Home Cart 0 Sign in  
X

[ CAS No. 14062-25-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 14062-25-0
Chemical Structure| 14062-25-0
Chemical Structure| 14062-25-0
Structure of 14062-25-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 14062-25-0 ]

Related Doc. of [ 14062-25-0 ]

Alternatived Products of [ 14062-25-0 ]

Product Details of [ 14062-25-0 ]

CAS No. :14062-25-0 MDL No. :MFCD00016333
Formula : C10H11BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :ZFDCWHPNBWPPHG-UHFFFAOYSA-N
M.W : 243.10 Pubchem ID :7020609
Synonyms :

Calculated chemistry of [ 14062-25-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 4
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 54.81
TPSA : 26.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.67 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.73
Log Po/w (XLOGP3) : 2.97
Log Po/w (WLOGP) : 2.55
Log Po/w (MLOGP) : 2.99
Log Po/w (SILICOS-IT) : 3.06
Consensus Log Po/w : 2.86

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.3
Solubility : 0.123 mg/ml ; 0.000506 mol/l
Class : Soluble
Log S (Ali) : -3.19
Solubility : 0.159 mg/ml ; 0.000652 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.14
Solubility : 0.0175 mg/ml ; 0.0000721 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.7

Safety of [ 14062-25-0 ]

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

Application In Synthesis of [ 14062-25-0 ]

* 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 [ 14062-25-0 ]
  • Downstream synthetic route of [ 14062-25-0 ]

[ 14062-25-0 ] Synthesis Path-Upstream   1~32

  • 1
  • [ 557-21-1 ]
  • [ 14062-25-0 ]
  • [ 52798-01-3 ]
YieldReaction ConditionsOperation in experiment
38% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamideInert atmosphere; Reflux Step 2: To a solution of ethyl 2-(4-bromophenyl)acetate ( 3.24 g, 13.32 mmol) in anhydrous dimethylformamide was added zinc cyanide (939 mg, 7.99 mmol) , tetrakis(triphenylphosphine)palladium(0) (770 mg, 0.67 mmol). The reaction mixture was refluxed for overnight under N2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. 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 afford crude which was purified by column chromatography to afford ethyl 2-(4- (iminomethyl)phenyl)acetate. (962 mg, 38 percent)
Reference: [1] Patent: WO2013/45451, 2013, A1, . Location in patent: Page/Page column 51
  • 2
  • [ 14062-25-0 ]
  • [ 74-88-4 ]
  • [ 32454-36-7 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5 h;
Stage #2: at 20℃;
Example 13A
Ethyl 2-(4-bromophenyl)-2-methylpropanoate
2.0 g (8.2 mmol) of ethyl (4-bromophenyl)acetate were dissolved in 50 ml of DMF, and 0.7 g (18 mmol) of sodium hydride in mineral oil (60percent) were added at RT.
The mixture was stirred at RT for 30 minutes, after which 2.9 g (20.6 mmol) of iodomethane were added.
The mixture was then stirred at RT overnight.
The mixture was diluted with ethyl acetate and extracted first with water and then with saturated sodium chloride solution.
