Starting from 4-(aminomethyl)piperidine and afterwards benzyl bromide the a pure title compound was obtained as a yellow solid ( η= 40%), M.P. = 129-132°C). 1H NMR (300 MHz, DMSO-d6), (ppm): 1.241.38, 1.521.91, 3.44-3.50 (m, 9H,piperidine), 2.73 (d, 2H, J = 12.0 Hz, NCH2CH), 3.41 (s, 2H, NCH2Ph), 7.157.40 (m, 5H, Ph), 7.79-7.91(m, 4H, PhTh). M/z (ESI-MS): 335 (M + 1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 7h; | General procedure for the synthesis of compounds 9a-9n General procedure: 4-(6-Fluoro-1H-indol-3-yl)benzoic acid (8, 0.2 g, 0.78 mmol) was dissolved in DMF (10 mL), HATU (360 mg, 0.94 mmol) and DIPEA (302 mg, 2.34 mmol) were added, and the corresponding amine (0.94 mmol) was then added at room temperature. The mixture was stirred at room temperature for a time indicated in Table 1. After completion of the reaction (TLC), the mixture was quenched with water, and the precipitate was filtered off and washed with tert-butyl methyl ether-hexane. The reaction times, yields, and melting points of compounds 9a-9n are given in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 4-Aminomethylpiperidine; salicylaldehyde In methanol at 20℃; for 3h; Stage #2: With methanol; sodium tetrahydroborate for 2h; Cooling with ice; | Synthesis of 4-(N-o-hydroxybenzyl-aminomethyl) piperidine. 4-aminomethyl piperidine (500 ml, 4.17 mmol) and salicylaldehyde (435 ml, 4.17 mmol) in CH3OH (5 mL) were stirred for 3 hours at ambient temperature, and then NaBH4 (347 mg, 8.34 mmol) was added in an ice bath for 2 hours and the solvent was evaporated at reduced pressure. The solution was redissolved with 25 mL of AcOEt and washed with 3x10 mL of H2O, then anhydrified with Na2SO4. The organic solution was then filtered through a pleated filter and the solvent evaporated in the rotavapor, thus obtaining N-(o-hydroxybenzyl)-4-aminomethyl piperidine (328 mg, 45%). ESI+ MS: m/z. 221.2 (M+H+). 1H NMR (CDCl3, 500 MHz), d (ppm): 7.16, 7.17, 7.19, (t, 1 H, ring), 6.82 - 7.00 (m, 1 H, ring), 6.77 - 7.00 (m, 1H, ring), 7.19 (s, 1 H, ring), 3.10, 3.12, (d, 2 H, cycle), 2.62, 2.64, (m, 2 H, cycle), 2.56, 2.60, (m, 2 H, CH2- NH2), 1.20, 1.23 (m, 1 H , cycle). 13C NMR (CDCl3, 500 MHz), d (ppm): 159.0 (C, ring), 129.5 (CH, ring), 129.0 (CH, ring), 123.3 (C, ring), 119.2 (CH, ring), 117.1 (CH, ring), 53.7, 55.9, (CH2, CH2-NH), 47.0, 32.0, (CH2, ring), 37.0, (CH, ring). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate In acetonitrile at 20℃; for 5h; | Synthesis of 4-AMPTA(OtBu)3. 4-aminomethyl piperidine (500 mL, 4.17 mmol), tert- butyl bromoacetate (1.895 mL, 12.92 mmol) and K2CO3 (1.79 g, 12.93 mmol) in CH3CN (15 ml) were stirred for 5 hours at ambient temperature. After removing the solvent at reduced pressure, the crude product was purified by means of column chromatography (S1O2, acetone/hexane 10:90 > 30:70), thus obtaining 4-AMPTAtri(OtBu) as a solid compound (1.26 g, 66%). ESI+ MS, m/z: 457.4 (M+H+). 1H NMR (CDCl3, 500 MHz), d (ppm): 3.38 (s, 4H, CH2), 3.13 (s, 2H, CH2), 2.21-2.97 (d, 2H, CH2, cycle), 2.57-2.55 (d, 2H, CH2), 1.67 (s, 2H, CH2, cycle), 1.80-1.77 (d, 2H, CH2, cycle), 1.35-1.30 (m, 3H, CH2- CH). 13C NMR (CDCl3, 500 MHz), d (ppm): 171.6 (CO), 81.6 (C(CH3)3), 61.4 (CH2, cycle), 60.9 (NCH2COOt-Bu), 57.4 (N(CH2COOt-Bu)2), 54.0 (CH2, -NCH2, cycle), 34.9 (CH, cycle), 31.0 (CH2, CH, cycle), 28.9 (CH3, t-Bu). