* 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.
With hydrogenchloride In diethyl ether; ethanol; ethyl acetate
a) To a solution of 10 g (60 mmol) of 3-nitrophenylacetic acid in 120 ml of ethanol were added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate and the mixture was heated at reflux for 4 hours, cooled and left to stand at room temperature for 18 hours. The mixture was evaporated and the residue was partitioned between 120 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 10.3 g (82percent) of ethyl 3-nitrophenylacetate as a pale yellow oil. [NMR spectrum (250 MHz) δ1.25(t) (3H), δ3.68(s) (2H), δ4.6(q) (2H), δ6.5-δ6.7(m) (3H), δ7.09(dd) (1H)].
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1206 - 1217
[2] Journal of the American Chemical Society, 1995, vol. 117, # 8, p. 2123 - 2127
[3] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 350
[4] ChemMedChem, 2018, vol. 13, # 1, p. 30 - 36
4
[ 1877-73-2 ]
[ 52022-77-2 ]
Yield
Reaction Conditions
Operation in experiment
68%
With borane-THF In tetrahydrofuran at 20℃; for 12 h; Inert atmosphere
Under the condition of the protection of nitrogen, the 200 mg between meta-nitrophenylacetic acid dissolved in 2 ml of anhydrous tetrahydrofuran, and added dropwise 1 ml borane tetrahydrofuran solution (1M), room temperature reaction 12h. TLC monitoring reaction. After the reaction, a small quantity of water of added dropwise, quenching reaction. Adding excess saturated sodium bicarbonate solution, adjusted to the reaction system alkaline. Extraction with ethyl acetate, takes organically layer, drying, filtering, evaporating solvent under reduced pressure to obtain the crude product. Column chromatography purification to obtain 125 mg of meta-nitrobenzeneethanol (intermediate XVI), yield 68percent.
60%
With dimethylsulfide borane complex In tetrahydrofuranReflux
Into a 500-mL three neck round-bottom flask, was placed a solution of 2-(3-nitro- phenyl)acetic acid (2 g, 11.04 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This wasfollowed by the addition of BH3.SMe2 (1OM, 1.2 mL, 12.15 mmol, 1.10 equiv) drop wise with stirring, while the temperature was maintained at reflux over 10 mm. The resulting solutionheated to reflux overnight. The pH value of the solution was adjusted to 8 with sodium bicarbonate (aq). The resulting solution was extracted DCM/MeOH (10:1) and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:2) as eluent to yield 1.1 g (60percent) of 2-(3- nitrophenyl)ethan-1-ol as a brown oil.
60%
With dimethylsulfide borane complex In tetrahydrofuranReflux
Into a 500-mL three neck round-bottom flask, was placed a solution of 2-(3-nitrophenyl)- acetic acid (2 g, 11.04 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of BH3 SMe2 (10M, 1.2 mL, 12.15 mmol, 1.10 equiv) drop wise with stirring, while the temperature was maintained at reflux over 10 min. The resulting solution was heated to reflux overnight. The pH value of the solution was adjusted to 8 with sodium bicarbonate (aq). The resulting solution was extracted with DCM/MeOH (10: 1) and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2) as eluent to yield 1.1 g (60percent) of 2-(3-nitrophenyl)ethan-l-ol as a brown oil.
Reference：
[1] Patent: CN103787992, 2016, B, . Location in patent: Paragraph 0309-0312
[2] Patent: WO2014/182829, 2014, A1, . Location in patent: Page/Page column 55
[3] Patent: WO2016/191172, 2016, A1, . Location in patent: Page/Page column 78
[4] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[5] Journal of the American Chemical Society, 1982, vol. 104, # 7, p. 1937 - 1951
[6] Patent: US4990505, 1991, A,
[7] Patent: WO2007/18941, 2007, A2, . Location in patent: Page/Page column 44
[8] Patent: WO2011/60196, 2011, A1, . Location in patent: Page/Page column 156
[9] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[10] Patent: WO2018/83241, 2018, A1,
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1206 - 1217
[2] Journal of the American Chemical Society, 1982, vol. 104, # 5, p. 1391 - 1403
[3] Chemische Berichte, 1883, vol. 16, p. 2066
[4] Journal of the American Chemical Society, 1917, vol. 39, p. 1437
[5] J. Gen. Chem. USSR (Engl. Transl.), 1964, vol. 34, p. 1474 - 1477[6] Zhurnal Obshchei Khimii, 1964, vol. 34, # 5, p. 1469 - 1473
[7] Patent: US4873075, 1989, A,
With sulfuric acid; water; acetic acid; at 110℃; for 5h;Inert atmosphere; Schlenk technique;
2-(3-nitrophenyl)acetonitrile (27) (1.95 g, 12.0 mmol, 1.00 eq) was dissolved in H2O (7 mL) before concentrated H2SO4 (7 mL) and AcOH (7 mL) were added dropwise. The solution was stirred at 110 C for 5 h. After cooling to room temperature, H2O (40 mL) was added carefully. The solution was extracted with EtOAc (3 * 50 mL), then washed with H2O (90 mL) and saturated aqueous NaCl (90 mL), dried over MgSO4 and concentrated. The off-white solid 28 (2.15 g, 11.9 mmol, 99%) thus obtained was pure enough for further transformations. 1H NMR (400 MHz, CDCl3) delta = 8.17 (d, J = 7.0, 2H), 7.63 (d, J = 7.6, 1H), 7.58-7.48 (m, 1H), 3.79 (s, 2H).
