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Product Details of [ 1878-68-8 ]

CAS No. :1878-68-8 MDL No. :MFCD00004342
Formula : C8H7BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :QOWSWEBLNVACCL-UHFFFAOYSA-N
M.W : 215.04 Pubchem ID :74654
Synonyms :

Calculated chemistry of [ 1878-68-8 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 45.69
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.63
Log Po/w (XLOGP3) : 2.31
Log Po/w (WLOGP) : 2.08
Log Po/w (MLOGP) : 2.4
Log Po/w (SILICOS-IT) : 2.21
Consensus Log Po/w : 2.13

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.9
Solubility : 0.271 mg/ml ; 0.00126 mol/l
Class : Soluble
Log S (Ali) : -2.73
Solubility : 0.399 mg/ml ; 0.00186 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.04
Solubility : 0.198 mg/ml ; 0.000923 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 1878-68-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1878-68-8 ]

* 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.

  • Upstream synthesis route of [ 1878-68-8 ]
  • Downstream synthetic route of [ 1878-68-8 ]

[ 1878-68-8 ] Synthesis Path-Upstream   1~42

  • 1
  • [ 1670-14-0 ]
  • [ 1878-68-8 ]
  • [ 23449-08-3 ]
Reference: [1] European Journal of Organic Chemistry, 2018, vol. 2018, # 18, p. 2098 - 2102
  • 2
  • [ 1878-68-8 ]
  • [ 52798-01-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2647 - 2652
[2] Patent: WO2013/45451, 2013, A1,
  • 3
  • [ 557-21-1 ]
  • [ 1878-68-8 ]
  • [ 5462-71-5 ]
YieldReaction ConditionsOperation in experiment
42% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 80℃; for 18 h; Preparative Example 9B; A solution of commercially available 4-bromophenyl-acetic acid (1.5 g), Zn(CN)2 (492 mg) and Pd(PPh3)4 (403 mg) in DMF was stirred at 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, chloroform/MeOH, 95:5) to afford the title compound (470 mg; 42percent). [MH]+=162.
Reference: [1] Patent: US2008/21024, 2008, A1, . Location in patent: Page/Page column 79
  • 4
  • [ 1878-68-8 ]
  • [ 5462-71-5 ]
Reference: [1] Organometallics, 2012, vol. 31, # 2, p. 729 - 738
  • 5
  • [ 108-24-7 ]
  • [ 1878-68-8 ]
  • [ 6186-22-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 17, p. 5309 - 5312[2] Angew. Chem., 2016, vol. 128, # 17, p. 5395 - 5398,4
  • 6
  • [ 616-47-7 ]
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  • [ 6186-22-7 ]
Reference: [1] Chemical Communications, 2016, vol. 52, # 79, p. 11850 - 11853
  • 7
  • [ 1878-68-8 ]
  • [ 4654-39-1 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 3 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0 - 80℃; for 0.5 h;
4-r2-(2-Bromoethoxy)ethvnbenzonitrile(T) 2-(4-BromophenvDethanol To a chilled solution (about O0C) of 4-bromophenyl acetic acid (25 g, 0.116 mol) in THF (250 mL), borane methyl sulphide (13.2 g, 0.174 mol) was added, dropwise, under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. After cooling the mixture to between 0 and 5°C, the reaction was quenched by adding 1.5 NHCl (80 mL), dropwise. After warming for 30 min at about 800C, the reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water and brine and then dried. The product was obtained as colourless liquid after concentration (yield: 23.3 g, 99percent).
18.7g With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; for 2 h; The specific operation is as follows: The bromophenylacetic acid was added to 200ml of tetrahydrofuran,Stirring cooled to 0 ° C after adding lithium aluminum hydride in batches, the end of the addition,After the reaction was heated to 25 ~ 30 ° C for 2h, 300ml of water and 400ml of dichloromethane were separated,The organic phase was added to 20g of anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30-35 ° C.Obtained light yellow oil (brominated S1-1): 18.7g, under ice bath,To bromine S1-1 was added dropwise phosphorus tribromide, dropping temperature during the control at 0 ~ 10 ,Dropping is completed, incubated 10min insulation, a white smoke generated, stirring, warming to 75 ~ 80 ,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,Stirring 20min liquid separation, the organic phase 40 ~ 45 filtrate was concentrated under reduced pressure,A yellow liquid (bromination S2) was obtained: 22.1 g. Yield: 90.0percent.
