* 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.
Stage #1: With pyridine; boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 75℃; for 1.5 h; Stage #2: With phosphorus pentachloride In N,N-dimethyl-formamide at 55℃; for 0.5 h;
In the first reaction flask, resorcinol (0.72 g, 6.5 mmol), p-nitrophenylacetic acid (1.0 g, 6.0 mmol), BF 3 / Et 2 O (10 mL) was added and stirred at 75 ° C Reaction for 90 min. The reaction was completed, cooled to below 10 ° C, and DMF (10 mL) was added slowly with stirring. (0.72g6.5mmol)(1.0g6.0mmol)BF 3 /Et 2 O(10mL)75°C90min 10°CDMF(10mL) In a second reaction flask, DMF (20 mL) was added, cooled to below 10 ° C, and PCl 5 (2.0 g, 9 mmol) was added portionwise and stirred at 55 ° C for 30 min. The reaction was completed, cooled to below 10 ° C, slowly added to the first reaction flask, room temperature reaction 1h. After completion of the reaction, the reaction solution was poured into hot dilute hydrochloric acid (0.1 N) with stirring, and the solid was precipitated, suction filtered, washed with water and dried. The crude product was recrystallized from methanol to give 0.36 g of product, yield 16.4percent. MS (ESI): m / z = 284 [M + H] & lt; + & gt ;.
Stage #1: at 85℃; for 1.5 h; Stage #2: at 10 - 25℃; for 2 h;
4.1.2 7-Hydroxy-3-(4-nitrophenyl)-4H-benzopyran-4-one (9) A mixture of 4-nitrophenylacetic acid (7; 1.0 g, 6.0 mmol), resorcinol (8; 0.72 g, 6.5 mmol) and BF3/Et2O (10 ml) was heated at 85 °C for 1.5 h with stirring, then cooled down to 10 °C and 10 ml DMF was added slowly. In another flask, 10 ml DMF was added and cooled to 10 °C, PCl5 (2.0 g, 9 mmol) was added in batches, afterwards the mixture was heated to 55 °C and stirred for 0.5 h, after that cooled to 10 °C. Then the mixture was added by droplet into the first flask and stirred at 25 °C for 2 h. Then the reaction mixture was poured into heated dilute hydrochloric acid (0.5 mol/L). The product was filtered, and purified by recrystallization from methanol to yield 9 (0.36 g, 1.26 mmol, 21percent) as a white solid. 1H NMR (DMSO, 300 MHz): δ 8.48 (s, 1H, H-2), 8.28 (2H, J = 8.8 Hz, H-3', H-5'), 8.07 (d, 1H, J = 8.8 Hz, H-5), 7.96 (d, 2H, J = 8. 8 Hz, H-2', H-6'), 7.05 (dd, 1H, J = 8.8, 2.4 Hz, H-6), 6.97 (d, 1H, J = 2.4 Hz, H-8); MS (ESI): m/z = 282 [M-H]-.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4428 - 4433
3
[ 104-03-0 ]
[ 19733-56-3 ]
Reference：
[1] Patent: CN106883166, 2017, A,
4
[ 104-03-0 ]
[ 25026-34-0 ]
Reference：
[1] Biochemische Zeitschrift, 1910, vol. 27, p. 102
5
[ 104-03-0 ]
[ 100-27-6 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
With lithium aluminium tetrahydride In diethyl ether at 50℃; for 3 h; Inert atmosphere
(1) Dissolve p-nitrophenylacetic acid in ether.Heat to 50°C under nitrogen protectionAfter adding lithium aluminum hydride and mixing evenly,Add water, continue stirring for 3h,After the reaction is completed,Reduce the temperature to 0 °C,Add sodium hydroxide solution and water,The concentration of sodium hydroxide solution is 12percent.After standing for 20 minutes, warm to room temperature and add anhydrous MgSO4.After stirring for 30min,The solvent in the filtrate is distilled off,Obtained p-nitrophenyl ethanol;(2) dissolving the obtained p-nitrophenyl ethanol in ethanol,The catalyst was added, nitrogen was introduced, and the temperature was raised to 80°C.Hydrogen gas is introduced under atmospheric pressureStir the reaction for 3h,Filter after cooling,Ethanol is distilled,After the resulting solid is recrystallized,Obtained p-aminophenyl ethanol;The catalyst is a mixture of CeO2, MnO, and ZnO.The mass ratio of lithium aluminum hydride used in step (1) to p-nitrophenylacetic acid is 1:2; the volume of water added dropwiseThe mass ratio to lithium aluminum hydride is 1:1; the mass ratio of sodium hydroxide to lithium aluminum hydride is 3:2 and the second additionThe mass ratio of water to lithium aluminum hydride is 5:2.The catalyst in step (2) is a mixture of CeO2, MnO and ZnO in a mass ratio of 1:2:5;The mass ratio of nitrobenzene ethanol is 3:167. The step (1)
Reference：
[1] Patent: CN108033888, 2018, A, . Location in patent: Paragraph 0019-0057
[2] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 11, p. 3008 - 3014