94%
With sulfuric acid; acetic acid; In water; at 110℃;
Into a 50-mi. round-bottom flask, was placed a mixture of 2-(3-nitrophenyl)acetonitrile24.67 mmol, 1.00 equiv), water (8 mL), sulfuric acid (8 mL), and acetic acid (8 mL). The resulting solution was stirred overnight at 1100 C, and then it was diluted with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers wereconcentrated under vacuum to yield 4.2 g (94%) of 2-(3-nitrophenyl)acetic acid as a yellow solid
94%
With sulfuric acid; acetic acid; In water; at 110℃;
Step 1 Into a 50-mL round-bottom flask, was placed a mixture of 2-(3-nitrophenyl)acetonitrile (4 g, 24.67 mmol, 1.00 equiv), water (8 mL), sulfuric acid (8 mL), and acetic acid (8 mL). The resulting solution was stirred overnight at 110 C, and then it was diluted with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers were concentrated under vacuum to yield 4.2 g (94%) of 2-(3-nitrophenyl)acetic acid as a yellow solid.
With sulfuric acid; water; acetic acid; at 110℃; for 4h;
b. 2-(3-nitrophenyl)ethanol; A solution of 3-nitro-phenyl acetonitrile (220 g, 1.078 moles) in water (440 imL), H2SO4 (440 ml_), and acetic acid (440 ml_) was heated at 110 0C for 4 hours. The reaction mixture was diluted with water, and extracted with EtOAc (3 x 1 L). The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated to give the product carboxylic acid (20Og). This crude acid was dissolved in THF (3L), cooled to 0 0C, and treated with borane dimethyl sulfide (150 mL, 1.618 moles), allowed to warm to room temperature, and stirred overnight. The reaction mixture was evaporated to dryness and the resulting syrup was dissolved in EtOAc (3L), washed with water and brine, dried (Na2SO4), filtered and concentrated to a brown liquid (175 g).
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 80℃; for 2h;
Intermediate B2a: 2-(3-Nitrophenyl)acetyl chloride; A mixture of commercially available 2-(3-nitrophenyl)acetic acid [CAS no. 1877-73-2] (25.8 g, 142 mmol, Eq: 1.00) and thionyl chloride (25.4 g, 15.5 ml, 214 mmol, Eq: 1.5) in toluene (141 ml) and DMF (208 mg, 221 mul, 2.85 mmol, Eq: 0.02) was stirred at 80 C. for 2 h. The hot solution was filtered through a Sartorius filter, the filtrate was evaporated and dried in HV to give the 2-(3-nitrophenyl)acetyl chloride (28.12 g, 141 mmol, 98.9% yield) as a yellow solid, which was used without further purification.
98.9%
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 80℃; for 2h;
Intermediate B2a: 2-(3-Nitrophenyl)acetyl chloride A mixture of commercially available 2-(3-nitrophenyl)acetic acid [CAS no. 1877 2](25.8 g, 142 mmol, Eq: 1.00) and thionyl chloride (25.4 g, 15.5 ml, 214 mmol, Eq: 1.5) in toluene (141 ml) and DMF (208 mg, 221 mu?, 2.85 mmol, Eq: 0.02) was stirred at 80 C for 2 h. The hot solution was filtered through a Sartorius filter, the filtrate was evaporated and dried in HV to give the 2-(3-nitrophenyl)acetyl chloride (28.12 g, 141 mmol, 98.9 % yield) as a yellow solid, which was used without further purification.
In thionyl chloride;
(a) (3-Nitrophenyl)acetyl chloride A stirred solution of 3-nitrophenylacetic acid (10.0 g, 55.2 mmol) in thionyl chloride (100 ml, 1.37 mol) was heated at reflux for 2 hours, then concentrated to yield 11.1 g of (3-nitrophenyl)acetyl chloride as a tan solid.
With thionyl chloride;
EXAMPLE 5; Preparation of 4-[4-(benzyloxy)-3-chlorophenyl]amino}-5-(3-nitrophenyl)nicotinonitrile 142; <strong>[1877-73-2]3-Nitrophenylacetic acid</strong> (9.5 g, 52 mmol) and SOCl2 (20 mL) were stirred overnight at room temperature, then evaporated to dryness. In a separate flask NaH (60% dispersion in oil, 5.5 g, 1.4 mmol) was suspended in THF (100 mL). The mixture was cooled to 0 C. and tert-butylcyanoacetate (8.8 g, 62 mmol) was added. After 15 minutes, a solution of 3-nitrophenylacetyl chloride from above in THF was added dropwise. The cooling bath was removed and the mixture allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched by the addition of brine, and extracted with ethyl acetate (EtOAc, 2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude 2-cyano-4-(3-nitrophenyl)-3-oxo-butyric acid tert-butyl ester was used in the next step without further purification.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;
To a stirred solution of 3-nitrophenyl acetic acid (LOOg, 5.53 mmol) and dimethylformamide (catalytic, 3 drops) in dichloromethane (50 ml) was added oxalyl chloride (0.59 ml, 6.91 mmol) dropwise via syringe and the reaction stirred at room temperature for 30 minutes. Lambda/-hydroxysuccinamide (0.667g, 5.80 mmol) and triethylamine (1.92 ml, 13.81 mmol) were added in one portion and the reaction left to stir at room temperature overnight. The reaction was washed with water, separated, the organic layer dried over sodium sulfate, filtered and concentrated onto silica in vacuo. The reaction was purified by column chromatography eluting with 5%MeOH:DCM to afford the named product (0.937g). Rf (2%MeOH:DCM) 0.10; LCMS Rt=3.43 min, m/z (ES+) 296 (M+H2O).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 6h;
[0166] 2-(3-nitrophenyl)acetyl chloride. To a solution of 3-nitrophenyl acetic acid (5g, 27.6 mmol; Sigma- Aldrich) was added oxalyl chloride (12 mL, 138 mmol) and DMF (0.1 mL) in 40 mL CH2Cl2. The reaction mixture was stirred for 6 hours at room temperature yielding a clear yellow solution. Solvent was removed in vacuo to afford a yellow solid of the acid chloride, which was washed with CH2Cl2 three times and carried on directly to the next step.
