| 92% |
With thionyl chloride; for 2.0h;Reflux; |
A solution of 2-(4-bromophenyl)acetic acid (20.0 g, 93.46 mmol, 1.00 equiv) in thionyl chloride (40 mL) was refluxed for 2 h. The resulting mixture was concentrated under vacuum to give 20 g (92%) of 2-(4-bromophenyl)acetyl chloride as a white solid. |
| 92% |
With thionyl chloride; for 2.0h;Reflux; |
A solution of 2-(4-bromophenyl)acetic acid (20.0 g, 93.46 mmol, 1.00 equiv) in thionyl chloride (40 mL) was refluxed for 2 h. The resulting mixture was concentrated under vacuum to give 20 g (92%) of 2-(4-bromophenyl)acetyl chloride as a white solid. |
|
With thionyl chloride; for 1.0h;Heating / reflux; |
Step 15A: (4-Bromophenyl)-acetic acid (5.0 g, 23.2 mmol, 1 eq.) dissolved in thionyl chloride (50 mL) was heat to reflux for 1 hr. under nitrogen atmosphere. The solution was cool to room temperature and solvent was evaporated. Residue thus obtained was dissolved in anhydrous methylene chloride and used in Step 15B. |
| 54 g (100%) |
In thionyl chloride; |
Preparation 85 4-Bromophenylacetyl chloride A solution of 50.0 g (232 mmol) of 4-bromophenylacetic acid in 150 mL of thionyl chloride was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo to afford 54 g (100%) of the title compound. |
|
With thionyl chloride; |
A. 4-bromophenylacetyl chloride To a 250 ml round bottom flask fitted with a magnetic stirrer was added 4-bromophenylacetic acid (100.0 g; 0.465 mol) and 100 ml of thionyl chloride (163.1 g; 1.37 mol). The resulting slurry was stirred at room temperature for 22.5 hrs. The excess thionyl chloride was evaporated under vacuum to afford 108.5 g of the subtitle compound as a brown liquid. |
|
With thionyl chloride; |
A. 4-bromophenylacetyl chloride. To a 250 ml round bottom flask fitted with a magnetic stirrer was added 4-bromophenylacetic acid (100.0 g; 0.465 mol) and 100 ml of thionyl chloride (163.1 g; 1.37 mol). The resulting slurry was stirred at room temperature for 22.5 hrs. The excess thionyl chloride was evaporated under vacuum to afford 108.5 g of the subtitle compound as a brown liquid. |
|
In thionyl chloride; |
REFERENCE EXAMPLE 1 4-Bromophenylacetyl chloride 4-Bromophenylacetic acid (20 g, 0.093 mol) in thionyl chloride (29.46 mL, 0.4 mol) was heated under an argon atmosphere at 60 C. for 2 h. Removal of excess thionyl chloride in vacuo yielded a colourless oil (21.5 g), which was directly used in the next step as obtained. 1 H-NMR-(CDCl3) delta (TMS): 4.07 (s, 2H), 7.08 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 2H). |
| 10.86 g (100%) |
With thionyl chloride; In dichloromethane; |
(4-Bromophenyl)acetyl Chloride To a stirred solution of 4-bromophenylacetic acid (10 g, 46.5 mmoles, 1 eq) in dry CH2Cl2 (100 ml, 0.47M) was added thionyl chloride (20.2 ml, 0.280 moles, 6 eq) and refluxed for 36 hours. After cooling to room temperature the reaction was concentrated in vacuo to yield 10.86 g (100%) of acid chloride. 1H (CDCl3) 300 MHz delta 7.50 (d, 2H, J=8.38 Hz), 7.14 (d, 2H, J=8.38 Hz), 4.09 (s, 2H), |
|
With thionyl chloride; at 0 - 5℃; |
To a solution of 4-bromophenylacetic acid (50 g) in methanol (250 ml) was added dropwise thionyl chloride (34.2 mL) while the temperature of the reaction mixture was kept at 0-50C. Upon complete addition cooling was stopped and the mixture was allowed to warm to rt. Stirring was continued for 75 min before the solvent was removed in vacuo. The yellow oil was dissolved in benzene and again concentrated. The residue was dissolved in EA, washed with water, brine, 2 N aq. Na2CO3, and again brine. The org. extract was dried over MgSO4, filtered, concentrated and dried under HV at 85C for 30 min to give the expected product as a yellow oil (52.4 g). 1H-NMR (D6-DMSO): delta 3.60 (s, 3H); 3.67 (s, 2H); 7.22 (d, 8.5, 2H); 7.50 (d, J = 8.5 Hz, 2H). |