Reference: [1] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 64
[2] European Journal of Inorganic Chemistry, 2011, # 14, p. 2238 - 2246
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
[4] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
[5] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 786 - 801
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 756 - 760
[7] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
[8] Chemical and Pharmaceutical Bulletin, 1977, vol. 25, # 7, p. 1732 - 1739
[9] Tetrahedron, 1990, vol. 46, # 20, p. 7247 - 7262
[10] Tetrahedron Letters, 1989, vol. 30, # 46, p. 6291 - 6294
[11] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2882 - 2891
[12] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 10, p. 1856 - 1861
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[14] Synthetic Communications, 1998, vol. 28, # 5, p. 823 - 832
[15] Journal of the American Chemical Society, 2010, vol. 132, # 12, p. 4076 - 4077
[16] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
[17] Synthesis, 2011, # 18, p. 2935 - 2940
[18] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13349 - 13357
[19] Patent: WO2015/66413, 2015, A1,
[20] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329
[21] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[22] Patent: CN106478506, 2017, A, . Location in patent: Paragraph 0133; 0134
  • 8
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  • [ 27200-79-9 ]
Reference: [1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
  • 9
  • [ 1878-68-8 ]
  • [ 4654-39-1 ]
  • [ 1313039-90-5 ]
Reference: [1] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
  • 10
  • [ 7677-24-9 ]
  • [ 1878-68-8 ]
  • [ 57775-08-3 ]
Reference: [1] Synthesis (Germany), 2013, vol. 45, # 23, p. 3233 - 3238
  • 11
  • [ 5188-07-8 ]
  • [ 1878-68-8 ]
  • [ 16188-55-9 ]
YieldReaction ConditionsOperation in experiment
76.1% With copper(I) bromide In N,N-dimethyl-formamide at 130℃; Inert atmosphere 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 0010
  • 12
  • [ 64-17-5 ]
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  • [ 14062-25-0 ]
YieldReaction ConditionsOperation in experiment
97% for 24 h; Reflux Preparation of Intermediate 1-bromo-4-(2-methoxy-2-methylDroDyl)benzene (1AG-1); 2-(4-Bromophenyl)acetic acid (75g, 340mmol) suspended in ethanol (341 mL) . Concentrated sulfuric acid (0.682mL, 12.79mmol) was added and reaction heated to reflux for 24 hours. Reaction concentrated and residue diluted with diethyl ether and saturation sodium bicarobonate. Layers carefully separated and organic was washed with brine, dried over sodium sulfate, filtered and concentrated to give ethyl 2-(4- bromophenyl)acetate (80.2g, 97percent) as off-white solid.
96% at 100℃; Step 1: To a solution of 2-(4-bromophenyl)acetic acid (3 g, 13.95 mmol) in ethanol was slowly added sulfuric acid (0.3 mL, cat.) at room temperature.
The reaction mixture was heated to 100° C. for overnight. TLC showed complete consumption of starting material.
The reaction mixture was cooled to room temperature and neutralized with NaHCO3.
The mixture was extracted with ethyl acetateand washed with water and brine.
The extract was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-(4-bromophenyl)acetate (3.24 g, 96percent).
96% With sulfuric acid In ethanol at 20 - 100℃; Step 1 : To a solution of 2-(4-bromophenyl)acetic acid (3 g, 13.95 mmol) in ethanol was slowly added sulfuric acid (0.3 ml_, cat.) at room temperature. The reaction mixture was heated to 100 °C for overnight. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature and neutralized with NaHC03. The mixture was extracted with ethyl acetateand washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-(4- bromophenyl)acetate (3.24 g, 96 percent).
95% at 80℃; for 12 h; 2-(4-bromophenyl)acetic acid (15 g, 69.8 mmol) was added to ethanol (125 mL). Then, sulfuric acid (0.186 mL, 3.49 mmol) was added to the reaction and the reaction was heated to 80° C for 12 h. The reaction was confirmed complete based on TLC. Solid NaHCO3 was added to the reaction and then the ethanol was evaporated.The product was extracted with ether and washed 2 with water and 1 with brine. The organic layer was collected, dried with MgSO4, and condensed to generate compound 2 as a clear oil (16.113 g, 95percent). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 243.