With thionyl chloride; for 2h;Reflux;
A solution of 2-(3-nitrophenyl)acetic acid (1.0 g, 5.5 mmol) in thionyl chloride (15 mL), was refluxed for 2 hours. The solution was stripped via rotavap and co-stripped with DCM (2x30 mL) to remove residual thionyl chloride, and is used as is in the following step.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 5h;Inert atmosphere; Schlenk technique;
2-(3-nitrophenyl)acetic acid (28) (1.62 g, 9.00 mmol, 2.00 eq) was dissolved in CH2Cl2 (28 mL) and cooled to 0 C before oxalyl chloride solution (2 M, 5.90 mL, 11.7 mmol, 2.60 eq) was added dropwise over 30 min, followed by addition of DMF (70 muL, 0.90 mmol, 0.20 eq) over 2 min. The solution was warmed to room temperature and stirred for 5 h. After this time, the solvent was removed in a nitrogen stream. The residue was redissolved in 1,2-dichloroethane (30 mL) and methyl 2-amino-4-chlorobenzoate (29) (835 mg, 4.50 mmol, 1.00 eq) was added in one portion. The dark-yellow solution was stirred at 80 C for 15 h, then cooled to room temperature. Saturated aqueous NaHCO3 (20 mL) was added and the solution was extracted with CH2Cl2 (3 * 60 mL), then washed with H2O (50 mL) and saturated aqueous NaCl (90 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography (hexanes:EtOAc 4:1) to yield 30 (1.18 g, 3.38 mmol, 75%) as a white solid. Rf 0.38 (hexanes:EtOAc 3:1) 1H NMR (400 MHz, CDCl3) delta = 11.32 (s, 1H), 8.79 (d, J = 2.1, 1H), 8.25 (d, J = 2.0, 1H), 8.19 (dt, J = 8.2, 1.5, 1H), 7.94 (d, J = 8.6, 1H), 7.72 (d, J = 7.6, 1H), 7.56 (t, J = 7.9, 1H), 7.07 (dd, J = 8.6, 2.1, 1H), 3.89 (s, 3H), 3.88 (s, 2H).
43.90 g
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;Reflux;
As shown in the reaction equation below, 40 g of 2-(3-nitrophenyl)acetic acid, 1.60 g of DMF and 160 mL of CH2Cl2 were mixed. Oxalyl dichloride in an amount of 30.71 g was dropped to the mixture and then refluxed by heating for 2 hours. The obtained solution was concentrated, and 43.90 g of 2-(3-nitrophenyl)acetyl chloride was thus obtained.
EXAMPLE 1 3-Aminophenylacetic acid was prepared from a solution of 3-nitrophenylacetic acid (5.08 g, 28 mmol) in absolute ethanol (100 ml) which was hydrogenated at 40 C. and 40 psi in the presence of 5% Pd/C catalyst for 3 hours. The catalyst was removed by filtration, and upon removal of the solvent in vacuo, a highly viscous yellow oil remained which resisted crystallization. A solution of 3-aminophenylacetic acid was prepared by mixing 3.8 g (25 mmol) of the acid in 200 ml water and 10 ml concentrated HCl.
With borane-THF; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere;
Under the condition of the protection of nitrogen, the 200 mg between meta-nitrophenylacetic acid dissolved in 2 ml of anhydrous tetrahydrofuran, and added dropwise 1 ml borane tetrahydrofuran solution (1M), room temperature reaction 12h. TLC monitoring reaction. After the reaction, a small quantity of water of added dropwise, quenching reaction. Adding excess saturated sodium bicarbonate solution, adjusted to the reaction system alkaline. Extraction with ethyl acetate, takes organically layer, drying, filtering, evaporating solvent under reduced pressure to obtain the crude product. Column chromatography purification to obtain 125 mg of meta-nitrobenzeneethanol (intermediate XVI), yield 68%.
60%
With dimethylsulfide borane complex; In tetrahydrofuran;Reflux;
Into a 500-mL three neck round-bottom flask, was placed a solution of 2-(3-nitro- phenyl)acetic acid (2 g, 11.04 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This wasfollowed by the addition of BH3.SMe2 (1OM, 1.2 mL, 12.15 mmol, 1.10 equiv) drop wise with stirring, while the temperature was maintained at reflux over 10 mm. The resulting solutionheated to reflux overnight. The pH value of the solution was adjusted to 8 with sodium bicarbonate (aq). The resulting solution was extracted DCM/MeOH (10:1) and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:2) as eluent to yield 1.1 g (60%) of 2-(3- nitrophenyl)ethan-1-ol as a brown oil.
