* 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.
Reference：
[1] Synthetic Communications, 2013, vol. 43, # 8, p. 1127 - 1137
[2] Pharmazie, 1958, vol. 13, p. 619,621
[3] Patent: US2820738, 1954, ,
[4] Patent: DE947473, 1954, ,
[5] Journal of Organic Chemistry, 1980, vol. 45, # 18, p. 3618 - 3620
[6] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4052 - 4060
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 16, p. 2769 - 2772
[8] Organic Letters, 2009, vol. 11, # 20, p. 4712 - 4715
[9] Patent: DE947473, 1954, ,
2
[ 1878-66-6 ]
[ 95-54-5 ]
[ 5468-66-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: at 110℃; Stage #2: at 120℃; for 1 h;
(101.8 mmol) of 4-chlorophenylacetic acid and 0.37 mg (0.46 mmol) of sodium benzoate were added to a 50 ml reaction flask equipped with a mechanical stirrer, thermometer, water separator and reflux condenser. The temperature was increased to 110 C, and 10 g (92.5 mmol) of o-phenylenediamine was added thereto, and the temperature was raised to 120 ° C for 1 hour. The reaction process and reaction endpoint were monitored by TLC (Developing solvent: ethyl acetate: petroleum ether = 1: 1, Rf = 0.41). The reactants were neutralized with 5 wtpercent Na0H solution and stirred until the pH was 7. 0 to 8.5; filter, washed with water to neutral crude, with ethanol - water mixed solvent recrystallization (volume ratio of 1: 2 ~ 1: 3), filtration, drying in pure 21 3g, the
85%
With boric acid In 5,5-dimethyl-1,3-cyclohexadiene for 16 h; Reflux
General procedure: To a stirred solution of benzene-1,2-diamine 1 (1.85 mmol)in xylenes (10 mL) were added carboxylic acid 2 (2.77 mmol)and boric acid (0.185 mmol). The resulting solution wasrefluxed for 16 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and diluted withEtOAc (50 mL). The organic phase was washed with saturatedNaHCO3 solution (2 50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (elutingwith 10–15percent Ethyl acetate in hexanes) to afford the title compounds3a–y and 5.6.2.5 2-(4-Chlorobenzyl)-1H-benzo[d]imidazole (3e) Yield 85percent; Off white solid; mp 191-194 °C; IR (KBr) 2850, 2751, 1512, 1451, 1410, 1241, 1181, 1025, 812, 749 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (br s, 1H), 7.52 (br s, 1H), 7.31-7.45 (m, 5H), 7.07-7.16 (m, 2H), 4.17 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 153.2, 136.7, 134.5, 131.3, 130.8, 128.5, 121.8, 121.1, 118.3, 111.0, 34.1; HRMS calcd for C14H11ClN2 m/z 242.0625, found 242.0621.
Reference：
[1] Patent: CN103483266, 2016, B, . Location in patent: Paragraph 0054; 0055; 0056
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1872 - 1878
[3] Journal of the American Chemical Society, 1954, vol. 76, p. 1883,1886
[4] Pharmazie, 2003, vol. 58, # 5, p. 303 - 307
Reference：
[1] Bulletin de la Societe Chimique de France, 1956, p. 776,780, 781
8
[ 1878-66-6 ]
[ 24091-92-7 ]
Yield
Reaction Conditions
Operation in experiment
37%
With thionyl chloride; bromine In methanol
Step A: Preparation of methyl 2-bromo-2-(4-chlorophenyl)acetate A mixture of 4-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.25 eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes. The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature. Methanol (30 mL, 25 eq) was then added slowly, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5percent NaHSO3, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (170*45 mm) eluted with 15percent ethyl acetate/hexane to yield 2.89 g (37percent) of the title compound. 1 H NMR (300 MHz, CDCl3, ppm): δ3.8 (s, 3H), 5.35 (s, 1H), 7.2-7.3 (d, 2H), 7.45-7.55 (d, 2H). EI-MS: m/e 262, 264, 266 (M+, 10:13:3 ratio).
Reference：
[1] Organic Letters, 2012, vol. 14, # 18, p. 4842 - 4845,4
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[3] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[4] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 404 - 408
[5] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
[6] Journal of the American Chemical Society, 1977, vol. 99, # 9, p. 3059 - 3067
[7] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 386 - 393
[8] Synthesis (Germany), 2013, vol. 45, # 23, p. 3233 - 3238
[9] Patent: CN106478506, 2017, A,
10
[ 1878-66-6 ]
[ 75-29-6 ]
[ 2012-74-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water
EXAMPLE 22 In the xylene dispersion of fine potassium hydroxide having particle diameter of less than 100μ obtained by the process of Example 1, 26 g. (0.33 mole) of isopropyl chloride was charged, and then a solution of 37.5 g. (0.22 mole) of 4-chlorophenylacetic acid in 50 ml. of xylene was added dropwise during about 10 minutes and then, the reaction was continued at 70°-80° C. for 50 minutes. After the reaction, the reaction mixture was poured into 300 ml. of water and the organic layer was separated and concentrated to distil off xylene and the product was distilled under a reduced pressure to obtain 43 g. (yield of 91percent) of α-isopropyl-4-chlorophenylacetic acid (m.p. 88°-89° C.).
Reference：
[1] Patent: US4307034, 1981, A,
11
[ 1878-66-6 ]
[ 5188-07-8 ]
[ 16188-55-9 ]
Yield
Reaction Conditions
Operation in experiment
79.3%
With copper(I) bromide In N,N-dimethyl-formamide at 130℃; for 24 h; Inert atmosphere
10g of 4-bromophenylacetic acid was added to 20 mL of DMF, 20 mL of DMF was added, 5.0 g of sodium methanethiol was added,Copper 0.5g, nitrogen replacement, stirring to increase the reaction temperature to 130 ° C under nitrogen protection, stirring reaction 24 hours, cooling reactionAnd the remainder were the same as in Example 1 of the present invention, and the yield was 79.3percent.; Taking 4- bromobenzene acetic acid 10g in 100 ml in three-mouth bottle, by adding DMF20mL, adding a thiol sodium 5.0g, adding cuprous bromide 0.1g, after the replacement of nitrogen, to improving the reaction temperature under stirring 130 °C, under the protection of nitrogen stirring for 4 hours, cooling the reaction liquid, by adding 40percent NaOH5mL, stirring 10 minutes. Cooling the reaction liquid, by adding ethyl acetate 25 ml extraction two, by adding ethyl acetate in 50 ml, by adding 10percent dilute sulfuric acid adjusted to pH 2-4, collecting ethyl acetate, ethyl acetate with water 10 ml after washing, distillation of the ethyl acetate to 20 ml left and right, by adding hexane 20 ml, raise the reaction temperature to reflux, after to be solid entirely dissolved, a slow cooling to room temperature, filtered, scaled to obtain yellowish crystalline, to obtain a target product after drying 6.38g, yield 76.1percent.