|
With thionyl chloride; at 60℃; for 0.5h; |
4-bromophenyl acetic acid (2.15 g, 10 mmol) was dissolved in 10 mL SOCl2 and heated to 60C for 30 minutes. The solvent was distilled off to obtain the acyl chloride as a yellow liquid. 2-aminophenol (1.09 gr, 10mmol) was suspended in dichloromethane (20 mL), Et3N (2.77 mL, 20mmol) was added and the mixture was cooled at 0C. The acyl chloride was added drop-wise to the mixture, which was stirred overnight while it warmed to room temperature. The reaction mixture was diluted with EtOAc (30 mL) and extracted with a saturated aqueous Na2CO3solution (3 x 50 mL), 1 N aqueous HCl (3 x 50 mL) and brine (1 x 50 mL). The organic phase was dried with Mg2SO4 and the solvent was evaporated to obtain the corresponding amide. |
|
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 2.0h;Inert atmosphere; |
The sluggish solution was cooled to 0 C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The desired acid chloride was obtained and dissolved in 4 mL of dichloromethane to make a 1M solution. |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.0h; |
In a dry flask under argon, 4-bromophenylacetic acid (860 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The desired acid chloride was obtained and dissolved in 4 mL of dichloromethane to make a 1M solution. In a dry flask under argon, the [2-amino-2-(5-bromo-1H-indol-3-yl)ethyl]carbamic acid tert-butyl ester (1b) (60 mg, 0.17 mmol) and triethylamine (0.033 mL, 0.24 mmol) were dissolved in 1 mL of dry dichloromethane. After cooling this solution to 0 C, the 1M solution of 2-(4-bromophenyl)acetyl chloride previously obtained (0.204 mL, 0.204 mmol) was added dropwise and the mixture was stirred at 0 C for one hour. The reaction was then quenched with water and diluted with ethyl acetate. The organic layer was washed with a 1M aqueous solution of HCl and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 1/1 then 8/2). After recrystallization in a mixture of ethyl acetate and pentane, the desired product 12a (50 mg, 0.09 mmol) was obtained as a white solid. Yield: 54 %. |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.0h; |
In a dry flask under argon, 4-bromophenylacetic acid (860 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The desired acid chloride was obtained and dissolved in 4 mL of dichloromethane to make a IM solution.In a dry flask under argon, the [2-amino-2-(5-bromo-lH-indol-3-yl)ethyl]carbamic acid tert-butyl ester (lb) (60 mg, 0.17 mmol) and triethylamine (0.033 mL, 0.24 mmol) were dissolved in 1 mL of dry dichloromethane. After cooling this solution to 0 C, the IM solution of 2-(4-bromophenyl)acetyl chloride previously obtained (0.204 mL, 0.204 mmol) was added dropwise and the mixture was stirred at 0 C for one hour. The reaction was then quenched with water and diluted with ethyl acetate. The organic layer was washed with a IM aqueous solution of HCl and water, dried over anhydrous MgSC>4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 1/1 then 8/2). After recrystallization in a mixture of ethyl acetate and pentane, the desired product 12a (50 mg, 0.09 mmol) was obtained as a white solid. Yield: 54 %.Mp: 131 C. IR (ATR): 3425, 3338, 1678, 1634, 1533, 1488, 1458, 1276, 1169 cm"1. 1H NMR (400 MHz, DMSO-de): delta = 1.34 (s, 9H, CH3), 3.29-3.43 (m, 2H, CH2), 3.41 (s, 2H, CH2), 5.17- 5.23 (m, 1H, CH), 6.82 (t, J= 6.0 Hz, 1H, NH), 7.17 (dd, J= 1.6 and 8.4 Hz, 1H, CH), 7.21 (d, J = 8.4 Hz, 2H, CH), 7.29-7.31 (m, 2H, CH), 7.45 (d, J = 8.4 Hz, 2H, CH), 7.66 (s, 1H, CH), 8.30 (d, J = 8.8 Hz, 1H, NH), 11.13 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): delta = 29.1(CH3), 42.6 (CH2), 45.1 (CH2), 46.3 (CH), 78.6 (C), 112.1 (C), 114.3 (CH), 115.2 (C), 120.4 (C),122.0 (CH), 124.5 (CH), 124.8 (CH), 128.9 (C), 131.9 (CH), 132.1 (CH), 135.8 (C), 136.8 (C),156.6 (C), 170.0 (C) ppm. LRMS (ESI): m/z = 572, 574 and 576 and [(M+Na)+]. |