60%
With dimethylsulfide borane complex; In tetrahydrofuran;Reflux;
Into a 500-mL three neck round-bottom flask, was placed a solution of 2-(3-nitrophenyl)- acetic acid (2 g, 11.04 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of BH3 SMe2 (10M, 1.2 mL, 12.15 mmol, 1.10 equiv) drop wise with stirring, while the temperature was maintained at reflux over 10 min. The resulting solution was heated to reflux overnight. The pH value of the solution was adjusted to 8 with sodium bicarbonate (aq). The resulting solution was extracted with DCM/MeOH (10: 1) and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2) as eluent to yield 1.1 g (60%) of 2-(3-nitrophenyl)ethan-l-ol as a brown oil.
49%
With diborane; In tetrahydrofuran; at 60℃; for 6h;Sealed tube;
A solution of borane (3 g, 217 mmol) THF (80 mL) was treated with 2-(3-nitrophenyl)acetic acid (10 g, 55.2 mmol) and the mixture was stirred in sealed vessel at 60 C for 6 hr. The mixture was cooled to room temperature then treated with 10% aq. NaOH (10 mL) and evaporated. The residue was washed with DCM (100 mL) and the solids purified by chromatography (silica gel, 0-40% EtOAc in pet.ether) to afford the desired product (5.0 g; 49%) as a colorless solid. LCMS m/z 130.1 (M-HN02)+.
With borane; In tetrahydrofuran; methanol;
3-Nitrobenzeneethanol Borane in THF (1 M, 220 ml) was added dropwise over 1 h to 3-nitrophenylethanoic acid (20.0 g) in dry THF (100 ml) at room temperature under nitrogen with stirring. The reaction mixture was stirred for 3 h, methanol was added dropwise and the mixture was evaporated to give an oil (26.8 g). The oil was purified by [FCS] eluding with cyclohexane-EA (2:1) to give the title compound (18.3 g) T.l.c. (Cyclohexane-EA, 2:1) Rf 0.17.
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃;
b. 2-(3-nitrophenyl)ethanol; A solution of 3-nitro-phenyl acetonitrile (220 g, 1.078 moles) in water (440 imL), H2SO4 (440 ml_), and acetic acid (440 ml_) was heated at 110 0C for 4 hours. The reaction mixture was diluted with water, and extracted with EtOAc (3 x 1 L). The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated to give the product carboxylic acid (20Og). This crude acid was dissolved in THF (3L), cooled to 0 0C, and treated with borane dimethyl sulfide (150 mL, 1.618 moles), allowed to warm to room temperature, and stirred overnight. The reaction mixture was evaporated to dryness and the resulting syrup was dissolved in EtOAc (3L), washed with water and brine, dried (Na2SO4), filtered and concentrated to a brown liquid (175 g).
With borane-THF; In tetrahydrofuran; at 0 - 20℃;
0357] To a solution of 2-(3-nitrophenyl)acetic acid (1.8 g, 0.01 mol) in THF (20 ml) at 0C, was added BH3THF dropwise (1 M, 22 ml, 0.022 mol), removed ice bath and stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc, washed with water and brine, dried over Na2S04.Concentrated to get crude 2-(3-nitrophenyl)ethanol as light yellow solid ( 0.9 g).
Example 118 N- (3- {1-METHYL-2- [4- (2-METHYL-5-QUINOLINYL)-1-PIPERAZINYL] ETHYL} PHENYL) acetamide (E118) Methyl (3-nitrophenyl) acetate; Trimethylsilyl chloride (5.6 mL, 2.0 equiv. ) was added to a stirred solution of (3- nitrophenyl) acetic acid (4.0 g) in methanol (60 ML). The resulting solution was stirred at room temperature for 18 hours, then concentrated at reduced pressure and partitioned between DCM and aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound as a colourless liquid (4.2 g, 100%). 1H-NMR (300 MHz, CDCI3) 8 (ppm): 8. 15 (s, 1H), 8.07 (d, 1H), 7.60 (d, 1H), 7.47 (t, 1H), 3. 85 (s, 2H), 3.80 (s, 3H).
98.6%
With thionyl chloride; for 1h;Heating / reflux;
Thionyl Chloride (1.61 ML, 22.1 mmol) was pipetted dropwise into methanol (75 mL) in a 250 ML round-bottomed flask. Then a solution of 3-nitrophenylacetic acid (2g, 11.0 mmol) in methanol (10 mL) was added. The mixture was REFLUXED for 1 hour and concentrated in vacuo to yield 11-A (2.12g, 98.6%). The crude product was used on the next step.
96%
With hydrogenchloride; at 70℃; for 1h;
To a stirring solution of 3-nitrophenylacetic acid (10.4 g, 57.3 mmol) in MeOH (250 ml) at RT was added HCl gas until saturation was achieved. The resulting solution was stirred at 70 C for Ih. The reaction was cooled and concentrated under reduced pressure. The semisolid residue was dissolved in Et2O, washed with H2O (2x), satd. NaHCO3 (2x), brine (Ix) and dried (MgSO4). Filtration and evaporation provided methyl 2-(3-nitrophenyl)acetate as a low-melting solid (10.7 g, 96% yield), which was used without further purification.