Reference：
[1] Patent: CN105646306, 2016, A, . Location in patent: Paragraph 0011
12
[ 1878-66-6 ]
[ 19677-37-3 ]
Reference：
[1] Canadian Journal of Chemistry, 1994, vol. 72, # 11, p. 2312 - 2317
[2] Patent: WO2005/123724, 2005, A1,
13
[ 1878-66-6 ]
[ 130754-19-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 49, # 1, p. 115 - 126
[2] Journal of Fluorine Chemistry, 1990, vol. 49, # 1, p. 115 - 126
14
[ 373-91-1 ]
[ 75581-01-0 ]
[ 1878-66-6 ]
[ 74590-69-5 ]
Reference：
[1] Patent: US4215044, 1980, A,
15
[ 1878-66-6 ]
[ 74590-69-5 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 14, p. 4845 - 4846
16
[ 1878-66-6 ]
[ 85-44-9 ]
[ 53242-76-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 240 - 250℃; for 3 h; Stage #2: With water; sodium hydroxide In water for 4 h; Reflux
Proportionion of p-chlorophenylacetic acid, phthalic anhydride and freshly melted sodium acetate in a reaction kettle,Rapidly heated to about 250 ° C,Stirring reaction at 240-250 ° C for 3 hours, the water produced during the reaction is discharged from the tail pipe;The reaction mixture is then placed in an open heat-resistant container while hot.Cool with stirring and add cold absolute ethanol.Heating to dissolve the solid as much as possible, cooling and filtering.Wash with absolute ethanol,filter,dry.The obtained solid is added to a solution of sodium hydroxide and water, stirred under reflux for 4 hours, cooled, diluted with water, acidified to pH 2-3 with 20percent hydrochloric acid, and stirred, cooled, and precipitated as a solid oil. , filtered, dried to obtain a crude product, the crude product was dissolved in acetone, the insoluble matter was filtered off, and acetone was evaporated.The residue was recrystallized from ethyl acetate.Get the product. MP 142-144 ° C, yield 80percent.
Reference：
[1] Patent: CN108003005, 2018, A, . Location in patent: Paragraph 0010; 0011; 0012
17
[ 1878-66-6 ]
[ 53242-76-5 ]
Reference：
[1] Archiv der Pharmazie, 1988, vol. 321, # 4, p. 205 - 208
The starting material 4-chlorophenylacetic acid (intermediate 11, 40 mmol) was dissolved in 25 ml of methanol, and 5 drops of concentrated sulfuric acid was added, The reaction mixture was refluxed for 5h. The solvent was evaporated under reduced pressure to give an oil. 25ml of ethyl acetate was added to dissolve, washed with 25ml saturated sodium bicarbonate solution, water and saturated sodium chloride solution was washed three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford intermediate 12, as a pale yellow oil. The yield was 97.6%.
97.6%
With sulfuric acid; at 60℃; for 5h;
A solution of 9 (40mmol) in dry methanol (25mL) was treated with 5 drops of concentrated H2SO4(cat.) at room temperature. The reaction resulting mixture was stirred and heated at reflux for 5h to completion and was concentrated under reduced pressure. The crude product was dissolved in 25mL ethyl acetate, washed with saturated aqueous sodium bicarbonate, water (3×25mL) and brine (3×25mL), dried over Na2SO4, filtered and concentrated to get the titled compound 10 as a yellow oil, yield 97.6%, 1H NMR (400MHz, DMSO-d6) delta (ppm): 7.39 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 3.70 (d, 2H), 3.61 (s, 3H). MS (ESI) m/z: 185 [M+H]+.
92%
With sulfuric acid; at 20℃;
Example 45; 2-(4-chlorophenylVl-(4-((5R.7R)-7-hvdroxy-5-methyl-6J-dihvdro-5H-cvclopentardlpyrimidin-4- yl)piperazin-l -yl)-3-(2,2,2-trifluoroethylamino)propan-l -one; Step 1 :; A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in dry methanol (235 rtiL) was treated with 5 drops of concentrated H2SO4 (cat.) at room temperature. The mixture was stirred overnight to completion, and then concentrated in vacuo to about 40 milliliters. The concentrate was partitioned between ether and half saturated NaHCO3 solution. The aqueous portion was back-extracted once with ether, and the organics were combined. The organic portion was washed with water, then brine, dried over MgSO4, and concentrated in vacuo. The material was placed under high vacuum for one hour to afford the pure methyl 2-(4- chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). 1H NMR (CDCl3, 400 MHz) delta 7.30 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 3.70 (s, 3H), 3.60 (2, 2H).
92%
sulfuric acid; at 20℃;
Example 39; 2-(4-chlorophenyl)-l-(4-((R)-5-methyl-6J-dihydro-5H-cvclopentardlpyrimidin-4-yl)piperazin-l- yl)-3-(2,2.2-trifluoroethylamino)propan-l-one; [00394] Step 1 : A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in dry methanol (235 mL) was treated with 5 drops of concentrated H2SO4 (cat.) at room temperature. The mixture was stirred overnight to completion and was concentrated in vacuo to about 40 mL. <n="115"/>The concentrate was partitioned between an ether and half saturated NaHCO3 solution. The aqueous portion was back-extracted once with ether, and the organics were combined. The organic portion was washed with water, then brine, dried over MgSO4, and concentrated in vacuo. The material was placed under high vacuum for one hour to afford the pure methyl 2-(4- chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). 1H NMR (CDCl3, 400 MHz) delta 7.30 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 3.70 (s, 3H), 3.60 (2, 2H).
87.02%
With thionyl chloride; at 0 - 20℃; for 3h;Inert atmosphere; Schlenk technique;
General procedure: Thionyl chloride (1.06 mL, 14.63 mmol) was added to dropwise the solution of phenyl aceticacid derivatives (1 g, 4.877 mmol) in methanol (10 mL) at 0 . The reaction was allowed to room temperature for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved ethyl acetate and water. The mixture was extracted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6a-f.
86%
With sulfuric acid; at 0 - 70℃;
2- (4-chlorophenyl)acetic acid (2b) (5.12 g, 30.0 mmol) and methanol (150 mL) were placed in a 500 mL three-necked flask and stirred at 0 C. Sulfuric acid (30 mL) was slowly added and stirred at 70 C. overnight. After completion of the reaction was confirmed by thin layer chromatography, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained compound was separated and purified by silica gel column chromatography (mobile phase hexane: ethyl acetate = 9: 1) to obtain methyl 2-(4-chlorophenyl)acetate (2 bMe) as a transparent liquid (4.75 g, 86% yield).
With hydrogenchloride; for 14h;Heating / reflux;
2-(4-Chlorophenyl)-2-cyclopentylacetic acid 4-Chlorophenylacetic acid (5.0 g) was dissolved in 10% hydrogen chloride -methanol solution (50 ml) and heated under reflex for 14 hours. The solvent then was removed under reduced pressure and saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and condensed under reduced pressure to provide methyl 2-(4-chlorophenyl)acetate (5.35 g) as a colorless, oily substance.
With sulfuric acid; for 5h;Reflux;
General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.% sulfonic acid (0.28 mL) inmethanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted withsaturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (38) (1.13 g, 99% yield) as a colorless oil. The crude product was used without purification. (Step 2)10 A solution of 38 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide11 (1.16 g, 5.88 mmol) in acetonitrile(9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 C and the mixture was stirred for overnight at roomtemperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Theresidue was purified by chromatography on silica gel (n-hexane/ethyl acetate = 10/1 as the eluent) to afford 2a(1.22 g, 98% yield) as an orange solid.