91% Reflux Step 0 (Intermediate A): see example 85.[0556]Step 1: To a stirred solution of 2-(4-bromophenyl)acetic acid (2 g, 9.3 mmol) in ethanol (10 mL) were added sulfuric acid (0.3 mL). The reaction mixture was refluxed for overnight and cooled to room temperature. The solvent was evaporated. The residue was dissolved with ethylacetate and neutralized with NaHCO3. The organic layer was washed with water two times, then dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. ethyl 2-(4-bromophenyl)acetate (2.1 g) was obtained as 91percent yield.[0557]Step 2: To a stirred solution of ethyl 2-(4-bromophenyl)acetate (2.1 g, 8.445 mmol) in anhydrous dimethylformamide were added zinc cyanide (1.5 g, 12.668 mmol) and tetrakis(triphenylphosphine) palladium (1.0 g, 0.845 mmol). The reaction mixture was refluxed for overnight then cooled to room temperature. The mixture was filtered using celite pad and the filtrate was evaporated. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filterate was concentrated under reduced pressure to get the crude. The crude was purified by column chromatography. Ethyl 2-(4-cyanophenyl)acetate (0.8 g) was obtained as 49percent yield.[0558]Step 3: To a stirred solution of ethyl 2-(4-cyanophenyl)acetate (0.8 g, 4.101 mmol) in anhydrous dimethylformamide were added 60percent sodium hydride (180 mg, 4.511 mol) and Iodo methane were added after 10 min with an ice bath. The reaction mixture was stirred for 1 h hours, quenched with water and extracted with ethylacetate which is washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The residue was purified by column chromatography. Ethyl 2-(4-cyanophenyl)propanoate (453 mg) was obtained as 48percent[0559]Step 4: To a stirred solution of ethyl 2-(4-cyanophenyl)propanoate (453 mg, 1.968 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (197 mg, 4.919 mmol). The reaction mixture was stirred for overnight at room temperature, then acidified to pH 3-4 with acetic acid. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude 2-(4-cyanophenyl)propanoic acid (422 mg) was obtained as 99percent yield.[0560]Step 5: To a stirred solution of 2-(4-cyanophenyl)propanoic acid (148 mg, 0.85 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (243 mg, 1.27 mmol), 1-hydroxybenzotriazole (171 mg, 1.27 mmol), (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (247 mg, 0.93 mmol) and triethylamine (0.29 mL, 2.11 mmol). The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (311 mg) was obtained as 87percent yield.[0561]Step 6: To a stirred solution of 2-(4-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (305 mg, 0.72 mmol) in ethanol was cooled to 0° C. and added NiCl2.6H2O (17 mg, 0.072 mmol) and stirred more then 15 min. Sodium borohydride (191 mg, 5.04 mmol) was then added in small portions. The reaction was exothermic and effervescent. The resulting reaction mixture was allowed to warm to room temperature and left to stir for 2 hour. The mixture was filtered using celite pad. The filtrate was concentrated was evaporated. The residue was dissolved in ethylacetate and washed with water and brine, but when it does not separate easily, small amount of 1N HCl and saturated NaHCO3 was used. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(Aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg) was obtained as 64percent yield.[0562]Step 7: To a stirred solution of 2-(4-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) in dichloromethane the intermediate (A) (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) was added was stirred for overnight. The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with dichloromethane and washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography. Tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (118 mg) was obtained as 50percent yield.[0563]Step 8: To a stirred solution of tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (118 mg, 0.19 mmol) in dichloromethane (5 mL) cooled by ice bath and trifluoroacetic acid (4.0 mL) was added. The reaction mixture was stirred for overnight. The mixture was diluted with dichloromethane and then washed with NaHCO3, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and purified by column chromatography. 2-(4-((Sulfamoylamino)methyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 88) (79 mg) was obtained as 79percent yield.[0564]1H NMR (300 MHz, CDCl3) δ 7.76 (d, 1H, J=7.86 Hz), 7.58 (s, 1H, J=7.86 Hz), 7.27-7.32 (m, 3H), 7.10-7.24 (m, 5H), 5.59 (bs, 1H), 4.69 (bs, 1H), 4.58 (s, 2H), 4.44 (d, 2H, J=6.03 Hz), 4.26 (d, 2H, J=6.21 Hz), 3.50 (m, 1H), 2.38 (s, 3H), 1.46 (d, 3H, J=7.14 Hz).
91% Reflux Step 1 : To a stirred solution of 2-(4-bromophenyl)acetic acid (2 g, 9.3 mmol) in ethanol (10 mL) were added sulfuric acid (0.3 mL). The reaction mixture was refluxed for overnight and cooled to room temperature. The solvent was evaporated. The residue was dissolved with ethylacetate and neutralized with NaHC03. The organic layer was washed with water two times, then dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography, ethyl 2-(4-bromophenyl)acetate (2.1 g) was obtained as 91 percent yield.
80% for 8 h; Reflux A solution of 63 grams (0.29 mole) of 4-bromophenyl acetic acid and 50 milliliters of concentrated sulfuric acid in 500 milliliters of absolute ethanol was refluxed for 8 hours then allowed to stand overnight.
After pouring over 600 grams of ice, the mixture was extracted with ether/hexanes.
The ether extracts were washed thoroughly with water and sodium bicarbonate solution then dried over anhydrous sodium sulfate.
Removal of the solvent by rotary evaporation yielded 57 grams (0.24 mole, 80percent isolated yield) of an oil which crystallized upon cooling.
Filtration and washing with hexane afforded pure product.