The organic phase was separated off, dried over magnesium sulphate and filtered, and the filtrate was concentrated.
The residue was purified by preparative HPLC [Reprosil C18, 10 μm, 250 mm*40 mm (30percent methanol/70percent water to 100percent methanol) over a run time of 25 min].
After HPLC control, the product-containing fractions were combined and concentrated.
This gave 1.75 g (78percent of theory) of an oil.
GC-MS [Method 5]: Rt=5.10 min; MS(ESIpos): m/z=270/272 (M+)
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.11 (t, 3H), 1.48 (s, 6H), 4.06 (q, 2H), 7.24-7.29 (m, 2H), 7.50-7.54 (m, 2H)
73% With sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 2 h; Step 1 :To a solution of ethyl 4-bromophenylacetate (4.5 g, 18.5 mmol) in 40 mL of DMF was added iodomethane (4.03 mL, 64.8 mmol) and sodium t-butoxide (4.45 g, 46.3 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water, and the mixture was extracted with EtOAc and hexane. The organic layer was separated and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over MgS04, and concentrated to give ethyl 2-(4-bromophenyl)-2-methylpropanoate (3.64 g, 73percent).
71%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
To a mixture of NaH (0.96 g, 40 mmol) in THF (30 mL) was added compound, 12-a, (2.43 g, 10 mmol) in THF (10 mL) at 0 °C under a nitrogen atmosphere. After stirring for 1 h, iodomethane (1.6 g, 4.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved with EA, filtrated and the filtration was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 12-b, (1.92 g, 71percent).1H NMR (300 MHz, CDCI3) 51.16-1.20 (m, 3H), 1.55 (s, 6H), 4.10-4.12 (m, 2H), 7.20-7.23 (m, 2H), 7.42-7.45 (m,2H). LC-MS (M+H)+271, 273
71%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
Step B: Ethyl 2-(4-bromophenvO-2-methylpropanoate (12-b) To a mixture of NaH (0.96 g, 40 mmol) in THF (30 mL) was added compound, 12-a, (2.43 g, 10 mmol) in THF (10 mL) at 0 °C under a nitrogen atmosphere. After stirring for 1 h, iodomethane (1.6 g, 4.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved with EA, filtrated and the filtration was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 12-b, (1.92 g, 71percent). NMR (300 MHz, CDCI3) 51.16- 1.20 (m, 3H), 1.55 (s, 6H), 4.10-4.12 (m, 2H), 7.20-7.23 (m, 2H), 7.42-7.45 (m, 2H). LC-MS (M+H)+ 271, 273.
42% With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 18 h; (4-bromophenyl)-acetic acid ethyl ester (0.1 g, 0.41 mmol) was dissolved in 1 mLof THF. t-BuOK (0.092 g,0.82 mmol) was added thereto, and iodomethane (0.051 mL, 0.82 mmol) was added thereto at 0°C. The mixture wasstirred at room temperature for 18 hours. After addition of 1N HCl and water, the reaction solution was extracted withEtOAc. The organic layer was separated, dried with MgSO4 and purified by column chromatography to obtain the titlecompound (0.047 g, 42percent).1H-NMR (CDCl3) δ 7.42 (2H, d), 7.21 (2H, d), 4.11 (2H, q), 1.54 (6H, s), 1.18 (3H, t).

