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CAS No. : | 10406-25-4 | MDL No. : | MFCD00025578 |
Formula : | C8H8N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LFIWXXXFJFOECP-UHFFFAOYSA-N |
M.W : | 132.16 | Pubchem ID : | 82608 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.83 |
TPSA : | 49.81 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.79 cm/s |
Log Po/w (iLOGP) : | 1.41 |
Log Po/w (XLOGP3) : | 0.44 |
Log Po/w (WLOGP) : | 0.87 |
Log Po/w (MLOGP) : | 0.85 |
Log Po/w (SILICOS-IT) : | 1.41 |
Consensus Log Po/w : | 1.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.31 |
Solubility : | 6.4 mg/ml ; 0.0485 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.05 |
Solubility : | 11.7 mg/ml ; 0.0883 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.49 |
Solubility : | 0.424 mg/ml ; 0.00321 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.16 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With hydrogen In ammonia; 1,3,5-trimethyl-benzene at 50℃; | EXAMPLE 5 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 molpercent, the yield of 4-cyanobenzylamine was 88.8 molpercent and the yield of p-xylynenediamine was 5.8 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 molpercent, the yield of 4-cyanobenzylamine was 0.2 molpercent and the yield of p-xylynenediamine was 92.1 molpercent. |
87.7% | With hydrogen In ammonia; 1,3,5-trimethyl-benzene at 50℃; | EXAMPLE 2 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 molpercent, the yield of 4-cyanobenzylamine was 88.8 molpercent and the yield of p-xylynenediamine was 5.8 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46percent by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 molpercent, the yield of 4-cyanobenzylamine was 0.5 molpercent and the yield of p-xylynenediamine was 87.7 molpercent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8% | With hydrogen In ammonia; 1,3,5-trimethyl-benzene at 50℃; | EXAMPLE 2 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 molpercent, the yield of 4-cyanobenzylamine was 88.8 molpercent and the yield of p-xylynenediamine was 5.8 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46percent by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 molpercent, the yield of 4-cyanobenzylamine was 0.5 molpercent and the yield of p-xylynenediamine was 87.7 molpercent. EXAMPLE 5 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 molpercent, the yield of 4-cyanobenzylamine was 88.8 molpercent and the yield of p-xylynenediamine was 5.8 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 molpercent, the yield of 4-cyanobenzylamine was 0.2 molpercent and the yield of p-xylynenediamine was 92.1 molpercent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate; dimethyl sulfoxide; trifluoroacetic acid; sodium nitrite In water | Example 1 p-Cyanobenzylamine (26.2 g), sodium nitrite (20.8 g), and dimethyl sulfoxide (200 ml) were mixed, and the mixture was vigorously stirred at room temperature (about 20 to 30° C.). Trifluoroacetic acid (45.6 g) was added dropwise to the mixture over a one hour period. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. The reaction mixture was analyzed by use of high performance liquid chromatography, to thereby obtain proportions (on the mol basis) of predominant reaction products: p-cyanobenzyl alcohol:p-cyanobenzaldehyde:p-cyanobenzoic acid=72:18:10. Dimethyl sulfoxide was removed through distillation under vacuum, and water (300 ml) was added to the residue. Sodium carbonate was added to the thus-formed solution, to thereby adjust pH to 8. The resultant aqueous solution was subjected to extraction with toluene (300 ml*2). Toluene was removed through distillation under reduced pressure, and the resultant solution was subsequently distilled under vacuum, to thereby obtain 16.2 g of p-cyanobenzyl alcohol (bp. 175-178° C./1.5 kPa) (yield 61percent). The purity of the product was 98percent. |
51% | With sulfuric acid; sodium nitrite In water; toluene | Example 3 p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt percent aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51percent). The purity of the product was 98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In dichloromethane at 20℃; | To a round-bottom flask equipped with a stir bar was added 17a-b (1.0 eq), Boc2O (1.1 eq), CH2Cl2 (10mL/mmol), and triethylamine (1.5 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo and partitioned between ethyl ether and 1M HCl. The organic layer were separated, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give a white crystalline solid. 4.2.4.2 128 tert-Butyl (4-cyanobenzyl)carbamate (18a) Yield: 93percent. MP: 114–116°C. 1H NMR (400MHz, CDCl3) δ 7.62 (d, J=7.9Hz, 2H, -ArH), 7.39 (d, J=8.5Hz, 2H, -ArH), 4.96 (s, 1H, -NH-), 4.37 (d, J=5.9Hz, 2H, -CH2-), 1.46 (s, 9H, -CH3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride In ethyl acetate | In a 200 ml four-neck flask equipped with an agitator, a thermometer, a gas conduit, and a reflux condenser, p-cyanobenzylamine (10.0 g) obtained in Preparation Example 3 was dissolved in ethyl acetate (90.0 g). While the reactor was cooled in a water bath, hydrogen chloride gas was fed into the vapor phase of the reactor while stirring. Immediately after the introduction of hydrogen chloride, heat generation was confirmed, and a white solid was precipitated. After the reaction mixture was cooled to room temperature, the white solid was separated through filtration and dried in a desiccator under vacuum, thereby yielding 12.6 g of p-cyanobenzylamine hydrochloride (yield based on p-cyanobenzylamine: 99percent). Through high-performance liquid chromatographic analysis of the thus-obtained p-cyanobenzylamine hydrochloride, the p-cyanobenzylamine content in the hydrochloride was found to be 77 mass percent. In addition, the hydrogen chloride content in p-cyanobenzylamine hydrochloride was found to be 23 mass percent through anion chromatographic analysis. The thus-obtained p-cyanobenzylamine hydrochloride has a bulk density of 0.3 g/ml. |
75% | With hydrogenchloride In water | In a 200 ml three-neck flask equipped with an agitator, a thermometer, and a dropping funnel, p-cyanobenzylamine hydrate (32.5 g) obtained in Preparation Example 2 and water (20.2 g) were placed. Concentrated hydrochloric acid (35 mass percent aqueous solution of hydrogen chloride, hereinafter the same solution was employed) (20.5 g) was added dropwise to the mixture through the dropping funnel under stirring, thereby forming a white solid. The white solid was separated through filtration and dried in a desiccator under vacuum, thereby yielding 24.5 g of p-cyanobenzylamine hydrochloride (yield based on p-cyanobenzylamine hydrate: 75percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With hydrazine hydrate | |
With hydrazine hydrate | ||
With hydrazine hydrate In ethanol |
With hydrazine hydrate In ethanol; water | R.43 4-(Aminomethyl)benzonitrile REFERENCE EXAMPLE 43 4-(Aminomethyl)benzonitrile A solution of 4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]benzonitrile (4.6 g, 18 mmol) and hydrazine monohydrate (8.9 g, 180 mmol) in ethanol (90 mL) was heated under reflux for 33 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was combined with water, basified with potassium hydroxide, and then extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.9 g, yield: 81%). An oil. 1H NMR (CDCl3) δ 3.96 (2H, s), 7.45 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J = 8.0 Hz). | |
With hydrazine | ||
With hydrazine In methanol at 65℃; for 2.5h; | 42 Reference Example 42 0.90 g of hydrazine hydrate was dropped to mixture of 4.00 g of N-(4-cyano-benzyl)phthalimide and 15 ml of methanol, and stirred at 65 °C for 2 hours and half. Then the reaction mixture was cooled to room temperature, then water was added to it, and concentrated under reduced pressure. 1N hydrochloric acid was added to the residue, and it was filtered. Ethyl acetate was added to the filtrate, and it was washed successively with 25 % aqueous solution of caustic soda, saturated aqueous solution of sodium sulfate, dried by magnesium sulfate, and concentrated under reduced pressure to obtain 0.84 g of crude 4-cyanobenzylamine.1H-NMR (CDCl3, TMS) δ (ppm): 7.61 (2H, d, J=8.2 Hz), 7. 44 (2H, d, J=7.9 Hz), 3.95 (2H, s), 1.55 (2H, br.s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 0 - 20℃; for 0.333333h; Inert atmosphere; Green chemistry; | |
69% | With 2,6-dimethylpyridine; 2,2,6,6-tetramethyl-piperidine-N-oxyl; water; lithium perchlorate In acetonitrile at 23℃; electrolysis, a platinum gauze electrode, +0.33 V (vs. Ag/Ag(1+)); | |
26% | With potassium permanganate; sulfuric acid In water | 1 EXAMPLE 1 EXAMPLE 1 13.2 g of p-cyanobenzylamine was added dropwise to 200 ml of water and 15.8 g of potassium permanganate with vigorous stirring at room temperature over 20 minutes. The mixture was adjusted to pH 1 by sulfuric acid and stirred at room temperature for 5 hours. The p-cyanobenzaldehyde obtained had a yield of 26% (on a basis of cyanobenzylamine compound, hereafter the same) determined by the analysis of high performance liquid chromatography. |
Multi-step reaction with 3 steps 1: N-chloro-succinimide / 0.17 h / 20 °C / Milling 2: triethylamine / 0.17 h / 20 °C / Milling 3: water; hydrogenchloride / tetrahydrofuran / 2 h / 20 °C | ||
With 4-phenylnaphthalene-1,2-dione; tetra-(n-butyl)ammonium iodide In water; acetonitrile at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-(azidomethyl)benzonitrile With triphenylphosphine In tetrahydrofuran Heating; Stage #2: With sodium hydroxide In ethanol at 60 - 65℃; for 0.666667h; | |
93% | With hydrogen In ethyl acetate for 11h; | |
93% | In ethyl acetate | 26 Preparation of p-cyanobenzylamine (34) Example 26 Preparation of p-cyanobenzylamine (34) 10% Pd-on-C (Aldrich, 800 mg) catalyst was added to a solution of α-azido-4-cyanotoluene (compound 33, 8 g, 51 mmol) in EtOAc (150 mL). The reaction mixture was hydrogenated (H2, 45 psi) in a Parr apparatus for 11 hours. Catalyst was removed by filtering and the solvent was removed under vacuum to give the title compound (6.3 g, 93%). 1H-NMR (CDCl3) δ3.85 (s, 2H), 7.45 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1 Hz), 7.78 (s, 2H, NH2). |
93% | In ethyl acetate | 6 Preparation of 4-(aminomethyl)benzylnitrile (6) Example 6 Preparation of 4-(aminomethyl)benzylnitrile (6) The catalyst of 10% Pd-on-C (Aldrich, 800 mg) was added to a solution of α-azido-4-cyanotoluene (compound 5, 8 g, 51 mmol) in EtOAc (150 ml). The reaction mixture was hydrogenated (H2, 45 psi) in a Parr apparatus for 11 hours. Catalyst was filtered and the solvent was removed under vacuum to give the title compound (6.3 g, 93%). 1H NMR (CDCl3): δ3.85 (s, 2H) 7.45 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1 Hz), 7.78 (s, 2H, NH2). |
93% | In ethyl acetate | 86 Preparation of p-cyanobenzylamine (4-3) Example 86 Preparation of p-cyanobenzylamine (4-3) 10% Pd-on-C (Aldrich, 800 mg) catalyst was added to a solution of α-azido-4-cyanotoluene (compound 4-2, 8 g, 51 mmol) in EtOAc (150 ml). The reaction mixture was hydrogenated (H2, 45 psi) in a Parr apparatus for 11 hours. Catalyst was removed by filtering and the solvent was removed under vacuum to give the title compound (6.3 g, 93%). 1H NMR (CDCl3): δ 3.85 (s, 2H), 7.45 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1 Hz), 7.78 (s, 2H, NH2). |
90% | With hydrogen In methanol; chloroform | |
With hydrogen In tetrahydrofuran at 20℃; for 2h; | ||
