* 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.
Concentrated sulfuric acid (98percent, 4.5 g, 54.8 mmol) was added dropwise to a solution of 2- (4-cyanophenyl) acetic acid (3 g, 180 mmol)In 40 ml of methanol, and the reaction was stirred for 4 hours at 75 ° C.Cool to room temperature and adjust pH to 8 with saturated aqueous sodium bicarbonate.The mixture was extracted with ethyl acetate. The extract was dried and concentrated to give 3.2 g (98percent) of the title compound.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 6, p. 2598 - 2600
[2] Patent: CN107474024, 2017, A, . Location in patent: Paragraph 0602; 0603; 0604
[3] Patent: WO2013/8162, 2013, A1, . Location in patent: Page/Page column 58; 59
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
2
[ 5462-71-5 ]
[ 52798-01-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 548 - 551
3
[ 1197-55-3 ]
[ 5462-71-5 ]
Yield
Reaction Conditions
Operation in experiment
78.9%
Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 0 - 40℃; for 0.75 h; Stage #2: With sodium cyanide; copper(l) cyanide In water; acetic acid at 0 - 5℃; for 3.66667 h;
To a suspension of 4-amino-phenylacetic acid (18.2 g, 120.4 mmol), concentrated HC1 (24.7 mL) and water (90 mL) warmed by a 40 °C water bath, acetic acid (13 mL) was added. This solution was cooled to 0-5 °C by an ice- water bath and a solution of sodium nitrite (9 g, 130.4 mmol) in water (32 mL) was added dropwise within 20 minutes. The orange solution was stirred for another 25 minutes at 0- 5 °C and then it was added by a glass pipette (10 mL) slowly to a solution of sodium cyanide (29.5 g, 602 mmol), copper cyanide (21.6 g, 241 mmol) and water (280 mL) at 4- 5 °C within 40 minutes. The black suspension was kept stirring at 4°C for 1 hr and room temperature for 2 hr. The suspension was filtrated through celite and the precipitate was washed with EtOAc (50 mL, twice). The filtration was extracted with EtOAc three times. The combined organic layers were dried over anhydrous NA2S04 and the solvent was concentrated under reduced pressure. The residue was applied to a column CHROMATOGRAPHY (SIO2, 20percent MEOH in EtOAc) to give 44 (15.3 g, 78.9percent) as yellow solid.
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 80℃; for 18 h;
Preparative Example 9B; A solution of commercially available 4-bromophenyl-acetic acid (1.5 g), Zn(CN)2 (492 mg) and Pd(PPh3)4 (403 mg) in DMF was stirred at 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 95:5) to afford the title compound (470 mg; 42percent). [MH]+=162.
Reference：
[1] Chemical Communications, 1997, # 11, p. 1041 - 1042
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 21, p. 3197 - 3204
Reference：
[1] Canadian Journal of Chemistry, 1992, vol. 70, # 3, p. 992 - 999
[2] Canadian Journal of Chemistry, 1992, vol. 70, # 3, p. 992 - 999
24
[ 64-17-5 ]
[ 5462-71-5 ]
[ 1528-41-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
for 3 h; Reflux
Preparation 26 Ethyl (4-cyanophenyl)acetate 2-(4-cyanophenyl)acetic acid (1 g, 6.21 mmol) was dissolved in 1.25M solution of HCl in ethanol (11ml) and the mixture heated to reflux for 3h. After cooling down to room temperature the solid formed was filtered off and dried in the vacuum oven. Yield=89percent. LRMS: m/z 207 (M+17)+ Retention time: 5.33 min (Method B) 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.26 (t, 3 H) 3.64 (s, 2 H) 4.16 (q, 2 H) 4.90 (s, 2 H) 7.33 (d, J=8.51 Hz, 2 H) 7.60 (m, 2 H)
Reference：
[1] Chemical Communications, 1997, # 11, p. 1041 - 1042
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 21, p. 3197 - 3204
With hydrogenchloride; In methanol; acetic acid; ethyl acetate;
a) 4-Cyanophenylacetic acid 1 g (7.03 mMol) of 4-cyanophenylacetonitrile was added to conc. hydrochloric acid preheated to 105C and kept at this temperature for 5 minutes. It was cooled to 0C, the precipitate formed was collected and washed thoroughly with ice water. After purification by column chromatography on silica gel (Macherey-Nagel, 35-70 mesh ASTM) using ethyl acetate/methanol/glacial acetic acid = 95/5/0.5 (v/v/v) as eluant, 0.5 g (44% of theory) of colourless crystals were obtained Mp. 152.154C. IR (KBr): 2229.6 (C N), 1697.2 (Carboxylic acid-C=O) cm-1
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.5h;
Example 26; The title compound from Preparative Example 2000 (470 mg) was dissolved in dichloromethane (15 mL). DMF (10 muL) and oxalylchloride (1.27 mL of a 2M solution in dichloromethane) were added and the mixture was stirred at rt for 2.5 h. The mixture was concentrated to afford the crude acid chloride. The title compound from Preparative Example 2100, Step C (170 mg) was added as a solution in pyridine (5 mL). The mixture was stirred at 60° C. for 16 h, concentrated and dissolved in ethyl acetate. The organic layer was washed with saturated ammonium chloride and brine, dried (MgSO4), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 4:6) to afford the title compound (69 mg; 30percent). [MH]+=390.
With oxalyl dichloride; In dichloromethane;
Synthesis of (1R,3aS,5aR,5bR,9S,11aR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-icosahydro-cyclopenta[a]chrysene-3a-carboxylic acid 3-[5-(4-cyano-benzyl)-[1,2,4]oxadiazol-3-yl]-benzylamide (276): Betulinic acid (2.29 g, 5 mmol) was coupled to 3-aminomethyl-benzonitrile (900 mg, 7 mmol) in DMF (10 mL) under the standard conditions outlined above using EDCI (1.2 g, 6 mmol), HOBT (340 mg, 2.5 mmol) and N-methyl morpholine (1.5 mL) to provide amide (2.0 g, 70percent yield) after column chromatography (SiO2). This material (350 mg, 0.61 mmol) was dissolved in EtOH (25 mL) and heated at reflux with 50percent aqueous NH2OH solution (0.5 mL). After 1 h the mixture was concentrated, dried, and was used as such without further purification. To a solution of hydroxyamidine (100 mg, 0.165 mmol) in THF (10 mL) in a microwave reaction vial was added (iPr)2NEt (64 mg, 0.48 mmol) and (4-cyanophenyl)-acetyl chloride (29 mg, 0.165 mmol, generated from corresponding acid and oxalyl chloride in CH2Cl2). The reaction vial was sealed, heated in a microwave reactor at 180° C. for 15 minutes and then stirred at room temperature for 30 minutes. The mixture was concentrated and the residue purified by column chromatography (SiO2, EtOAc-hexane eluent) providing 276 (40 mg, 33percent yield).
With thionyl chloride; In dichloromethane; at 50℃; for 2h;Inert atmosphere;
[00232] To a solution of compound 93 (100 mg, 0.62 mmol) in anhydrous CH2C12 (1 mL) was added 50C12 (0.2 mL) at rt under N2. The mixture was stirred at 50 °C for 2h. The mixture was concentrated under reduced pressure to afford crude compound 94 (120 mg, 100percent) as a white solid, which was used for next step without further purification.
With thionyl chloride; In dichloromethane; for 1h;Reflux;
A solution of <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (1 .5 g, 1 .0 eq.), thionylchloride (10 ml) and methylene chloride (5 ml) was heated unter reflux for one hour. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to afford the title compound (1.7 g) that was used directly without further purification.
With oxalyl dichloride;
4-Cyanophenylacetic acid was synthesized according a method by Jaeger et al. (J. Chez. Soc., 1941,744-747) and converted to the corresponding acetyl chloride by treatment with oxalylchloride. The title compound was prepared following the same method as described for 117NLS87-A using [4-CYANOPHENYLACETYL] chloride and 128NLS52 (116 mg, 0.32 mmol). Yield: 60 mg, 40percent. Rf= 0.40 [(MEOH/CH2CL2 1] : 9). LCMS [M/Z] 466 [[M+H] +. IH-NMR (CDC13,] rotamers 0.7 : 0.3) [6] 7.62-6. 89 (m, 8H, Ar-H), 4.97 (d, [1H,] [J=] 6.1, dioxane-H), 4.63 (m, 1H, dioxane- H), 4.59-4. 47 (m, 2.7H, pip-H, benzyl-H), 4.06-4. 02 (m, 1H, dioxane-H), 3.86 (s, 0.6H, benzyl-H), 3.69-3. 55 (m, 3.7H, benzyl-H, pip-H, dioxane-H), 2.91-2. 86 (m, 2H, pip-H), 2.47-2. 30 (m, 2H, NCH2), 2.05-1. 39 (m, [10H,] pip-H, dioxane-H, [NCH2CH2).] HPLC [TR =] 4.3 min.