74% Reflux 4-Bromophenylacetic acid, 7-c, (30 g, 0.14 mol) was dissolved in ethanol (150 mL) at reflux along with p-toluenesulphonic acid (2.4 g, 0.014mol). The reaction mixture was then stirred overnight. The ethanol was the removed in vacuo and the residue was taken up in EA. Combined organic layers were washed with water and the aqueous layer was re-extracted with EA. Combined organic layers were then dried over Na2S04 and concentrated to afford the titled compound, 12-a, (25 g, 74percent).1H NMR (300 MHz, CDCI3) δ 1.23-1.29 (m, 3H), 3.56 (s, 2H), 4.11-4.18 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H). LC-MS (M+H)+243, 245
74% Reflux Step A: Ethyl 2-(4-bromophenyl)acetate (12-a 4-Bromophenylacetic acid, 7-c, (30 g, 0.14 mol) was dissolved in ethanol (150 mL) at reflux along with p-toluenesulphonic acid (2.4 g, 0.014mol). The reaction mixture was then stirred overnight. The ethanol was the removed in vacuo and the residue was taken up in EA. Combined organic layers were washed with water and the aqueous layer was re-extracted with EA. Combined organic layers were then dried over Na2S04 and concentrated to afford the titled compound, 12-a, (25 g, 74percent).1H NMR (300 MHz, CDCI3) δ 1.23-1.29 (m, 3H), 3.56 (s, 2H), 4.1 1-4.18 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H). LC-MS (M+H)+ 243, 245
70% at 80℃; for 15 h; Cooling with ice To an ice cooled solution of 2-(3-bromophenyl)acetic acid (2.5 g, 11.62 mmol) in EtOH (25 mL), thionyl chloride (1.6 mL, 23.24 mmol) was added dropwise. The reaction mixture was heated at 80° C. for 15 h. The reaction was monitored by TLC and after completion of the reaction, the reaction mixture was concentrated under vacuum and water was added to the residue. A saturated aqueous solution of NaHCO3 was added to the solution until the pH of the solution was 9. Then, the aqueous solution was extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (silica gel) to yield ethyl 2-(3-bromophenyl)acetate (2 g, 70percent).LCMS: 99.80percent (254 nm, R.T.=2.99)

Reference: [1] Patent: WO2010/86820, 2010, A1, . Location in patent: Page/Page column 53
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6665 - 6681
[3] Patent: US2013/79320, 2013, A1, . Location in patent: Paragraph 0473; 0474
[4] Patent: WO2013/45451, 2013, A1, . Location in patent: Paragraph 51
[5] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 714 - 723
[6] Chemical Communications, 2018, vol. 54, # 26, p. 3231 - 3234
[7] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[8] Patent: US2013/79377, 2013, A1, . Location in patent: Paragraph 0554; 0556
[9] Patent: WO2013/45447, 2013, A1, . Location in patent: Page/Page column 82
[10] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6640 - 6658
[11] Patent: EP1476416, 2015, B1, . Location in patent: Paragraph 0053
[12] Patent: WO2013/40790, 2013, A1, . Location in patent: Page/Page column 59; 60
[13] Patent: WO2013/43624, 2013, A1, . Location in patent: Page/Page column 59; 60
[14] Patent: US2012/295874, 2012, A1, . Location in patent: Page/Page column 230
[15] Journal of the American Chemical Society, 2003, vol. 125, # 46, p. 13948 - 13949
[16] Journal of Organic Chemistry, 2009, vol. 74, # 14, p. 5100 - 5103
[17] Patent: US6344561, 2002, B2, . Location in patent: Page column 70
[18] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6608 - 6612
[19] Chemistry - A European Journal, 2013, vol. 19, # 36, p. 11904 - 11915
[20] Journal of Organic Chemistry, 2016, vol. 81, # 24, p. 12116 - 12127
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YieldReaction ConditionsOperation in experiment
99% With sulfuric acid In ethanol (1)
Concentrated sulfuric acid (10 ml) was added to an ethanol (300 ml) solution of 4-bromophenylacetic acid (25 g, 120 mmols), and heated under reflux for 15 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was poured into water with ice, and extracted with ethyl acetate.
The extract was washed with water, and then dried with anhydrous magnesium sulfate.
This was concentrated under reduced pressure to give an oil of ethyl 4-bromophenylacetate (28 g, 99percent).
1H-NMR (CDCl3) δ: 1.25(3H,t,J=7.2Hz), 3.56(2H,s),
Reference: [1] Patent: EP1123918, 2001, A1,
[2] Patent: US5776951, 1998, A,
  • 14
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  • [ 1878-68-8 ]
  • [ 14062-25-0 ]
YieldReaction ConditionsOperation in experiment
89% at 80℃; for 24 h; Inert atmosphere; Sealed vial General procedure: Carboxylic acid (0.5 mmol) and MImC (2a, 1.0 mmol) were placed in a dry 20 mL vial with a Teflon tape-coated thread. A magnetic stirbar was added, followed by dry MeCN (1.0 mL), and the vial was quickly sealed with a plastic cap (gas is evolved during the course of the reaction. All experiments should be performed behind a blast shield if a sealed container is used.). The reaction mixture was then stirred at 23 °C for 15 min and then heated to 80 °C using a heating block for 24 h. The mixture was cooled to room temperature and then the vial was carefully opened (CAUTION: vial under pressure.). The volatiles were removed in vacuo, the resulting residue was dissolved in diethyl ether (20 mL), and then washed with 1 M HCl (10 mL). The aqueous layer was back-extracted with diethyl ether (20 mL) and the organic fractions were combined, washed with a saturated solution of NaHCO3 and then brine, dried over MgSO4, and concentrated in vacuo to afford the desired ester.
Reference: [1] Tetrahedron, 2011, vol. 67, # 46, p. 8851 - 8859
[2] Organic Letters, 2012, vol. 14, # 8, p. 1970 - 1973
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YieldReaction ConditionsOperation in experiment
57% With potassium carbonate In ethyl acetate; acetonitrile A.