With sulfuric acid; for 8h;Reflux;
General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)
Reference Example-27 Concentrated sulfuric acid (287 mg) and ethanol (10.8 g, 234 mmol) were added to a solution of 2-(4-chlorophenyl)acetic acid (10.0 g, 59.6 mmol) in benzene (10 mL), followed by stirring for 6 hours while heating to reflux. After the reaction was completed, distilled water (100 mL) was added thereto, and the resultant product was extracted with ether (50 mL*3). The mixed organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, whereby ethyl 2-(4-chlorophenyl)acetate (yield: quantitative) was obtained as a colorless oily material. 1H-NMR (400 MHz, CDCl3): delta3.54 (s, 2H), 3.70 (s, 3H), 7.21-7.33 (m, 4H).
99%
sulfuric acid; at 20℃;
The (4-chlorophenyl) -acetic acid (20.0 g, 106 mmol) was dissolved in 220 mL of ethanol at ambient temperature. A catalytic amount of sulfuric acid (10 drops) was added to afford a light yellow solution. The reaction was allowed to stir overnight to completion and was concentrated to 30 mL. The concentrate was partitioned between ethyl acetate and half- saturated NaHC03 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired pure (4-chlorophenyl) -acetic acid ethyl ester as a pale yellow oil (21.0 g, 99%). 1H NMR (CDC13, 400 MHz) 5 7.29 (d, J= 8. 4 Hz, 2H), 7.22 (d, J= 8. 4 Hz, 2H), 4.15 (q, J= 7.2 Hz, 2H), 3.58 (s, 2H), 1.25 (t, J= 7.2 Hz, 3H).
82%
With sulfuric acid; for 4h;Heating / reflux;
(4-Chloro-phenyl)-acetic acid ethyl ester (Intermediate compound): A solution of 4-chlorophenylacetic acid (28.51 g, 167 mmol) in ethanol (99%, 85 ml_) was added cone, sulfuric acid (15 ml_) and refluxed for 4 hours after which the reaction mixture was concentarted to 40 ml_ and poured into water. The aqueous phase was extracted with diethyl ether, dried using MgSO4, filtered and evaporated in vacuo. The crude product was further purified by distillation (approx. 100C/1 Torr) to give 27.2 g (82%) of the title compound.
Example 68; 5-[2-(4-Chlorophenyl)-3-methoxymethoxypropoxy]-quinazoline- 2,4-diamine; [00217] Step 1; 4-Chlorophenyl acetic acid (5.0 g; 29.3 mmol) is dissolved in 50 mL absolute ethanol. With stirring, 100 muL sulfuric acid is added to the solution and the reaction is heated to reflux for 2 hours. The ethanol is removed by rotary evaporation and the resulting oil is dissolved in ethyl acetate. The organics are washed successively with saturated sodium bicarbonate, water, and brine, then dried over magnesium sulfate. After removing the ethyl acetate by rotary evaporation, the resulting oil is dried under vacuum at 35 C for two hours to give 5.60 grams of 4- chlorophenylacetic acid ethyl ester.
(101.8 mmol) of 4-chlorophenylacetic acid and 0.37 mg (0.46 mmol) of sodium benzoate were added to a 50 ml reaction flask equipped with a mechanical stirrer, thermometer, water separator and reflux condenser. The temperature was increased to 110 C, and 10 g (92.5 mmol) of o-phenylenediamine was added thereto, and the temperature was raised to 120 C for 1 hour. The reaction process and reaction endpoint were monitored by TLC (Developing solvent: ethyl acetate: petroleum ether = 1: 1, Rf = 0.41). The reactants were neutralized with 5 wt% Na0H solution and stirred until the pH was 7. 0 to 8.5; filter, washed with water to neutral crude, with ethanol - water mixed solvent recrystallization (volume ratio of 1: 2 ~ 1: 3), filtration, drying in pure 21 3g, the
88.2%
In toluene; at 110℃; for 6.08333h;
10.8 g of o-phenylenediamine and 20.4 g of 4-chlorophenylacetic acid were placed in a 250 ml three-neck round bottom flask.Add 120 ml of toluene, stir for 5 minutes, add 1 g of Zn/B2O3 catalyst, connect the water separator, and heat to reflux at 110 C for 6 hours.The solvent is recovered by using a distillation recovery device. When about 100 ml of toluene is recovered, the mixture is distilled under reduced pressure. When 110 ml of toluene is recovered, the distillation under reduced pressure is stopped, 150 ml of ethanol is added, and 10 ml of ammonia water is added.0.5 g of activated carbon, stirred and dissolved for 30 minutes,Filter the activated carbon and slowly add 50 ml of pure water to the filtrate.Stir while stirring, product precipitation, filtration, hot water wash twice,Filtration and drying gave 21.4 g of 2-(4-chlorobenzyl)benzimidazole, the yield was 88.2%, and the product color was good.
85%
With boric acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 16h;Reflux;
General procedure: To a stirred solution of benzene-1,2-diamine 1 (1.85 mmol)in xylenes (10 mL) were added carboxylic acid 2 (2.77 mmol)and boric acid (0.185 mmol). The resulting solution wasrefluxed for 16 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and diluted withEtOAc (50 mL). The organic phase was washed with saturatedNaHCO3 solution (2 50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (elutingwith 10-15% Ethyl acetate in hexanes) to afford the title compounds3a-y and 5.6.2.5 2-(4-Chlorobenzyl)-1H-benzo[d]imidazole (3e) Yield 85%; Off white solid; mp 191-194 C; IR (KBr) 2850, 2751, 1512, 1451, 1410, 1241, 1181, 1025, 812, 749 cm-1; 1H NMR (400 MHz, DMSO-d6) delta 12.26 (br s, 1H), 7.52 (br s, 1H), 7.31-7.45 (m, 5H), 7.07-7.16 (m, 2H), 4.17 (s, 2H); 13C NMR (100 MHz, DMSO-d6) delta 153.2, 136.7, 134.5, 131.3, 130.8, 128.5, 121.8, 121.1, 118.3, 111.0, 34.1; HRMS calcd for C14H11ClN2 m/z 242.0625, found 242.0621.
With lithium aluminum hydride In diethyl ether at 35℃; for 2h;
92%
With tin(II) trifluoromethanesulfonate; tris(2,4-pentanedionato)ruthenium(III); hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In water; toluene at 160℃; for 48h; Autoclave;
87%
With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere;
80%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
24 4.1.4 Synthetic procedure 3: reduction of carboxylic acid with LiAlH4
In a 3-neck flask, LiAlH4 (8.0mmol) was dissolved in anhydrous tetrahydrofuran (THF) (10mL), under nitrogen atmosphere at 0°C. A solution of phenyl acetic acid (4.0mmol) in anhydrous THF (10mL), was added dropwise to the reaction mixture over 20min, followed by addition of 5mL of anhydrous THF. The mixture was allowed to warm to rt, after which the reaction was quenched with EtOAc (50mL) and water (50mL). The mixture was washed with water (3×50mL) and the organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure.