|
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 2.0h;Inert atmosphere; |
In a dry flask under argon, 4-bromophenylacetic acid (860 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The desired acid chloride was obtained and dissolved in 4 mL of dichloromethane to make a 1M solution. |
|
With thionyl chloride; In dichloromethane; at 20℃; |
V. 6-oxo-5,6,7, 8-Tetrahydronaphthalene-2-carbonitrile A solution of 2-(4-bromophenyl)acetic acid (300 g, 1.4 mol) and SOCl2 (500 mL) in DCM (500 mL) was stirred at room temperature overnight. The reaction was evaporated to yield crude 2-(4-bromophenyl)acetyl chloride (350 g), which was immediately used in the next step. To a mixture of AICI3 (400 g, 3 mol) in DCM (2 L) in an ice bath was added dropwise 2-(4-bromophenyl)acetyl chloride (350 g) and, at the same time, ethylene gas was introduced. After 30 min, the addition was complete, and the reaction mixture was stirred in an ice bath for another 30 min. The mixture was poured into ice/water, the separated organic layer was dried over Na2S04 and evaporated to yield crude 2-bromo-6-oxo-5,6,7,8- tetrahydronaphthalene (300 g, 95.5% for 2 steps) as a yellow solid, which was used immediately in the next step: lR NMR (400 MHz, CDC13) delta 7.39 (d, J = 2.4 Hz, 1H), 7.39- 7.33 (m, 1H), 7.00-6.98 (m, 1H), 3.52 (s, 2 H), 3.05-3.02 (m, 2H), 2.55-2.51 (m, 2H); EC- LCMS m/z dosen't ionized. 2-Bromo-6-oxo-5,6,7,8-tetrahydronaphthalene (300 g, 1.74 mol), tetrakis (triphenylphosphine)palladium (100.4 g, 0.087mol) and zinc cyanide (607.7 g, 5.24 mol) were combined under nitrogen in DMF (2 L) and heated at 140C overnight. The reaction mixture was cooled to ambient temperature, was filtered and evaporated in vacuo. The residue was redissoloved in CH2CI2 and filtered. The organic layer was evaporated in vacuo. The residue was purified by column chromatography to give the title compound as a yellow solid (150 g, 32%): lR NMR (400 MHz, CDC13) delta 7.54-7.51 (m, 2H), 7.26-7.23 (m, 1H), 3.64 (s, 2 H), 3.1 1 (t, J= 6.8 Hz, 2H), 2.57 (t, J= 6.8 Hz, 2H); EC-LCMS m/z 172.1 (M+H). |
|
With thionyl chloride; In dichloromethane; at 20℃; |
X. -5,6,7, 8-tetrahydronaphthalene-2-carbonitrile A solution of 2-(4-bromophenyl)acetic acid (300 g, 1.4 mol) and SOCl2 (500 mL) in DCM (500 mL) was stirred at room temperature overnight. The reaction was evaporated to yield crude 2-(4-bromophenyl)acetyl chloride (350 g), which was immediately used in the next step . |
|
With thionyl chloride; at 80℃; for 3.0h; |
General procedure: For the synthesis of compounds 4a-4h and 5a-5h was depicted in Scheme 2. Firstly, 2-phenylacetic acid (1 mmol) and SOCl2 (4-6 mL) were refluxed at 80 C for 3 h. The reaction liquid was cooled to room temperature and then evaporated to give reactive acyl chloride. The product was obtained as an oil matter, which would be dissolved in acetone (5-6 mL) in the next step. Treatment of 3a (5-phenylthiazol-2-amine) with 2-phenylacetyl chloride in acetone for 5 h at ice-bath afforded the aimed amine. Meanwhile, K2CO3 (0.8 g) was added to the mixture. Then the mixture was evaporated under reduced pressure and the resulting solid was washed with diluted NaOH liquid. The aimed amide was extracted from the NaOH liquid with ethyl acetate for column chromatography. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether to give the aimed amine (4a). Compounds of 4b-4h and 5a-5h could begot with corresponding acids by the procedures above. |