Ethyl 4-bromophenylacetate

A solution of 25.0 g (116.3 mmol) of 4-bromophenylacetic acid, 24.1 g (174.4 mmol) of potassium carbonate and 10.2 mL (127.9 mmol) of iodoethane in 250 mL of acetonitrile was heated at 70° C. for 16 hours.
The mixture was cooled to ambient temperature, diluted with 200 mL of ethyl acetate and washed once with 200 mL of saturated aqueous sodium bicarbonate.
The organic layer was separated and the aqueous layer was extracted three times with 75 mL each of ethyl acetate.
The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford 16.2 g (57percent) of the title compound.
57% With potassium carbonate In ethyl acetate; acetonitrile A.
Ethyl 4-bromophenylacetate

A solution of 25.0 g (116.3 mmol) of 4-bromophenylacetic acid, 24.1 g (174.4 mmol) of potassium carbonate and 10.2 mL (127.9 mmol) of iodoethane in 250 mL of acetonitrile was heated at 70° C. for 16 hours.
The mixture was cooled to ambient temperature, diluted with 200 mL of ethyl acetate and washed once with 200 mL of saturated aqueous sodium bicarbonate.
The organic layer was separated and the aqueous layer was extracted three times with 75 mL each of ethyl acetate.
The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford 16.2 g (57percent) of the title compound.
Reference: [1] Patent: US6303816, 2001, B1,
[2] Patent: US6500865, 2002, B1,
  • 16
  • [ 1878-68-8 ]
  • [ 14062-25-0 ]
Reference: [1] Patent: US5489584, 1996, A,
  • 17
  • [ 1878-68-8 ]
  • [ 1528-41-2 ]
Reference: [1] Patent: WO2013/45447, 2013, A1,
  • 18
  • [ 74-88-4 ]
  • [ 1878-68-8 ]
  • [ 41841-16-1 ]
YieldReaction ConditionsOperation in experiment
75% With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; for 2 h; Preparation Example 26-1
The synthesis of methyl 2-(4-bromophenyl)acetate
20 ml acetonitrile was added to 4-bromophenylacetic acid (2 g, 9.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-2-ene (1.7 g, 11.2 mmol) was added at 0° C. Iodomethane (1.98 g, 14.0 mmol) was slowly dropped to the mixture and stirred for 2 hours at room temperature.
After the reaction is complete, the mixture was extracted using water (100 ml*2) and dichloromethane (100 ml).
The title compound (1.7 g, 75percent) was obtained by column chromatography (ethylacetate/n-hexane, 1/15).
1H-NMR (600 MHz, CDCl3); δ 7.45 (d, J=12.6 Hz, 2H), 7.15 (d, J=12.6 Hz, 2H), 3.69 (s, 3H), 3.58 (2H),
63.69% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; methyl(4-bromophenyl)acetate
To a stirred solution of (4-bromophenyl) acetic acid (1.5 g, 6.9 mmol) in DMF (10 mL), potassium carbonate (1.92 g, 14 mmol) and methyl iodide (1.46 g, 10 mmol) was added at 0° C. in a RB flask.
Reaction mixture was kept at RT for 2 h.
Then the reaction mixture was cooled to RT, poured into water and extracted with ethyl acetate.
The combined extracts were washed with water and brine solution.
The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum.
The crude product obtained was purified by column chromatography to get the title compound as a yellow liquid (1 g, yield: 63.69percent).
Reference: [1] Patent: US2013/72482, 2013, A1, . Location in patent: Paragraph 0299-0301
[2] Patent: US2016/333004, 2016, A1, . Location in patent: Paragraph 0668
[3] Patent: US6541505, 2003, B1,
[4] Patent: EP1813611, 2007, A1, . Location in patent: Page/Page column 26
  • 19
  • [ 67-56-1 ]
  • [ 1878-68-8 ]
  • [ 41841-16-1 ]
YieldReaction ConditionsOperation in experiment
100% at 65℃; Preparative Example 12; Step A; A solution of commercially available (4-bromophenyl)-acetic acid (4.05 g) and ion exchange resin IR-120(H+) in dry MeOH (100 mL) was stirred at 65° C. overnight. After addition of NEt3 the resin was filterd and the solution evaporated to dryness to afford the title compound (4.46 g; quant.) as a colourless oil. [MH]+=229/231.
100% for 16 h; Reflux Preparation of Intermediate methyl 2-(4-bromoohenyl)-2-methylorooanoate (1D-D; A solution of 4-bromophenylacetic acid (10g, 47mmol) in methanol (194ml, 46.5/W) and sulfuric acid (2.48ml, 46.5mmol) was heated to reflux for 16 hours. Reaction was concentrated, diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. Organic was dried over sodium sulfate, filtered and concentrated to give methyl 2-(4-bromophenyl)acetate (10.63g ,100percent) as a colorless oil.1 H NMR (400 MHz, CHLOROFORM-d) d ppm 3.56 (s, 2 H) 3.68 (s, 3 H) 7.14 (d, J=8.59 Hz, 2 H) 7.43 (d, J=8.59 Hz, 2 H)
100% at 0 - 20℃; for 2 h; Concentrated sulfuric acid (30 ml) was added to a solution of (4-bromophenyl)acetic acid (101 g, 468 mmol) in methanol (1000 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and, after ethyl acetate was added to the residue, the mixture was successively washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=5/1) to obtain methyl (4-bromophenyl)acetate (107 g, yield: 100percent). 1H-NMR (400MHz, CDCl3) : δ 7.43 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 3.69 (3H, s), 3.57 (2H, s).