76%
With dimethylsulfide borane complex In tetrahydrofuran
With lithium aluminium tetrahydride In tetrahydrofuran
With lithium aluminium tetrahydride
With lithium aluminium tetrahydride In tetrahydrofuran for 4h; Heating;
With lithium aluminium tetrahydride In diethyl ether
With lithium aluminium tetrahydride In tetrahydrofuran Heating;
Multi-step reaction with 2 steps
1: 89 percent / H2SO4 / 8 h / Heating
2: LiAlH4 / diethyl ether / 3 h / Heating
Multi-step reaction with 2 steps
2: LiAlH4
Multi-step reaction with 2 steps
1: sulfuric acid / 12 h / Reflux
2: lithium aluminium tetrahydride / diethyl ether / 0 °C / Reflux; Inert atmosphere
Stage #1: 4-chlorophenylacetic Acid With lithium aluminium tetrahydride In tetrahydrofuran at 18 - 26℃; for 2h;
Stage #2: With water; ammonium chloride In tetrahydrofuran
4.2. General procedure for the synthesis of aldehydes
General procedure: To a suspension of LiAlH4 in dry THF was added the corresponding acid dissolved in dry THF dropwisely at room temperature. Then the mixture was stirred for 2 h and quenched with saturated NH4Cl. The mixture was extracted with chloroform and dried over anhydrous Na2SO4. Then the solvent was evaporated and the product was used without further purification. The crude alcohol was dissolved in dry DCM and DMP (Dess-Martin Periodinane) was added. The resulting mixture was stirred at room temperature for 2 h and quenched with Na2S2O3/NaHCO3 (v/v=1/1). The aqueous phase was extracted with DCM and dried over anhydrous Na2SO4. The solvent was evaporated to afford the corresponding aldehydes.
With samarium diiodide; tributyl-amine; water In tetrahydrofuran at 23℃; Inert atmosphere; chemoselective reaction;
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Multi-step reaction with 2 steps
1: sulfuric acid / 6.5 h / Inert atmosphere; Reflux
2: diisobutylaluminium hydride; hydrogenchloride / tetrahydrofuran; hexane; water / 0 - 20 °C / pH 1 / Inert atmosphere
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 4.5h; Reflux;
Preparation of phenylethyl alcohols
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.
36.7 g
With lithium aluminium tetrahydride In tetrahydrofuran at 25 - 30℃; for 20h;
2.3
The present invention uses SM-A and LCS-1 condensation to prepare Impurity F.Specific operations are as follows: 40g of p-chlorophenylacetic acid was added to 400ml of tetrahydrofuran,Stirring at room temperature dissolved; lithium aluminum hydride in batches, temperature control at 25 ~ 30 ,After the reaction was stirred for 20 hours, 200 ml of water was added slowly and the addition was completed.Add ethyl acetate 400ml stirred 30min, liquid separation, organic phase plus 200ml saturated brine and dried over 20g anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure 40 ~ 45 ,36.7 g of oil (S2) was obtained; S2 was added to the reaction flask, the temperature was lowered to 0 to 5 ° C in ice water,Slowly dropping phosphorus tribromide, dropping temperature during the course of 0 ~ 5 , the dropwise addition is completed,Heated to 25 ~ 30 , incubated for 3h,Add water 80ml, stirred 30min, liquid separation, the aqueous phase was extracted with dichloromethane 100ml × 2,The organic phases were combined and concentrated under reduced pressure to give an oil (S3): 48.8 g. Yield: 94.9%.
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide; In methanol; at 180℃; under 11251.1 Torr; for 6h;Autoclave;
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,Palladium acetate 1.37g,Add to the autoclave reactor,Stir the catalyst for 5 minutes, displace the air in the kettle 3 times with CO, raise the temperature to 180 C, and flush the CO to the pressure to 1.5 MPa. Within 1 hour,At the same time, 82.2 g (0.4 mol) of p-chlorobenzyl bromide and 160 g (1.2 mol) of 30% NaOH 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 p-chlorophenylacetic acid, the purity is:99.32%, the yield was 95.2%.
General procedure: The derivatives were synthesized by heating 2,4-diaminophenoldihydrochloride (1) (0.01 mol) with suitable acid (2a-2l) (0.01 mol) in polyphosphoric acid (PPA) (24 g) and stirring at170-200 Cfor 1.5-2.5 h.At the end of the reaction period, theresidue was poured into an ice-water mixture and neutralizedwith an excess of NaOH (10 %) solution, and the residue wasfiltered and boiled with charcoal (200 mg) in ethanol and filtered.After the evaporation of solvent in vacuo, the crudeproduct was obtained and recrystallized from ethanol-water(1:3) mixture (Yildiz-Oren et al., 2004a; Sener et al., 1987;Wynne et al., 2009).
4-(3-bromo-8-chloro-6,11-dihydro-5<i>H</i>-benzo[5,6]cyclohepta[1,2-<i>b</i>]pyridin-11-yl)-1-[(4-chloro-phenyl)-acetyl]-piperazine-2-carboxylic acid methylamide[ No CAS ]
Preparation 1.2 2-(4-Chlorophenyl)l-1(2,4-dichlorophenyl)ethanone 417 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to -60 C., under a nitrogen atmosphere, 350 ml of THF are added, followed by dropwise addition of a solution of 57 g of 4-chlorophenylacetic acid in 70 ml of THF and the mixture is stirred for 2 hours while allowing the temperature to rise to -40 C. The reaction mixture is cooled to -60 C., 65.3 g of <strong>[35112-28-8]methyl 2,4-dichlorobenzoate</strong> are added dropwise and the mixture is stirred while allowing the temperature to rise to 0 C. The reaction mixture is poured into a mixture of ice/1 liter of 2N HCl and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is concentrated under vacuum to a volume of 150 ml. The remaining solution is poured into 300 ml of pentane and the crystalline product formed is filtered off by suction. 60 g of the expected compound are obtained.
420 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to -60 C., under a nitrogen atmosphere, 350 ml of THF are added, and then, dropwise, a solution of 57.6 g of 4-chlorophenylacetic acid in 70 ml of THF and the mixture is kept stirred for 1 hour at -60 C. 66 g of <strong>[35112-28-8]methyl 2,4-dichlorobenzoate</strong> are then added, dropwise and at -60 C., the mixture is kept stirred for 40 minutes at -60 C. and then the temperature is allowed to rise to 0 C. The reaction mixture is poured over an ice/1 liter of 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, with water, the organic phase is dried over Na2SO4, the solvent is concentrated under vacuum to a volume of 150 ml, 200 ml of pentane are added and the crystallized product formed is drained. 60 g of the expected compound are obtained.
With thionyl chloride; bromine; In methanol; water;
Example 1 This example relates to the preparation of Methyl Bromo-(4-chlorophenyl)-acetate. The initial compound listed in Scheme 1, i.e., 4-chlorophenylacetic acid, is readily available from several commercial sources (e.g., Aldrich and Fluka). A 5-L Morton reactor equipped with a magnetic stirrer, a pot temperature control, and addition funnel was vented through a gas scrubber and charged with p-chlorophenylacetic acid (720 gm, 4.2 moles) and SOCl2 (390 ml, 630 gm, 5.3 moles). The reaction was stirred, heated and held at 55+-5 C. for 1 hour. Bromine (220 ml., 670 gm, 5.3 moles) was then added over 20 min. and stirred at 55+-5 C. for 16 hours. The temperature was raised to 80 C. for 7 hours and then cooled to 9 C. in an ice-water bath. Methanol (2.0 L, 1.6 kg, 49.4 moles) was then carefully added. The solvent was stripped to obtain 2 liquids weighing 1.28 kg. These were dissolved in a mixture of 0.84 L water and 2.1 L ether and separated. The organic phase was washed once with 0.78 L 25% (w:w) aqueous NaCl and dried over 0.13 kg MgSO4. This was filtered through Whatman #1 filter paper and stripped of solvent to obtain 0.985 kg of orange liquid.