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 1, p. 109 - 114
[5] Patent: WO2004/29066, 2004, A2, . Location in patent: Page/Page column 302
[6] Patent: WO2007/18941, 2007, A2, . Location in patent: Page/Page column 63
[7] Synthesis, 2011, # 18, p. 2935 - 2940
[8] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
6
[ 104-03-0 ]
[ 19910-33-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 11, p. 1704 - 1711
7
[ 104-03-0 ]
[ 5339-26-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 1, p. 109 - 114
8
[ 104-03-0 ]
[ 1798-06-7 ]
Reference：
[1] Journal of the Chemical Society, 1934, p. 161,164
9
[ 104-03-0 ]
[ 1197-55-3 ]
Yield
Reaction Conditions
Operation in experiment
97.6%
With iron(III) chloride; hydrazine hydrate In water at 90℃; for 1 h; Inert atmosphere
The preparation method of p-aminophenylacetic acid comprises the following steps: mixing water, ferric chloride and p-nitrophenylacetic acid,Heating to 90 ° C in a nitrogen atmosphere, dropping hydrazine hydrate solution, incubating for 1 hour, cooling to 5 ° C, filtering the filter cake,Washing and drying to obtain p-aminophenylacetic acid, wherein the weight ratio of water, iron chloride, p-nitrophenylacetic acid and hydrazine hydrate is 10: 0.2:1: 1, where the amount of water used to wash the filter cake is not taken into account.
Reference：
[1] ChemCatChem, 2014, vol. 6, # 11, p. 3153 - 3159
[2] Patent: CN106083631, 2016, A, . Location in patent: Paragraph 0017; 0023; 0024
[3] Tetrahedron Letters, 1984, vol. 25, # 32, p. 3415 - 3418
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1985, vol. 24, p. 1185
[5] Journal of the Chemical Society, 1934, p. 161,164
[6] Organic Syntheses, Coll. Vol. 1 <New York 1932>, S. 44,
[7] Journal of the Chemical Society, 1880, vol. 37, p. 91
[8] Chemische Berichte, 1869, vol. 2, p. 209[9] Chemische Berichte, 1870, vol. 3, p. 648
[10] Journal of the American Chemical Society, 1917, vol. 39, p. 1437
[11] Journal of the American Chemical Society, 1921, vol. 43, p. 180
[12] Journal of Organic Chemistry, 1963, vol. 28, p. 2347 - 2350
[13] J. Gen. Chem. USSR (Engl. Transl.), 1964, vol. 34, p. 1474 - 1477[14] Zhurnal Obshchei Khimii, 1964, vol. 34, # 5, p. 1469 - 1473
[15] Australian Journal of Chemistry, 1967, vol. 20, p. 1413 - 1428
[16] Patent: US2011/288329, 2011, A1, . Location in patent: Page/Page column 2
[17] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[18] Patent: CN106380413, 2017, A, . Location in patent: Paragraph 0012; 0013
10
[ 104-03-0 ]
[ 5438-70-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[3] ChemMedChem, 2018, vol. 13, # 1, p. 30 - 36
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307
13
[ 104-03-0 ]
[ 61367-39-3 ]
[ 76325-96-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, p. 1689 - 1694[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 10, p. 2374 - 2379
14
[ 64-17-5 ]
[ 104-03-0 ]
[ 76308-26-4 ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: With hydrogen In water at 44 - 58℃; Inert atmosphere; Autoclave; Industry scale Stage #2: With hydrogenchloride In waterReflux; Industry scale
Preparation of trans 4-amino-cyclohexyl-acetic acid ethyl ester HClA 2500 1 enamelled autoclave is charged with 1000 kg of deionizated water and 210 kg (1.16 kM) of 4-nitrophenyl-acetic acid at room temperature under nitrogen atmosphere. After inertisation by nitrogen to the mixture obtained a suspension of 21 kg of 10percent Pd/C in 20 kg of deionized water is added and the catalyst measuring gauge is rinsed by additional 20 kg of deionizated water. After rinsing the reaction vessel by hydrogen gas the hydrogenation is carried out at a temperature between 44-46°C and under up to 0,6 bar overpressure until the hydrogen uptake is slowed. After reducing the nitro group the temperature is brought to 55- 58°C and the hydrogenation continued maintaining hydrogen pressure on max. 4.0 bar overpressures. After completion of the hydrogen uptake, the mixture is cooled to a temperature between 25-30°C, purged with nitrogen and the catalyst is filtered on a Spakler filter under pressurized nitrogen. The reaction vessel, the filter and the lines are washed additional 200 g of deionized water. The filtrates are combined and in a 2500 1 enamelled doubler 1200 kg of distillate is distilled at up to 80°C inner temperature in vacuum. The residue obtained is cooled to a temperature below 30°C and 430 kg of ethyl alcohol is added, then 500 1 of distillate is collected at up to 80°C under vacuum. After completion of the distillation the mixture is cooled to a temperature between 25-30°C, (water content is max. 10 wpercent, in terms of absolute value is about 32 kg), and 550 kg of ethyl alcohol, then 170 kg of 30percent hydrochloric ethyl alcohol are added and the reaction mixture is heated to reflux for approx. 