[00198] 2-(4-cyanophenyl)acetic acid (400 mg, 2.5 mmol) was added to conc.H2S04 (4 ml_). The mixture was stirred at 40 C for 1 h. The reaction was cooled to 20 C, and then poured into water (8 mL). The suspension was filtered, and the filter cake was collected to afford 2-(4- carbamoylphenyl)acetic acid Core-1 b_F1 (300 mg, yield 67%) as white solid. The product was used in next step without further purification; 1H NMR (400 MHz, DMSO-cfe) d 7.81 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 3.64 (s, 2H).
With sulfuric acid; nitric acid; at -9 - 15℃; for 2h;
To a solution of fuming nitric acid (60.7 ML) cooled by an ice-water bath, concentrated sulfuric acid (135. 0 mL) was added and reaction temperature was controlled by the adding rate below 15 °C. 44 (38.9 g, 241.4 mmol) was added in by several portions while the temperature of the mixture was BETWEEN-9 °C AND-4 °C. After the mixture was stirred at 3-5 °C for another 2 hr. , it was poured into the crushed ice (1500 g). The precipitate was filtrated out and washed by water to give 45 (45. 8 g, 92percent) as yellow solid after dried over vacuum.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 18h;
Preparative Example 9B; A solution of commercially available 4-bromophenyl-acetic acid (1.5 g), Zn(CN)2 (492 mg) and Pd(PPh3)4 (403 mg) in DMF was stirred at 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 95:5) to afford the title compound (470 mg; 42percent). [MH]+=162.
To a suspension of 4-amino-phenylacetic acid (18.2 g, 120.4 mmol), concentrated HC1 (24.7 mL) and water (90 mL) warmed by a 40 °C water bath, acetic acid (13 mL) was added. This solution was cooled to 0-5 °C by an ice- water bath and a solution of sodium nitrite (9 g, 130.4 mmol) in water (32 mL) was added dropwise within 20 minutes. The orange solution was stirred for another 25 minutes at 0- 5 °C and then it was added by a glass pipette (10 mL) slowly to a solution of sodium cyanide (29.5 g, 602 mmol), copper cyanide (21.6 g, 241 mmol) and water (280 mL) at 4- 5 °C within 40 minutes. The black suspension was kept stirring at 4°C for 1 hr and room temperature for 2 hr. The suspension was filtrated through celite and the precipitate was washed with EtOAc (50 mL, twice). The filtration was extracted with EtOAc three times. The combined organic layers were dried over anhydrous NA2S04 and the solvent was concentrated under reduced pressure. The residue was applied to a column CHROMATOGRAPHY (SIO2, 20percent MEOH in EtOAc) to give 44 (15.3 g, 78.9percent) as yellow solid.
With Jones reagent; In acetone; at 20℃; for 0.166667h;
To a solution of 4- (2- hydroxyethyl) benzonitrile (120 mg, 0.816 mmol) in acetone (3 ML), Jone's reagent (1. 5ML, 4.005 mmol) was added.. After stirring for 10 minutes at room temperature, the crude reaction mixture was poured into water (10 ML) and extracted with CHC13 (6 x 10 mL). Combined organics were dried over magnesium sulfate, filtered, and concentrated to give (4-cyanophenyl- acetic acid which was used without purification. To a solution of (4-cyanophenyl) acetic acid (131 MG, 0.816 mmol) in ETOH (0.5 ML) at 0°C was bubbled HCl (g) until saturation. Reaction mixture was allowed to warm to room temperature slowly. After overnight stirring, the crude reaction mixture was concentrated in vacuo. This residue was taken up in ETOH (4 ML) and ethylene diamine (0.1 mL, 1.49 mmol) was added. After stirring at room temperature for two hours, the crude reaction mixture was concentrated under reduced pressure and then re-dissolved in DMF (2 mL). To this solution was added 1M NAOH (2 mL, 2 mmol) and the reaction stirred at room temperature for three hours. Crude reaction mixture was neutralized with 1M HC1 to a pH 6 and extracted with CHC13 (4 x 15 ML). Product was found in the water layer, so combined all layers and concentrated in vacuo, re-dissolved in CHCL3/MEOH, and filtered to remove precipitate. Concentration of the filtrate gives [4- (4, 5-dihydro-lH-imidazol-2-yl) phenyl] acetic acid, which was used without further purification. LCMS (ES) 205.1 771/Z (M +H) +
With sodium periodate;ruthenium trichloride; In tetrachloromethane; water; acetonitrile; at 20℃;
Reference Example 76 4-Cyanophenylacetic acid A catalytic amount of ruthenium chloride (28 mg) and sodium periodate (5.80 g) were added to a carbon tetrachloride-acetonitrile-water (2:2:3) solvent solution (20 ml) of 4-(2-hydroxyethyl)benzonitrile (1.00 g), followed by stirring overnight at room temperature. The reaction solution was extracted with dichloromethane and dried over sodium sulfate to obtain the title compound (755 mg) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 3.73 (2H, s), 7.40 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz).
With Jones reagent; In acetone; at 20℃; for 0.166667h;
To a solution of 4-(2-hydroxyethyl)benzonitrile (120 mg, 0.816 mmol) in acetone (3 mL), Jone's reagent (1.5 mL, 4.005 mmol) was added.. After stirring for 10 minutes at room temperature, the crude reaction mixture was poured into water (10 mL) and extracted with CHCl3 (6.x.10 mL). Combined organics were dried over magnesium sulfate, filtered, and concentrated to give (4-cyanophenyl)acetic acid which was used without purification
Reference Example 77 4-Formylphenylacetic acid Diisobutylaluminum hydride (5.0 ml, 0.93 M hexane solution) was added dropwise to a THF solution (10 ml) of <strong>[5462-71-5]4-cyanophenylacetic acid</strong> (500 mg) at -78C, followed by stirring at the same temperature for 2 hours. Methanol (5.0 ml) was added dropwise to the reaction solution and subsequently mixed with silica gel, followed by stirring overnight at room temperature. The solvent was evaporated, the thus obtained residue was purified by silica gel column chromatography, and the fraction obtained from the elude of dichloromethane: methanol = 10:1 was concentrated under reduced pressure to obtain the title compound (220 mg) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 3.76 (2H, s), 7.47 (2H, d, J=8.1 Hz), 7.87 (2H, d, J=8.1 Hz), 10.01 (1H, s).
4-[(5-(2-oxo-piperidin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; acetic acid;
e. 4-[(5-(2-oxo-piperidin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from 4-(2-oxo-piperidin-1-yl)-2-amino-N-methyl-aniline, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid. Yield: 35percent of theory, Rf value: 0.23 (silica gel, methylene chloride/ethanol=19:1).
4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
d. 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from 2-amino-4-phenyl-N-methyl-aniline, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid. Yield: 100percent of theory,
4-[(5-(1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; acetic acid;
i. 4-[(5-(1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-yl]-acetic acid, N,N'-carbonyldiimidazole and <strong>[5462-71-5]4-cyanophenylacetic acid</strong> in tetrahydrofuran/glacial acetic acid. Yield: 37percent of theory, Rf value: 0.67 (silica gel; methylene chloride/methanol=9:1).
4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; acetic acid;
e. 4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from methyl 3-[(3-amino-4-methylamino-phenyl)-cyclopentyl-sulphamoyl]-propionate, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid. Yield: 72percent of theory, Rf value: 0.41 (silica gel; methylene chloride/ethanol=50:1).
4-(cyclohexylcarbonyl)-2-amino-N-methyl-aniline[ No CAS ]
[ 5462-71-5 ]
4-[(5-cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
e. 4-[(5-cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from 4-(cyclohexylcarbonyl)-2-amino-N-methyl-aniline, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran, and glacial acetic acid. Yield: 74percent of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol=50:1).
4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; acetic acid;
c. 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from methyl [1-(4-methylamino-3-amino-benzoyl)-cyclohexyl]-acetate, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid. Yield: 66percent of theory, Rf value: 0.5 (silica gel; methylene chloride/ethanol=50:1).
ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-yl]-propionate[ No CAS ]
[ 5462-71-5 ]
4-[(5-(2-ethoxycarbonyl-ethyl-benzimidazol-1-yl)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
g. 4-[(5-(2-ethoxycarbonyl-ethyl-benzimidazol-1-yl)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile Prepared analogously to Example 24f from ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-yl]-propionate, <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and N,N'-carbonyldiimidazole in tetrahydrofuran, glacial acetic acid. Yield: 100percent of theory.