|
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20 - 25℃; for 5.0h;Inert atmosphere; |
Synthesis of Compound 1 To a solution of (4-bromophenyl) acetic acid (20 mmol) in dichloromethane (30 mL) were added thionyl chloride (30 mmol) and two drops of N, N-dimethylformamide (DMF) (0.1 mL) , and the resulting solution was stirred at room temperature (20-25) for 5 hours under N2atmosphere. After that, excessive thionyl chloride was evaporated under vacuum and the residue was stirred with benzene (60 mmol) at 0 under N2atmosphere. Aluminum (III) chloride (22 mmol) was added slowly in three portions and then stirred at room temperature for 4 hours. The reaction mixture was then poured onto chopped ice in a flask, extracted with dichloromethane (40 mL x 3) , and washed with brine. The resulting organic phase was dried under reduced pressure and washed with hexane to give Compound 1 with a yield of 90. |
|
With thionyl chloride; at 80℃; for 4.0h;Inert atmosphere; |
General procedure: A dry flask containing the corresponding carboxylic acid (1 mmol) and SOCl2 (0.6 mL) was heated at 80 C for 4 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated under reduced pressure to remove the volatiles and then, the resultant crude reaction mixture was diluted with anhydrous DCM (2 mL). The DCM solution of corresponding acid chloride was slowly added to another RB flask containing the corresponding amine (1 mmol), Et3N (111 mg, 1.1mmol) and DCM (4 mL) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 12 h. After this period, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous NaHCO3 solution (twice). The combined organic layers were dried over anhydrous Na2SO4 and then, the solvent was evaporated in vacuo to afford a crude reaction mixture. Purification of the crude reaction mixture by column chromatography (neutral alumina (EtOAc/hexanes=25:75) furnished the corresponding products 1f-j. |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 3.0h; |
To a solution of 2-(4- bromophenyl)acetic acid (10.0 g, 46 mmol) in DOM (1 50 mL) was slowly added oxalyl chloride (28 mL, 2M in DOM, 56 mmol) followed by DME (20 pL). The reaction mixture was then stirred at ambient temperature for three hours and concentrated in vacuo to afford 2-(4-bromophenyl)acetyl chloride as a light yellow liquid. The crude product was used for the next step without further purification. IR (film) 1790, 1489, 1407,1318,1180,1072,1013, 959cm1. |
|
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; for 8.0h; |
Acyl chloride preparation: To a stirred solution of 4-bromophenylacetic acid (1.10 g, 5.12 mmol) and oxalyl chloride (565 muL, 6.68 mmol) in CH2Cl2 (15 mL), catalytic amounts of DMF were added. After stirring for 8 h until TLC indicated complete turnover, the solvent was removed under reduced pressure and the acyl chloride was used without further purification. Amide formation: To a stirred solution of the freshly prepared acyl chloride in CH2Cl2 (15 mL), 30 (500 mg, 3.93 mmol) and saturated aqueous NaHCO3 solution (excess) were added. After vigorous stirring for 15 h, the layers were separated and the organic phase was washed successively with aqueous HCl solution (1.0 M, 20 mL), saturated aqueous NaHCO3 solution (20 mL), H2O (20 mL), brine (20 mL) and dried (MgSO4). The solution was filtered and solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with a gradient from 10% to 50% EtOAc in petroleum ether 40-60 to yield the title compound as a colourless oil (901 mg, 2.78 mmol, 71%). Rf = 0.30 (50% EtOAc in petroleum ether 40-60). IR: lambdamax = 3290 (w, C-H), 2953 (w, C-H), 1743 (s, C=O), 1652 (s, C=O). 