100% for 4 h; Reflux A mixture of 2-(4-bromophenyl)acetic acid (10 g, 46.5 mmol) in MeOH (100 mL, with 2 mL of conc. H2504) was refluxed for 4 h. The mixture was concentrated and diluted with EtOAc. The organic was washed with water and brine, dried and concentrated to give the title product (10.6 g, yield 100percent). MS (ES+) C9H9BrO2 requires: 229 found 230 [M+H].
99.8% at 20℃; for 18 h; Methyl 2-(4-bromophenyl)acetate. To a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8percent).
99% for 5 h; Reflux General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.percent 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, 99percent 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, 98percent yield) as an orange solid.
99% at 5℃; Reflux (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.percent sulfonic acid (0.28 mL) in methanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (18) (1.13 g, 99percent yield) as a colorless oil. The crude product was used without purification. (Step 2)4 A solution of 18 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide5 (1.16 g, 5.88mmol) 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 room temperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (n-hexane/ethyl acetate= 10/1 as the eluent) to afford 4 (1.22 g, 98percent yield) as an orange solid
99.8% at 20℃; for 18 h; To a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8percent).
98% at 50℃; for 18 h; Reflux Sulfuric acid (56.5 mL) was very slowly added to a solution of 206.6 g of 4- bromophenyl acetic acid in methanol (800 mL). After completion of the addition, the mixture was heated to reflux for 2h. The reflux condenser was replaced by a distillation head and 400 mL of methanol was atmospherically distilled. The temperature was the reduced to 50 0C and the reaction stirred for additional 16h, when the mixture was then cooled to room temperature and partitioned between dichloromethane (1 L) and water (600 mL). The organic phase was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Concentration under reduced pressure provided 220. I g (98percent yield) colorless oil. HNMR: CDCl3, 3.59 (s, 2H), 3.70 (s, 3H), 7.16 (d, 2H), 7.45 (d, 2H)
98% for 2 h; Reflux Step 3: 4-Bromophenyl acetic acid methyl ester Sulfuric acid (56.5 mL) was very slowly added to a solution of 206.6 g of 4-bromophenyl acetic acid in methanol (800 mL). After completion of the addition, the mixture was heated to reflux for 2h. The reflux condenser was replaced by a distillation head and 400 mL of methanol was atmospherically distilled. The temperature was the reduced to 50 °C and the reaction stirred for additional 16h, when the mixture was then cooled to room temperature and partitioned between dichloromethane (1 L) and water (600 mL). The organic phase was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Concentration under reduced pressure provided 220. lg (98percent yield) colorless oil. HNMR: CDCI3, 3.59 (s, 2H), 3.70 (s, 3H), 7.16 (d, 2H), 7.45 (d, 2H)
96% at 0 - 5℃; for 4.16667 h; Reflux 6.2.3
Methyl-2-(4-bromophenyl)acetate (1c)
Colourless oil. Yield: 17.5 g (96percent).
1H NMR (300 MHz, CDCl3): δ 3.58 (s, 2H, -CH2-CO2CH3), 3.70 (s, 3H, -CO2CH3), 7.17 (d, 2H, J = 8.2 Hz, Ar-H), 7.47 (d, 2H, J = 8.3 Hz, Ar-H). Anal. Calcd. for C9H9BrO2: C, 47.19; H, 3.96. Found: C, 47.49; H, 3.99.
95%
Stage #1: at 75℃; for 2 h;
Stage #2: With sodium hydrogencarbonate In water
4-Bromophenylacetic acid (4.9 g, 22.79 mmol) in methanol (15 mL) and sulfuric acid (0.05 mL, 0.9 mmol) was heated to 75° C. for 2 hours.
Reaction concentrated and saturated aqueous sodium bicarbonate (40 mL) added and reaction mixture extracted with ethyl acetate.
Organics washed with brine, dried over magnesium sulfate, filtered and concentrated to give methyl 2-(4-bromophenyl)acetate (4.99 g, 95percent).
95% for 5.5 h; Reflux Add 500g of p-bromophenylacetic acid to the 5.0L reaction flaskAnd 250g of solid acid catalyst,Add 2.7 L of methanol,Stirring,Reflux reaction for 5.5 h;The reaction solution was cooled to 25 ° C.Filtering and recovering the solid acid catalyst,The filtrate obtained is subjected to reduced pressure distillation,Remove methanol,Add 2.0 L of toluene and stir to dissolve.Wash the toluene with water,Concentrated under reduced pressure,505.6g of intermediate 1, The yield was 95.0percent.