N5 4-Cyanophenyl-N-methylacetamide This compound was prepared from <strong>[5462-71-5]4-cyanophenylacetic acid</strong> and methylamine in a similar manner to N2.
With sodium hydroxide; In ethanol; dichloromethane;
A suspension of 4-cyanophenylacetic acid (31.2 g, prepared as described in J.C.S. 744, (1941)), concentrated sulphuric acid (5 ml) and absolute ethanol (300 ml) was boiled under reflux with stirring for 48 hours. The solvent was removed under reduced pressure and dilute aqueous sodium hydroxide solution was added to neutralise the sulphuric acid. Dichloromethane was added. The mixture was filtered and extracted with further dichloromethane. The organic extracts were dried and evaporated to give ethyl 4-cyanophenylacetate, m.p. 94-95 C.
With ammonia; 1,1'-carbonyldiimidazole; In tetrahydrofuran; methanol; ethyl acetate;
b) 4-Cyanophenylacetamide To a solution of 1.6 g (9.93 mMol) of <strong>[5462-71-5]4-cyanophenylacetic acid</strong> in 20 ml of anhydrous tetrahydrofuran were added, with stirring, 1.8 g (11.1 mMol) of N,N'-carbonyldiimidazole and then dry ammonia gas was introduced until a slightly alkaline reaction was obtained. The mixture was stirred for a further hour at ambient temperature, after which the solvent was distilled off in vacuo . After purification on silica gel (Baker, 0.03 to 0.06 mm) using ethyl acetate/methanol = 1/1 (v/v) as eluant and working up in the usual way, 0.7 g (44percent of theory) of colourless crystals were obtained, Mp. 196-197°C (diethylether). IR (KBr): 3447.2, 3309.0, 3203.7 (N-H), 2242.8 (C N), 1663.6 (Amide-C=O) cm-1
350 mg
Under a nitrogen atmosphere,(4-cyanophenyl) acetic acid (500 mg)In chloroform (6.0 mL) solution,Ice bath under cooling,Oxalyl chloride (620 mg) and N,After the addition of N- dimethylformamide (1 drop),And the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure.Residue of tetrahydrofuran (7.0 mL) ice bath under cooling to a suspension,28percentAfter adding aqueous ammonia (3.00 mL),And the mixture was stirred at room temperature for 1 hour.Reaction solution of saturated sodium hydrogen carbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether to give the title compound (350 mg) as a pale yellow solid.
methyl 2-[2-(4-cyano-phenyl)-acetylamino]-5-nitro-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In dichloromethane; chlorobenzene; Petroleum ether;
c. Methyl 2-[2-(4-cyano-phenyl)-acetylamino]-5-nitro-benzoate 4.8 g (3 mmol) of (4-cyano-phenyl)-acetic acid are suspended in 25 ml of methylene chloride and refluxed for 15 minutes after the addition of 5 ml thionyl chloride. The solvent is distilled off, the residue dissolved in 100 ml chlorobenzene and after the addition of 4.9 g (2.5 mmol) of methyl 2-amino-5-nitro-benzoate refluxed for 2 hours. Three-quarters of the volume of chlorobenzene is distilled off and the residue is combined with ether/petroleum ether. The crystalline product is suction filtered and dried. Yield: 5.7 g (69.4% of theory).
With N-[([(1E)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(dimethylamino)-methylidene]-N-methylmethanaminium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
1.41 g 4-(4-Methoxyphenyl)-1 ,3-thiazol-2-amine was dissoveld in 2 ml dimethylformamide. 3.0 ml N,N-Diisopropylethylamine, 1.O g commercially available (4- Cyano-phenyl)-acetic acid and 2.25 g O-((Ethoxycarbonyl)cyanomethyleneamino)- N,N,N',N'-tetramethyluronium tetrafluoroborat were added. The reaction mixture was stirred at room temperature overnight. Then 200 ml ethylacetate were added and the mixture was washed three times with portions of 50 ml saturated NaHCO3 solution and then dried over MgSO4. The solvents were removed in vacuo and the residue purified by RP-HPLC to obtain 610 mg 2-(4-Cyano-phenyl)-N-[4-(4-methoxy-phenyl)-thiazol-2- yl]-acetamide as yellow solid. C19H15N3O2S (349.41), MS (ESI): 350.1 (M+H+).
Example 1A. 4-(4-(4-chlorophenyl)-2-oxo-2,5-dihydrofuran-3-yl)benzonitrile; To a stirred and cooled (-15° to -10°C) solution of <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (35 g, 217.18 mmol) in DMF (250 mL) was added potassium t-butoxide (95percent, 25.66 g, 217.22 mmol) under argon in small portions keeping the temperature below-10°C. After the addition was complete a solution of 2-bromo-l-(4-chlorophenyl)ethanone (50.71 g, 217.18 mmol) in DMF (75 mL) was added slowly over 30 min. The reaction mixture was stirred for 1 hr keeping the temperature between -10° to 0° C. Et3N (12.0 mL, 86.1mmol) was added at 0° C and the reaction mixture was allowed to warm to room temperature over 1.5 hr. Then EtOH (70 mL) was added at room temperature and the reaction mixture was stirred for 10 min. The reaction mixture was cooled in an ice bath and water (300 mL) was added slowly. The light green precipitate formed was collected by filtration, washed thoroughly with water followed by hexanes. The solid thus obtained was dried in a vacuum oven overnight at 50°C to obtain 4-(4-(4-chlorophenyl)-2-oxo-2,5-dihydrofuran-3-yl)benzonitrile (58.2 g, 91percent yield) as a light green solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 70℃; for 16h;
Scheme 87: 4-Cyano-phenylacetic acid (75 mg, 0.47 mmol, 1.03 eq), Example 2 (150 mg, 0.45 mmol, 1 eq), EDCI (86 mg, 0.45 mmol, 1 eq), and HOBt (61 mg, 0.45 mmol, 1 eq) were combined in MeCN (2 mL) and heated at 700C for 16 h. The reaction was then partitioned between 10percent MeOH in EtOAc and diluted brine. The aqueous layer was discarded and the organic layer was washed with saturated NaHCO3, evaporated, and the resulting residue subjected to silica gel chromatography (60percent to 100percent EtOAc in hexanes) to afford Example 263 as a foam (110 mg).
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile;
To a solution of 4-cyano-pheny] arpt i c acid (724 rrg, 4.49 gammaCUTLOI) in DMF (15 mL) were added while stirring HOBt (774 mg; 5.C5 mmol) , T3TU (1.62 g; 5.05 mmol), 4-amino-piperidine-l- carboxylic acid tert-butyl ester (750 mg; 3.74 mmol) in ACN (15 ml) followed by TEA (2.08 IPL; 15 mmol). The reaction mixture was stirred overnight. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM and 'dshed with an aqueous solution of NaHCC_, and water. The organic phase was transferred to an ISOLUTE1 PEA-X/SCX2 <n="95"/>column and washed with DCM, The organic fraction was then concentrated under reduced pressure to afford the title intermediate as a yellow solid (838 mg; Y: 65 percent) .MS: (M+H)+ = 288 TR = 3.05 min .
With N-Bromosuccinimide; sulfuric acid; In water; for 18h;
A solution of <strong>[5462-71-5]4-cyanophenylacetic acid</strong> (1.6 g, 9.93 mmol) in 50percent aqueous sulfuric acid (10 mL) was treated with N-bromosuccinimide (1.8 g, 10.1 1 mmol). The mixture was stirred in the dark for 18h then diluted with water and extracted with diethyl ether to give 2- bromo-<strong>[5462-71-5]4-cyanophenylacetic acid</strong> (2.1 g, 7.00 mmol, 70.5 percent yield) as a white solid containing about 25percent of starting material.[M-CO2H]" 194 and 196
Concentrated sulfuric acid (98percent, 4.5 g, 54.8 mmol) was added dropwise to a solution of 2- (4-cyanophenyl) acetic acid (3 g, 180 mmol)In 40 ml of methanol, and the reaction was stirred for 4 hours at 75 ° C.Cool to room temperature and adjust pH to 8 with saturated aqueous sodium bicarbonate.The mixture was extracted with ethyl acetate. The extract was dried and concentrated to give 3.2 g (98percent) of the title compound.
With thionyl chloride; at 0 - 20℃; for 21.5h;
Thionyl chloride (1.1 mL, 15.07 mmol) was added to cool MeOH (70 mL) at 0 °C. After 5 min 2- <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> (1 g, 6.21 mmol) was added. After 30 min, cooling was removed and the mixture stirred for 21 h at RT. The solvent was removed and toluene was added and evaporated 3 times to give a sticky yellow solid. The product was used crude for the next step. RtMsi= 1.48min, ESIMS [M+H]+ = 176.1 , sticky yellow solid 1 H NMR (400 MHz, chloroform-c ) delta ppm: 7.65 (m, J=8.31 Hz, 2 H), 7.42 (m, J=8.56 Hz, 2 H), 3.69 - 3.76 (m, 5 H).