1H NMR (500 MHz, d6-DMSO, 120 C): deltaH = 7.48 (2H, d, J = 8.4 Hz, H11), 7.21 (2H, d, J = 8.4 Hz, H10), 4.30-4.21 (4H, m, H3, H4), 3.76 (2H, br s, H8), 3.68 (3H, s, H1), 3.02 (1H, br s, H6). 13C NMR (126 MHz, d6-DMSO, 120 C): deltaC = 170.6, 169.6 (C2, C7), 135.1 (sp2-C), 131.9, 131.4 (C10, C11), 120.2 (sp2-C), 79.2 (C2/C5), 52.0 (C1), 38.9 (sp3-C). Due to the rotameric effects of the amide, carbons 5/6 and 2 from 3/4/8 were not observed. HRMS (ESI+): m/z found [M+H]+ 324.0225, C14H15O3N79Br required 324.0230. |
|
With oxalyl dichloride; In benzene; for 6.0h;Heating / reflux; |
The intermediate 2-(4-bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (31) was prepared as follows: A solution of 4-bromo-phenylacetic acid (10.06 g, 46.8 mmol) and oxalyl chloride (101.9 g, 0.8 mol) in 400 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 4-bromo-phenylacetic acid chloride (1.1 mol. equiv.) in CH2Cl2 was added to a mixture of 300 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (6.55 g, 36.1 mmol) in 300 mL of CH2Cl2. The reaction mixture was stirred overnight at room temperature. Another portion of acid chloride (0.1 eq.) in 20 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixture. Yield is 11.54 g (84.5%). |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4.0h;Inert atmosphere; |
Into a 250-mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-bromophenyl)acetic acid (2.50 g, 11.63 mmol, 1.0 equiv) in dichloromethane (150 mL), to which were added oxalyl chloride (1.77 g, 13.95 mmol, 1.20 equiv) and N,N-dimethylformamide (170 mg, 2.33 mmol, 0.20 equiv). The resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile (150 mL). To the above solution was added a solution of (trimethylsilyl)diazomethane (3.98 g, 34.85 mmol, 3.00 equiv) in hexanes (17.4 mL) at room temperature. The resulting solution was stirred for another 2 hours at room temperature, and then was cooled to 0C in an ice/water bath. To the cooled mixture was added a solution of hydrogen bromide in acetic acid (40%, 8.48 g, 41.85 mmol, 3.60 equiv) slowly. Then reaction mixture was allowed to react for an additional 2 hours at room temperature. The reaction was quenched by the addition of 100 mL water. The resulting mixture was extracted with ethyl acetate (250 mL x3) and the combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with (2796) dichloromethane/petroleum ether (1:10). This resulted in 1.80 g (53.03%) of 1-bromo-3-(4- bromophenyl)propan-2-one as a light yellow oil. |
|
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 23℃; for 1.0h;Inert atmosphere; |
General procedure: Oxalyl chloride (1.65 equiv) was added to a solution of arylacetic acid (1.5 equiv), dimethylformamide (10 ml), anddichloromethane (2.0 M) at 0 C. After 10 min, the solution was warmed to 23 C and stirred for 1 h (bubbling stops). Thesolution was concentrated in vacuo. In a separate flask, n-butyllithium (1.1 equiv, 2.42 M in hexanes) was added to asolution of (S)-4-benzyl-5,5-dimethyloxazolidin-2-one (1.0 equiv) in THF (0.3 M) at -78 C under argon. The solution wasstirred for 30 min at -78 C. A solution of the crude acyl chloride in THF was added dropwise at -78 C. After stirring at -78 C for 2 h, the reaction mixture was quenched with saturated ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried with sodium sulfate andconcentrated in vacuo. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