1.74 g (50%) | With sodium hydroxide; triphenylphosphine In tetrahydrofuran; water | 23 4-(Aminomethyl)benzonitrile Triphenylphosphine (7.67 g) is added to a solution of 4-(azidomethyl)-benzonitrile (4.19 g) in THF (30 mL) and stirred for 1 hr. Water (10 mL) is added, and the solution is stirred for 16 hrs. The reaction mixture is diluted with ether (50 mL) and extracted with HCl (3 N, 3*25 mL) and water (1*25 mL). The aqueous phases are combined and washed with ether (50 mL). Sodium hydroxide is added until the pH =12. After extracting with ether (2*50 mL), the solution is dried with MgSO4 and filtered. The solvent is evaporated under reduced pressure. The resulting crude mixture is then purified via bulb to bulb distillation at 150° C. and 1 torr to afford 1.74 g (50%) of the title compound as a clear, colorless oil. Physical characteristics are as follows: 1 H NMR (DMSO-d6) 7.7, 7.5, 3.8, 1.9. |
1.74 g (50%) | With sodium hydroxide; triphenylphosphine In tetrahydrofuran; water | 32 4-(Aminomethyl)benzonitrile Triphenylphosphine (7.67 g) is added to a solution of 4-(azidomethyl)-benzonitrile (4.19 g) in THF (30 mL) and stirred for 1 hr. Water (10 mL) is added, and the solution is stiffed for 16 hrs. The reaction mixture is diluted with ether (50 mL) and extracted with HCl (3 N, 3*25 mL) and water (1*25 mL). The aqueous phases are combined and washed with ether (50 mL). Sodium hydroxide is added until the pH=12. After extracting with ether (2*50 mL), the solution is dried with MgSO4 and filtered. The solvent is evaporated under reduced pressure. The resulting crude mixture is then purified via bulb to bulb distillation at 150° C. and 1 torr to afford 1.74 g (50%) of the title compound as a clear, colorless oil. Physical characteristics are as follows: 1H NMR (DMSO-d6) δ7.7, 7.5, 3.8, 1.9 |
0.43 g | With triphenylphosphine In dichloromethane at 0 - 20℃; | b b) 4-(aminomethyl) benzonitrile b) 4-(aminomethyl) benzonitrile Triphenyl phoshine (2.25 g, 0.009 moles) was added portion wise to a stirred mixture of 4-(azidomethyl) benzonitrile as obtained in step a) (0.88 g, 0.006 moles) in dichloromethane (10 ml.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was quenched with cold water and the residue was extracted with dichloromethane (3 x 50 ml_). The organic layer was washed with water, brine solution, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (silica gel, 4 % MeOH in chloroform) provided the title compound as pale yellow colored gummy compound (0.43 g, 56%). 1 H NMR (400 MHz, CDCI3): δ 7.63 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 3.96 (s, 2H); |
92 %Chromat. | With formic acid; 2,6-dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 30h; Irradiation; | |
515 mg | With tin(II) chloride dihdyrate In methanol at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; at 20℃; | To a round-bottom flask equipped with a stir bar was added 17a-b (1.0 eq), Boc2O (1.1 eq), CH2Cl2 (10mL/mmol), and triethylamine (1.5 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo and partitioned between ethyl ether and 1M HCl. The organic layer were separated, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give a white crystalline solid. 4.2.4.2 128 tert-Butyl (4-cyanobenzyl)carbamate (18a) Yield: 93%. MP: 114-116C. 1H NMR (400MHz, CDCl3) delta 7.62 (d, J=7.9Hz, 2H, -ArH), 7.39 (d, J=8.5Hz, 2H, -ArH), 4.96 (s, 1H, -NH-), 4.37 (d, J=5.9Hz, 2H, -CH2-), 1.46 (s, 9H, -CH3) |
93% | With triethylamine; In dichloromethane; at 20℃; | General procedure: To a round-bottom flask equipped with a stir bar was added 27a-b (1.0 eq), Boc2O (1.1 eq), CH2Cl2 (10 mL/mmol), and triethylamine (1.5 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo and partitioned between ethyl ether and 1 M HCl. The organic layer were separated, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give a white crystalline solid. Example 86 Synthesis of 210 tert-Butyl (4-cyanobenzyl) carbamate (28a) (0243) The synthesis follows the general procedure described in Example 85. Yield: 93%. MP: 114-116 C. 1H NMR (400 MHz, CDCl3) delta 7.62 (d, J=7.9 Hz, 2H, -ArH), 7.39 (d, J=8.5 Hz, 2H, -ArH), 4.96 (s, 1H, -NH-), 4.37 (d, J=5.9 Hz, 2H, -CH2-), 1.46 (s, 9H, -CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With trifluoroacetic acid at 25℃; for 0.25h; | 247.B B. 4- (AMINOMETHYL) BENZONITRILE 4- (DI-TERT-BUTOXYCARBONYLAMINOMETHYL) BENZONITRILE (2G, 6. Ommoles) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4mL) and the solution was stirred at 25 C for 0.25h. The reaction mixture was diluted with dichloromethane and extracted with 1 N sodium hydroxide. The organic layer was dried (MGS04), filtered and evaporated to dryness. The residue was chromatographed on a SILICA GEL COLUMN (15X5CM) using 3% (10% CONC. ammonium hydroxide in METHANOL)-DICHLOROMETHANE as the eluant to give 4- (aminomethyl) benzonitrile (108mg, 68%): FABMS: m/z 133.1 (MH+) ; HRFABMS: M/Z133. 0764 (MH+). CALCD. FOR C8H9N2 : m/z 133.0766 ; 8H (CDCI3) 2.04 (2H, S,-CH2NH2), 3.89 (2H, s, -CH2NH2), 7.40 (2H, d, Ar-H) and 7. 59 ppm (2H, d, Ar-H); 5c (CDCI3) CH2 : 45.7 ; CH: 127.8, 127.8, 132.4, 132.4 ; C: 110.6, 118.9, 148.0. |
With trifluoroacetic acid In dichloromethane | ||
With trifluoroacetic acid In dichloromethane at 20℃; for 3h; | 169A 4-(aminomethyl)benzonitrile EXAMPLE 169A 4-(aminomethyl)benzonitrile A solution of N,N-bis(tert-butoxycarbonyl)-4-cyanobenzylamine (0.75 g, 2.25 mmol, prepared according to the literature described in Synthetic Communications 4419:28 (1998), in CH2Cl2 (15 mL) was treated with trifluoroacetic acid (8 mL). After stirring at room temperature for 3 hours, the mixuture was concentrated under reduced pressure and the residue was azeotroped with diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium tris(acetoxy)borohydride; acetic acid; In methanol; dichloromethane; | EXAMPLE 1E 4-([(1-methyl-1H-imidazol-5-yl)methyl]amino}methyl)benzonitrile A mixture of 4-cyanobenzyl amine (prepared according to the procedure described in WO 00/01691, 310 mg, 2.35 mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (prepared according to the procedure described in J. Org. Chem. 1993, 58, 1159-1166, 258 mg, 2.35 mmol) in dichloromethane (15 mL) was treated with acetic acid (2 drops), stirred for 40 minutes, treated with sodium triacetoxyborohydride (1 g, 4.7 mmol), and stirred overnight. The mixture was treated with methanol (15 mL), stirred for two hours, and concentrated. The concentrate was partitioned between saturated NaHCO3 and dichloromethane and the aqueous phase was extracted twice with dichloromethane. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product (270 mg, 51%). MS (DCI(NH3) m/e 227 (M+H)+; 1H NMR (300 MHz, CDCl3) delta7.63 (d, J=8.1 Hz, 2H), 7.45 (m, 3H), 6.93 (s, 1H), 3.86 (s, 2H), 3.76 (s, 2H), 3.67 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 4; Step A; 4-Cyanolbenzylamine (132 mg, 1 mmol), <strong>[37131-91-2]6-chloro-4-pyrimidine carboxylic acid</strong> (158 mg, 1 mmol) were mixed with EDCI (216 mg, 1.1 mg) and HOBt (149 mg, 1.1 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature overnight. Normal aqueous workup and pourification with ethyl acetate and hexane (gradient) to give product as white solid (225.6 mg). MS (M+H): 272 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In N,N-dimethyl-formamide; at 60℃; | Example 5; Step A; 4-Cyanolbenzylamine (1.1 g, 8.33 mmol), 4,6-pyrimidine dicarboxylic acid methyl ester (1.77 g, 8.33 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction was stirred 60 C. overnight and concentrated. The brown solid was purification with ethyl acetate and hexane (gradient) to give product as light brown solid (1.18 g, 48% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.8% | With ammonia In methanol at 80℃; | 73 Preparation 73; 4-Aminomethyl-benzonitrile; Stir 4-bromomethyl-benzonitrile (2. Og, 0. 010 mmoles) in sealed vessel in a solution of 2N ammonia in methanol at 80°C until completion. Reduce solvent in volume. Dissolve residue in ethyl acetate and wash with IN HC1. Basify aqueous layer with 5N NaOH. Extract aqueous layer into dichloromethane. Dry organic layer over MgS04 and reduce in volume to isolate 0.223g. Yield = 16.8%. Mass Spectrum (m/e): (M-). |
Multi-step reaction with 2 steps 1: aq. NaN3 / tetrahydrofuran / 18 h / 20 °C 2: H2 / 5 percent Pd/C / tetrahydrofuran / 2 h / 20 °C / 2327.17 Torr | ||
Multi-step reaction with 2 steps 1.1: 100 percent / NaN3; nBu4NHSO4; LiI / aq. ethanol / 1 h / 80 °C 2.1: PPh3 / tetrahydrofuran / Heating 2.2: 95 percent / NaOH (50 percent) / aq. ethanol / 0.67 h / 60 - 65 °C |
Multi-step reaction with 2 steps 1: NaH / tetrahydrofuran 2: TFA / CH2Cl2 | ||
Multi-step reaction with 2 steps 1: 96 percent / NaN3 / dimethylformamide / 5 h / 20 °C 2: 93 percent / H2 / Pd/C / ethyl acetate / 11 h / 2327.17 Torr | ||
With hydrogenchloride In ethanol; dichloromethane; water; ethyl acetate | 24.A.1 Step 1 Step 1 Preparation of 4-Cyanobenzylamine Method 1 (Hydrochloride salt): A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (2.98 kg) and HMTA (2.18 kg) at ambient temperature. The mixture was heated to about 72-75° C. over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirring. The batch was aged at about 72-75° C. for about 30 min. The mixture was allowed to cool to about 20° C. over about 60 min. and HCl gas (2.20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65° C. The mixture was heated to about 70-72° C. and aged for about 1 hour. The slurry was cooled to about 30° C. and ethyl acetate (22.3 L) added over about 30 min. The slurry was cooled to about -5° C. over about 40 min and aged at about -3 to about -5° C. for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3*3 L). The solid was dried under a N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30° C. At about 25° C., methylene chloride (2.8 L) was added and stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2*2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25° C. to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25° C. The solution was cooled to about 15° C. and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40° C. At about 20-25° C., ethyl acetate (5.8 L) was added to the slurry, followed by cooling to about -5° C. over about 1 hour. The slurry was aged at about -5° C. for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1*3.8 L), then the cake was washed with chilled EtOAc (2*3.8 L). The solids were dried in vacuo at about 25° C. to provide the above-titled compound. 1H NMR (250 MHz, CDCl3): δ 7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H), 4.25 (s, 2H); 13C NMR (62.9 MHz, CDCl3): δ 149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8. | |