With thionyl chloride; for 3h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15percent, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85percent yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100percent yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85percent yield by column chromatography.
To a solution of 4- (2- hydroxyethyl) benzonitrile (120 mg, 0.816 mmol) in acetone (3 ML), Jone's reagent (1. 5ML, 4.005 mmol) was added.. After stirring for 10 minutes at room temperature, the crude reaction mixture was poured into water (10 ML) and extracted with CHC13 (6 x 10 mL). Combined organics were dried over magnesium sulfate, filtered, and concentrated to give (4-cyanophenyl- acetic acid which was used without purification. To a solution of (4-cyanophenyl) acetic acid (131 MG, 0.816 mmol) in ETOH (0.5 ML) at 0°C was bubbled HCl (g) until saturation. Reaction mixture was allowed to warm to room temperature slowly. After overnight stirring, the crude reaction mixture was concentrated in vacuo. This residue was taken up in ETOH (4 ML) and ethylene diamine (0.1 mL, 1.49 mmol) was added. After stirring at room temperature for two hours, the crude reaction mixture was concentrated under reduced pressure and then re-dissolved in DMF (2 mL). To this solution was added 1M NAOH (2 mL, 2 mmol) and the reaction stirred at room temperature for three hours. Crude reaction mixture was neutralized with 1M HC1 to a pH 6 and extracted with CHC13 (4 x 15 ML). Product was found in the water layer, so combined all layers and concentrated in vacuo, re-dissolved in CHCL3/MEOH, and filtered to remove precipitate. Concentration of the filtrate gives [4- (4, 5-dihydro-lH-imidazol-2-yl) phenyl] acetic acid, which was used without further purification. LCMS (ES) 205.1 771/Z (M +H) +
To a solution of <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> (131 mg, 0.816 mmol) in EtOH (0.5 mL) at 0° C. was bubbled HCl(g) until saturation. Reaction mixture was allowed to warm to room temperature slowly. After overnight stirring, the crude reaction mixture was concentrated in vacuo. This residue was taken up in EtOH (4 mL) and ethylene diamine (0.1 mL, 1.49 mmol) was added. After stirring at room temperature for two hours, the crude reaction mixture was concentrated under reduced pressure and then re-dissolved in DMF (2 mL). To this solution was added 1M NaOH (2 mL, 2 mmol) and the reaction stirred at room temperature for three hours. Crude reaction mixture was neutralized with 1M HCl to a pH 6 and extracted with CHCl3 (4.x.15 mL). Product was found in the water layer, so combined all layers and concentrated in vacuo, re-dissolved in CHCl3/MeOH, and filtered to remove precipitate. Concentration of the filtrate gives [4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]acetic acid, which was used without further purification. LCMS (ES) 205.1 m/z (M+H)+
Preparation 26 Ethyl (4-cyanophenyl)acetate <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (1 g, 6.21 mmol) was dissolved in 1.25M solution of HCl in ethanol (11ml) and the mixture heated to reflux for 3h. After cooling down to room temperature the solid formed was filtered off and dried in the vacuum oven. Yield=89%. LRMS: m/z 207 (M+17)+ Retention time: 5.33 min (Method B) 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.26 (t, 3 H) 3.64 (s, 2 H) 4.16 (q, 2 H) 4.90 (s, 2 H) 7.33 (d, J=8.51 Hz, 2 H) 7.60 (m, 2 H)
With triethylamine; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃;
To a solution of <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> (1.043 g, 6.47 mmol), ethyl 3-amino-1-(4- bromophenyl)-1 H-pyrrole-2-carboxylate (Intermediate 3) (2 g, 6.47 mmol) and triethylamine (0.992 mL, 7.12 mmol) in acetonitrile (30 mL) at RT was added drop- wise a solution of DCC (2.002 g, 9.70 mmol) in acetonitrile (5 mL). The reaction mixture was stirred for 2h before being filtered off. The filtrate was concentrated under reduced pressure and extracted with EtOAc/ water then washed successively with sat. NaHC03 and brine. The organic layer was dried over Na2S04 and evaporated. The product was dissolved in DCM and precipitated in cyclohexane before being filtered and dried to give ethyl 1 -(4-bromophenyl)-3-[(4- cyanophenyl)acetyl]amino}-1 H-pyrrole-2-carboxylate (1.46 g, 3.23 mmol, 49.9 percent yield) as a white solid. LCMS: (M+H)+ : 452, 454; Rt: 3.74 min.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%).
With hydroxylamine hydrochloride; potassium hydroxide; In ethanol; for 15h;Reflux;
To a suspension of commercially available 20b (882 mg, 5.5 mmol) in ethanol (100 mL) was added KOH (767 mg, 13.7 mmol) and hydroxylamine hydrochloride (570 mg, 8.2 mmol), and the solution was held at reflux for 15 h. After cooling to room temperature, the solid KCl was filtered away from the solution, and the filtrate was concentrated in vacuo to give a white solid. The solid was purified using the Flash+ system and a mobile phase of 3:2 dicholoromethane-methanol (Rf = 0.27), to yield 21b (white solid, 286 mg, 27percent yield). 1H NMR (300 MHz, DMSO): delta 12.50 (s, 1H, br), 9.59 (s, 1H, br), 7.59 (d, J = 7.3 Hz, 2H), 7.24 (d, J = 7.6 Hz, 2H), 5.78 (s, 2H), 3.53 (s, 2H).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; at 50℃; for 16h;
Example 2322-(4-Cyanophenyl)-N-[5-({7-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide4-Cyanophenylacetic acid (19 mg, 0.10 mmol) was added to (5-aminopyridin-3-yl){7-[2-[tert-butyl(dimethyl)silyl]oxy}-1-([tert-butyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Preparation 116, 54 mg, 0.97 mmol), 1-propylphosphonic acid cyclic anhydride (0.17 mL, 0.291 mmol) and triethylamine (0.047 mL, 0.291 mmol) in tetrahydrofuran (3 mL).The mixture was stirred at 50° C. for 16 hours.Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with dichloromethane (3*7 mL).The combined organic phases were dried over magnesium sulphate and evaporated in vacuo.The residue was dissolved in tetrahydrofuran (3 mL) and a tetrabutylammonium fluoride solution in THF (1 mL of a 1M solution, 1 mmol) was added and the solution was stirred for 1 hour.Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with dichloromethane (3*5 mL).The combined organic phases were dried over magnesium sulphate, evaporated in vacuo and purified by preparative HPLC (method 2).LCMS (system 4): Rt=2.52 min; m/z 471 [M+H]+
A solution of 2-(4- cyanophenyl)acetic acid (2 g, 12.41 mmol) and hydroxylamine (50percent in H20) (1.901 ml_, 31 .0 mmol) was refluxed in ethanol (40 ml.) overnight. The reaction was concentrated under reduced pressure and dried overnight in a vacuum oven. The resulting white solid was taken up in THF (40 ml_), and Et3N (3.87 ml_, 27.8 mmol) and TFAA (3.87 ml_, 27.8 mmol) were added at 0 °C. The reaction was allowed to warm to rt and stirred for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue taken up in water. The aqueous phase was extracted with DCM, and the combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was taken on without purification as a waxy cream solid (3.27 g, 12.02 mmol, 96percent yield). 1H NMR (400 MHz, METHANOL-^) delta 8.08 (d, J = 8.22 Hz, 2H), 7.51 (d, J = 8.22 Hz, 2H), 3.72 (s, 2H), LCMS: fR = 0.83 min, 92percent. MS m/z = 542 (M+H)+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Iodine(18.80 g, 74.1 mmol) was added to 1-(2,5-dichlorophenyl)ethanone (10.67 ml,74.1 mmol) and thiourea (11.27 g, 148.0mmol). Thereaction mixture was stirred and heatedto 100 °C overnight. After cooling to room temperature, the reaction mixture was triturated with diethylether (about 50 mL) to remove any unreacted iodine and1-(2,5-dichlorophenyl)ethanone. Thesolid residue was put in cold distilled water (100 mL) and treated withammonium solution to pH 9-10. The precipitated thiazole was collected togive 4-(2,5-dichlorophenyl)-1,3-thiazol-2-amine (11.2 g, 62percentyield) as a yellow solid. MS(ES+) m/z 245.0, 247.0 (MH+).A solution of[4-(ethylsulfonyl)phenyl]acetic acid (0.239 g, 1.1 mmol), 4-(2,5-dichlorophenyl)-1,3-thiazol-2-amine(0.245 g, 1.0 mmol), EDC (0.230 g, 1.2 mmol) and HOBt (0.184 g, 1.2 mmol) in dichloromethane(DCM) (10 mL) was stirred at room temperature overnight. The mixture was pouredinto water, and extracted with DCM. The organic phase was washed with water andbrine, dried over anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the crude product. The crude was purified by mass directedautopreparation (MDAP) to afford N-[4-(2,5-dichlorophenyl)-1,3-thiazol-2-yl]-2-[4-(ethylsulfonyl)phenyl]acetamide(6a) (177 mg, 37percent yield) as a white solid.