92.4%
With thionyl chloride; at 0℃; for 3h;Heating;
(3-Nitro-phenyl)-acetic acid methyl ester To a stirred solution of (3-Nitro-phenyl)-acetic acid (0.50 g; 2.76 mmol) in dry Methanol (30.00 ml) cooled to 0 C, thionyl Chloride (0.31 ml; 4.14 mmol) was added slowly. The reaction mixture was heated for 3h. After removal of the solvent, the crude was basified with 10% sodium bicarbonate solution and extracted with dichloromethane (2x40ml) washed with brine solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to get (3-Nitro-phenyl)-acetic acid methyl ester 0.50 g (92.4 %) as a brown oil. HPLC MS (Agilent - Waters Xbridge C8 (50x4.6 mm, 3.5 muetaeta); 1.0 mL/min; 254nm; buffer A: 10mM NH4HC03/H20, buffer B: ACN; (0.0-8.0min 5%-100% buffer B; 8.0-8.1 min 100% buffer B; 8.1-8.5min 100%-5% buffer B; 8.5-10.0min 5%-5% buffer B): (M-H) 194.0; Rt 5.03 min.
79%
With chloro-trimethyl-silane; for 2h;
Example 43 methyl 2-(3-((3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl)amino)phenyl)-2 methylpropanoate a) methyl 2-(3-nitrophenyl)acetate. To 2-(3-nitrophenyl)acetic acid (1 g, 5.52 mmol) in methanol (20 ml.) was added trimethylchlorosilane (1 .41 1 ml_, 1 1 .04 mmol). The reaction was kept stirring for 2 h, then was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over MgS04, filtered, concentrated under reduced pressure and purified via flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford methyl 2- (3-nitrophenyl)acetate (850 mg, 4.36 mmol, 79 % yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.74 (s, 3 H) 3.76 (s, 2 H) 7.50 - 7.55 (m, 1 H) 7.64 (d, J=7.83 Hz, 1 H) 8.12 - 8.21 (m, 2 H). LCMS (ES+) m/e 391 [2M+H]+
With sulfuric acid; at 50℃; for 14h;
Combine (3-nitrophenyl)acetic acid (20.0 g, 110 mmol) and anhydrous methanol (125 mL). Add 7 drops of concentrated sulfuric acid. Heat to 50C. After 14 hours, cool to ambient temperature. Evaporate in vacuo to give a residue. Partition the residue between water and diethyl ether. Separate the organic layer and extract with aqueous saturated sodium bicarbonate solution and brine. Dry the organic layer over MgSO4 and filter. Slowly evaporate to give methyl (3-nitrophenyl)acetate. 1H NMR (CDCl3) delta 8.17 (d, 1H, J=1.1 Hz), 8.14 (dd, 1H, J=1.0, 7.7 Hz), 7.63 (dd, 1H, J=1.1, 7.7 Hz), 7.52 (t, 1H, J=7.7 Hz), 3.75 (s, 2H), 3.73 (s, 3H).
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 (15%, 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 50-85% 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 100% 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 70-85% yield by column chromatography.
A mixture of 1-(3-nitrophenyl)ethanone (82.5 g, 0.5 mol), p-TsOH (3 g) and sulfur (32 g, 1.0 mol) in morpholine (100 mL) was heated at reflux for 3h. After removal of the solvent, the residue was dissolved in dioxane (100 mL). The mixture was treated with cone. HCl (100 mL) and then heated at reflux for 5h. After removal of the solvent, the residue was extracted with EtOAc (3x150 mL). The combined organic extracts were washed with brine, dried (Na2SCU), filtered, and concentrated. The residue was dissolved in EtOH (250 mL) and SOCl2 (50 mL) and heated at reflux for 2h. After removal of the solvent, the residue was extracted with EtOAc (3x150 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford ethyl (3-nitrorhohenyI)acetate (40 g).
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, 86.4 g (0.4 mol) of m-nitrobenzyl bromide and 30% 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 30% hydrochloric acid, and filtered.Dry to obtain m-nitrophenylacetic acid, the purity is:97.35%, the yield was 41%.
Boc2O (4.82 mmol, 22.2 mmol) and DMAP (400 mg, 3.3 mmol)were added to a solution of 2-(3-nitrophenyl)acetic acid (2g, 11 mmol) in tert-butanol (50 mL) and the reaction mixturewas stirred at room temperature for 1 h. After removal of the solvent by distillation under reduced pressure, the cruderesidue was purified by column flash chromatography (cyclohexane/ EtOAc 9:1) to give tert-butyl 2-(3-nitrophenyl)acetate(2.11 g, 81% yield) as yellowish oil.
N-[(3-nitrophenyl)acetyl]methionine ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example B65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine Ethyl Ester Following General Procedure BG above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1H-nmr (CDCl3): delta=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).
Example B65 Synthesis of N-[(3-Nitrophenyl)acetyl]methionine Ethyl Ester Following General Procedure BG above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Example 65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester Following General Procedure G above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1 H-nmr (CDCl3): delta=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).
EXAMPLE A65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester Following General Procedure G' above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1H-nmr (CDCl3): delta=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).