With hydrogenchloride In ethanol; dichloromethane; water; ethyl acetate | 1.1 Step 1 Step 1 Preparation of 4-Cyanobenzylamine Method 1 (Hydrochloride salt): A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (2.98 kg) and HMTA (2.18 kg) at ambient temperature. The mixture was heated to about 72-75° C. over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirring. The batch was aged at about 72-75° C. for about 30 min. The mixture was allowed to cool to about 20° C. over about 60 min, and HCl gas (2.20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65° C. The mixture was heated to about 70-72° C. and aged for about 1 hour. The slurry was cooled to about 30° C. and ethyl acetate (22.3 L) added over about 30 min. The slurry was cooled to about -5° C. over about 40 min and aged at about -3 to about -5° C. for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3*3 L). The solid was dried under an N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30° C. At about 25° C., methylene chloride (2.8 L) was added and stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2*2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25° C. to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25° C. The solution was cooled to about 15° C. and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40° C. At about 20-25° C., ethyl acetate (5.8 L) was added to the slurry, followed by cooling to about -5° C. over about 1 hour. The slurry was aged at about -5° C. for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1*3.8 L), then the cake was washed with chilled EtOAc (2*3.8 L). The solids were dried in vacuo at about 25° C. to provide the above-titled compound. 1H NMR (250 MHz, CDCl3) δ 7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H), 4.25 (s, 2H); 13C NMR (62.9 MHz, CDC13) δ 149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8. | |
With hydrogenchloride In ethanol; dichloromethane; water; ethyl acetate | 1.1 Step 1 Step 1 Preparation of 4-Cyanobenzylamine Method 1 (Hydrochloride salt): A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (2.98 kg) and HMTA (2.18 kg) at ambient temperature. The mixture was heated to about 72-75° C. over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirring. The batch was aged at about 72-75° C. for about 30 min. The mixture was allowed to cool to about 20° C. over about 60 min, and HCl gas (2.20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65° C. The mixture was heated to about 70-72° C. and aged for about 1 hour. The slurry was cooled to about 30° C. and ethyl acetate (22.3 L) added over about 30 min. The slurry was cooled to about -5° C. over about 40 min and aged at about -3 to about -5° C. for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3*3 L). The solid was dried under a N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30° C. At about 25° C., methylene chloride (2.8 L) was added and stinting continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2*2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25° C. to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25° C. The solution was cooled to about 15° C. and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40° C. At about 20-25° C., ethyl acetate (5.8 L) was added to the slurry, followed by cooling to about -5° C. over about 1 hour. The slurry was aged at about -5° C. for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1*3.8 L), then the cake was washed with chilled EtOAc (2*3.8 L). The solids were died in vacuo at about 25° C. to provide the above-titled compound. 1H NMR (250 MHz, CDCl3) δ 7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H). 4.25 (s, 2H); 13C NMR (62.9 MHz, CDCl3) δ 149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8. | |
Stage #1: 4-cyanobenzyl bromide With sodium azide Stage #2: With hydrogen | E.5 Treatment of the 5-nitro-isophthalic acid monomethyl ester (1) with an amine alcohol results in the formation of a 5-nitro-N-alkylisophthalamic acid (2). Reduction of the nitro group, by catalytic hydrogenation, yields the corresponding 5-amino-N-hydroxylalkylisophthalamic acid (3). Catalytic hydrogenation of the 5-nitro-N-hydroxylalkylisophthalamic acid is carried out on the free acid, dissolved in ethanol. The 5-amino-N-hydroxylalkylisophthalamic acid (3) is converted to the corresponding triiodo compound (4) by iodination with iodine monochloride. Treatment of the iodinated amino compound (4) with acyl halide alcohol in the presence of sulfuric, results in the formation of a 5-alkanamido-2,4,6-triiodo-N-hydroxylalkylisophthalamic acid (36). Conversion of this acid to an acid halide (37) is accomplished with thionyl chloride (Hoey, U.S. Pat. No. 3,145,197). Treatment of p-cyanobenzyl bromide (38) with sodium azide followed by hydrogenation with Pd/C results in the formation of the p-cyanobenzyl amine (39). The p-cyanobenzyl amine is treated with a hydroxylamine, followed by hydrogenation with Pd/C to produce the Boc protected 4-aminomethylbenzamidine (40). Amide coupling of Fmoc-aminohexanhydroazepinoindole-4-one-2-carboxylic acid with the amino benzamidine, followed by removal of the FMOc protecting group produces the free amine compound (42). (Ho, et al., Bioorg Med Chem Lett 2002; 12:743-8). The acid chloride (37) is condensed with the primary amine (42), followed by the removal of hydroxyl protecting groups results in the formation of Compound V. | |
Multi-step reaction with 2 steps 1: sodium azide / dimethyl sulfoxide / 0 - 20 °C 2: triphenylphosphine / dichloromethane / 0 - 20 °C | ||
With hydrogenchloride In ethanol; dichloromethane; water; ethyl acetate | 1.1 Step 1 Step 1 Preparation of 4-Cyanobenzylamine Method 1 (Hydrochloride salt): A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (2.98 kg) and HMTA (2.18 kg) at ambient temperature. The mixture was heated to about 72-75° C. over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirring. The batch was aged at about 72-75° C. for about 30 min. The mixture was allowed to cool to about 20° C. over about 60 min, and HCl gas (2.20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65° C. The mixture was heated to about 70-72° C. and aged for about 1 hour. The slurry was cooled to about 30° C. and ethyl acetate (22.3 L) added over about 30 min. The slurry was cooled to about -5° C. over about 40 min and aged at about -3 to about -5° C. for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3*3 L). The solid was dried under a N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30° C. At about 25° C., methylene chloride (2.8 L) was added and stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2*2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25° C. to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25° C. The solution was cooled to about 15° C. and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40° C. At about 20-25° C., ethyl acetate (5.8 L) was added to the slurry, followed by cooling to about -5° C. over about 1 hour. The slurry was aged at about -5° C. for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1*3.8 L), then the cake was washed with chilled EtOAc (2*3.8 L). The solids were dried in vacuo at about 25° C. to provide the above-titled compound. 1H NMR (250 MHz, CDCl3) δ7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H), 4.25 (s, 2H);13C NMR (62.9 MHz, CDCl3) δ149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8. | |
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-formamide / 2 h / Heating 2: tin(II) chloride dihdyrate / methanol / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride In ethyl acetate | 1 EXAMPLE 1 In a 200 ml four-neck flask equipped with an agitator, a thermometer, a gas conduit, and a reflux condenser, p-cyanobenzylamine (10.0 g) obtained in Preparation Example 3 was dissolved in ethyl acetate (90.0 g). While the reactor was cooled in a water bath, hydrogen chloride gas was fed into the vapor phase of the reactor while stirring. Immediately after the introduction of hydrogen chloride, heat generation was confirmed, and a white solid was precipitated. After the reaction mixture was cooled to room temperature, the white solid was separated through filtration and dried in a desiccator under vacuum, thereby yielding 12.6 g of p-cyanobenzylamine hydrochloride (yield based on p-cyanobenzylamine: 99%). Through high-performance liquid chromatographic analysis of the thus-obtained p-cyanobenzylamine hydrochloride, the p-cyanobenzylamine content in the hydrochloride was found to be 77 mass %. In addition, the hydrogen chloride content in p-cyanobenzylamine hydrochloride was found to be 23 mass % through anion chromatographic analysis. The thus-obtained p-cyanobenzylamine hydrochloride has a bulk density of 0.3 g/ml. |
75% | With hydrogenchloride In water | 3 EXAMPLE 3 In a 200 ml three-neck flask equipped with an agitator, a thermometer, and a dropping funnel, p-cyanobenzylamine hydrate (32.5 g) obtained in Preparation Example 2 and water (20.2 g) were placed. Concentrated hydrochloric acid (35 mass % aqueous solution of hydrogen chloride, hereinafter the same solution was employed) (20.5 g) was added dropwise to the mixture through the dropping funnel under stirring, thereby forming a white solid. The white solid was separated through filtration and dried in a desiccator under vacuum, thereby yielding 24.5 g of p-cyanobenzylamine hydrochloride (yield based on p-cyanobenzylamine hydrate: 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid In ethyl acetate at 0℃; | 2 EXAMPLE 2 In a 100 ml three-neck flask equipped with an agitator, a thermometer, and a dropping funnel, p-cyanobenzylamine (6.61 g) obtained in Preparation Example 3 was dissolved in ethyl acetate (60 ml). While the reactor was cooled with an ice bath, sulfuric acid (5.1 g) was added dropwise. Immediately thereafter, heat generation was observed, and a white solid was precipitated. After the reaction mixture was cooled to room temperature, the white solid was separated by filtration, washed with ethyl acetate and dried under normal pressure at 40° C. Thus, 11.4 g of secondary sulfate of p-cyanobenzylamine was obtained (yield: 99%). Through high performance liquid chromatographic analysis of the obtained secondary sulfate of p-cyanobenzylamine, the p-cyanobenzylamine content in the sulfate was found to be 57 mass %. Further, the sulfate ion content in the sulfate was found to be 43 mass % through anion chromatographic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8%; 5.8% | With hydrogen;Pd-alumina; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr; | EXAMPLE 2 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 mol%, the yield of 4-cyanobenzylamine was 88.8 mol% and the yield of p-xylynenediamine was 5.8 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46% by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 mol%, the yield of 4-cyanobenzylamine was 0.5 mol% and the yield of p-xylynenediamine was 87.7 mol%. EXAMPLE 5 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 mol%, the yield of 4-cyanobenzylamine was 88.8 mol% and the yield of p-xylynenediamine was 5.8 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 mol%, the yield of 4-cyanobenzylamine was 0.2 mol% and the yield of p-xylynenediamine was 92.1 mol%. |
With hydrogen;sponge nickel (R-2400, product of W.R. Grace & Co.); In methanol; at 150℃; under 750.075 - 3750.38 Torr; for 1h; | Crude p-cyanobenzylamine was synthesized in accordance with the process described in Japanese Unexamined Patent Publication (kokai) No. 9-40630 as follows. Into a 100 ml autoclave, methanol (30 ml) and sponge nickel (R-2400, product of W.R. Grace & Co.) (1.0 g) were placed, and the internal pressure of the autoclave was elevated to 1.0 MPa by introducing hydrogen. The mixture contained in the autoclave was stirred while heating at 150 C. for one hour. Terephthalonitrile (5.0 g) and sodium hydroxide (0.1 g) were introduced into the reactor, and the internal pressure was elevated to 0.5 MPa at ambient temperature while introducing hydrogen. Under monitoring of the hydrogen absorbing rate, when the hydrogen pressure was dropped to 0.1 MPa, the pressure was elevated again to 0.5 MPa. This pressure control operation was repeated. Reaction was terminated when the hydrogen absorption ratio reached 115% of the theoretical value. From the thus-obtained reaction mixture, methanol was removed through distillation. The resultant mixture was subjected to a further distillation at a high temperature under a reduced pressure, thereby removing crude p-cyanobenzylamine. Through high-performance liquid chromatographic analysis of the distillate, the p-cyanobenzylamine content and the p-xylylenediamine content were found to be 93 mass % and 7 mass %, respectively. | |