With pyridine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 50℃; for 16h;
4-Cyanophenylacetic acid (17 mg, 0.1 1 mmol) was added to (2-aminopyridin-4-yl)[7-(2- [tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Preparation 21 , 35 mg, 0.80 mmol) and HATU (47 mg, 0.12 mmol) in pyridine (1 mL). The mixture was stirred at 50°C for 16 hours. Saturated aqueous sodium bicarbonate (1 mL) was added then extracted with ethyl acetate (5 mL). The organic phase was dried over magnesium sulphate and evaporated in vacuo. The crude solid was purified by silica gel column chromatography eluting with a gradient of DCM:MeOH 100:0 to 95:5 to afford the title compound as a green oil (56percent, 26 mg). LCMS (system 2): Rt = 1.64 minutes MS m/z 569 [M+H]+
With iron(III) trifluoromethanesulfonate; sodium nitrite In dimethyl sulfoxide at 50℃; for 10h; Inert atmosphere; Sealed tube;
Nitriles 2a-r: General Procedure
General procedure: A tube of approximate volume 45 mL was charged with theappropriate arylacetic acid (0.5 mmol), NaNO2 (3 mmol),Fe(OTf)3 (1 mmol), and undried DMSO (2 mL), and the air in thetube was replaced by argon gas. The tube was sealed and themixture was heated with magnetic stirring at 50 °C for 10 h,then cooled to r.t. The solvent was evaporated, and the residuewas purified by column chromatography (silica gel).
66%
With oxygen; copper(II) trifluoroacetate; urea In dimethyl sulfoxide at 110℃; for 24h; Green chemistry;
N2-[(4-cyanophenyl)acetyl]-N-[(9-ethyl-9H-carbazol-3-yl)methyl]alanine amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With triethylamine; HATU; In N,N-dimethyl-formamide; at 10 - 35℃; for 16h;
(Step 3) A solution of the compound obtained in Step 2 (242 mg, 0.82 mmol), <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (198 mg, 1.23 mmol), HATU (468 mg, 1.23 mmol) and TEA (0.343 mL, 2.46 mmol) in DMF (3 mL) was stirred at room temperature for 16 hr. To the reaction solution was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give the title compound (50.3 mg, 0.115 mmol, 14percent) as a white powder. 1H-NMR(300MHz,DMSO-d6):delta1.23-1.40(6H,m), 3.61(2H,s), 4.24-4.52(5H,m), 7.11-7.21(1H,m) 7.33(1H,dd,J=8.3,1.5Hz), 7.39-7.61(5H,m), 7.67-7.75(2H,m), 7.97-8.10(2H,m), 8.37-8.51(2H,m).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 70℃; for 36h;
To 37.5 mg (0.15 mmol) 3-(1 -benzofuran-2-yl)imidazo[1 ,2-b]pyridazin-6-amine in 2 mL ethyl acetate were added 0.16 mL (0.9 mmol) N-ethyl-N-isopropylpropan-2- amine. 29 mg (0.18 mmol) <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> in 0.3 mL DMF and 0.26 mL (0.225 mmol) 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (25vol percent in ethyl acetate) were added and the mixture was heated to 70°C for 12 h. Another 0.16 mL (0.9 mmol) N-ethyl-N-isopropylpropan-2-amine and 0.26 mL (0.225 mmol) 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (25vol percent in ethyl acetate) were added and the mixture was heated for another 12 h 70°C. Yet another 0.16 mL (0.9 mmol) N-ethyl-N-isopropylpropan-2-amine and 0.26 mL (0.225 mmol) 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (25vol percent in ethyl acetate) were added one more time and the mixture was heated to 70°C for 12 h. The resulting mixture was concentrated. The remainder was diluted in DMSO to yield a total volume of 2 mL. This crude mixture was subjected to HPLC purification to yield 27 mg of the title compound as solid material. 1H-NMR (400 MHz, DMSO-de), delta [ppm]= 3.98 (2H), 7.26-7.38 (2H), 7.57 (2H), 7.63- 7.67 (1 H), 7.68-7.73 (1 H), 7.78-7.83 (2H), 7.86 (1 H), 8.00 (1 H), 8.21 -8.28 (2H), 11.27 (1 H). LC-MS (Method 4): Rt = 1 .23 min; MS (ESIpos) m/z = 394 [M+H]+.
To a 25 mL round bottom flask, were added <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (2.0 g, 0.0124 mol) and 20 mL aqueous potassium hydroxide solution (3.47 g, 0.062 mol). The reaction mixture was stirred at reflux temperature for 4 h. The reaction mixture was acidified to pH 3.0 with 3 N hydrochloric acid to get the precipitate. The precipitate was collected by filtration and dried under vacuum to get the title compound [1.8 g, 81 %]. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-ife): delta 12.64 (brs, 2H), 7.88 (d, = 8.1 Hz, 2H), 7.38 (d, [M+H]+.
(R)-methyl 3-(3-amino-4-(diisobutylamino)phenyl)butanoate[ No CAS ]
C28H37N3O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 35C enantiomer 1 (0.030 g, 0.094 mmol) in DMF (0.936 ml) was added <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (0.030 g, 0.187 mmol), lH-benzo[d][l,2,3]triazol-l- ol (0.025 g, 0.187 mmol), HOBT (0.029 g, 0.187 mmol) and EDC (0.036 g, 0.187 mmol). This mixture was stirred at RT for 10 minutes and then DIEA (0.049 ml, 0.281 mmol) was added. The reaction was stirred at RT for 3 h and then diluted with EtOAc. This was then washed once with 1 N HC1, twice with water and once with brine. The organics were dried over MgSC^, filtered and concentrated to give the crude product as a yellow solid. To this material was added 2.0 mL THF, 0.4 mL MeOH and 0.4 mL 1 N NaOH. This mixture was heated at 55°C for 72 hours and then cooled to RT and 0.5 mL of IN HC1 was added to neutralize the solution and this was extracted thrice with EtOAc. The organics were dried over MgSC^, filtered and concentrated to give the crude acid. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge CI 8, 19 x 150 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100percent B over 15 minutes, then a 5 -minute hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 45 (21.9 mg, 0.048 mmol, 51percent). LC-MS Anal. Calc'd for C^Hss sOs 449.6, found [M+H] 450.3, Tr = 1.957 min (Method E).
(1R,2S)-ethyl 2-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
(1R,2S)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 109(1R,2S)-2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylic acid 1 09A. (1R,2S)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4- (cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylateTo a solution of 80E (29.5 mg, 0.082 mmol) in DMF (1029 tl) at rt was added 2- <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> (26.5 mg, 0.165 mmol), EDC (31.5 mg, 0.165 mmol), 1-Hydroxybenzotriazole hydrate (25.2 mg, 0.165 mmol), and Hunig?s Base (28.7 tl, 0.165 mmol). The reaction was stirred at rt for 1 6h. The reaction was quenched with 1 N NaOH and diluted with water. Layers were separated. The aqueous phase was extracted with EtOAc (2X). The organic phases were combined, washed with water (lx), brine(lx), dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was purified via preparative HPLC to give 109A (18 mg, 0.036 mmol, 45percent yield). LC-MS Anal. Calc?d for C3,H39N303 501.30, found [M+H] 502.3, T = 2.19 mm (Method G).
(1R,2S)-ethyl 2-(3-amino-4-(cyclohexyl(3,3,3-trifluoropropyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
(1R,2S)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3-trifluoropropyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 107(1R,2S)-2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3-trifluoropropyl)amino)phenyl)cyclopropanecarboxylic acid 1 07A. (1R,2S)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3- trifluoropropyl)amino)phenyl)cyclopropanecarboxylateTo a solution of 87F (26.1 mg, 0.066 mmol) in DMF (936 tl) at RT was added 2- <strong>[5462-71-5](4-cyanophenyl)acetic acid</strong> (21.11 mg, 0.13 1 mmol), EDC (25.1 mg, 0.13 1 mmol), 1- Hydroxybenzotriazole hydrate (20.06 mg, 0.13 1 mmol), and Hunig?s Base (22.88 tl,0.131 mmol). The reaction was stirred at rt for 1 6h. The reaction was quenched with 1 N NaOH and diluted with water. Layers were separated. The aqueous phase was extracted with EtOAc (2X). The organic phases were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered, and concentrated to afford a yellow residue. LC-MS Anal. Calc?d for C30H34F3N303 541.26, found [M+H] 542.2, T = 2.26 mm (Method G).