EXAMPLE A65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine Ethyl Ester Following General Procedure G' above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1H-nmr (CDCl3): delta=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).
Example A65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester Following General Procedure G' above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1H-nmr (CDCl3): delta=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 4 - 17h;
Example 65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester Following General Procedure G above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 1H-nmr (CDCl3): delta = 8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H). Optical Rotation: [alpha]23-30 (c 5, MeOH). GENERAL PROCEDURE GEDC Coupling of Acid and Amine A round bottom flask was charged with carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in EtOAc (or similar solvent)/water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1N HCl, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage while, in other cases, purification via chromatography and/or recrystallization was required prior to biological evaluation.
2-[(3-nitrophenyl)acetamido]Butyric Acid Iso-butyl Ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example B20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
Example B20 Synthesis of 2-[(3-Nitrophenyl)acetamido]butyric Acid iso-Butyl Ester Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1-nmr (CDCl3): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3 H).
Example 20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
EXAMPLE A20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
Example A20 Synthesis of 2-[(3-nitrophenyl)acetamido]Butyric Acid Iso-butyl Ester Following General Procedure I' above and using 3-nitrophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
EXAMPLE A20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl): delta=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide; In chloroform; at 23℃; for 96h;
Example 20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): delta = 8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below.Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
Example 7; Step 1; An oven-dried, round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,N-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Tert-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-1-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) To a solution of 3-nitrophenylacetic acid (10 g, 55.2 mmol) in tetrahydrofuran (100 ml) was added carbonyldiimidazole (10.5 g, 65.0 mmol). After stirring at room temperature for 6 hours, magnesium salt of monoethyl malonate (9.3 g, 32.5 mmol) were added thereto. The mixture was stirred at 60 C. for 3 hour. Then, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline. After drying with sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate (1:1)] to obtain ethyl 4-(3-nitrophenyl)-3-oxobutanoate (10.0 g, 39.8 mmol, 72%) as a colorless amorphous powder. IR numax (KBr) cm-1: 1745, 1722 (C=O). 1H-NMR (CDCl3) delta: 1.297 (3H, t, J=7.4 Hz), 3.544 ({fraction (9/10)}*2H, s), 3.606 ({fraction (1/10)}*2H, s), 4.005 ({fraction (9/10)}*2H, s), 4.195 ({fraction (1/10)}*2H, q, J=7.4 Hz), 4.223 ({fraction (9/10)}*2H, q, J=7.4 Hz), 4.982 ({fraction (1/10)}*1H, s), 7.52-7.55 (2H, m), 8.08-8.19 (2H, m).
EXAMPLE 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (2*25 mL), water (1*50 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.
97.9%
In methanol; dichloromethane;
EXAMPLE 109 3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuiric acid. The reaction mixture was refluxed for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (2*25 mL), water (1*50 mL) and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS mle calcd for C9H9NO4 (M+) 195.053 1, found 195.0532.
97.9%
sulfuric acid; In methanol; dichloromethane;
EXAMPLE 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (2*25 mL), water (1*50 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.
97.9%
sulfuric acid; In methanol; dichloromethane;
EXAMPLE 109 3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (2*25 mL), water (1*50 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.
With triethylamine; In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide;
1. N-(2-Hydroxyethyl)-2-(3-nitrophenyl)acetamide To a solution of 3-nitrophenylacetic acid (3.21 g, 17.7 mmol), ethanolamine (2.8 g, 46 mmol), and triethylamine (3.0 mL, 22 mmol) in anhydrous DMF (110 mL) was added a solution of <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (PyBOP, 9.37 g, 18.0 mmol) in anhydrous DMF (80 mL). After stirring 16 hours at ambient temperature (under nitrogen), the reaction mixture was concentrated in vacuo, dissolved in DCM and filtered. The filtrate was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, pH 7 buffer, and brine, dried over Na2SO4 and filtered. The evaporated filtrate was then purified by flash chromatography (10% methanol in DCM) giving the title compound (1.02 g, 26%) as a light yellow solid. 1H NMR (300 MHz, CDCl3/CD3OD) delta 8.18 (m, 1H), 8.11 (ddd, 1H, J=8.1 Hz, 2.4 Hz, 1.1 Hz), 7.72 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 3.62 (s, 2H), 3.44 (t, 2H, J=5.9 Hz), 3.16 (t, 2H, J=5.9 Hz).
With hydrogenchloride; In diethyl ether; ethanol; ethyl acetate;
a) To a solution of 10 g (60 mmol) of 3-nitrophenylacetic acid in 120 ml of ethanol were added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate and the mixture was heated at reflux for 4 hours, cooled and left to stand at room temperature for 18 hours. The mixture was evaporated and the residue was partitioned between 120 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 10.3 g (82%) of ethyl 3-nitrophenylacetate as a pale yellow oil. [NMR spectrum (250 MHz) delta1.25(t) (3H), delta3.68(s) (2H), delta4.6(q) (2H), delta6.5-delta6.7(m) (3H), delta7.09(dd) (1H)].
With sulfuric acid; In ethanol; ethyl acetate;
3-Nitrophenylacetic acid (9.78 g, 54 mmol) was dissolved in ethanol (110 mL), added with a concentrated sulfuric acid (1 mL), and the mixture was allowed to reflux under heating for 3 hours. The solvent was evaporated off, and the residue was dissolved in ethyl acetate (300 mL). The solution was successively washed with water and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, to thereby obtain ethyl 3-nitrophenylacetate (yield: 11 g, yield ratio: 97%) as a syrup.