With ammonia; hydrogen;nickel; In methanol; m-xylylene; at 80 - 120℃; under 60006 Torr; for 4.5 - 6h;Conversion of starting material; | EXAMPLE 3; Hydrogenation; Into a 1-L autoclave equipped with an electromagnetic stirrer, 4 g of Raney nickel catalyst ("NDHT" manufactured by Kawaken Fine Chemicals Co., Ltd.) was charged. Then, 60 g of terephthalonitrile, 60 g of MX and 120 g of methanol were charged into the autoclave and the inner atmosphere thereof was replaced with nitrogen. After introducing 120 g of NH3, the autoclave was heated to 80C. Then, hydrogen gas was introduced into the autoclave to perform the hydrogenation under 8 MPaG at 80C. After initiating the hydrogenation, the reaction liquids were sampled at regular time intervals and analyzed by gas chromatography. After three hours from the initiation, the nitrile conversion reached 97.9 mol%. At this time, the residue of terephthalonitrile was 0.0 mol%, the yield of p-xylylenediamine was 79.0 mol%, and the yield of 4-cyanobenzylamine was 4.3 mol%. After three hours from the initiation, the reaction temperature was raised to 120C to continue the hydrogenation for 1.5 h (overall reaction time = 4.5 h). The results of gas chromatographic analysis showed that the nitrile conversion was 99.99 mol%, the residue of terephthalonitrile was 0.0 mol%, the yield of p-xylylenediamine was 83.9 mol%, and the yield of 4-cyanobenzylamine was 0.015 mol%. Purification of Xylylenediamine After releasing the pressure, MX and methanol were removed from the recovered reaction liquid in a rotary evaporator. By distilling the resultant solution under 0.5 kPa, p-xylylenediamine was obtained as the major distillate. The purity was 99.9% by weight or more and the content of 4-cyanobenzylamine was 0.016% by weight. COMPARATIVE EXAMPLE 3; Hydrogenation; The procedure of Example 3 was repeated except for performing the hydrogenation for 6 h at a constant reaction temperature of 80C. After 6 h of the initiation of hydrogenation, the reaction liquid was analyzed by gas chromatography. The residue of terephthalonitrile was 0.0 mol%, the yield of p-xylylenediamine was 82.2 mol%, and the yield of 4-cyanobenzylamine was 0.4 mol%. Although the hydrogenation was continued longer than in Example 3, a larger amount of the intermediate 4-cyanobenzylamine remained.Purification of Xylylenediamine After releasing the pressure, MX and methanol were removed from the recovered reaction liquid in a rotary evaporator. By distilling the resultant solution under 0.5 kPa, p-xylylenediamine was obtained as the major distillate. The obtained p-xylylenediamine contained 0.4% by weight of 4-cyanobenzylamine. COMPARATIVE EXAMPLE 4; The procedure of Example 3 was repeated except for performing the hydrogenation for 4.5 h at a constant reaction temperature of 120C. The results of gas chromatographic analysis showed that the residue of terephthalonitrile was 0.0 mol%, the yield of p-xylylenediamine was 74.2 mol%, and the yield of 4-cyanobenzylamine was 0.01 mol%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With hydrogen;catalyst A; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr; | EXAMPLE 5 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 mol%, the yield of 4-cyanobenzylamine was 88.8 mol% and the yield of p-xylynenediamine was 5.8 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 mol%, the yield of 4-cyanobenzylamine was 0.2 mol% and the yield of p-xylynenediamine was 92.1 mol%. |
87.7% | With hydrogen;Ni-diatomaceous earth; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr; | EXAMPLE 2 Hydrogenation of Terephthalonitrile Into a 100-ml autoclave, were charged 3.2 g of terephthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 94.8 mol%, the yield of 4-cyanobenzylamine was 88.8 mol% and the yield of p-xylynenediamine was 5.8 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46% by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of terephthalonitrile was 100 mol%, the yield of 4-cyanobenzylamine was 0.5 mol% and the yield of p-xylynenediamine was 87.7 mol%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | With N-ethyl-N,N-diisopropylamine In toluene at 0 - 20℃; for 0.75h; | A7.1 To a solution of 4-cyanobenzylamine (13.21 g, 0.1 mole) and N,N-diisopropylethylamine (12.93 g, 0.11 mole) in toluene (75 mL) under argon at 0° C., chloroacetyl chloride (11.30 g, 0.1 mole) was added dropwise. After the addition was complete, the reaction mixture was stirred for 45 min at room temperature. Ethyl acetate (250 mL) was added, followed by a solution of sat NH4Cl (250 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were dried over MgSO4 and treated with charcoal. The drying agent was removed by filtration, and the filtrate was concentrated to a volume of ~50 mL. A solid precipitated which was removed by filtration. The solid was dried under vacuum to yield 14.25 g (68.3%) of 4-cyanobenzyl-5-methyl-1,2,4-triazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With NMM; hydroxylamine hydrochloride In methanol | 27 Preparation of 4-(aminomethyl)phenyl-N-hydroxyamidine (35) Example 27 Preparation of 4-(aminomethyl)phenyl-N-hydroxyamidine (35) Hydroxylamine hydrochloride (7 g) was added to a solution of compound 34 (7 g) and NMM (4 mL) in methanol (100 mL). The mixture was stirred at ambient temperature for 3 days. The compound was purified by RP HPLC to give the title compound (7 g, 89%). MS (electrospray) 166 (M+1). |
89% | With NMM; hydroxylamine hydrochloride In methanol | 87 Preparation of 4-(aminomethyl)phenyl-N-hydroxyamidine (4-4) Example 87 Preparation of 4-(aminomethyl)phenyl-N-hydroxyamidine (4-4) Hydroxylamine hydrochloride (7 g) was added to a solution of compound 4-3 (7 g) and NMM (4 ml) in methanol (100 ml). The mixture was stirred at ambient temperature for 3 days. The compound was purified by RP HPLC to give the title compound (7 g, 89%). MS (electrospray): 166 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | 48 Example 48 Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 13.5 g of p-cyanobenzoic acid (yield 92%, based on p-cyanobenzylamine). The p-cyanobenzoic acid obtained had a purity of 96%. | |
90% | 47 Example 47 Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 11.9 g of p-cyanobenzoic acid (yield 90%, based on p-cyanobenzylamine). The p-cyanobenzoic acid obtained had a purity of 96%. | |
82% | With sodium hypochlorite; sulfuric acid; iron(III) chloride; urea In water | 45 Example 45 Example 45 A mixture containing p-cyanobenzylamine (13.2 g), water (50 g), and ferric chloride (0.2 g) was stirred, and a 14 wt. % aqueous solution (200 g) of sodium hypochlorite was added dropwise thereto at room temperature over two hours. The reaction mixture was further stirred for one hour. Subsequently, water (100 g) and urea (4 g) were added to the mixture, and the resultant mixture was further stirred for minutes. The pH of the mixture was adjusted to four through addition of 98 wt. % sulfuric acid. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 12.1 g of p-cyanobenzoic acid (yield 82%, based on p-cyanobenzylamine). |
76% | 46 Example 46 Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 10.4 g of p-cyanobenzoic acid (yield 76%, based on p-cyanobenzylamine). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 95%. | |
Multi-step reaction with 2 steps 1: 4-phenylnaphthalene-1,2-dione; tetra-(n-butyl)ammonium iodide / acetonitrile; water / 24 h / 80 °C 2: tert.-butylhydroperoxide / water / 24 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | 85.b b b 4-[[(6-Methyl-4(3H)-oxopyrimidin-2-yl)amino]methyl]-benzonitrile Prepared analogously to Example 84b) from 6-methyl-2-(methylthio)pyrimidin-4(3H)-one and 4-cyanobenzenemethanamine in a yield of 67% of theory. Crystals, Mp. 222-224° C. (Methanol). IR (KBr): 3359.8 (N--H), 2227.7 (C N), 1664.5 (C=O) cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In hexane; water; ethyl acetate; N,N-dimethyl-formamide; | a Boc-D-Phenylalanylproline (p-cyanobenzyl)amide 2.0 g (14.6 mmol) of isobutyl chloroformate were added in 2 min to a solution of 5.1 g (14.2 mmol) of <strong>[38675-10-4]Boc-D-Phe-Pro-OH</strong> and 1.53 g (15.2 mmol) of N-methylmorpholine in 15 ml of DMF at -15 C., the mixture was stirred for 10 min and then a solution of 1.9 g (14.2 mmol) of p-cyanobenzylamine (W. Walter et al., Ann. 660, 1962, 60) and 1.53 g of N-methylmorpholine in 3 ml of DMF was added. After stirring at -15 C. for 3 h, a TLC check (CH2 Cl2 /MeOH, 9/1) showed no detectable starting compounds. For isolation, the reaction mixture was poured into 200 ml of water, when an oil separated out and, after a short time, solidifed and was broken up and filtered off with suction. The still moist residue was dissolved in a mixture of 250 ml of ethyl acetate and 50 ml of ether and washed successively with a 5% strength aqueous citric acid, bicarbonate and saturated sodium chloride solutions. After drying over Na2 SO4, the solvent was removed by distillation under reduced pressure, and the residue was mixed with n-hexane and then filtered off with suction. Recrystallization from 50 ml of ethyl acetate afforded 5.6 g of TLC-pure product, m.p. 156-157 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With acetic acid; sodium nitrite In dichloromethane; water | 7 Example 7 Example 7 p-Cyanobenzylamine (13.2 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Acetic acid (18 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over a one hour period. The mixture was stirred at the same temperature for four hours. The reaction mixture was subjected to extraction with methylene chloride, and the organic solvent was concentrated. Water was added to the concentrated solution, and the residual organic solvent was removed through distillation, to thereby obtain 14.7 g of p-cyanobenzyl acetate (yield 84%). The purity of the product was 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate; dimethyl sulfoxide; trifluoroacetic acid; sodium nitrite; In water; | Example 1 p-Cyanobenzylamine (26.2 g), sodium nitrite (20.8 g), and dimethyl sulfoxide (200 ml) were mixed, and the mixture was vigorously stirred at room temperature (about 20 to 30 C.). Trifluoroacetic acid (45.6 g) was added dropwise to the mixture over a one hour period. After completion of addition, the mixture was further allowed to react at 100 C. for one hour. The reaction mixture was analyzed by use of high performance liquid chromatography, to thereby obtain proportions (on the mol basis) of predominant reaction products: p-cyanobenzyl alcohol:p-cyanobenzaldehyde:p-cyanobenzoic acid=72:18:10. Dimethyl sulfoxide was removed through distillation under vacuum, and water (300 ml) was added to the residue. Sodium carbonate was added to the thus-formed solution, to thereby adjust pH to 8. The resultant aqueous solution was subjected to extraction with toluene (300 ml*2). Toluene was removed through distillation under reduced pressure, and the resultant solution was subsequently distilled under vacuum, to thereby obtain 16.2 g of p-cyanobenzyl alcohol (bp. 175-178 C./1.5 kPa) (yield 61%). The purity of the product was 98%. |