(1S,2R)-ethyl 2-(3-amino-4-(cyclohexyl(3,3,3-trifluoropropyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
(1S,2R)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3-trifluoropropyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11 mg
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 108(1 S,2R)-2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3- trifluoropropyl)amino)phenyl)cyclopropanecarboxylic acid 1 08A. (1 S,2R)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(3,3,3- trifluoropropyl)amino)phenyl)cyclopropanecarboxylateTo a solution of 91A (22.7 mg, 0.057 mmol) in DMF (814 tl) at rt was added <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (18.36 mg, 0.114 mmol), EDC (21.84 mg, 0.114 mmol), 1-Hydroxybenzotriazole hydrate (17.45 mg, 0.114 mmol), and Hunig?s Base (19.90 tl, 0.114 mmol), The reaction was stirred at rt for 16h. The reaction was quenched with 1 N NaOH and diluted with water. Layers were separated. The aqueous phase was extracted with EtOAc (2X). The organic phases were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered, and concentrated to afford a yellow residue. This material was purified via preparative HPLC to give 108A (11 mg, 0.020 mmol). LC-MS Anal. Calc?d for C30H34F3N303 541.26, found [M+H] 542.3, T = 2.26 mm (Method G).
ethyl (1S,2R)-2-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropane-1-carboxylate[ No CAS ]
(1S,2R)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 110(1 S,2R)-2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)cyclopropanecarboxylic acid 11 OA. (1 S,2R)-ethyl 2-(3-(2-(4-cyanophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino) phenyl)cyclopropanecarboxylateTo a solution of 95B (28.5 mg, 0.079 mmol) in DMF (1 mL) at rt was added 2-(4- cyanophenyl)acetic acid (25.6 mg, 0.159 mmol), EDC (30.5 mg, 0.159 mmol), 1-Hydroxybenzotriazole hydrate (24.35 mg, 0.159 mmol), and Hunig?s Base (0.028 mL,0.159 mmol). The reaction was stirred at rt for 16h. The reaction was quenched with 1 NNaOH and diluted with water. Layers were separated. The aqueous phase was extractedwith EtOAc (2X). The organic phases were combined, washed with water (lx), brine(lx), dried over Na2SO4, filtered, and concentrated to afford a yellow residue. Thecrude material was purified via preparative HPLC to give 11OA (13 mg, 0.026 mmol,33percent yield). LC-MS Anal. Calc?d for C3,H39N303 501.30, found [M+H] 502.3, T = 2.16 mm (Method G).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 1h;
4-[2-(Morpholin-4-yl)-2-oxoethyl]benzonitrile (9n). A solution of <strong>[5462-71-5]4-cyanophenylacetic acid</strong>(0.5 g, 3.1 mmol) and morpholine (0.27 g, 3.1 mmol) in DCM (20 ml) was cooled to 0°C and a mixture of DCC (0.64 g, 3.1 mmol) and DMAP (6 mg, 0.046 mmol) in DCM (5 ml) was added dropwise. After 1 h at it the suspension was filtered over hyflo and the filtrate was concentrated at reduced pressure, the residue was dissolved in EtOAc (20 ml), and washed with aq. sat. NH4C1 (30 ml). The inorganic layer was extracted with EtOAc (2 x 30 ml). Theorganic layers were combined, washed with aq. sat. NaC1 (60 ml), dried over Na2SO4 and concentrated at reduced pressure to afford a white solid 9n (0.71 g, 99percent).
2-(4-cyanophenyl)-N-((trans)-4-phenylcyclohexyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;
To a stirred solution of carboxylic acid (4.4 mmol) in dimethylformamide (DMF, 15 mL) was added aniline (6.6 mmol), diisopropylethylamine (1.53 mL, 8.8 mmol) and 1- [bis(dimethylamino)methylene]- 1 H- 1,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (HATU) (2.00 g, 5.28 mmol). The resulting reaction mixture was stirred at rt for 3 h, at which point 3 M HC1 (30 mL) and CH2C12 (30 mL) were added.The layers were separated, and the aqueous layer was extracted with CH2C12 (2 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography to afford the desired product(s). The following compound was made in the manner of General Procedure A, employing trans-4-phenyl-cyclohexanamine (PCT Publication No. WO 200 1/092204) (138 mg, 0.79 mmol), <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (138 mg, 0.86 mmol), 1- [bis(dimethylamino)methylene]- 1H- 1,2,3 -triazolo[4,5 -b]pyridinium 3 -oxidhexafluorophosphate (360 mg, 0.95 mmol), and DMF (4 mL). The residue was purified to by preparative TLC (33percent EtOAc in hexanes), followed by preparative HPLC (Varian ProStar using Hamilton C18 PRP-1 column (15 x 250 mm) with flow rate of 20 mL/min, Mobile Phase A: 0.5percent formic acid in water; Mobile Phase B: 0.5percent formic acid in acetonitrile; 0percent to 100percent B gradient elution during 30 minutes) to give the desiredproduct. ?H NMR (300 MHz; CDC13): oe 7.64 (dd, J= 8.4, 1.8 Hz, 2H), 7.40 (dd, J 8.4,1.8 Hz, 2H), 7.32-7.24 (m, 2H), 7.21-7.16 (m, 3H), 5.31 (d, J 7.5 Hz, 1H), 3.89-3.79(m, 1H), 3.60 (s, 2H), 2.45 (tt, J= 16.0, 3.6 Hz, 1H), 2.10-1.90 (m, 4H), 1.66-1.56 (m,2H), 1.30-1.16 (m, 2H) ppm. m/z 319 (M+H).
4-[2-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-2-oxo-ethyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10.4 g
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h;Cooling with ice;
To a solution of 5,5-dimethyl-cyclohexane-1,3-dione (8.7 g, 62.0 mmol) and (4-cyano-phenyl)- acetic acid (10 g, 62.0 mmol) in 200 mL of DCM cooled in an ice bath is added 4- dimethylaminopyridine (3.8 g, 31.0 mmol) and 1.0 M dicyclohexylcarbodiimide solution in DCM (62.0 mL, 62.0 mmol). The reaction is allowed to warm to room temperature and is stirred for 16 hours. The mixture is filtered through a pad of diatomaceous earth, washing with DCM. The filtrate is concentrated to dryness. The crude mixture is purified by silica gel chromatography eluting with EtOAc in heptane to provide 10.4 g of 4-[2-(2-hydroxy-4,4- dimethyl-6-oxo-cyclohex- 1 -enyl)-2-oxo-ethylj -benzonitrile.
10.4 g
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h;Cooling with ice;
To a solution of 5,5-dimethyl-cyclohexane-1,3-dione (8; 8.7 g, 62.0 mmol) and <strong>[5462-71-5](4-cyano-phenyl)-acetic acid</strong> (S1;10 g, 62.0 mmol) in 200 mL of CH2Cl2 cooled in an ice bath was added DMAP (3.8 g, 31.0 mmol) and 1.0 MDCC solution in CH2Cl2 (62.0 mL, 62.0 mmol). The reaction was allowed to warm to room temperature andstirred for 16 hours. The mixture was filtered through a pad of diatomaceous earth, washing with CH2Cl2. The filtrate was concentrated to dryness. The crude mixture was purified by silica gel chromatography eluting withEtOAc in heptane to provide 10.4 g of 9c:
methyl (2R)-2-amino-2-[4-(2-methylpentyloxy)phenyl]acetate hydrochloride[ No CAS ]
methyl (2R)-2-[4-(2-methylpentyloxy)phenyl]-2-[2-(4-cyanophenyl)acetamido]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 5h;Inert atmosphere;
General procedure: To a solution of 8a (90 mg, 0.33 mmol) in MeCN (10 mL) at room temperature under nitrogen was added TEA (0.14 mL,0.99 mmol), followed by (S)-2-phenylpropionic acid (50 mg,0.33 mmol) and HBTU (152 mg, 0.4 mmol). After stirring for 5 h, the reaction was quenched by H2O (5 mL), followed by addition of EtOAc (50 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (10 mL), brine (10 mL), dried (Na2-SO4) and concentrated under reduced pressure. Flash column chromatography of the crude product on silica gel using 0?30percent EtOAc in hexanes afforded 3 (65 mg, 53percent) as an off-white solid.