With thionyl chloride; bromine; In methanol; water;
Example 1 This example relates to the preparation of Methyl Bromo-(4-chlorophenyl)-acetate. The initial compound listed in Scheme 1, i.e., 4-chlorophenylacetic acid, is readily available from several commercial sources (e.g., Aldrich and Fluka). A 5-L Morton reactor equipped with a magnetic stirrer, a pot temperature control, and addition funnel was vented through a gas scrubber and charged with p-chlorophenylacetic acid (720 gm, 4.2 moles) and SOCl2 (390 ml, 630 gm, 5.3 moles). The reaction was stirred, heated and held at 55 +-5 C. for 1 hour. Bromine (220 ml., 670 gm, 5.3 moles) was then added over 20 min. and stirred at 55+-5 C. for 16 hours. The temperature was raised to 80 C. for 7 hours and then cooled to 9 C. in an ice-water bath. Methanol (2.0 L, 1.6 kg, 49.4 moles) was then carefully added. The solvent was stripped to obtain 2 liquids weighing 1.28kg. These were dissolved in a mixture of 0.84 L water and 2.1 L ether and separated. The organic phase was washed once with 0.78 L 25% (w:w) aqueous NaCl and dried over 0.13 kg MgSO4. This was filtered through Whatman #1 filter paper and stripped of solvent to obtain 0.985 kg of orange liquid.
2.89 g (37%)
With thionyl chloride; bromine; In methanol;
Step A: Preparation of methyl 2-bromo-2-(4-chlorophenyl)acetate A mixture of 4-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.25 eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes. The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature. Methanol (30 mL, 25 eq) was then added slowly, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5% NaHSO3, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (170*45 mm) eluted with 15% ethyl acetate/hexane to yield 2.89 g (37%) of the title compound. 1 H NMR (300 MHz, CDCl3, ppm): delta3.8 (s, 3H), 5.35 (s, 1H), 7.2-7.3 (d, 2H), 7.45-7.55 (d, 2H). EI-MS: m/e 262, 264, 266 (M+, 10:13:3 ratio).
With thionyl chloride; bromine; In methanol; water;
Example 1 This example relates to the preparation of Methyl Bromo-(4-chlorophenyl)acetate. The initial compound listed in Scheme 1, i.e., 4-chlorophenylacetic acid, is readily available from several commercial sources (e.g., Aldrich and Fluka). A 5-L Morton reactor equipped with a magnetic stirrer, a pot temperature control, and addition funnel was vented through a gas scrubber and charged with p-chlorophenylacetic acid (720 gm, 4.2 moles) and SOCl2 (390 ml, 630 gm, 5.3 moles). The reaction was stirred, heated and held at 55+-5 C. for 1 hour. Bromine (220 ml., 670 gm, 5.3 moles) was then added over 20 min. and stirred at 55+-5 C. for 16 hours. The temperature was raised to 80 C. for 7 hours and then cooled to 9 C. in an ice-water bath. Methanol (2.0 L, 1.6 kg, 49.4 moles) was then carefully added. The solvent was stripped to obtain 2 liquids weighing 1.28 kg. These were dissolved in a mixture of 0.84 L water and 2.1 L ether and separated. The organic phase was washed once with 0.78 L 25% (w:w) aqueous NaCl and dried over 0.13 kg MgSO4. This was filtered through Whatman #1 filter paper and stripped of solvent to obtain 0.985 kg of orange liquid.
Reference Example 67 phosphorus pentachloride (2.27 g) was added to methanesulfonic acid (8 ml), and the mixture was stirred at 120C for 1 hour.. To the solution were added <strong>[38191-34-3]2-amino-5-bromophenol</strong> (1.50 g) and 4-chlorophenylacetic acid (1.36 g) and the mixture was stirred at 100C for 1 hour.. The mixture was poured onto ice, neutralized with 8 N sodium hydroxide and extracted with ethyl acetate - tetrahydrofuran (3: 1, v/v).. The organic layer was washed with water and dried over MgSO4.. The solvent was distilled off under reduced pressure.. The residue was subjected to silica gel column chromatography and the fraction eluted with ethyl acetate - hexane (1: 4, v/v) was concentrated under reduced pressure.. The resulting crystals were collected by filtration to obtain 6-bromo-2-(4-chlorobenzyl)benzoxazole (1.83 g, 71 %).1H NMR (CDCl3) delta 4.22 (2H, s), 7.32 (4H, s), 7.43 (1H, dd, J = 8.4, 1.4 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 1.8 Hz) ppm IR (KBr) nu 1564, 1493, 1424 cm-1HPLC (220 nm) Purity 99 % (Retention time 4.76 minutes) MS (APCI+, m/e) 322 (M+1)
With hydrogenchloride; In tetrahydrofuran; hexane;
Step A 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)ethanone A 5 L round bottom flask equipped with an addition funnel, N2 inlet, thermometer and a mechanical stirrer was charged with 387 mL of 1M sodium bis-trimethylsilylamide in THF and cooled to -60 C. A solution of 230 g (1.35 mol) of 4-chlorophenylacetic acid in 300 mL of THF was added keeping the temperature below -40 C. After stirring the mixture for 90 min at -70 C., 264 g (1.29 mol) of <strong>[35112-28-8]methyl 2,4-dichlorobenzoate</strong> was added over 20 min. The solution was stirred for 40 min at -70 C., the cooling bath was removed and the mixture was allowed to warm to 0 C. Reaction was quenched by pouring into 4 L of 2N HCl and ice and extracted with ether. Each ether layer was washed with saturated NaHCO3, brine, dried with MgSO4 and filtered through a 2" plug of silica gel. The filtrate was concentrated to ca. 1 lit of a slushy liquid which was diluted with 1 L of hexane and cooled in a refrigerator. The solid formed was filtered, washed with hexane and dried. A second crop was isolated by concentrating the mother liquors. The two crops of crystals were combined. 1H NMR: (500 MHz, CDCl3): delta 4.21 (s, 2H), 7.2-7.5 (m, 7H).
EXAMPLE 7 2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) in ethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellow solid: mp 39-41 C.; EI-HRMS m/e calcd for C10H11C2 (M+) 198.0448, found 198.0452.
88%
sulfuric acid; In ethanol;
EXAMPLE 7 2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) in ethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellow solid: mp 39-41 C.; EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0452.
96.30 g (96.9%)
With sulfuric acid; In ethanol; water; benzene;
PREPARATION 3 Ethyl p-chlorophenylacetate To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9%) of the title compound as a colorless liquid, b.p. 105-106 C./2.5 mmHg (lit. 130 C./13 mmHg).
96.30 g (96.9%)
With sulfuric acid; In ethanol; water; benzene;
Preparation 3 Ethyl p-chlorophenylacetate To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9 %) of the title compound as a colorless liquid, b.p. 105-106C/2.5 mmHg (lit. 130C/13 mmHg).