Multi-step reaction with 2 steps
1.1: 2-chloro-1-methyl-pyridinium iodide / dichloromethane / 0.25 h / Inert atmosphere
1.2: 18 °C / Inert atmosphere
2.1: 2 h / 70 °C
With sulfuric acid In methanol
5.a a
a 3-Methoxy-2-(3-nitrophenyl)-propenoic acid, methyl ester Combine (3-nitrophenyl)acetic acid (20.0 g, 110 mmol) and anhydrous methanol (125 mL). Add 7 drops of concentrated sulfuric acid. Heat to 50° C. After 14 hours, cool to ambient temperature. Evaporate in vacuo to give a residue. Partition the residue between water and diethyl ether. Separate the organic layer and extract with aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4 and filter. Slowly evaporate to give methyl (3-nitrophenyl)acetate. 1 H NMR (CDCl3) δ8.17 (d, 1H, J=1.1 Hz), 8.14 (dd, 1H, J=1.0, 7.7 Hz), 7.63 (dd, 1H, J=1.1, 7.7 Hz), 7.52 (t, 1H, J=7.7 Hz), 3.75 (s, 2H), 3.73 (s, 3H).
(A) 40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of 10M borane-methyl sulfide in 200 ml of THF, and the mixture was stirred at 25 C. for 3 hr. The solution was then acidified with HCl in methanol, followed by evaporation of the solvent. The product 3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether (Et2 O) and aqueous sodium carbonate, and the Et2 O layer dried over sodium sulfate. Evaporation of the Et2 O afforded 34.8 g of 3-nitrophenylethanol (IV, A=H) as an oil.
5 1-[3'-(Dimethylamino-sulfonyl-amino)-phenyl]-2-amino-propane and its maleate by method B
By refluxing m-nitro-benzyl chloride with sodium cyanide in aqueous-ethanolic solution for five hours in the presence of potassium iodide, m-nitro-benzyl cyanide (m.p. 58° C.) was prepared which was subsequently hydrolized by boiling with concentrated hydrochloric acid to form m-nitrophenyl-acetic acid.
With hydrogenchloride
1 1-[3'-(Dimethylamino-sulfonyl-amino)-phenyl]-2-amino-propane and its maleate by method B
By refluxing m-nitro-benzyl chloride with sodium cyanide in aqueous-ethanolic solution for five hours in the presence of potassium iodide, m-nitro-benzyl cyanide (m.p. 58° C.) was prepared which was subsequently hydrolized by boiling with concentrated hydrochloric acid to form m-nitrophenyl-acetic acid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
26
2-(3-nitrophenyl)-Λ/-r3-(2-oxo-1 -pyrrolidinvDpropyllacetamideTo a solution of 1-(3-aminopropyl)-2-pyrrolidinone (Aldrich, 5.8g, 30mmol) in methylene chloride (69ml) at O0C were added 1-hydroxybenzotriazole (3.7g, 28mmol), meta-nitrophenylacetic acid (5.0Og, 28mmol), 1-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride (5.8g, 30mmol), and /V,Λ/-diisopropylethylamine (28ml, 170mmol) respectively. The reaction mixture was was allowed to warm to room temperature overnight, then diluted with methylene chloride (100ml), washed EPO with hydrochloric acid (1N, 3 x 150ml) and a solution of saturated sodium bicarbonate (3 x 150ml). The organic layer was dried over anhydrous sodium sulfate, gravity filtered, and concentrated under reduced pressure to afford 2-(3-nitrophenyl)-Λ/-[3-(2- oxo-1-pyrrolidinyl)propyl]acetamide as a yellow oil which was used, without purification, in the next reaction.
POCl3 (26 g, 0.18 mol) was added over 1 h to anhydrous DMF (66 g) while keeping the temperature at 15-20 C. After the solution had stirred at RT for Ih, 3-nitrophenyl acetic acid (10 g, 0.06 mol) was added. The solution was heated to 85 C and stirred for 18h. The solution was cooled to RT and poured onto 160 g of ice with vigorous stirring. A solution of sodium perchlorate (H g, 0.09 mol) in H2O was added, and a crystalline precipitate formed over 10 min. The precipitate was filtered, washed with H2O, and dried in vacuo at 50 C to yield a tan power (E)-N-[3-(dimethylamino)-2-(3-nitrophenyl)-2-propenylidene]-N-methylmethanaminium monoperchlorate (12 g, 58% yield).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Step 1 An oven-dried, round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,N-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Tert-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-1-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
An oven-dried, round-bottom flask was charged with tert-buty rhoiperazine-1- carboxylate ( 1.1 eq), 3-nitrophenylacetic acid (7 A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,7V-dimethylforrnamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with HfeO, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Terf-butyl 4-(2-(3- nitrophenyl)acetyl)piperazine-l-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
An oven-dried, round-bottom flask was charged with telambdat-butyl piperazine-1- carboxylate ( 1.1 eq), 3-nitrophenylacetic acid (7 A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,N-dimethylformarnide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCOs, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in <n="99"/>vacuo. 7e/*-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-l-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Example 7 Step 1. An oven-dried, round-bottom flask was charged with tert-buty] piperazine-1- carboxylate ( 1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and -V,iV-dimethylformamide (about 0.5 M 7A in DMF) and <n="57"/>triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO-J, filtered and concentrated in vacuo. 7erf-butyl 4-(2-(3- nitrophenyl)acetyl)piperazine-l-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
An oven-dried, round-bottom flask was charged with ferr-butyl piperazine-1 - carboxylate ( 1.1 eq), 3-nitrophenylacetic acid (7 A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and LambdazetaN-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Terr-butyl 4-(2-(3- nitrophenyl)acetyl)piperazine-l -carboxylate (7B) was isolated as a solid (80%) and used without further purification.