(+/-)-methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate[ No CAS ]
(+/-)-methyl 3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78 mg
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In tetrahydrofuran; at 20℃; for 87h;Sealed tube;
To a homogeneous mixture of (+/-)-methyl 3-(3-amino-4-(diisobutylamino) phenyl)pentanoate (50 mg, 0.15 mmol) in anhydrous THF (2 mL), at room temperature in a sealable vial, was added <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (28.9 mg, 0.18 mmol) followed by BOP (79 mg, 0.18 mmol) and TEA (0.1 mL, 0.72 mmol). The vial was capped and the mixture was stirred at ambient temperature for 87 hours. The reaction mixture was quenched with water then thoroughly extracted with Et2O. The organic layers were combined and washed with brine then concentrated in vacuo to afford (+/-)-methyl 3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoate as an oil (78 mg) which was used without further purification. MS(ES): m/z=478 [M+H]+, Tr=1.15 min (Method A).
(5H-imidazo[5,1-a]isoindol-5-yl)methanamine[ No CAS ]
C20H16N4O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 10 - 35℃;
Diisopropylethylamine (0.28 mL,(462 mg, 1.21 mmol) was added to a solution of compound 10 (150 mg, 0.81 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluorophosphate Mmol)And p-cyanophenylacetic acid (157 mg, 0.97 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature overnight and then water was added10 mL, the organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water and saturated brine, and anhydrous sulfuric acidDried in sodium and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound 11 (200 mg, 75percent) as a white solid
With [2,2]bipyridinyl; nitromethane; copper(II) sulfate; In nitromethane; N,N-dimethyl-formamide; at 130℃; for 8h;
General procedure: A round-bottom flask was charged with arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or 4 (1.0 mmol), CuSO4 (10 molpercent), and 2,2?-bipyridyl (20 molpercent). A pre-oxygen degassed solvent system of DMF/nitroalkane (1.5:0.5 mL) was added to above mixture. The resulting mixture was heated at 130 °C for 8 h. The reaction progress was monitored by using TLC. After completion of the reaction, water was added to the mixture and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (anhyd Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (230?400 mesh silica gel, EtOAc/n-hexane) to afford imidazoles 3 or 5.
With ammonium hydroxide; hydrogen; In water; at 20℃; for 48h;
A solution of <strong>[5462-71-5]2-(4-cyanophenyl) acetic acid</strong> (3 g, 18.63 mmol) in water (50 mL) and concentrated aqueousammonia (20 mL) was stirred at room temperature and raney nickel (2.0 g) was added. The resultingsuspension was stirred under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered throughCeite pad and the filtrate was concentrated under reduced pressure to afford the title compound (2.9 g, 94percent)as a bluish solid. LC-MS (method 1 ): Rt = 0.23 min; m/z = 166.15 (M+H+).
3-(4-bromophenyl)-5-(isocyanomethyl)imidazo[2,1-b]thiazole[ No CAS ]
2-(((3-(4-bromophenyl)imidazo[2,1-b]thiazol-5-yl)methyl)amino)-2-oxoethyl 2-(4-cyanophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In dichloromethane;Reflux;
General procedure: To a solution of 3-(4-bromophenyl)-5-(isocyanomethyl)imidazo[2,1-b]thiazole 5 (1 eq) in dry CH2Cl2, 37percent aqueous formaldehyde solution (5 eq) and carbossilic acid (1 eq) are added and the resulting mixture is stirred at reflux. The reaction is completed after 2-5 hours. The organic phase is washed with a saturated aqueous solution of Na2CO3 (except for the compounds 7d, 7e and 7f and 7g which are washed with a saturated aqueous solution of NaHCO3), dried over sodium sulfate and evaporated. Ethyl acetate is added to the crude material and the precipitated white solid is collected by filtration using a Buchner funnel and rinsed with ethyl acetate. In case that no precipitation occurs (7a, 7c, 7d, 7g, 7h, 7j), the crude material is purified by chromatography column.
With acetic anhydride; potassium carbonate; at 130℃; for 4h;
General procedure: A mixture of 100.0 mg (0.58 mmol, 1.00 mol eq) 1,4-dihydro-4-oxoquinoline-3-carbaldehyde 1a together with 87.0 mg (0.639 mmol, 1.10 mol eq) of phenylacetic acid(2a) and 8.00 mg (0.639 mmol, 0.10 mol eq) of K2CO3 (abs) was stirred in 3 mL of freshly distilled Ac2O at 130 °C for 4 h. After cooling the reaction mixture to rt, the solid product 3a was filtered off, washed with H2O (2 9 5 mL), Et2O (1 9 5 mL) and dried under vacuum to yield 129 mg (0.46 mmol, 80percent) of 3a (Scheme 2). Here we are showing physico-chemical characteristics for the compound 3a. The characteristics for all sixteen novel compounds 3 together with their spectral figures are published in the Supporting Information.
N-(4-bromo-2-iodophenyl)-2-(4-cyanophenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine; HATU; In dichloromethane; at 20℃; for 22h;
The 2 - (4 - cyano-phenyl) acetic acid (1.00 g, 6 . 21 mmol), HATU (3.00 g, 7 . 89 mmol), 4 - bromo -2 - iodo aniline (1.80 g, 6 . 04 mmol) and TEA (2.30 ml, 17 . 00 mmol) dissolved in DCM (50 ml) in the, room temperature reaction 22 h. A large number of white solid in the reaction solution (target product) precipitation, filtration, the filtrate is concentrated under reduced pressure, the crude product by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), to obtain the product as a white solid (2.52 g, 92percent).
N-(4-amino-3-(isopropylamino)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide[ No CAS ]
N-(2-(4-cyanobenzyl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
In toluene; at 120℃; for 39h;
The N - (4 - amino -3 - (isopropyl amino) phenyl) -2 - (4 - (ethyl sulfonyl) phenyl) acetamide (400 mg, 1 . 07 mmol) and 2 - (4 - cyano-phenyl) acetic acid (520 mg, 3 . 23 mmol) is added to the toluene (8 ml) in, 120 °C oil bath heating reflux reaction 39 h. The reaction cooling to room temperature, concentrated under reduced pressure, the residue is added to 50 ml DCM, followed by HCl aqueous solution for (1.0 M, 15 ml) washing, saturated NaHCO3Aqueous solution (15 ml) and saturated NaCl aqueous solution (15 ml) washing, anhydrous Na2SO4Dry, filtered, concentrated under reduced pressure, the crude product by silica gel column chromatography (eluent: DCM/MeOH (v/v)=20/1), to obtain the product as a white solid (80 mg, 15percent).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
General procedure: 1.1 eq of the appropriate acid and 1 eq of 25 was dissolved in 1 ml of HOBt solution in DMF (9.5percent wt). Then 1.2 eq of EDC was added and reaction mixture was left stirring at rt overnight (16-18h). After completion of the reaction, monitored by LCMS, the reaction mixture was diluted with 4 ml of distilled water and left at ultrasonic bath for 30-40 min. The resulting residue was filtered off, washed by water and dried under high vacuum to give the target compound. If there was no residue formed the aqueous solution was extracted by 4 ml of DCM and the organic layer was washed by water (2*4ml) and the solvent was removed under reduced pressure to give the target compound. In case of low purity of the final compound was subjected to preparative HPLC purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
General procedure: Reactions were conducted on a 100 mg scale.1.1 eq of the appropriate acid and 1 eq of 30 was dissolved in 1 ml of HOBt solution in DMF (9.5percent wt). Then 1.2 eq of EDC was added and reaction mixture was left stirring at rt overnight (16-18h). After completion of the reaction, monitored by LCMS, the reaction mixture was diluted with 4 ml of distilled water and left at ultrasonic bath for 30-40 min. The resulting residue was filtered off, washed by water and dried under high vacuum to give the target compounds. If there was no residue formed the aqueous solution was extracted by 4 ml of DCM and the organic layer was washed by water (2*4ml) and the solvent was removed under reduced pressure to give the target compounds. In cases of low purity, the final compound was subjected to preparative HPLC purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
General procedure: Reactions were conducted on a 100 mg scale.1.1 eq of the appropriate acid and 1 eq of 32 was dissolved in 1 ml of HOBt solution in DMF (9.5percent wt). Then 1.2 eq of EDC was added and reaction mixture was left stirring at rt overnight (16-18h). After completion of the reaction, monitored by LCMS, the reaction mixture was diluted with 4 ml of distilled water and left at ultrasonic bath for 30-40 min. The resulting residue was filtered off, washed by water and dried under high vacuum to give the target compounds. If there was no residue formed the aqueous solution was extracted by 4 ml of DCM and the organic layer was washed by water (2*4ml) and the solvent was removed under reduced pressure to give the target compounds. In case of low purity of the final compound was subjected to preparative HPLC purification
Stage #1: 4-cyanophenylacetic acid; 3-Hydroxypropionitrile With hydrazine hydrate; 3-mercaptopropionic acid In ethanol at 0 - 40℃; for 15h; Inert atmosphere;
Stage #2: With hydrogenchloride; sodium nitrite In ethanol; water
69%
Stage #1: 4-cyanophenylacetic acid; 3-Hydroxypropionitrile With hydrazine hydrate; 3-mercaptopropionic acid at 20℃; for 15h;
Stage #2: With hydrogenchloride; sodium nitrite In water at 0℃;
7
Add 4-cyanophenylacetic acid (32.2mg, 0.2mmol), 3-hydroxypropionitrile (54.4μL, 0.8mmol), 3-mercaptopropionic acid (7.2μL, 0.08mmol) was added to the 10ml reaction tube, the reaction tube was placed in an ice bath, and hydrazine hydrate (156μL, 3.2mmol) was added, then, stir at room temperature for 15h, the reaction is complete; pour the reaction solution into sodium nitrite (206mg, 3mmol) ice water solution, slowly add hydrochloric acid (1M) at 0°C until the pH of the solution is 4, and react, after the completion of the reaction detected by TLC, the resulting solution was extracted with ethyl acetate 3 times, 20 ml of ethyl acetate each time, separated by a separatory funnel, and the organic phases extracted three times were combined. Wash once with saturated saline (20ml), separate with a separatory funnel to obtain the organic phase, the organic phase was dried with anhydrous sodium sulfate and filtered with a glass sand funnel, the filtrate was obtained, and the filtrate was transferred to a round bottom flask, and concentrated under reduced pressure to obtain a crude red solid. After purification by silica gel column chromatography, a pink solid compound 10 (36 mg) was obtained, with a yield of 69%.