94% at 20℃; for 2 h; 2-(4-Bromophenyl) acetic acid (10.0 g, 46.5 mmol, 1.0 equiv) was dissolved in methanol (30 mL). Concentrated H2S04 (7 mL) was added drop wise at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.5a (10 g, 94 percent yield). 1H NMR (400 MHz, DMSO) 6 7.52 (d, J= 8.4 Hz, 2H), 7.26 (t, J= 14.0 Hz, 2H), 3.69 (s, 2H), 3.62 (s, 3H).
94.83% at 70℃; To a stirred solution of 100 g 4-bromophenylacetic acid (8,0.46 mol) in 300 cm3 methanol, 30 cm3 sulfuric acid was added in 1 h. The reaction mass was heated to 70 C and the temperature maintained until the completion of the reaction (monitored by HPLC). After completion of the reaction, methanol was distilled under reduced pressure at70 C, the resulting solution was cooled to 25–30 C,diluted with 200 cm3 water and the product was extracted into 300 cm3 dichloromethane. The dichloromethane layer was washed with 5percent solution of sodium bicarbonate and concentrated under reduced pressure to offer 9 as lightbrown oil. Yield: 101 g (94.83percent); purity by HPLC: 99percent;b.p.: 265–270 C. The spectral data of compound 9 werefound to agree with the reported data [8].
94% at 20℃; for 2 h; Inert atmosphere; High pressure To a solution of 2-(4-bromophenyl)acetic acid (5.0 g, 23.25 mmol) in methanol (50 mL) was added catalytic amount of thionyl chloride at room temperature under nitrogen atmosphere, the solution was refluxed for 2 hours, methanol was removed under vacuum to get methyl 2-(4-bromophenyl)acetate (37) (5 g, 94 percent) as pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.67 (s, 3H), 3.56 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 171.45, 132.96, 131.67, 131.03, 121.16, 52.12, 40.49; IR (Neat) νmax 2952.37, 1739.41 cm-1 ; ESI-MS: m/z 229.2 (M+H)+.
93% for 3 h; Reflux (4-bromophenyl)acetic acid (10 g, 1 eq) was dissolved in methanol. 10 ml conc. H2SO4 was added into the solution and the mixture was heated and refluxed for 3 hours. When the reaction was completed, the mixture was vacuum distilled and extracted with ethyl acetate and water. After the organic layer was washed with saturated NaHCO3, the target compound (4-bromophenyl)acetic acid methyl ester was obtained by drying the layer with anhydrous magnesium sulfate and removing the solvent at low pressures (9.87 g, 93percent).1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.4 Hz, 2H) , 7.16 (d, J=8.4 Hz, 2H) 3.70 (s, 3H), 3.59 (s, 2H)
85% Inert atmosphere; Reflux; Cooling with ice To a solution of 4-bromophenylacetic acid, 7-c, (10 g, 47 mmol) in methanol (100 mL) was added SOC12 (3.4 mL, 47 mmol) dropwise under a nitrogen atmosphere in an ice-water bath. After stirred in the ice- water bath for 30 min, the resulting solution was refluxed with stirring overnight. The cooled reaction solution was concentrated and treated with cooled saturated NaHCC"3 solution. The layers were separated and the aqueous layer was extracted by EA. Combined organic layers were washed by brine, dried over Na2SC"4 and concentrated to afford the title compound, 7-d, as pink oil (9.0 g, 85percent).1H NMR (300 MHz, CDCI3) 53.58 (s, 2H), 3.69 (s, 3H), 7.15 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H).
85% With thionyl chloride In methanolInert atmosphere; Reflux; Cooling with ice Step C: Methyl 2-f4-bromophenvD acetate (7-d) To a solution of 4-bromophenylacetic acid, 7-c, (10 g, 47 mmol) in methanol (100 mL) was added SOC12 (3.4 mL, 47 mmol) dropwise under a nitrogen atmosphere in an ice-water bath. After stirred in the ice-water bath for 30 min, the resulting solution was refluxed with stirring overnight. The cooled reaction solution was concentrated and treated with cooled saturated NaHC03 solution. The layers were separated and the aqueous layer was extracted by EA. Combined organic layers were washed by brine, dried over Na2S04 and concentrated to afford the title compound, 7-d, as pink oil (9.0 g, 85percent). NMR (300 MHz, CDCI3) 83.58 (s, 2H), 3.69 (s, 3H), 7.15 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H).
79.8% at 20℃; for 16 h; To a stirred solution of compound XCVI-1 (20 g, 93.5 mmol) in MeOH (200 mL) was added S0C12(33 g, 208.5 mmol) dropwise and the reaction mixture was stirred at r.t. for 16 h. The reaction was quenched with water and the mixture was adjusted to pH = 9 with aqueous NaHC03, extracted with EtOAc, combined the organic layer, washed with water and brine, dried over Na2S04, filtered and concentrated. The mixture was purified by column (PE:EA = 100: 1) to give compound XCVI-2 (17 g, yield: 79.8percent).