Reference: [1] Patent: US2016/318866, 2016, A1, . Location in patent: Paragraph 0639; 0640; 0641
[2] Patent: WO2011/44187, 2011, A1, . Location in patent: Page/Page column 94
[3] Patent: WO2013/40790, 2013, A1, . Location in patent: Page/Page column 60
[4] Patent: WO2013/43624, 2013, A1, . Location in patent: Page/Page column 59; 60
[5] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0339
[6] Helvetica Chimica Acta, 1971, vol. 54, p. 868 - 897
[7] Journal of the American Chemical Society, 1971, vol. 93, p. 6877 - 6887
[8] Patent: US2006/149070, 2006, A1, . Location in patent: Page/Page column 30-31
[9] Patent: US2010/152257, 2010, A1, . Location in patent: Page/Page column 21
[10] Patent: WO2013/40863, 2013, A1, . Location in patent: Page/Page column 98-99
  • 3
  • [ 14062-25-0 ]
  • [ 4654-39-1 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2785 - 2788
  • 4
  • [ 64-17-5 ]
  • [ 1878-68-8 ]
  • [ 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
  • 5
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 106-38-7 ]
  • [ 14062-25-0 ]
YieldReaction ConditionsOperation in experiment
73% at 120℃; for 16 h; p-Bromotoluene (2.72 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol percent) 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-bromoacetate was obtained by column chromatography, in a yield of 73percent. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 3.56 (s, 2H), 4.12 (q, J=6.8 Hz, 2H), 7.15-7.17 (m, 2H), 7.43-7.45 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.8, 61.0, 121.1, 131.0, 131.6, 133.1, 171.1; HRMS (ESI) calcd. for C10H11BrNaO2 [M+Na]: 264.9835. found: 264.9837. The ethyl p-bromophenylacetate 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, 73 mg product p-bromophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93percent.
Reference: [1] Patent: US2013/303798, 2013, A1, . Location in patent: Paragraph 0064; 0065
[2] Journal of the American Chemical Society, 2012, vol. 134, # 24, p. 9902 - 9905
  • 6
  • [ 589-87-7 ]
  • [ 5764-82-9 ]
  • [ 14062-25-0 ]
YieldReaction ConditionsOperation in experiment
81% With [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 65℃; for 1.5 h; Inert atmosphere; Sealed tube General procedure: To a 20 mL vial with a stir bar was added aryl halide 1 (2.00 mmol), Pd(dba)2 (28.8 mg, 2.5 mol percent), Xantphos (28.9 mg, 2.5 mol percent). The vial was sealed with a Teflon-lined cap and THF (6.0 mL) was added. The mixture was vacuumed and backfilled with nitrogen (3×). A solution of ethyl 2-bromozincacetate (2a) in THF (0.40 M, 6.0 mL, 1.2 equiv) filtered through a Target® Nylon 0.45 μm filter (1.25-inch OD) was syringed in and the reaction mixture was then heated to 65 °C and monitored by HPLC. Upon reaction completion based on HPLC analysis (≥95percent conversion unless the reaction was stalled), the mixture was cooled to room temperature and quenched with 1 M aq HCl (5.0 mL), followed by addition of brine (5.0 mL). The organic layer was separated and concentrated in vacuum. The residue was purified by silica gel column chromatography using gradient EtOAc in hexanes.
Reference: [1] Tetrahedron, 2014, vol. 70, # 7, p. 1508 - 1515
  • 7
  • [ 1878-68-8 ]
  • [ 14062-25-0 ]
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,
  • 8
  • [ 19213-72-0 ]
  • [ 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
  • 9
  • [ 589-87-7 ]
  • [ 141-97-9 ]
  • [ 14062-25-0 ]
YieldReaction ConditionsOperation in experiment
50% With caesium carbonate In 1,4-dioxane at 100℃; for 12 h; General procedure: A mixture of aryl iodide (5 mmol), ethyl acetoacetate(7.5 mmol), Cu2+/4A (0.5 g, 0.1 mol percent copper) and Cs2CO3 (12.5 mmol) indioxane (10 ml) was stirred at 100 C for 12 h. The solid was filtered and thefiltrate was evaporated in vacuo. The products were purified by columnchromatography (silica gel, hexane/acetone 4:1 eluent). The products werecharacterized by 1H NMR and GC–MS.
Reference: [1] Tetrahedron Letters, 2015, vol. 56, # 46, p. 6389 - 6392
  • 10
  • [ 75-03-6 ]
  • [ 1878-68-8 ]
  • [ 14062-25-0 ]
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,