51% | With sulfuric acid; sodium nitrite; In water; toluene; | Example 3 p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51%). The purity of the product was 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In dichloromethane at 0 - 20℃; for 2.25h; | 63 Preparation 63; 4-[(2,2-Dimethyl-propionylamino)-methyl]-benzylamine; 4-r(2,2-Dimethyl-propionylamino)-methyll-benzonitrile; Add triethylamine (0.3 mL, 2.12 mmol) to a solution of 4-cyano-benzylamine (1.0 g, 7.58 mmol) in DCM (11 mL) and cool the mixture at 00C. Add 2,2-dimethyl-propionyl chloride (0.93 mL, 7.58 mmol) dropwise and allow to stir the mixture at 0 °C for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (1.23 g, 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide for 16h; | Synthesis of intermediate 13: 4~(4-Cyano- benzylcarbamoyl) -piperidine-1-carboxylic acid tert- butyl esterA solution of HOBt (1.54 g; 10 mmol) and TBTU (3.22 g; 10 mmol) in DMF (10ml) was added to a solution of N- Boc-piperidine-1-carboxylic acid (2 g; 8.72 mmol) and 4-cyanobenzylamine (8.72 mmol) in DMF (10 ml) followed by TEA (4.85 ml; 35 mmol). After 16h, water was added to the reaction mixture and the mixture was extracted with DCM (3 times) . The combined organics were washed with an aqueous solution of NaHCO3 and water and dried (MgSO4) . The residue was purified by silica gel chromatography (eluent:DCM and MeOH/DCM: 5/95) to afford after dry evaporation the title intermediate as an oil (2.4g; Y:80%) .MS: (M+H)+ = 344. |
67% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h; | General procedure for the synthesis of 14a-r General procedure: To a solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.23g, 1.00mmol) in DCM (10.00ml), EDC·HCl (1.00mmol), 13a-r (1.00mmol) and triethylamine (15.00μL, 0.10mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 18h at the same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE 1/1) to furnish the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With carbon dioxide; Rh/Al2O3; hydrogen at 80℃; for 6h; chemoselective reaction; | |
68% | With methanol; samarium diiodide In tetrahydrofuran for 0.5h; Inert atmosphere; Irradiation; | |
61% | Stage #1: terephthalonitrile With cobalt(III) acetylacetonate; tris(2-(dicyclohexylphosphanyl)ethyl)phosphane In <i>tert</i>-butyl alcohol Sealed tube; Inert atmosphere; Stage #2: With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol Sealed tube; Inert atmosphere; Stage #3: With hydrogen In <i>tert</i>-butyl alcohol at 80℃; for 18h; Autoclave; |
95 %Chromat. | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); 1,1'-bis(diphenylphosphino)ferrocene; potassium <i>tert</i>-butylate; hydrogen In toluene at 140℃; for 2h; Inert atmosphere; Autoclave; chemoselective reaction; | |
With isopropyl alcohol at 120℃; for 48h; Schlenk technique; Inert atmosphere; | ||
With hydrogen In ethanol at 110℃; for 1h; | 5 (5) In a 1L hydrogenation tank, 100 g of 4-cyanobenzonitrile and 3 g of Raney-Ni, 400 mL of ethanol are added, and H2 is continuously charged, so that the pressure of the system is always maintained at 8 MPa during the reaction. After the reaction was performed at a reaction temperature of 110°C for 1 hour, the temperature was lowered. After the temperature in the reaction vessel was lowered to room temperature, the mixture was degassed and 4-cyanobenzylamine (purity: 99% or more) was obtained by filtration and recrystallization. The yield was 94% by weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-bromo-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.5h; Stage #2: 4-aminobenzyl cyanide In N,N-dimethyl-formamide at 0 - 20℃; | 30.2 4-Bromo-5-methyl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid (0.79 mmol) in N,N dimethylformamide (5 ml) is added HATU (450 mg, 1.2 mmol) followed by N,N-diisopropylethylamine (437 uL, 2.4 mmol). The reaction is stirred for 1/2 hour. 4-Aminomethyl-benzonitrile (200mg, 1.2 mmol) is added at 0 0C. The reaction mixture is stirred for 3 hours at room temperature. The solvent is evaporated and the residue is purified on silica with ethyl acetate/hexane as the eluent to give product, 300 mg, 85%, LC/MS ESI m/z (M+H)+ = 451.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In 1,4-dioxane for 24h; Inert atmosphere; Reflux; | 4.2.15. 2,5-Bis(4-cyanophenyl)-1-N-hydroxy-1H-benzimidazole (34) 3-Bromo-6-fluoronitrobenzene 25 (1.7 mL, 13.6 mmol) was added to a solution of 4-cyanobenzylamine 31 (3.4 g, 20.3 mmol) and K2CO3 (5.6 g, 40.5 mmol) in dioxane (150 mL). The resulting solution was heated to reflux under nitrogen for 24 h. The inorganics were filtered from the mixture, the solution was concentrated, hexane was added and the product, orange crystals were filtered and recrystalized from ethyl acetate to give 4.4 g of 4-(N-4-cyanobenzylamino)-3-nitro-bromobenzene 32 in 98% yield, mp 153-154 °C. Compound 32 was used in the next step without further characterization. DAPCy (0.2 g, 0.37 mmol %) and K3PO4 (3.1 g, 15 mmol) were added to a solution of 32 (2.65 g, 7.5 mmol) and p-cyanophenylboronic acid (1.1 g, 7.5 mmol) in deaireated absolute ethanol (60 mL). The vigorously stirred mixture was warmed to 80 °C for 72 h under a nitrogen atmosphere. The precipitated product was filtered. The solid was dissolved in acetone, filtered through celite and recrystalized from EtOAc/MeOH to give 4-(4-cyanobenzylamino-3-nitrophenyl)-benzonitrile (33) (2.1 g, 80% yield), mp 181-182 °C. 1H NMR (DMSO-d6, 300 MHz) δ 8.86 (br s, 1H), 8.43 (d, 1H, J = 2.1 Hz), 7.85 (m, 7 H), 7.57 (d, 2H, J = 8.1 Hz), 6.96 (d, 1H, J = 9.0 Hz), 4.80 (d, 2H, J = 6.3 Hz). 13C NMR (DMSO-d6, 75 MHz) δ 144.4, 144.3, 142.4, 134.5, 132.8, 132.0, 132.1, 127.8, 126.5, 125.5, 124.3, 118.7, 118.6, 115.6, 109.9, 109.5, 45.4. ESI-MS: m/z calcd for C21H14N4O2: 354.36, found: 355.1 (M++1). Compound 33 was used in the next step without further characterization. A solution of sodium methoxide (0.3 g, 5.6 mmol) and 33 (1 g, 2.8 mmol) in 30 mL dry methanol was heated at reflux for 24 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, brought to pH 7 with 20% HCl, the resulting yellow crystals were filtered and dried to give 34 (0.9 g, 93%). Mp 244.4-244.5 °C; 1H NMR (DMSO-d6, 300 MHz) δ 8.46 (d, 2H, J = 8.7 Hz), 7.94 (d, 2H, J = 8.1 Hz), 7.90 (d, 2H, J = 5.7 Hz), 7.86 (m, 2H), 7.81 (m, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.61 (dd, 1H, J = 1.5, J = 8.1 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 144.9, 138.4, 134.2, 132.8, 132.7, 132.6, 128.7, 128.5, 127.8, 122.3, 120.3, 118.8, 118.4, 112.3, 109.7, 109.9, 107.9. HRMS (ESI) calcd for C21H13N4O m/z: 337.1090 (M++1); found m/z: 337.1173. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; | 2-(4-(Aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (777.14 mg, 7.68 mmol, 1.07 mL) and 4-(aminomethyl)benzonitrile (507.6 mg, 3.84 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Removal of solvent after washing produced a viscous orange oil. Trituration under petrol yielded a yellow/orange solid which was recrystallised from a minimum amount of boiling ethyl acetate and excess petrol to produce the title product as a fine pale yellow crystalline solid (665 mg, 1.83 mmol, 50%). 1H NMR: (300 MHz, DMSO) δ ppm 4.31 (d, 2H, J=16.12 Hz, H9), 4.55 (d, 2H J=16.15 Hz, H9'), 7.26 (m, 5H, H1-H5), 7.37 (d, 2H J=8.29 Hz, H10, H13), 7.58 (m, 2H, H6-H7), 7.64 (d, 2H J=8.26 Hz, H11-H12), 7.77 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.51 (N-CH2), 60.02 (CN) 90.57 (O-C-N), 109.82, 119.08, 123.06, 123.25, 128.40, 128.62, 129.16, 129.83, 130.54, 132.03, 133.19, 133.26, 133.52, 139.19, 144.24, 149.48 (Ar), 167.23 (CO). IR: 1397, 1655, 2227 cm-1. |
With triethylamine In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | Stage #1: L-Cysteine; 4-aminobenzyl cyanide In methanol at 20℃; for 72h; buffer; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In methanol for 2h; | 3; 5 4-(Aminomethyl)benzonitrile (25.09 g, 0.149 mol) and L-cysteine (18.1 g, 0.149 mol) were suspended in 500 mL MeOH and pH 6.4 buffer solutions (1 : 1) and stirred for 3 days at RT. Triethylamine (30 mL) was added to the mixture and Boc20 (68 g, 0.31mol) was added to this mixture and stirred for 2 h. The solvents were removed and filtered to yield white solid (R)-2-(4-((½ri-butoxycarbonylamino)methyl)phenyl)-4,5-dihydrothiazole-4- carboxylic acid (38.4 g, 76.8%). Compound 67a was obtained from this acid following the same method as used for 38d. Yield: 84.4 %. 1H NMR (500 MHz, CDC13) δ 7.75 - 7.77 (d, 2 H, J = 7.5 Hz), 7.27 - 7.26 (d, 2 H, J = 7.5 Hz), 7.23 (s, 1 H), 5.62 (br, 1 H), 4.87 (br, 1 H), 4.30 (br, 2 H), 3.86 (s, 3 H), 3.78 (t, J = 10.0 Hz, 1 H), 3.48 - 3.4 (m, 1 H), 3.25 (s, 3 H), 1.42 (s, 9 H). MS (ESI) m/z 402.1(M + Na)+, 378.0 (M - H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-aminobenzyl cyanide; 1,1'-carbonyldiimidazole With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Stage #2: 2-((piperidin-4-yl)methyl)pyridine dihydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; | INTERMEDIATE 61`N-[(4-Cyanophenyl)methyl]-4-(pyridin-4-ylmethyl)piperidine-1-carboxamideCDI (90.9 mg, 0.56 mmol) was dissolved in DCM (5 mL) at 0<€ and 4- inomethyl-benzonitrile (90.0 mg, 0.53 mmol) and DIPEA (72.4 mg, 0.56 mmol) were added. The reaction mixture was warmed to room temperature over 1 h. The reaction mixture was cooled to C and a solution of 4-piperidin-4-ylmethyl pyridine dihydrochloride (139 mg, 0.56 mmol) and DIPEA (21 7 mg, 1 .68 mmol) in DCM (5 mL) was added. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was purified by HPLC to give the title compound (139 mg, 78%) as a colourless solid. LCMS: purity 100%, ES+ 335.6 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-benzyl-1H-pyrazole-4-carboxylic acid; 4-aminobenzyl cyanide With oxalyl dichloride; triethylamine In dichloromethane at 20℃; for 3h; Stage #2: With hydroxylamine hydrochloride In ethanol; dichloromethane at 80℃; for 3h; | 3 20.8 g of 1-benzylpyrazole-4-carboxylic acid was reacted with 1 equivalent of 4-(aminomethypbenzonitrile, in the presence of 1.1 equivalents of oxalyl chloride, 3 equivalents of triethylamine in dichloromethane at room temperature for 3 h. The product was then reacted with hydroxylamine hydrochloride (3 equivalents) in ethanol at 80° C. for 3h. The target compound (17.5 g) was obtained as a off-white powder following solvent removal by evaporation. Purity assessed by HPLC was 98.7%, and mass was verified by LC/MS/MS (predicted m+1=350.2, obtained m+1=350.2). 1H-NMR (DMSO): δ 4.39-4.40 (2H), 5.34 (2H), 5.76 (2H), 7.25-7.30 (4H), 7.34-7.36 (3H), 7.59-7.62 (2H), 7.91 (1H), 8.27 (1H), 8.63 (1H), 9.57 (1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In tetrahydrofuran at 20℃; | 10 Pyridin-3-ylmethyl 4-cyanobenzylcarbamate: Pyridin-3-ylmethanol (0.546 g, 5 mmol) in THF (2ml) was added to a suspension of 1 , 1 '-carbonyldiimidazole (0.81 1 g, 5.00 mmol) in THF (8ml) at 10 °C. The mixture was stirred for 1 h at rt. The resultant solution was added to the solution of 4-(aminomethyl)benzonitrile (0.661 g, 5.00 mmol), DBU (0.754 ml_, 5.00 mmol), and Et3N (0.697 ml_, 5.00 mmol) in THF (10 ml). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was recrystallized in EtOAc/hexanes to afford the title compound as a white solid (0.85 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1 H), 8.57 (d, J = 3.91 Hz, 1 H), 8.03 (t, J = 5.87 Hz, 1 H), 7.75 - 7.89 (m, 3H), 7.40 - 7.52 (m, 3H), 5.12 (s, 2H), 4.32 (d, J = 6.07 Hz, 2H). LCMS: fR = 0.44 min, 88%.. MS (ESI): m/z 268 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 5.33333h; Inert atmosphere; | 37.a Example 37: N-benzenesulfonyl-D-leucyl-L-prolyl-[(4-aminomethyl phenyl) methyl] amide hydrochloride a) Preparation of N-benzenesulfonyl-D-leucyl-L-proline- [(4-cyanophenyl)methyl] amide[0170] N- benzenesulfonyl- D- leucyl- L- proline (737mg) , p- aminomethyl cyanophenyl hydrochloride (337mg) andDIEA (569mg) were dissolved in DMF (20ml) , cooled down to 0°C under the protection of nitrogen, HOBt (270mg) andEDCI (460mg) were added. The resulting mixture was stirred at 0°C for 20min and allowed to warm up naturally to roomtemperature and react for 5 hours. The organic layer was washed in turn with 5% potassium hydrosulphate solution,saturated sodium hydrogencarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressue to give 1.1g crude product, which was purified with column chromatographyto give a colourless oil (650mg, yield: 67.3%) .Rf = 0.65Developer: petroleum ether: ethyl acetate = 1: 1Color development: ultraviolet and iodineMS: 505 (M+Na+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3h; | 3- Phenylbenzene-l-sulfonyl chloride (250mg, 0.99mmol), Et3N (412uL, 2.97mmol) and 4- (aminomethyl)benzonitrile (261mg, 1.98mmol) were dissolved in DCM (lOmL) and stirred for 3h. The reaction mixture was quenched with water and diluted with DCM (50mL). The organic fraction was washed with brine (30mL), dried (MgSO/i) and concentrated in vacuo to give the crude title compound (345mg) as a yellow liquid. LCMS: ES+ 349.0 [MH]+. | |