70% for 4 h; Reflux Concentrated sulfuric acid (1.0 mL, 18.4 mmol) was added dropwise over 15 minutes to a stirred solution of 2-(4-bromophenyl)acetic acid (4.0 g, 18.6 mol) in methanol (40 mL) and the resulting mixture heated to reflux for 4 hours. The solution was allowed to cool to room temperature and the solvents evaporated under reduced pressure. Saturated NaHCC>3 solution was added to the residue to adjust the pH to -8, then the aqueous phase was extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2S04) and evaporated under reduced pressure to leave the title compound (3.0 g, 70percent) which was used without further purification.
49 g for 2 h; Reflux Step 1:
Preparation of methyl 2-(4-bromophenyl)acetate
2-(4-bromophenyl)acetic acid (50 g) was introduced to methanol (50 mL), sulfuric acid (20 mL) was added thereto, followed by refluxing the mixture for 2 hrs.
The reactant thus obtained was cooled down, and the solvent was concentrated to obtain the title compound (49 g).
1H NMR (300 MHz, CDCl3): 7.45 (d, 2H), 7.16 (d, 2H), 3.70 (s, 3H), 3.59 (s, 2H)
49 g for 2 h; Reflux Step 1:
Preparation of methyl 2-(4-bromophenyl)acetate
2-(4-bromophenyl)acetic acid (50 g) was introduced to methanol (50 mL), sulfuric acid (20 mL) was added thereto, followed by refluxing the mixture for 2 hrs.
The reactant thus obtained was cooled down, and the solvent was concentrated to obtain the title compound (49 g).
1H NMR (300 MHz, CDCl3): 7.45 (d, 2H), 7.16 (d, 2H), 3.70 (s, 3H), 3.59 (s, 2H)

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  • [ 41841-16-1 ]
YieldReaction ConditionsOperation in experiment
93% at 80℃; for 24 h; Inert atmosphere; Sealed vial General procedure: Carboxylic acid (0.5 mmol) and MImC (2a, 1.0 mmol) were placed in a dry 20 mL vial with a Teflon tape-coated thread. A magnetic stirbar was added, followed by dry MeCN (1.0 mL), and the vial was quickly sealed with a plastic cap (gas is evolved during the course of the reaction. All experiments should be performed behind a blast shield if a sealed container is used.). The reaction mixture was then stirred at 23 °C for 15 min and then heated to 80 °C using a heating block for 24 h. The mixture was cooled to room temperature and then the vial was carefully opened (CAUTION: vial under pressure.). The volatiles were removed in vacuo, the resulting residue was dissolved in diethyl ether (20 mL), and then washed with 1 M HCl (10 mL). The aqueous layer was back-extracted with diethyl ether (20 mL) and the organic fractions were combined, washed with a saturated solution of NaHCO3 and then brine, dried over MgSO4, and concentrated in vacuo to afford the desired ester.
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  • 21
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YieldReaction ConditionsOperation in experiment
11.3 mmoles, 97 % With sulfuric acid In methanol A.
4-Bromobenzeneacetic acid, methyl ester
A solution of 2.5 g (11.6 mmoles) of p-bromophenylacetic acid and 0.25 mL of concentrated sulfuric acid in 75 mL of methanol was heated at reflux for 2 hours.
After cooling, the solution was evaporated to dryness and the residue diluted with ethyl acetate.
The solution was washed with saturated sodium bicarbonate (twice) and brine (twice), dried (MgSO4), and the solvent removed to give a clear light orange oil.
Distillation (kugelrohr, 125° C, 0.1 mm) afforded 2.6 g (11.3 mmoles, 97 percent) of compound A as a clear colorless oil.
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YieldReaction ConditionsOperation in experiment
50.7% With hydrogenchloride In carbon disulfide; thionyl chloride; aqueous KOH; ethyl acetate; benzene 16A.
5-Bromo-2-carboxymethyl-benzoic acid
(4-Bromo-phenyl)-acetic acid (20 g, 93 mmol) in thionyl chloride (40 ml) was heated at 850° C. for two hours after which time thionyl chloride was removed under vacuum.
The resulting acid chloride was combined with lead thiocyanate (Pb(SCN)2, 30 g, 93 mmol) in benzene (300 ml).
The reaction mixture was refluxed for 3 hours.
After cooled to room temperature, it was filtered through celite.
The filtrate was evaporated to yield an orange liquid.
This was then dissolved in carbon disulfide (30 ml) and was added dropwise into a solution of aluminum chloride (AlCl3, 24.7 g, 186 mmol) in carbon disulfide (60 ml) at 0° C.
The reaction mixture was heated to reflux for 12 hours.
The reaction mixture was cooled to 0° C. and 1N aqueous HCl (200 ml) was added.
The resulting orange precipitate was collected and then suspended in ethyl acetate.
After filtration obtained an orange solid.
This solid was dissolved in 25percent aqueous KOH (80 ml).
The solution was heated to reflux for 15 hours.
After cooling to 0° C., the reaction mixture was adjusted to pH 3 with 6N aqueous HCl.
The aqueous solution was extracted with ethyl acetate repeatedly.
The combined organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum to provide the title compound of 16A as a yellow solid (12.22 g, 50.7percent yield).
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