2 hours. When the esterification is complete 800 1 of solvent is distilled off at up to 80°C, under vacuum. Additional 800 1 of ethyl alcohol is added and further 750-800 1 of solvent is distilled off at up to 80°C, under vacuum. To the residue obtained 700 kg of acetonitrile is added and 140 1 of distillate is collected at up to 80°C under vacuum. The vacuum is stopped by introducing nitrogen and the solution is cooled to a temperature between 0-(-)5°C. The crystals obtained is centrifuged, washed with 100 kg of acetonitrile in two portions during which the temperature is kept at 0-(-)5°C. The solid obtained is dried to a constant weight at up to 6O0C. In this manner 90 kg of title product is obtained. Yield: 40 percent. Melting point: 173-1760C.
Reference：
[1] Patent: WO2010/70368, 2010, A1, . Location in patent: Page/Page column 4
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, p. 1689 - 1694[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 10, p. 2374 - 2379
15
[ 110-91-8 ]
[ 104-03-0 ]
[ 144-55-8 ]
[ 262368-47-8 ]
Reference：
[1] Patent: US2003/199478, 2003, A1,
16
[ 104-03-0 ]
[ 890839-11-9 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 20, p. 4798 - 4803
Preparation of trans 4-amino-cyclohexyl-acetic acid ethyl ester HClA 2500 1 enamelled autoclave is charged with 1000 kg of deionizated water and 210 kg (1.16 kM) of 4-nitrophenyl-acetic acid at room temperature under nitrogen atmosphere. After inertisation by nitrogen to the mixture obtained a suspension of 21 kg of 10% Pd/C in 20 kg of deionized water is added and the catalyst measuring gauge is rinsed by additional 20 kg of deionizated water. After rinsing the reaction vessel by hydrogen gas the hydrogenation is carried out at a temperature between 44-46C and under up to 0,6 bar overpressure until the hydrogen uptake is slowed. After reducing the nitro group the temperature is brought to 55- 58C and the hydrogenation continued maintaining hydrogen pressure on max. 4.0 bar overpressures. After completion of the hydrogen uptake, the mixture is cooled to a temperature between 25-30C, purged with nitrogen and the catalyst is filtered on a Spakler filter under pressurized nitrogen. The reaction vessel, the filter and the lines are washed additional 200 g of deionized water. The filtrates are combined and in a 2500 1 enamelled doubler 1200 kg of distillate is distilled at up to 80C inner temperature in vacuum. The residue obtained is cooled to a temperature below 30C and 430 kg of ethyl alcohol is added, then 500 1 of distillate is collected at up to 80C under vacuum. After completion of the distillation the mixture is cooled to a temperature between 25-30C, (water content is max. 10 w%, in terms of absolute value is about 32 kg), and 550 kg of ethyl alcohol, then 170 kg of 30% hydrochloric ethyl alcohol are added and the reaction mixture is heated to reflux for approx. 2 hours. When the esterification is complete 800 1 of solvent is distilled off at up to 80C, under vacuum. Additional 800 1 of ethyl alcohol is added and further 750-800 1 of solvent is distilled off at up to 80C, under vacuum. To the residue obtained 700 kg of acetonitrile is added and 140 1 of distillate is collected at up to 80C under vacuum. The vacuum is stopped by introducing nitrogen and the solution is cooled to a temperature between 0-(-)5C. The crystals obtained is centrifuged, washed with 100 kg of acetonitrile in two portions during which the temperature is kept at 0-(-)5C. The solid obtained is dried to a constant weight at up to 6O0C. In this manner 90 kg of title product is obtained. Yield: 40 %. Melting point: 173-1760C.