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 12h; | 2-Methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N4-(piperidin-4-ylmethyl)benzene-1,4-diamine (X06): General procedure: A mixture of M2 (2.0 g, 5.1 mmol), N1,N1,N2-trimethylethane-1,2-diamine (0.5 g, 5.1 mmol) and N,N-diisopropylethylamine (0.7 g,5.1 mmol) was dissolved in 4 mL of N,N-dimethyl formamide and heatedto 80 C for 12 h. After cooling, the reaction liquid was added to 100 mLof water and extracted with ethyl acetate. The ethyl acetate layer wasseparated, washed with brine, dried with anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (dichloromethane:methanol = 50:1) to obtain X02(1.4 g, 58.5%) as an orange solid. 1H NMR (600 MHz, DMSO-d6) δ 8.63(s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 5.3 Hz, 2H), 8.08 (s, 1H),7.52 (d, J = 8.2 Hz, 1H), 7.27-7.23 (m, 1H), 7.21 (dd, J = 5.3, 2.8 Hz,1H), 7.12 (t, J = 7.4 Hz, 1H), 6.85 (s, 1H), 3.96 (d, J = 2.2 Hz, 3H), 3.88(s, 3H), 3.27 (t, J = 6.9 Hz, 2H), 2.86 (s, 3H), 2.48 (d, J = 6.8 Hz, 2H),2.16 (s, 6H). 13C NMR (151 MHz, DMSO-d6) δ 162.6, 160.6, 157.6,155.3, 144.3, 138.1, 133.5, 132.7, 125.9, 122.7, 122.5, 121.8, 121.3,119.8, 112.8, 110.9, 107.8, 102.6, 56.9, 56.8, 53.3, 45.9, 41.0, 33.5. HRMS(ESI): C25H29N7O3, [M + H] +: 476.2413. |
80.2% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 12h; | 2-Methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N4-(piperidin-4-ylmethyl)benzene-1,4-diamine (X06): General procedure: A mixture of M2 (2.0 g, 5.1 mmol), N1,N1,N2-trimethylethane-1,2-diamine (0.5 g, 5.1 mmol) and N,N-diisopropylethylamine (0.7 g,5.1 mmol) was dissolved in 4 mL of N,N-dimethyl formamide and heatedto 80 C for 12 h. After cooling, the reaction liquid was added to 100 mLof water and extracted with ethyl acetate. The ethyl acetate layer wasseparated, washed with brine, dried with anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (dichloromethane:methanol = 50:1) to obtain X02(1.4 g, 58.5%) as an orange solid. 1H NMR (600 MHz, DMSO-d6) δ 8.63(s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 5.3 Hz, 2H), 8.08 (s, 1H),7.52 (d, J = 8.2 Hz, 1H), 7.27-7.23 (m, 1H), 7.21 (dd, J = 5.3, 2.8 Hz,1H), 7.12 (t, J = 7.4 Hz, 1H), 6.85 (s, 1H), 3.96 (d, J = 2.2 Hz, 3H), 3.88(s, 3H), 3.27 (t, J = 6.9 Hz, 2H), 2.86 (s, 3H), 2.48 (d, J = 6.8 Hz, 2H),2.16 (s, 6H). 13C NMR (151 MHz, DMSO-d6) δ 162.6, 160.6, 157.6,155.3, 144.3, 138.1, 133.5, 132.7, 125.9, 122.7, 122.5, 121.8, 121.3,119.8, 112.8, 110.9, 107.8, 102.6, 56.9, 56.8, 53.3, 45.9, 41.0, 33.5. HRMS(ESI): C25H29N7O3, [M + H] +: 476.2413. |
Tags: 7144-05-0 synthesis path| 7144-05-0 SDS| 7144-05-0 COA| 7144-05-0 purity| 7144-05-0 application| 7144-05-0 NMR| 7144-05-0 COA| 7144-05-0 structure
[ 126579-26-8 ]
N-Methyl-1-(piperidin-4-yl)methanamine
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[ 35307-80-3 ]
3-(Piperidin-3-yl)propan-1-amine
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[ 1772-29-8 ]
4-(Piperidin-3-yl)butan-1-amine
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[ 1220168-31-9 ]
N-(Piperidin-4-ylmethyl)ethanamine
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[ 1772-29-8 ]
4-(Piperidin-3-yl)butan-1-amine
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[ 1220168-31-9 ]
N-(Piperidin-4-ylmethyl)ethanamine
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H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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