With triethylamine; In dichloromethane; for 3h; | 3-Phenylbenzene-1-sulfonyl chloride (250mg, 0.99mmol), Et3N (412uL, 2.97mmol) and4-(aminomethyl)benzonitrile (261mg, 1.98mmol) were dissolved in DCM (lOmL) andstirred for 3h. The reaction mixture was quenched with water and diluted with DCM (5OmL). The organic fraction was washed with brine (3OmL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (345mg) as a yellow liquid.LCMS: ES 349.0 [IVIHf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: Biphenyl-3-carboxylic acid (500mg, 2.52mmol) and 4-aminomethyl-benzonitrile (425mg, 2.52mmol) were suspended in DCM (25mL) and DIPEA (873uL, 5.04mmol), EDC (484mg, 2.52mmol) and HOBt (386mg, 2.52mmol) were added. The reaction mixture was stirred overnight, concentrated in vacuo and partitioned between EtOAc (lOOmL) and water (lOOmL). The organic fraction was washed with water (l OOmL), sat aq NaHCC>3 (50mL), brine (50mL), dried (MgSC ) and concentrated in vacuo to give the title compound (738mg, 94percent) as a brown solid. LCMS: ES+ 313.0 [MH]+. |
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; | Biphenyl-3 -carboxylic acid (500mg, 2. 52mmol) and 4-aminomethyl-benzonitrile (425mg, 2.S2mmol) were suspended in DCM (25mL) and DIPEA (873uL, 5.O4mmol), EDC (484mg, 2.S2mmol) and HOBt (3 86mg, 2.S2mmol) were added. The reactionmixture was stirred overnight, concentrated in vacuo and partitioned between EtOAc (lOOmL) and water (lOOmL). The organic fraction was washed with water (lOOmL), sat aq NaHCO3 (5OmL), brine (5OmL), dried (MgSO4) and concentrated in vacuo to give the title compound (738mg, 94percent) as a brown solid. LCMS: ES 313.0 [IVIHf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (2-hydroxyethyl)trimethylazanium urea chloride; hydroxylamine hydrochloride In neat (no solvent) at 140℃; for 0.166667h; Microwave irradiation; Green chemistry; | Benzonitrile by One-Pot Synthesis from Benzaldehyde; Typical Procedures General procedure: Microwave irradiation: A mixture of benzaldehyde (0.106 g, 1 mmol), hydroxylamine hydrochloride (0.083 g, 1.2 mmol) and catalyst (15 mol%) was irradiated in microwave oven at 140 °C for 10 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to r.t. The product was extracted into EtOAc. The solid product was obtained after evaporation of EtOAc. The obtained solid was purified by column chromatography (silica gel). The pure product was characterized by GC-MS and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.8% | With triethylamine; HATU In N,N-dimethyl-formamide at 10 - 35℃; for 16h; | 33.1 Example 33 (Step 1) A solution of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (200 mg, 0.98 mmol), 4-(aminomethyl)benzonitrile (130 mg, 0.98 mmol), HATU (486 mg, 1.28 mmol) and TEA (0.411 mL, 2.95 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 67% ethyl acetate/hexane) to give tert-butyl (3-((4-cyanobenzyl)amino)-2-methyl-3-oxopropyl)carbamate (221 mg, 0.696 mmol, 70.8%) as a white powder. 1H-NMR (300MHz, DMSO-d6) : δ1.00(3H,d,J=7.2Hz), 1.37(9H,s), 2.90(1H,dt,J=13.2,6.6Hz), 3.03-3.16(1H,m), 4.23-4.42(2H,m), 6.77(1H,t,J=5.5Hz), 7.42(2H,d,J=8.3Hz), 7.72-7.82(2H,m), 8.44(1H,t,J=6.0Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 48h; | Preparation 28 6-chloro-N-(4-cyanobenzyl)nicotinamide Preparation 28 6-chloro-N-(4-cyanobenzyl)nicotinamide [0191] Combined 6-chloronicotinic acid (1.0 g, 6.35 mmol), 4-(aminomethyl)benzonitrile (1.007 g, 7.62 mmol), and EDC (1.825 g, 9.52 mmol) in methylene chloride (50 mL) then added Hunig's base (2.328 mL, 13.33 mmol) and the mixture stirred at 20°C for 2 h. More 4- (aminomethyl)benzonitrile (250 mg), EDC (750 mg) and Hunig's base (1 mL) was added and stirring continued for 2 days. The reaction was concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 80% EtOAc in hexanes to give the title compound (1.1 g, 63.8 % yield) as a white solid. MS m/z 272, 274 [M+H]+. NMR (400 MHz, DMSO-i) δ ppm 4.58 (d, J=6.1 Hz, 2 H) 7.53 (d, J=8.6 Hz, 2 H) 7.68 (dd, J=8.3, 0.8 Hz, 1 H) 7.77 - 7.85 (m, 2 H) 8.28 (dd, J=8.3, 2.5 Hz, 1 H) 8.89 (dd, J=2.5, 0.5 Hz, 1 H) 9.40 (t, J=5.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | In ethanol; at 130℃; for 35h;Inert atmosphere; | Example 7C. 4-[(lH-Pyrrolo[3,2-c]pyridin-4-ylamino)-methyl]-benzonitrile4-(Aminomethyl)benzonitrile.HCI was partitioned between chloroform (50 mL) and saturated NaHC03 (10 mL), dried over Na2S04, filtered and evaporated to afford 4-(aminomethyl)benzonitrile free base as a yellow oil. To 4-(aminomethyl)benzonitrile (250mg, 1.89mmol) was added <strong>[60290-21-3]4-chloro-5-azaindole</strong> (289mg, 1.89mmol) in ethanol (1 mL) and the mixture was heated at 130 C for 35 hours, adding minimum ethanol when evaporated. The crude residue was purified by flash chromatography eluting with 4% to 12% MeOH-DCM to give a pale yellow gum identified as the title compound (300mg, 1.21mmol, 64% yield). [M+H]+ = 248.7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With water; sodium hydroxide In ethanol at 95℃; for 98h; | 27.3 3) hydrolysis: the above-mentioned 1 - diphenyl - 3, 4 - (4 - cyano phenmethyl) - 1H - pyrrole - 2, 5 - dione with NaOH (120.0 mg, 3 . 0mmol), water (3.0 ml), ethanol (1.5 ml) is added in the reaction bottle, water bath heated to 95 °C stirring reaction 8 hours; the to be cooled, dropping 20% sulfuric acid to pH value to 5.0, oscillation to the solid-liquid two-phase layer, filter to get solid, and in order to 3mL5% sulfuric acid two times washing the solid, the solid dried constant weight, to obtain raw material 3, 4 - diphenyl-furan - 2, 5 - dione (94.7 mg), the percent recovery is 95%; the filtrate is mixed with an aqueous acid wash, to the mixed liquid to carry out polyreaction 20% NaOH aqueous solution to pH value to 10.0, with 60 ml methyl tert-butyl ether extraction three times, combined with the organic layer, adding anhydrous magnesium sulfate drying; filtering to remove the drying agent after the anhydrous magnesium sulfate, the recovery of solvent under reduced pressure, column chromatography for purification of the residue, to obtain the 4 - cyano-benzylamine (40.7 mg), the product yield is 77% (to raw material 4 - cyano animal pen mellow benzenesulphur diethylene glycol dinitrate idea). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane at 150℃; for 32h; Sealed tube; Inert atmosphere; | General procedure: A sealed tube is charged with 7-chloro-5-(1 -methyl- 7 - -indol-6-yl)-quinoxaline (60.00 mg; 0.20 mmol; 1.0 eqr.) (Intermediate 4), 1-pyridin-3-yl-ethylamine (0.05 ml0.41 mmol; 2.0 eqf.), NaOtBu (58.77 mg; 0.61 mmol; 3.00 eqf.) and toluene (2.0 ml_). RM is purged with argon and then BINAP (25.39 mg; 0.04 mmol; 0.20 eqf.) and Pd2(dba)3 (18.67 mg; 0.02 mmol; 0.10 eq.) are added. RM is sealed and heated at 1 10°C for 16 h. After this time, the mixture is filtered through a Celite pad and the filtrate is diluted with EtOAc and extracted with water. Combined organic phases are washed with brine, dried over Na2S04. Solvent is evaporated and the residue is purified by FCC (hexane/EtOAc; gradient). [8-(1 -Methyl- 7H-indol-6-yl)-quinoxalin-6-yl]-(1 - pyridin-3-yl-ethyl)-amine is obtained as a yellow powder (60.00 mg; yield 79%; 97% by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In tetrahydrofuran; at 20℃; for 3h; | (3) 0.1 g of intermediate C was added3, With the raw material0.1g in THF as a solvent at room temperature for 3h, the intermediate D-AWY113, yield 66%; specific reaction equation is as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | In tetrahydrofuran; at 20℃; for 3h; | 0.1 g of intermediate C was added4, And0.1 g of thestarting materialwere reacted at room temperature for 3 h in solvent THF to give the intermediate D-AWY118 in 46% yield. The reaction equation was as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iron oxide In ethanol at 25℃; for 2h; | |
77% | With meso-tetraphenylporphyrin iron(III) chloride In ethanol at 25℃; for 2.5h; | |
63% | With manganese oxide octahedral molecular sieve-supported copper hydroxide; air In ethanol at 20℃; for 2h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 4-aminobenzyl cyanide With triethylamine In dichloromethane for 0.333333h; Stage #2: p-acetylaminobenzenesulfonyl chloride In dichloromethane at 20℃; for 4.5h; Cooling with ice; | 1 Synthesis of N-(4-(N-(4-cyanobenzyl)sulfamoyl)phenyl)acetamide (1a) cyanophenethylamine 1.00 g, 7.57 mmol) was dissolved in anhydrous dichloromethane (15 mL), triethylamine (1.26 mL, 8.75 mmol) was added, stirred for 20 min, A solution of p-acetamidobenzenesulfonyl chloride (1.93 g, .32 mmol) in anhydrous dichloromethane (5 mL) was added dropwise, the mixture was stirred in an ice bath for 30 minutes. The ice bath was removed and reacted at room temperature for 4 hours. water (25 mL), extracted with dichloromethane, dried over anhydrous magnesium sulfate and purified by column chromatography to give 2.18 g of a white solid, 87% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: N-Methylhydroxylamine; diethyl 2-ethoxymethylenemalonate With pyridine at 85℃; for 4h; Stage #2: 4-aminobenzyl cyanide With potassium carbonate In ethyl acetate at 20℃; | Cascade Synthesis of Compounds 3 General procedure: To a mixture of diethyl 2-(ethoxymethylene)malonate (4) (0.6 mmol) and hydroxylamine 5 (0.6 mmol) was added pyridine (0.1 mmol), andthe resulting mixture was stirred at 85 °C for 4 h. After cooling the reaction mixture to r.t., amine 2 (0.5 mmol), K2CO3 (0.5 mmol or 1.0mmol) and EtOAc (3 mL) were added. The mixture was stirred at r.t. until the reaction was complete (as detected by TLC monitoring). The insoluble salt (K2CO3) was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc, 10:1 to 4:1) to afford the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: (S)-1-(2-bromopyridin-4-yl)piperidine-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 21h; Inert atmosphere; Stage #2: 4-aminobenzyl cyanide In N,N-dimethyl-formamide at 50℃; for 24h; Inert atmosphere; | 1.3 (S) -l- (2-bromopyridin-4-yl) piperidine-3-carboxylic acid (4a) (290 mg, 1.02 mmol)Was dissolved in 8 mL of anhydrous DMF,Was added to CDI (198 mg, 1.23 mmol) under nitrogen,Heated to 50 ° C for 21 h,Cooled to room temperature, 4-cyanobenzylamine (202 mg, 1.53 mmol) was added,Continue to nitrogen protection, heating to 50 reaction 24h,After cooling to room temperature, quenched with 1M HClThe reaction was carried out by adding 50 mL of water and extracting three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and subjected to gradient gradient chromatographyThe column (ethyl acetate / petroleum ether = 5% to 100%) gave 289 mg of a white solid in 71% yield. |