4-(2-Morpholin-4-yl-ethyl)-phenylamine is prepared from (4-nitro-phenyl)-acetic acid by the following method: A room temperature solution of 1.8839 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (5 mL) is treated with 1.8069 gms. 1',1'-carbonyl-diimidizole. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 1.0 mL morpholine. The reaction is heated overnight at 35 C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The aqueous layer is re-extracted four more times with ethyl acetate. The combined organics are evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) Carbonyldiimidazole (8.7 g, 30.4 mmol) was added to a solution of 4-nitrophenylacetic acid (10 g, 55.2 mmol) in tetrahydrofuran (100 ml) at room temperature. After stirred at room temperature for 6 hours, a magnesium salt of malonic acid monoethyl ester (4.4 g, 15.2 mmol) was added. This mixture was stirred at 60 C. for 1.5 hours, The reaction solution was diluted with ethyl acetate (100 ml), washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate (3:1)] to obtain ethyl 4-(4-nitrophenyl)-3-oxobutanoate (10.3 g, 41.0 mmol, 74%) as a pale yellow powder. IR numax (KBr) cm-1: 1738, 1722 (C=O). 1H-NMR (CDCl3) delta: 1.280 ({fraction (1/7)}*3H, t, J=7.0 Hz), 1.289 ({fraction (6/7)}*3H, t, J=7.0 Hz), 3.529 ({fraction (6/7)}*2H, s), 3.603 ({fraction (1/7)}*2H, s), 4.000 ({fraction (6/7)}*2H, s), 4.194 ({fraction (1/7)}*2H, q, J=7.0 Hz), 4.216 ({fraction (6/7)}*2H, q, J=7.0 Hz), 4.973 ({fraction (1/7)}*1H, s), 7.36-7.46 (2H, m), 8.17-8.24 (2H, m). Elemental Analysis (C12H13NO5) Cal'd: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.42; H, 5.13; N, 5.72.
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)[ No CAS ]
Et2 O-pentane[ No CAS ]
EtOAc-SSB[ No CAS ]
[ 66793-76-8 ]
[ 104-03-0 ]
N-Ethyl-N-heptyl-4-nitrophenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; In N-methyl-acetamide; ethyl acetate;
PREPARATION 18 N-Ethyl-N-heptyl-4-nitrophenylacetamide, Chart IV; Step I A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3*50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2 SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2 O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25percent EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Step A (Scheme 1): Preparation of trans-1-Chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) and <strong>[34328-46-6]4-chloro-3-trifluoromethylbenzaldehyde</strong> (47.85 g, 0.23 mol) in piperidine (19.5 g, 0.23 mol) was heated under N2 atmosphere to 150 C. to 160 C. for 1 hour. The reaction mixture was cooled to 80 C. to 100 C. and refluxing i-PrOH (150 mL) was added. The mixture was continued to cool to room temperature and then placed under refrigeration for 5 hours. The crystalline precipitate was filtered off, rinsed with cold i-PrOH, and dried at room temperature in a vacuum oven overnight to yield trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene as an orange solid, 22.53 g (68.75 mmol, 30%). mp 173-174 C. MS: 327.0 (M+)
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