To a solution of 3-nitrophenylacetic acid (5.4 g, 29.8 mmol) in pyridine (12.5 mL) was added anhydridous acetic acid (28 mL). The reaction mixture was stirred under nitrogen for 4h at room temperature. The solvent was removed under reduced pressure and the crude was treated with ethanol (30 mL) and concentrated hydrochloric acid (3 mL). The mixture was refluxed for 1 hour. The reaction crude was treated with ciclohexane and water and the organic layer was washed with water, sodium hydroxide 1 N, dried and the solvent was removed under reduced pressure. The title compound was obtained as a yellow solid (4 g, 75%) and used in the next step without further purification.
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 N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;
[0481] To a stirred solution of 2-(3-nitrophenyl)acetic acid (5.0 g, 27.6 mmol) and hydrazine (2 mL, 41.4 mmol) in 10 mL of DMF were added HATU (15.7 g, 41.4 mmol) and DIEA (14.5 mL, 82.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, IN HC1 and brine. The organic layer was dried over Na2S04 and concentrated. The residue was purified by ISCO CombiFlash Rf silica chromatography eluted with 0-10% ethyl acetate in hexane to give the desired compound as a white solid (4.0 g, yield 74%).
Multi-step reaction with 2 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 50 °C
1.2: 24 h / 20 °C
2.1: palladium 10% on activated carbon; triethylsilane / methanol / 0.5 h / 20 °C
Multi-step reaction with 2 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 50 °C
1.2: 24 h / 22 - 26 °C
2.1: palladium 10% on activated carbon; triethylsilane / methanol / 0.5 h / 22 - 26 °C
Multi-step reaction with 2 steps
1: HATU; N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / Reflux
2: ammonium chloride; iron / tetrahydrofuran; water / 15 h / 55 °C
To a stirred solution of 2-(3-nitrophenyl) acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resulting mixture was heated at 50 C for lhr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and EteN (0.15 ml, 1.104 mmol) were added sequentially. Resulting reaction mixture was stirred for 24 h at ambient temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl) acetamide (0.192, 84% yield). HNMR (400 MHz, DMSO-d6), delta 8.1 1-8.08 (m, 2H), 7.68-7.58 (m, 2H), 3.89 (s, 2H), 3.05 (s, 3H), 2.85 (s, 3H). GCMS: 208.12 [M+].
84%
Step a: Synthesis of N,N-dimethyl-2-(3-nitrophenyl)acetamide To a stirred solution of 2-(3-nitrophenyl)acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resulting mixture was heated at 50 C. for 1 hr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et3N (0.15 ml, 1.104 mmol) were added sequentially. Resulting reaction mixture was stirred for 24 h at ambient temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl)acetamide (0.192, 84% yield). 1HNMR (400 MHz, DMSO-d6), delta 8.11-8.08 (m, 2H), 7.68-7.58 (m, 2H), 3.89 (s, 2H), 3.05 (s, 3H), 2.85 (s, 3H). GCMS: 208.12 [M+].
Step A: methyl (3-nitrophenyl)acetate
Step A: methyl (3-nitrophenyl)acetate: (3-Nitrophenyl)acetic acid (400 mg, 2.21 mmol) was dissolved in a 1:1 mixture of MeOHJEt2O (10 mL) and cooled to 0 °C. To this solution was added a 2M solution of trimethylsilyldiazomethane (5.5 mL, 11.05 mmol). The reaction was quenched by the addition of glacial acetic acid (7 mL) and concentrated in vacuo to afford crudetitle compound which was used without further purification: LC-MS: (M+H) 196;
In methanol; diethyl ether at 0℃;
1 Step 1 : Methyl 2-(3-nitrophenyl)acetate (Int 8a)
2-(3-Nitrophenyl)acetic acid (400 mg, 2.21 mmol) was dissolved in a mixture of MeOH: Et20 (10 mL, 1 :1 ) and cooled to 0 °C. To this solution was added a 2M solution of trimethylsilyldiazomethane (5.5 mL, 1 1 .0 mmol). The reaction was quenched by the addition of glacial acetic acid (7 mL) and concentrated to give the title compound as a colorless oil which was used without further purification.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Dissolve 300 mg of 3-nitrophenylacetic acid and 200 mg of methylamine hydrochloride in 15 ml of dimethylformamide. Under stirring, 476 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 336 mg of 1-hydroxybenzotriazole, 0.7 ml of triethylamine were successively added, and the mixture was stirred overnight at room temperature. The next day, add water, extract with dichloromethane, combine the organic phases, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and filter. The mixture was concentrated to dryness to give a slightly yellow solid of N-methyl-2-(3-nitrophenyl)acetamide, 301 mg in weight, yield: 94%.
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