With hydrogenchloride; 1,1'-carbonyldiimidazole; In tetrahydrofuran; diethyl ether;
(a) 4-(4-Chlorophenyl)-3-oxo-butanoic acid ethyl ester: 4-Chlorophenylacetic acid (34.1 g, 0.2 mol) is dissolved in tetrahydrofuran (260 ml) In an ice bath, carbonyldiimidazole (38.8 g, 1.1 eq) is added, followed by a further 100 ml of tetrahydrofuran. The white suspension is stirred at 0 C. for 2 hours. The mixture is allowed to rise to room temperature and bis-(malonic acid monoethyl ester) magnesium salt (68.6 g, 1.15 eq) is added. The mixture is stirred at room temperature overnight, then some of the solvent is concentrated by evaporation; 6N hydrochloric acid and diethyl ether are added. The organic phase is washed with bicarbonate solution and brine, dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained in the form of a yellow oil, Rf (dichloromethane/methanol 19:1)=0.83.
With sulfuric acid; In methanol; 1,2-dichloro-ethane;
REFERENCE EXAMPLE 1 Preparation of methyl-(4-chlorophenyl)-acetate STR5 4-Chlorophenylacetic acid (100 g, 0.59 mol) was dissolved in 1,2-dichloroethane (165 ml) and methanol (96 ml, 2.4 moles) and to the solution was added concentrated sulfuric acid (2.75 ml), followed by refluxing for 6 hours. The mixture was cooled and aqueous NaHCO3 was added, followed by stirring. The resulting organic layer was separated, dried over anhydrous sodium sulfate, collected by filtration and concentrated to dryness to obtain methyl-(4-chlorophenyl)-acetate (102 g, yield 94%). NMR (CDCl3) deltappm: 3.60 (2H, s), 3.70 *(3H, s), 7.15-7.35 (4H, s).
With potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 22 In the xylene dispersion of fine potassium hydroxide having particle diameter of less than 100mu obtained by the process of Example 1, 26 g. (0.33 mole) of isopropyl chloride was charged, and then a solution of 37.5 g. (0.22 mole) of 4-chlorophenylacetic acid in 50 ml. of xylene was added dropwise during about 10 minutes and then, the reaction was continued at 70-80 C. for 50 minutes. After the reaction, the reaction mixture was poured into 300 ml. of water and the organic layer was separated and concentrated to distil off xylene and the product was distilled under a reduced pressure to obtain 43 g. (yield of 91%) of alpha-isopropyl-4-chlorophenylacetic acid (m.p. 88-89 C.).
With sulfuric acid; In methanol; 1,2-dichloro-ethane;
REFERENTIAL EXAMPLE 1 Methyl (4-chlorophenyl)acetate STR6 To a solution of 100 g (0.59 mole) of 4-chlorophenylacetic acid in 165 ml of 1,2-dichloroethane and 96 ml (2.4 moles) of methanol was added 2.75 ml of concentrated sulfuric acid, and the mixture was refluxed for 6 hours. It was then cooled, poured into an aqueous sodium bicarbonate solution and stirred. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 102 g (94% yield) of methyl (4-chlorophenyl)acetate. NMR (CDCl3) delta ppm; 3.60 (2H, s), 3.70 (3H, s), 7.15-7.35 (4H, s)
94%
With sulfuric acid; In methanol; 1,2-dichloro-ethane;
Referential Example 1 Methyl (4-chlorophenyl)acetate To a solution of 100 g (0.59 mole) of 4-chloro-phenylacetic acid in 165 ml of 1,2-dichloroethane and 96 ml (2.4 moles) of methanol was added 2.75 ml of concentrated sulfuric acid, and the mixture was refluxed for 6 hours. It was then cooled, poured into an aqueous sodium bicarbonate solution and stirred. Tie organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 102 g (94% yield) of methyl (4-chlorophenyl)acetate. NMR (CDCl3) delta ppm; 3.60 (2H, s), 3.70 (3H, s), 7.15-7.35 (4H, s)
EXAMPLE 18 p-Chlorophenylacetic acid methyl ester: As described in Example 1, 80.5 g (0.5 mole) of p-chlorobenzyl chloride with 135 g of a 24 wt-% sodium methylate solution, 10 g of CoCl2. 6 H2 O, 4 g of manganese and 1 g of sodium dithionite were reacted with CO. The reaction and processing were performed as described in Example 1. 74 g of p-chlorophenylacetic acid methyl ester (yield 80%) was isolated in a purity of 96%, plus 4 g of p-chlorophenylacetic acid (4.6%).
With potassium permanganate; thionyl chloride;aluminium trichloride; In pyridine; dichloromethane; water; benzene;
EXAMPLE 8 Preparation of 4-chlorobenzil hydrazone A benzene solution containing 51.2 g 4-chlorophenylacetic acid and 39.3 g thionyl chloride is refluxed for 6 hours and the solvent removed. The crude reaction product is added dropwise to a slurry of 40 g aluminum chloride in 200 ml benzene maintaining the temperature below 50 C. After addition the reaction is refluxed for 1.5 hours. After cooling, the mixture is poured into ice and the resulting white solid is separated yielding 61.3 g of crude product. The product is taken up in methylene chloride and washed with 5% sodium hydroxide solution followed by water, dried over sodium sulfate and stripped yielding 49.3 g (71%) of >95% pure 4'-chlorodeoxybenzoin. 15 g of 4-chlorodeoxybenzoin is dissolved in 105 ml pyridine. An aqueous solution containing 15 g potassium permanganate is added and the reaction stirred for 6 hours at room temperature using dry ice to buffer the pH near 7. The mixture is extracted with methylene chloride, the extract washed with water, dried over Na2 SO4 and stripped. The residue is recrystallized from ethanol yielding 6.1 g of white plate-like crystals which is identified as starting material. Concentration of the mother liquor yields 4 g of 4-chlorobenzil.
The moisture sensitive product was stored under nitrogen. A solution of 29.92 g (0.095 mol) of the aforesaid beta,beta-bis(trimethylsiloxy)p-chlorostyrene in 300 ml of CFCl3 was cooled to -70 C. and 9.88 g (0.095 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 2 hours. The mixture was allowed to warm to room temperature and evaporated to dryness under reduced pressure. The resultant white solid residue was stirred with 10 ml of water for approximately 10 minutes. The solids were recrystallized from 1 l of hexane to give 9.38 g (53% yield) of p-chlorophenylfluoroacetic acid as shiny white crystals, mp 66-68 C.; 1 H NMR (CDCl3) delta5.75 (d, J?47 Hz, 1H), delta7.35 ppm (s, 4H), delta10.95 (s, 1H); 19 F NMR (CDCl3) delta-182.60 (d, J?47 Hz).