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide; In methanol; at 150℃; under 11251.1 Torr; for 6h;Autoclave;
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.The catalyst was dissolved by stirring for 5 minutes, and the air in the kettle was replaced with CO three times, and the temperature was raised to 150 ° C.Rush into the CO until the pressure rises to 1.5 MPa. Within 1 hour,At the same time, 78.4 g (0.4 mol) of p-cyanobenzyl bromide and 30percent NaOH 160 g (1.2 mol) were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, the catalyst was filtered off, and the pH was adjusted to 1 by adding 30percent hydrochloric acid, and filtered.Dry to obtain p-cyanophenylacetic acid, the purity is:98.27percent, the yield was 54percent.
4-(2-oxo-1,2-dihydroquinolin-3-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
With triethylamine; HATU; In N,N-dimethyl-formamide; at 60℃; for 2h;
121 mg (1.0 mmol) of 2-aminobenzaldehyde,177 mg (1.1 mmol) of <strong>[5462-71-5]4-cyanophenylacetic acid</strong>,0.35 mL (2.5 mmol) of triethylamine,Add 570 mg (1.5 mmol) of HATU in 10 mL of DMF,Stir at 60 ° C. for 2 hours. After the reaction, water,Ethyl acetate is added for extraction, sodium sulfate is added and left to stand,After filtration, the solvent is distilled off with an evaporator,Purification on silica gel column(Developing solvent; chloroform / methanol)Target compound8 mgObtained in (yield 3.0percent).
1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-amine[ No CAS ]
2-(4-cyanophenyl)-N-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
With propanephosphonic anhydride; triethylamine; In tetrahydrofuran; at 20℃;
To a stirred solution of intermediate 9 (200 mg, 0.81 mmol) in THF (20 mL), <strong>[5462-71-5]2-(4-cyanophenyl) acetic acid</strong> (157 mg, 0.97 mmol), TEA (0.35 mL, 2.43 mmol) followed by T3P (0.38 mL, 1.21 mmol) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC and then the mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 4percent methanol in DCM), then the obtained material was further purified by prep-HPLC (Method A) to afford the title compound. Yield: 3percent (9.48 mg, brown solid). 1H NMR (400 MHz, DMSO-tf6): delta 8.06 (d, J = 6.8 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1 H), 6.73 (d, J = 7.6 Hz, 1 H), 6.69 (s, 1 H), 4.50 (t, J = 8.8 Hz, 2H), 3.48 (s, 2H), 3.48-3.47 (m, 1 H), 3.13 (t, J = 8.8 Hz, 2H), 2.99-2.85 (m, 1 H), 2.35-2.33 (m, 2H), 1.97-1.91 (m, 2H), 1.71-1.64 (m, 2H), 1.40-1.30 (m, 2H), 1.2 (d, J = 6.4 Hz, 3H). LCMS: (Method A) 390.2(M +H), Rt. 2.8 min, 98.5percent (Max). HPLC: (Method A) , Rt. 2.8 min, 98.5percent (Max).
2-(4-cyanophenyl)-N-(imidazo[1,5-a]pyridin-5-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
Compound <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (60.4 mg, 0.375 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (97.1 mg, 0.75 mmol) and HATU (214 mg, 0.56 mmol) were added. The mixture was stirred at room temperature for 30 min, added with imidazo[1,5-a]pyridin-5-amine 1f (50 mg, 0.375 mmol) and stirred at room temperature for additional 2 h. The mixture was diluted with water and extracted with ethyl acetate (25 mL*2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to give the target compound 2-(4-cyanophenyl)-N-(imidazo[1,5-a]pyridin-5-yl)acetamide 11 (7.1 mg, white solid). Yield: 7percent. MS m/z (ESI): 277[M+1] 1H NMR (400 MHz, DMSO-d6) delta 10.63 (brs, 1H), 8.27 (s, 1H), 7.85 (d, J=7.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.47-7.43 (m, 2H), 6.85-6.74 (m, 2H), 3.97 (s, 2H).
2-(4-cyanophenyl)-N-(6-phenylimidazo[1,5-a]pyridin-5-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 30℃; for 4h;Inert atmosphere;
Compound 6-phenylimidazo[1,5-a]pyridin-5-amine 346 38b (28 mg, 0.13 mmol) was dissolved in a mixed solvent of 20 dichloromethane (1.5 mL) and 67 N,N-dimethylformamide (0.15 mL), and to which 66 <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (33 mg, 0.2 mmol), EDCI (52 mg, 0.26 mmol) and 348 DMAP (50 mg, 0.4 mmol) were added. The reaction mixture was stirred at room temperature for 4 h, diluted with water (50 mL) and extracted with dichloromethane (30 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer silica gel chromatography to give the target 342 compound 2-(4-cyanophenyl)-N-(6-phenylimidazo[1,5-a]pyridin-5-yl)acetamide 38 (10 mg, white solid). Yield: 21percent. MS m/z (ESI): 353[M+1] 1H NMR (400 MHz, DMSO-d6) delta 8.56 (brs, 1H), 8.12 (brs, 1H), 7.57-7.46 (m, 4H), 7.39-7.32 (m, 3H), 7.24-7.19 (m, 3H), 6.82 (d, J=8.9 Hz, 1H), 3.72 (s, 2H).
2-(4-(N'-hydroxycarbamimidoyl)phenyl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.5 g
With hydroxylamine; In ethanol; water; at 0 - 65℃; for 4h;
To a stirred solution of <strong>[5462-71-5]2-<strong>[5462-71-5](4-cyanophenyl)acetic acid</strong></strong> (5.0 g, 31.0 mmol) in ethanol (120 mL), 50% of aqueous hydroxylamine solution (4.8 mL, 155 mmol) was added at 0 C and stirred at 65 oC for 4 h. The reaction mixture was concentrated under vacuum to obtain 2-(4-(N'- hydroxycarbamimidoyl)phenyl)acetic acid (5.5 g).
With ammonium hydroxide; oxygen In neat (no solvent) at 120℃; for 6h; Sealed tube;
General Procedure for preparation of amides catalyzed by Fe3O4*SiO2-SMTU-Cu
General procedure: A sealed pressure vessel was charged with phenylacetic acids (68.0 mg, 0.5 mmol), Fe3O4*SiO2-SMTU-Cu catalyst (20 mg), and aqueous ammonia solution (28 wt% in H2O; 1.5 mL). The resulting solution was stirred at 120 °C under O2 (monitored by TLC and GC) for 6 hours. Upon completion of the reaction, the catalyst was separated using magnetic stirring bar and ethyl acetate (20 mL) was added, the organic layer was washed with saturate NaHCO3 (20 mL) solution twice, brine (20 mL) once, the combined aqueous layers was extracted with EtOAc (20 mL) twice. The combine organic layers were dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified with flash chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give amide products.
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