71% | With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Inert atmosphere; | 2 General procedure A for the synthesis of compounds (5a-5d) General procedure: To a solution of 4 (290mg, 1.02mmol) in DMF (1.5mL), CDI (198mg, 1.23mmol) was added under N2 protection. The resulting reaction was stirred 50°C. After 2h, the mixture was cooled to room temperature, and the corresponding benzylamine (1.53mmol) was added. The resulting reaction was stirred 50°C under N2 protection overnight. Then the mixture was cooled to room temperature, quenched with 1M hydrochloric acid, diluted with water (50mL), and extracted with CH2Cl2 (60mL×3). The combined organic layer were washed with saturated solution of NaCl (60mL×3), dried over MgSO4, concentrated and purified by flash chromatography eluting with 5-50% ethyl acetate in petroleum ether, to provide the desired products 5a-5d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 3-(1-((2-bromopyridin-4-yl)oxy)ethyl)benzoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: 4-aminobenzyl cyanide In dichloromethane at 20℃; for 24h; Inert atmosphere; | 5 4.1.5 3-(1-((2-bromopyridin-3-yl)oxy)ethyl)-N-(4-fluorobenzyl)benzamide (7a) General procedure: CDI (112 mg, 0.69 mmol) was added under nitrogen to a solution of 6 (200 mg, 0.62 mmol) in dry methylene chloride (15 mL). The solution was stirred at room temperature for 1 h, then (4-fluorophenyl)methanamine (116 mg, 0.93 mmol) was added, and stirred at room temperature under nitrogen or 24 h. After the complete conversion of the starting material, the reaction was quenched with 1 M HCl. The aqueous phase was extracted with methylene chloride (3 * 50 mL). The combined organic phases were washed with brine until neutral pH, dried on Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 7a (240 mg, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Cu((+)-indaPyBOX)<SUB>2</SUB>PF<SUB>6</SUB>; sodium carbonate In dichloromethane at 20℃; for 15h; Schlenk technique; Inert atmosphere; Sealed tube; enantioselective reaction; | |
63% | With Cu((+)-indaPyBOX)<SUB>2</SUB>PF<SUB>6</SUB>; sodium carbonate In dichloromethane at -5℃; for 72h; Inert atmosphere; Schlenk technique; enantioselective reaction; | 2. Supplemental Experimental Procedures for Copper-Catalyzed Dynamic Kinetic Ring-opening of Cyclic Diaryliodoniums General procedure: Under nitrogen atmosphere, a Schlenk tube was sequentially charged with cyclicdiaryliodonium salt (1.0 equiv), copper catalyst A1 or A2 (5.0 mol%), Na2CO3 (3.0 equiv) anddichloromethane (0.05 M). After the mixture was chilled to proper temperature, the appropriateamine (1.2 equiv) was added and stirred for the time indicated in the experimental procedures.The reaction mixture was filtered through a plug of celite with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was purified by column chromatographyon silica gel to deliver the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; Green chemistry; chemoselective reaction; | General Procedure for the Preparation of 3 General procedure: To a solution of benzylamine (0.6 mmol), indole (1.0 mmol) and CuI (0.1 mmol ) in CH3CN (1 mL) was added TEMPO (0.15 mmol) under atmosphere and the mixture was stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:4) to yield the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | With C26H36NP; 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid In dimethyl sulfoxide at 60℃; for 5h; | 3 Example 3 In an appropriate amount of organic solvent DMSO,Add 100 mmol of the compound of the above formula (I), 250 mmol of the compound of the above formula (II),3.5 mmol two-component composite catalyst (a mixture of 1 mmol PdCl 2 (cod) and 2.5 mmol ferrocene), 20 mmol of the above ligand L1150 mmol of oxidant m-chloroperoxybenzoic acid and 40 mmol of acid promoter trifluoroacetic acid,After joining,The temperature was raised to 60 ° C and the reaction was stirred at this temperature for 5 hours.After the reaction is over,Cool naturally to room temperature,Filter, wash the filtrate thoroughly with deionized water, then use acetic acidEster extraction 2-3 times,The organic phase is combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with a mixture of n-pentane and acetone in an equal volume ratio to give the compound of the above formula (III). The yield was 97.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate In tetrahydrofuran at 20 - 50℃; for 12h; | 26 Example 26: 5,6-bis(4-cyanobenzyl)amino-2,3-dicyanopyrazine In a 50 ml round bottom flask, 5,6-dichloro-2,3-dicyanopyrazine (99 mg, 0.5 mmol) was dissolved in 20 ml of tetrahydrofuran, and 4-cyanobenzylamine (198 mg, 1.5 mmol) was stirred. After stirring at room temperature, potassium carbonate (276 mg, 2 mmol) was added, and the reaction was carried out at 50 ° C for 12 hours. The reaction of the starting material was completed by TLC. The solvent was concentrated, 150 ml of ethyl acetate was added, and the mixture was washed with water and saturated aqueous sodium chloride. Dry, concentrated,Separated by silica gel column chromatography,154 mg of a white solid were obtained in a yield of 79.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (C5(CH3)5)IrCl2(1,3-diisoptopylimidazole); potassium carbonate; at 90℃; for 40h;Inert atmosphere; Schlenk technique; Sealed tube; | General procedure: In a stainless reactor bomb, the corresponding aliphatic amine (1.0mmol), 1c (0.50 mol%), K2CO3 (5.0 mol%), and MeOH (1.0 mL) were placed. Then, the reactor was sealed with a stainless stopper, and the mixture was stirred under indicated conditions. After removing MeOH under reduced pressure, the products were isolated by silicagel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 3-(2',2'-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere; Stage #2: 4-aminobenzyl cyanide With pyridine In dichloromethane at 20℃; for 2.5h; Inert atmosphere; | 2.1 Embodiment 2 model canadense amide quinones (DCA - CONH - 02) preparation of 1. Model canadense amide quinones (DCA - CONH - 02) preparation, comprising the following steps: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.416667h; | General Amide Formation Procedure: General procedure: Carborane-1-carboxylic acid (1.0 equiv) and COMU (1.1 equiv) dissolved in DMF, acetone or ethylacetate were reacted with the amine (1.2 equiv) and N,N-diisopropylethylamine (DIPEA, 2.0 equiv) dissolved in DMF, acetone or ethylacetate for 25minat room temperature and purified using the eluent ratio given below. Synthetic details of the optimized procedure in DMF and analytical data of compounds not listed below have recently been reported [33]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: DIPEA (7.2 mmol, 2.5 eq), PyBOP (3.6 mmol, 1.25 eq) and 6a-b(2.9 mmol, 1.0 eq) in CH2Cl2 (20 mL) was stirred at 25 C for 2 h. then,7a-l (3.2 mmol, 1.1 eq) was added. The mixture was stirred for another13 h and quenched with H2O (100 mL). The aqueous layer was extractedwith CH2Cl2 (30 mL X 3) and the combined organic layers werewashed with brine, and dried over anhydrous Na2SO4. Purification ofthe crude reaction mixture was progressed by column chromatography(5-30% EtOAc/PE). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium In methanol at 20℃; Inert atmosphere; | 3.24 Example 24 Synthesis of Compound 9p Compound 8 (50 mg, 0.123 mmol) was dissolved in methanol (3 mL), and p-cyanobenzylamine (18 mg, 0.135 mmol) was sequentially added under the protection of nitrogen.DMTMM (37.4 mg, 0.135 mmol), N-methylmorpholine (30 μL), reacted at room temperature overnight, TLC detection of starting materials disappeared (developing solvent: dichloromethane-methanol = 10: 1).The solvent was distilled off under reduced pressure, diluted with ethyl acetate, washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was separated by silica gel column chromatography (mobile phase: dichloromethane-methanol = 20: 1) Purification gave compound 9p (58 mg, 91%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tert.-butylhydroperoxide; N-iodo-succinimide; sodium carbonate In N,N-dimethyl acetamide at 50℃; for 16h; Inert atmosphere; | General procedure for synthesis of polysubstituted oxazoles from benzylamines and1,3-dicarbonyl derivatives General procedure: benzylamines (1, 0.2 mmol), 1,3-dicarbonyl derivatives (2,0.3 mmol), NIS (0.4 mmol), TBHP (0.6 mmol), Na2CO3 (0.4 mmol) were mixed under N2 atmosphere in 2 mL DMA. The reaction tube was heated in an oil bath at 50 °C for 16 hours. After completion of the reaction, the reaction mixture was extracted with EtOAc (15 mL × 3), and the solvent was removed under reduced pressure. The remaining crude product was then purified through column chromatography using silica gel (ethyl acetate/petroleum ether = 1/10) to afford 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine In acetonitrile at 20℃; for 0.166667h; | 3.3. General Procedure B: Synthesis of 4a-4al General procedure: A mixture of amine (0.5 mmol) or diamine (0.25 mmol), carbon disulfide (38 mg, 0.5 mmol),methyl (2-chloroacetyl)carbamate (76 mg, 0.5 mmol), and triethylamine (61 mg, 0.6 mmol) in MeCN(3 mL) was stirred at room temperature for 10 min. After disappearance of the reactant (monitoredby TLC), added 50 mL water to the mixture, then extracted with ethyl acetate 3 times (3 x 50 mL).The extract was dried over anhydrous Na2SO4 and evaporated. The residue was purified by columnchromatography on silica gel to give 4a-4al. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; 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 0 - 20℃; for 2h; | 5.5.1. General procedure for synthesis of compounds 18a-c General procedure: To a solution of 17a-c (10 mmol), 5-nitrothiophene-2-carboxylicacid (1.73 g, 10 mmol) and triethylamine (2.7 mL, 20 mmol) in DMF(30 mL) was added HATU (3.80 g, 10 mmol) at 0 C. The reactionmixture was allowed to warm to room temperature and stirred for2 h. Then, EA (100 mL) and water (100 mL) was added andextracted. The organic phase was evaporated to afford compounds18a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With ammonia; hydrogen In methanol at 30℃; for 24h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium azide; 1,10-Phenanthroline; copper(II) acetate monohydrate; sodium L-ascorbate In ethanol; water at 20℃; for 18h; | General procedure for the synthesis of 2-mercapto benzoxazolecoupled benzyl triazoles (BOTs) (1-19): General procedure: Sodium ascorbate (1.57 mmol) was added to a green coloured suspension of Cu(OAc)2·H2O (0.105 mmol) and 1,10-phenanthroline monohydrate (0.105 mmol) in 4:1 EtOH and H2O (8 mL: 2 mL) and stirred the reaction mixture for 5 min at room temperature, then added 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (2) (1.05 mmol), sodium azide (1.26 mmol) and benzyl bromide derivative (1.15 mmol) and the resulting orange coloured suspension was stirred at room temperature for 18 h. After 18 h, diluted the reaction mixture with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (30 mL) followed by brine (30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by column chromatography over silica gel (100-200 mesh) with eluent 50% to 70 % EtOAcin pet ether followed by recrystallization with diethyl ether to yield compound. |