EXAMPLES Example 1 Preparation of 2-(4-Chlorophenyl)-N-(2-hydroxypropyl)acetamide (1-3)1-3 Method A (Boronic Acid) Toluene (50 mL) was charged to a 3-neck round-bottom (500 triL) flask fitted with aDean-Stark condenser. 4-Chlorophenylacetic acid (51.2 g, 300 mmol) was added, followed by 2,5,6-trifluorophenylboronic acid (30 mmol, 5.28 g) and l-aminopropan-2-ol (24.8 g, 330 mmol). The reaction flask was heated at 120 0C for 23 h. The reaction mixture was cooled to room temperature, and then solvent was removed to afford the crude product as white solid. Then water (120 mL) was added to the crude product. The resulting product was filtered and dried in a vacuum oven overnight to yield 62.5 g of pure product as a white solid (91.5% yield).Method B (Ketal)To a 100 mL round-bottom flask equipped with a reflux condenser and a magnetic stirrer was charged 5 g (0.029 mol, 1.0 eq) of 2-(4-chlorophenyl)acetic acid and 0.279 g (1.5 mmol, 0.05 eq) p-toluenesulfonic acid (PTSA). Methanol (25 mL) was added to the flask followed by 3.4 mL (0.029 mol, 1.0 eq) of 2,2-dimethoxypropane (DMP). The resulting mixture was heated to reflux and held (about 4 h) until conversion to intermediate 2-(4- chlorophenyl)acetic acid methyl ester was greater than 95%. The methyl ester intermediate was not isolated.Amino 2-propanol (7.3 mL, 0.06 mol, 3.1 eq) was then charged to the reaction mixture. Reflux was maintained with an internal temperature up to 900C until conversion to the title compound exceeded 98% by LC/MS. The reaction was complete within 12 h. Methanol was distilled off during the reaction. The reaction mixture was then charged with 30 mL (6.0 <n="19"/>volumes) of water while maintaining the internal temperature around 1000C followed by cooling in an ice bath for 30 minutes to precipitate the product as a fine solid. Solids were filtered and washed with 2 X 20 mL water and the wet cake was dried in a vacuum oven at 60 0C to yield 5.83 g of the title compound (87.4% yield) as white solids.1H NMR (400 MHz, DMSO (J6, delta): 8.06 (s, IH), 7.38 (d, 2H), 7.30 (d, 2H), 4.71 (d, IH), 3.64(m, IH), 3.45 (s, 2H), 3.02 (m, 2H), 1.02 (d, 3H).LCMS: 455^57 (2M+H), 228-230 (MH), 210-212 (MH-H2O), 125-127.
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃;
Step B: 1-(4-Bromo-2-chlorophenyl)-2-(4-chlorophenyl)ethanone. A solution of sodium bis(tri-methylsilyl)amide in THF (1 M, 4.70 L, 4.702 mol) was cooled to -78 C. 4-Chlorophenylacetic acid (297 g, 1.742 mol) in THF (1 L) was added dropwise followed by the dropwise addition of a solution of product from Step A (434.5 g, 1.742 mol) in THF (1 L). The mixture was stirred overnight at rt. The reaction was quenched by adding it portion wise to HCl (2 N) and then extracted with EtOAc, washed with saturated aq NaHCO3, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the product.
A solution of (4-chlorophenyl) acetic acid (20.0 g, 0.12 mol) and conc sulfuric acid (2 g) in [ETOH] (150 mL) was heated under reflux for 19 h, cooled, and then concentrated. Diethyl ether (100 mL) was added and the solution was washed with sat'd NaHCO3 solution (40 mL x 2), dried, and the volatiles removed. This provided (4- chlorophenyl) acetic acid ethyl ester as an oil (22.3 g, 96%). Ethyl formate (7.46 g, 0. [101 MOL)] was added dropwise to a stirred ice-cooled suspension of (4-chlorophenyl) acetic acid ethyl ester (20.0 g, 0. [101] mol) and NaH (0.131 mol) in diethyl ether (100 mL). The mixture was then allowed to warm to room temperature overnight. The mixture neutralised (1 M HC1) ; the organic layer was isolated, dried, and the solvent removed to give [2- (4-CHLOROPHENYL)-3-OXO-PROPANOIC] acid ethyl ester as a colourless solid (19.8 g, [87%). 1H NMR (CDCL3)] : [No. ] 12.14 (d, J=12. 8,1 H), 7. [31-7.] 18 (m, 4 H), 4.29 (q, [J=7.] 2,2 H), 1.57 (br, [1] H), 1.29 (t, J=7, 2,3 H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To a round-bottom flask (500 mL) that contained a solution of aryl sulfonamide (6 mmol), 4-dimethyaminopyridine (DMAP, 13 mmol), and 1-[3-(dimethyamino)-propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 13 mmol) in CH2Cl2 (150 mL) was added the synthesized phenylacetic acid (6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h, then cooled to 5 C, and acidified to pH 1 with addition of HCl aqueous solution (10%), which was followed by extraction with CH2Cl2/MeOH (9:1, 3 × 100 mL). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to silica gel chromatography or crystallization if necessary to afford the compounds (20-44) (Scheme 2).
With n-butyllithium; In tetrahydrofuran; hexane; at -70 - 20℃; for 12h;Inert atmosphere;
2-(4-chlorophenyl)propanoic acidUnder a nitrogen atmosphere, to a mixture of (4-chlorophenyl)acetic acid (13.6 g) in THF (140 mL) was added n-butyllithium (1.6 M hexane solution, 100 mL) at -60 C. to -70 C., and the mixture was allowed to warm to 0 C. A mixture of methyl iodide (4.96 mL) in THF (40 mL) was added to the reaction mixture at 0 C.-10 C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.3 g).1H NMR (300 MHz, CDCl3) delta 1.49 (3H, d, J=7.2 Hz), 3.71 (1H, q, J=7.2 Hz), 7.22-7.25 (2H, m), 7.27-7.31 (2H, m).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;
General procedure for the synthesis of 2-phenyl-N-(4-phenylthiazol-2-yl) acetamide derivatives 3a-3l and 4a-4l
General procedure: For the synthesis of compounds 3a-3h, 3j, 3k, 4a-4h, 4j, 4k, a mixtureof corresponding acids (1 mmol), 4-phenylthiazol-2-ylamine derivatives (2a or 2b, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.5 mmol), 1-hydroxybenzotrizole (HOBt, 0.05 mmol) in CH2Cl2 (20-30mL) was stirred at room temperature for 24 h. After that, the solvent was removed in vacuo to afford a residue, which was extracted with EtOAc (3 ×20mL). The combined organic phases were dried with anhydrous Na2SO4. Removal of all the solvent in vacuo resulted in a residue, which was purified with recrystallization to give target products.
With water; sodium hydroxide; In 1,4-dioxane; at 60℃; for 2h;pH 10 - 14;
p-Chlorotoluene (1.89 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120 C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 89 mg ethyl p-chlorophenylacetate was obtained by column chromatography, in a yield of 90%. 1HNMR (400 MHz, CDCl3) delta 1.23 (t, J=7.2 Hz, 3H), 3.57 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19-7.23 (m, 2H), 7.27-7.30 (m, 2H); 13CNMR (100 MHz, CDCl3) delta 14.2, 40.7, 61.0, 128.7, 130.7, 132.6, 133.0, 171.2; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl p-chlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60 C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 75 mg product p-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 98%.
With copper(I) bromide; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere;
10g of 4-bromophenylacetic acid was added to 20 mL of DMF, 20 mL of DMF was added, 5.0 g of sodium methanethiol was added,Copper 0.5g, nitrogen replacement, stirring to increase the reaction temperature to 130 C under nitrogen protection, stirring reaction 24 hours, cooling reactionAnd the remainder were the same as in Example 1 of the present invention, and the yield was 79.3%.; Taking 4- bromobenzene acetic acid 10g in 100 ml in three-mouth bottle, by adding DMF20mL, adding a thiol sodium 5.0g, adding cuprous bromide 0.1g, after the replacement of nitrogen, to improving the reaction temperature under stirring 130 C, under the protection of nitrogen stirring for 4 hours, cooling the reaction liquid, by adding 40% NaOH5mL, stirring 10 minutes. Cooling the reaction liquid, by adding ethyl acetate 25 ml extraction two, by adding ethyl acetate in 50 ml, by adding 10% dilute sulfuric acid adjusted to pH 2-4, collecting ethyl acetate, ethyl acetate with water 10 ml after washing, distillation of the ethyl acetate to 20 ml left and right, by adding hexane 20 ml, raise the reaction temperature to reflux, after to be solid entirely dissolved, a slow cooling to room temperature, filtered, scaled to obtain yellowish crystalline, to obtain a target product after drying 6.38g, yield 76.1%.
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.
General procedure: To 15 mmol of appropriate phenylacetic acid in 45 mL of dried toluene 15 mmol of DBU was added and the reaction mixture was stirred in roomtemperature for 1 h. After that time 15 mmol of iodomethane was added and stirring was continued for 2 days. Then, the solvent was evaporated, the residuewas dissolved in ethyl acetate and washed with 0.5% NaOH and brine. Organic layer was dried over anhydrous Na2SO4. Finally, the solvent was evaporated togive the product as colorless oils.
2-(4-chlorophenyl)-N-[2-(trifluoromethoxy)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.
With tetra-N-butylammonium tribromide; dibromoisocyanuric acid; In dichloromethane; at 20℃; for 2h;UV-irradiation;
EXAMPLE 12 (0564) Bromodecarboxylation of alkanoic acids (0565) bromoisocyanurate (0566) RC02H -1 · RBr (0567) hv (0568) [00169] A mixture of alkanoic acid RC02H (2 mmol), bromoisocyanurate, additive (optionally) and solvent (12 mL) was stirred under fluorescent room light irradiation (FL). The reaction mixture washed with 1 M aq Na2S03, dried over Na2S04, filtered through short silica gel pad and concentrated in vacuo to yield crude alkyl bromide RBr. Optionally, the crude bromide was purified by chromatography on silica gel. The results are presented in Table 11.
80%
With tetra-N-butylammonium tribromide; 1,3-dichloro-[1,3,5]triazinane-2,4,6-trione; In dichloromethane; at 20℃; for 1h;Photolysis;
General procedure: A mixture of 4-chlorophenylacetic acid (1 mmol), chloroisocyanurate, brominating agent and solvent (6 mL) was stirred under fluorescent room light irradiation (FL). An aliquot of the reaction mixture washed with 1 M aq Na2S03, dried over Na2S04, and filtered through short neutral silica gel pad. The yields of 4-chlorobenzyl bromide and chloride, and 4-chlorobenzal bromide were determined by gas chromatography (GC) using 1,2,4-trichlorobenzene as internal standard. The results are presented in Table 9
2-(4-chlorophenyl)-1-(6-(trifluoromethoxy)indolin-1-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3 g
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;
A mixture of <strong>[959235-95-1]6-(trifluoromethoxy)indoline</strong> [CAS 959235-95-1] (2 g, 9.84 mmol), 2-(4-chlorophenyl)acetic acid [CAS 1878-66-6] (1 .85 g, 10.8 mmol), HATU (5.6 g, 14.8 mmol) and diisopropylethylamine (4.9 ml_, 29.5 mmol) in DMF (40 ml_) was stirred at room temperature for 12 h. Water was added and the precipitate was filtered off. The residue was taken up with EtOAc. The organic solution was washed with a 10% aqueous solution of K2CO3, brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (15-40 muiotatauiota, 80 g, heptane/EtOAc gradient 90/10 to 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)- ethanone 4a (3 g).
3 g
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;
A mixture of <strong>[959235-95-1]6-(trifluoromethoxy)indoline</strong> [CAS 959235-95-1] (2 g, 9.84 mmol), 2-(4-chlorophenyl)acetic acid [CAS 1878-66-6] (1.85 g, 10.8 mmol), HATU (5.6 g, 14.8 mmol) and diisopropylethylamine (4.9 ml_, 29.5 mmol) in DMF (40 ml_) was stirred at room temperature for 12 h. Water was added and the precipitate was filtered off. The residue was taken up with EtOAc. The organic solution was washed with a 10% aqueous solution of K2CO3, brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (15-40 muiotatauiota, 80 g, heptane/EtOAc gradient 90/10 to 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 - yl)ethanone 7a (3 g).
7.33 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 20.0h;
A mixture of <strong>[959235-95-1]6-(trifluoromethoxy)indoline</strong> [CAS 959235-95-1 ] (5 g, 24.6 mmol), 2-(4-chlorophenyl)acetic acid [CAS 1878-66-6] (4.2 g, 24.6 mmol), HATU (14.3 g, 36.9 mmol) and diisopropylethylamine (12.2 mL, 73.8 mmol) in DMF (60 mL) was stirred at room temperature for 20 h. The mixture was poured out slowly into stirring H2O (275 mL) and the resulting suspension was stirred for 50 minutes. The solids were filtered off and washed (4x) with H2O. The solid residue was taken up in toluene (125 mL), filtered over a paper filter, and the filtrate was evaporated under reduced pressure. The solid residue was stirred up in Et2O/heptane 2/1 (30 mL), filtered off, washed (3x) with Et2O/heptane 1/1 , and dried under vacuum at 50C to provide 2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)ethanone 1 b (7.33 g).
Proportionion of p-chlorophenylacetic acid, phthalic anhydride and freshly melted sodium acetate in a reaction kettle,Rapidly heated to about 250 C,Stirring reaction at 240-250 C for 3 hours, the water produced during the reaction is discharged from the tail pipe;The reaction mixture is then placed in an open heat-resistant container while hot.Cool with stirring and add cold absolute ethanol.Heating to dissolve the solid as much as possible, cooling and filtering.Wash with absolute ethanol,filter,dry.The obtained solid is added to a solution of sodium hydroxide and water, stirred under reflux for 4 hours, cooled, diluted with water, acidified to pH 2-3 with 20% hydrochloric acid, and stirred, cooled, and precipitated as a solid oil. , filtered, dried to obtain a crude product, the crude product was dissolved in acetone, the insoluble matter was filtered off, and acetone was evaporated.The residue was recrystallized from ethyl acetate.Get the product. MP 142-144 C, yield 80%.
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(4-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.
With potassium ethoxide In 1,4-dioxane at 100℃; for 24h;
6 Example 6
To a 100 mL reaction flask equipped with a stirring bar, add 4-chlorobenzylboronic acid pinacol ester (0.3 mmol, 1 equivalent, 75.8 mg) in sequence,Potassium ethoxide (0.6mmol, 50.5mg), 5mL dioxane,Lyophilize the solvent in a liquid nitrogen bath and fill with carbon dioxide three times,The reaction bottle was closed and heated to 100 ° C to stir the reaction for 24 hours.After the reaction, the reaction mixture was freed from the solvent under reduced pressure,The mixture was transferred to a 125 mL separatory funnel via ethyl acetate, and 5 mL of dilute hydrochloric acid (1 mol / L) was added,Add 40mL ethyl acetate and 30mL water to extract three times,Combine the organic phases and remove the solvent under reduced pressure.Purified by column chromatography to obtain the desired product 4-chlorophenylacetic acid,The yield is 65%.
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