75% | With sodium azide; 1,10-Phenanthroline; copper(II) acetate monohydrate; sodium L-ascorbate In ethanol; water at 20℃; for 18h; | General procedure for the synthesis of 2-mercapto benzoxazolecoupled benzyl triazoles (BOTs) (1-19): General procedure: Sodium ascorbate (1.57 mmol) was added to a green coloured suspension of Cu(OAc)2·H2O (0.105 mmol) and 1,10-phenanthroline monohydrate (0.105 mmol) in 4:1 EtOH and H2O (8 mL: 2 mL) and stirred the reaction mixture for 5 min at room temperature, then added 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (2) (1.05 mmol), sodium azide (1.26 mmol) and benzyl bromide derivative (1.15 mmol) and the resulting orange coloured suspension was stirred at room temperature for 18 h. After 18 h, diluted the reaction mixture with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (30 mL) followed by brine (30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by column chromatography over silica gel (100-200 mesh) with eluent 50% to 70 % EtOAcin pet ether followed by recrystallization with diethyl ether to yield compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 5-phenylfuran-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: 4-aminobenzyl cyanide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | 4.2.4 General procedure 'b' for synthesis of compounds SH11, SH13 & SH19 General procedure: To an ice-cold suspension of 5-phenylfuran-2-carboxylic acid (4) (100mg, 0.53mmol, 1 equivalent) in dimethyl formamide (1.5mL), carbonyldiimidazole (1.5 to 2.0 equivalent) was added under nitrogen atmosphere, then the resulting reaction mixture was warmed to room temperature and allowed to stir for 1h. Thereafter, the reaction mixture was cooled to 0°C and different substituted amines (1.0 to 2.0 equivalent) were added and the resulting mixture was warmed to room temperature and stirred for 3 to 6h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to 0°C and then diluted with water, the separated product was filtered off, washed with water and dried. The resulting residues were purified by silica gel column chromatography to get final compounds SH11, SH13 & SH19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 50℃; for 1h; Sonication; | General procedure for the preparation of 2-aryl substituted 4,5-diphenyloxazoles (3) General procedure: A mixture of benzoin 1 (1.2 mmol), amine 2 (1 mmol) and IBX (1.2 equiv.) in DMSO (5 mL) was stirred at 50 °C for 1 h under open air in the presence of ultrasound using a laboratory ultrasonic bath Sonorex Super RK 510H model producing irradiation of 35 kHz. The temperature of the bath was maintained by adding cold water time to time in case any increase of temperature beyond 50 °C was observed due to the prolong irradiation with ultrasound. After completion of the reaction (monitored by TLC), the mixture was quenched with sat. NaHCO3 solution (3 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were collected, dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude compound was purified by column chromatography on silica gel using EtOAc / n-hexane as a solvent system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran at 90℃; for 24h; Inert atmosphere; | 13 Example 13 Under the protection of nitrogen, add 0.05 mmol of copper acetate, 0.05 mmol of 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, and 0.5 mmol of 4-phenyl-1 into the reaction vessel in sequence. , 2,3-thiodiazole, 0.5 mmoles of 4-cyanobenzylamine and 3 ml of tetrahydrofuran were stirred for 24 hours at 90°C, stopped heating and stirring, and cooled to room temperature. The reaction solution was washed with saturated brine and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the target product. The column layer used The eluent is a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 10:1, and the yield is 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With europium(III) trifluoromethanesulfonate In acetonitrile at 50℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.7% | With dmap; potassium carbonate In acetonitrile at 0 - 20℃; for 12h; | Synthesis of the Compounds 11-25 General procedure: Aniline (0.5 g,0.005 mol) and potassium carbonate (2.5 g, 0.018 mol) was dissolvedin anhydrous acetonitrile (20 mL) into a 150 mL roundbottomflask. Then the mixture was cooled to 0 °C, followingby adding the solution of compound 10 (1.6 g, 0.005 mol) inanhydrous acetonitrile (20 mL). The reaction was transferredto room temperature and catalyst 4-dimethylaminopyridine(DMAP) (1.00 g, 0.008 mol) was added. The mixture stirred atroom temperature for 12 h until TLC indicated that the reactantsreacted completely. Solvent was removed under reducedpressure to afford the crudes, which water (40 mL) was added.The pH of the aqueous phase was adjusted to weakly basicwith the solution of sodium bicarbonate, and extracted withethyl acetate. Combine the organic layers, dry over sodiumsulfate (Na2SO4), filter, and concentrate. The crude residuewas purified by column chromatography (SiO2, DCM : methanol= 120 : 1) to afford the white product 11 (1.21 g, 67%).Preparation of 12-25 were followed the procedure for 11 describedabove. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane at -78℃; for 0.666667h; | 1 Preparation methyl 3-[(4-cyanophenyl)methyl]amino}-3-oxopropanoate, (35a). To a solution of 4-cyanobenzylamine (34a) (3.1 g, 23.5 mmol) in DCM (50 mL) was added Et3N (9.8 mL, 70.5 mmol) and after cooling in a -78 °C bath, a solution of methyl 3-chloro- 3-oxopropionate (2a) (2.5 mL, 23.5 mmol) in DCM (20 mL) was added via a dropping funnel over 10 min. After 30 min, the -78 °C bath was removed. After overnight at room temperature, to the mixture was added a saturated NaHCO3 solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. To the crude material was added about 10 mL EtOAc followed by 200 mL hexanes. The precipitate was filtered, washed with hexanes and dried, which afforded (35a) as a light yellow solid (4.5 g, 82% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 36h; Inert atmosphere; | General coupling reaction for the preparation of amides 1a-7a, 10a, 10c-d and 13b General procedure: A mixture of the appropriate acid 23, 27, 33-34, 39, 42, 50 or 68 (1 mmol), the appropriate amine 24, 28-29,32, 37-38, 28, 51-53 or 60 (1 mmol) and TBTU (1.1 mmol) were dissolved in dry DMF (3-5 mL) at 0 °C undera N2 atmosphere. DiPEA (1.2 mmol) was added dropwise to the mixture and the reaction was then stirredat r.t. for 3-36 h, until completion (monitored by T.L.C.). The mixture was diluted with EtOAc and washedwith water, sat. aq. NaHCO3 solution and brine, dried over Na2SO4 and concentrated under vacuum. Thecrude residue was purified by automated flash column chromatography eluting with n-hexane-EtOAc100:0 v/v increasing to n-hexane-EtOAc 0:100 v/v in 10 CV unless otherwise indicated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In tetrahydrofuran at 100℃; for 3h; | Thioureidothiophene-3-carboxylates 3a-3i. General procedure: Amixture of 8 mmol of compound 2, 8 mmol of substitutedbenzylamine, and 8 mmol of triethylamine in 10 mL ofTHF was stirred at 100°C for 3 h and then cooled to roomtemperature and diluted with cold water under vigorousstirring. The precipitate that formed was collected byfi ltration and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 6-phenyl-12-(p-tolyl)-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine; sodium t-butanolate In toluene at 100℃; for 12h; | 25 Preparation Example 25 In a 25mL reaction tube, add 0.3mmol 2,2'-bisbromobiphenyl, 0.36mmol 4-cyanobenzylamine, 0.015mmol palladium chloride, 0.03mmol organoantimony ligand IV, 0.6mmol sodium tert-butoxide and 2.0mL toluene, react at 100°C for 12h. After the reaction was completed, the solvent was removed under reduced pressure, and the pure compound was separated by column chromatography with a yield of 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With iodine pentoxide In dimethyl sulfoxide at 100℃; for 7h; | 9 Example 9 First add to the dry reaction flaskThiocyanate,solvent,Pyridine-2-carbaldehyde,Amines and oxidizing agents,After mixing for a while at room temperature,The reaction solution was placed in an oil bath at 100 °C and stirred for 4 h.In the present embodiment, the R in the pyridine-2-carbaldehyde group is hydrogen,In the synthesis reaction, the addition amount of pyridine-2-carbaldehyde is 0.3 mmol;The R2 group in the amine is phenyl,In the synthesis reaction, the amount of amine added is 0.6 mmol;In the synthesis reaction, the X group in the thiocyanate is an NH4 group,The amount of NH4SCN added in the synthesis reaction was 0.6 mmol.The reaction equation looks like this:Among them, the oxidant is I2O5,The amount of I2O5 added is 0.3 mmol;The solvent is DMSO (dimethyl sulfoxide),The amount of DMSO added was 2mL,The obtained product is numbered as III-1.After the reaction is completed,added to the reaction solution10% aqueous sodium thiosulfate solution,The reaction solution was extracted with ethyl acetate,The organic phase was dried with anhydrous Na2SO4,filtered, the solvent was removed by distillation under reduced pressure,Then use silica gel as filler to separate through column chromatography (eluent is the mixture of petroleum ether and ethyl acetate),The product obtained is 3-phenylimidazo[1,5-a]pyridine-1-carbonitrile,The yield was 95%.The synthetic reaction operation steps of the present embodiment are the same as those of embodiment 1,But the raw materials are different.The R group in the pyridine-2-carbaldehyde in the present embodiment is hydrogen,In the synthesis reaction, the addition amount of pyridine-2-carbaldehyde is 0.3 mmol;The R2 group in the amine is 4-cyanophenyl,In the synthesis reaction, the amount of amine added is 0.6 mmol;In the synthesis reaction, the X group in the thiocyanate is NH4 group,The amount of NH4SCN added in the synthesis reaction was 0.6 mmol.The oxidant is I2O5,The amount of I2O5 added is 0.3 mmol;The solvent is DMSO,The amount of DMSO added was 2mL,The synthesis reaction temperature was 100°C,The reaction time is 7h,The product number obtained is III-9.After the reaction is completed, the operation steps are the same as in Example 1,The resulting product is 3-(4-cyanophenyl)imidazo[1,5-a]pyridine-1-carbonitrile,The yield was 97%. |
89% | Stage #1: pyridine-2-carbaldehyde; 4-aminobenzyl cyanide; ammonium thiocyanate In dimethyl sulfoxide at 20℃; for 0.0833333h; Stage #2: With iodine pentoxide In dimethyl sulfoxide at 100℃; for 5h; | 23 Example 23: Synthesis of 1-cyano-3-(4-cyano)imidazo[1,5-a]pyridine In a dry reactor, NH4SCN (0.6 mmol, 46 mg), pyridine-2-carbaldehyde (0.3 mmol) and 4-cyanobenzylamine (0.6 mmol) were added, followed by dimethyl sulfoxide (2 mL).After stirring the mixture at room temperature for 5 min, I 2 O 5 (0.3 mmol, 100 mg) was added, and the mixture was further stirred at 100° C. for 5 h.After the reaction (TLC) was completed, the reaction mixture was allowed to cool to room temperature and quenched with saturated Na2S2O3 solution. Then the reaction mixture was extracted with ethyl acetate.The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue.Finally, the organic phase is concentrated on a rotary evaporator. The crude product is purified by column chromatography to obtain 1-cyano-3-(4-cyano)imidazo[1,5-a]pyridine. Yield: 89%. |
Tags: 10406-25-4 synthesis path| 10406-25-4 SDS| 10406-25-4 COA| 10406-25-4 purity| 10406-25-4 application| 10406-25-4 NMR| 10406-25-4 COA| 10406-25-4 structure
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