  • 11
  • [ 77143-76-1 ]
  • [ 14062-25-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7676 - 7679[2] Angew. Chem., 2016, vol. 128, p. 7806 - 7810,5
[3] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7928 - 7938
  • 12
  • [ 5467-74-3 ]
  • [ 623-33-6 ]
  • [ 14062-25-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 39, p. 10510 - 10514[2] Angew. Chem., 2014, vol. 126, # 39, p. 10678 - 10682,5
  • 13
  • [ 1878-68-8 ]
  • [ 14062-25-0 ]
Reference: [1] Patent: US5489584, 1996, A,
  • 14
  • [ 1878-67-7 ]
  • [ 14062-25-0 ]
  • [ 14062-30-7 ]
Reference: [1] Patent: US5489584, 1996, A,
  • 15
  • [ 64-17-5 ]
  • [ 16532-79-9 ]
  • [ 14062-25-0 ]
Reference: [1] Chemische Berichte, 1909, vol. 42, p. 1938
[2] Justus Liebigs Annalen der Chemie, 1897, vol. 296, p. 361
  • 16
  • [ 14062-25-0 ]
  • [ 1528-41-2 ]
YieldReaction ConditionsOperation in experiment
66.5% With copper(l) iodide In 1-methyl-pyrrolidin-2-one at 160 - 180℃; for 7 h; Inert atmosphere Preparation 56 ethyl 2-(4-cyanophenyl)acetate [0247] Combined ethyl 2-(4-bromophenyl)acetate (30 g, 0.123 mol) and MP (200 mL). Then CuCN (33 g, 0.370 mol) was added in portions and then degassed and refilled with nitrogen three times. Then Cul (4.7 g, 0.0247mol) was added in one portion. The reaction was degassed and refilled with nitrogen three times and then heated to 160°C for 4 hours. Then the reaction was heated to 180°C for another 3 hours. The solution was then cooled to room temperature and diluted with EtOAc (500 mL) and water (500 mL). After stirring for 10 mins, the reaction was filtered and the aqueous layer was extracted with EtOAc (500 mLx2). The combined organic layers were washed with brine, dried over Na2S04 and concentrated to dryness to give the title compound (31 g, 66.5percent) as a brown solid.
Reference: [1] Patent: WO2014/160810, 2014, A1, . Location in patent: Paragraph 0246; 0247
  • 17
  • [ 14062-25-0 ]
  • [ 143-33-9 ]
  • [ 1528-41-2 ]
Reference: [1] Journal of the American Chemical Society, 2003, vol. 125, # 10, p. 2890 - 2891
  • 18
  • [ 557-21-1 ]
  • [ 14062-25-0 ]
  • [ 1528-41-2 ]
YieldReaction ConditionsOperation in experiment
49% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamideReflux 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).
38% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamideReflux; Inert atmosphere Step 2: To a solution of ethyl 2-(4-bromophenyl)acetate (3.24 g, 13.32 mmol) in anhydrous dimethylformamide was added zinc cyanide (939 mg, 7.99 mmol), tetrakis(triphenylphosphine)palladium(0) (770 mg, 0.67 mmol).
The reaction mixture was refluxed for overnight under N2. TLC showed complete consumption of starting material.
The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure.
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 afford crude which was purified by column chromatography to afford ethyl 2-(4-(iminomethyl)phenyl)acetate. (962 mg, 38percent)
Reference: [1] Patent: US2013/79377, 2013, A1, . Location in patent: Paragraph 0554; 0557
[2] Patent: US2013/79320, 2013, A1, . Location in patent: Paragraph 0473; 0475
  • 19
  • [ 14062-25-0 ]
  • [ 557-21-1 ]
  • [ 1528-41-2 ]
YieldReaction ConditionsOperation in experiment
49% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamideReflux 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 ethylacteate 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 49 percent yield.
Reference: [1] Patent: WO2013/45447, 2013, A1, . Location in patent: Page/Page column 83
  • 20
  • [ 773837-37-9 ]
  • [ 14062-25-0 ]
  • [ 1528-41-2 ]
Reference: [1] European Journal of Organic Chemistry, 2013, # 20, p. 4255 - 4261
  • 21
  • [ 14062-25-0 ]
  • [ 105986-54-7 ]
Reference: [1] Patent: WO2018/39386, 2018, A1,
  • 22
  • [ 1878-67-7 ]
  • [ 14062-25-0 ]
  • [ 14062-30-7 ]
Reference: [1] Patent: US5489584, 1996, A,
  • 23
  • [ 50-00-0 ]
  • [ 14062-25-0 ]
  • [ 331779-03-4 ]
YieldReaction ConditionsOperation in experiment
73% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h; Example 26; 2-(4-Bromo-phenyl)-acrylic acid ethyl esterTo a solution of (4-bromo-phenyl)-acetic acid ethyl ester (972.4 mg, 4 mmol), paraformaldehyde (240 mg, 8 mmol), and Bu4NCl (22 mg, 0.08 mmol) in DMF (10 mL) was added K2CO3 (1.32 g, 9.6 mmol). This mixture was heated at 60 degrees Celsius for 2 h. Then the mixture was cooled and diluted with EtOAc (30 mL) and washed with water (20 mL.x.3), brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel to give a white solid (0.74 g, 73percent). MS: calc'd 255 (MH+), exp 255 (MH+).
47.65% With tetrabutyl-ammonium chloride; potassium carbonate In dichloromethane at 60℃; for 3 h; Synthesis of compound 166.1. To a solution of ethyl 161.1 (5.0g, 20.6 mmol, l .Oeq) in CH2CI2 (50 mL) was added preraformaldehyde (0.938g, 24.69mmol, 1.2eq) followed by tetrabutylammonium chloride (0.571g, 2.05mmol, O. leq), and K2CO3 (6.2g, 45.26mmol, 2.2eq). The reaction was stirred at 60 °C 3h. The reaction mixture was quenched with ice cold water and product was extracted with CH2CI2 (50mL x 2). Organic layer were combined and dried over sodium sulphate and concentrated under reduced pressure to obtain 166.1 (2.5g, 47.65percent). MS (ES):256.4 m/z [M+H]+.
Reference: [1] Patent: US2010/69328, 2010, A1, . Location in patent: Page/Page column 31
[2] Journal of the American Chemical Society, 2015, vol. 137, # 9, p. 3169 - 3172
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00901; 00902
[4] Organic Letters, 2017, vol. 19, # 19, p. 5216 - 5219
  • 24
  • [ 14062-25-0 ]
  • [ 73183-34-3 ]
  • [ 859169-20-3 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With potassium acetate In 1,4-dioxane for 0.25 h;
Stage #2: at 100℃; for 2 h;
Ethyl (4-bromophenyl)-acetate (100 g, 411 mmol) Z?-(pinacolato)diboron (125.4 g,493.7 mmol) and potassium acetate (125.4 g, 493.7 mmol) were charged to a 2 L round bottom flask. 1,4-Dioxane (1 L) was added and the mixture was stirred under a nitrogen EPO <DP n="154"/>atmosphere for 15 minutes. [1,1 '-Z?w-(Diphenylphosphino)-ferrocene]dichloropalladium(II) CH2Cl2 complex (1:1) (3.36 g, 4.11 mmol) was added and the reaction was heated in an 100 0C oil bath for 2 hours. The reaction was determined complete by analytical HPLC. The solution was concentrated under reduced pressure to remove the dioxane and the residue was dissolved in ethyl acetate. The solution was filtered through a 6 x 4 inch silica gel plug with ethyl acetate (1.5 L) as eluant to give ethyl [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenylj-acetate (117 g, 98percent). 1H NMR (400 MHz, DMSO) δ ppm 7.63 (d, 2H5 J= 8 Hz), 7.27 (d, 2H, J= 8 Hz), 4.07 (q, 2H, J= 7 Hz), 3.68 (s, 2H), 1.28 (s, 12H), 1.16 (t, 3H, J= 7 Hz).
92% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 110℃; for 16 h; Inert atmosphere; Sealed tube Intermediate 1A ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate [0452] [0453] To a vial containing a degassed (3× vacuum/Ar) mixture of ethyl 2-(4-bromophenyl)acetate (1 g, 4.11 mmol), bis(pinacolato)diboron (1.25 g, 4.94 mmol), and potassium acetate (1.21 g, 12.3 mmol) in dioxane (10 mL), was added PdCl2(dppf) CH2Cl2 adduct (0.090 g, 0.123 mmol). The reaction mixture was degassed, sealed and heated at 110° C. for 16 h. The mixture was diluted with water, then extracted with EtOAc. The organic phase was concentrated and purified via flash chromatography (EtOAc/hexane) to afford 1.1 g (92percent) of Intermediate 1A. [0454] MS (ESI) m/z: 291.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ 7.84-7.71 (m, 2H), 7.34-7.28 (m, J=8.0 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.27 (s, 12H), 1.26-1.22 (m, 3H).
84.2% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 3 h; Inert atmosphere In a 350 mL reaction vial, ethyl 2-(4-bromophenyl)acetate (25 g, 103 mmol), BISPIN (31.3 g, 123 mmol) and potassium acetate (20.2 g, 206 mmol) were combined with 1,4 dioxane (190 mL) to give a white suspension. The mixture was purged with nitrogen for 5 min, PdCl2(dppf) (4.2 g, 5.14 mmol) was added and the vial was sealed and heated in an oil bath at 80 °C for 3 h. The reaction was filtered, rinsed with ethyl ether, concentrated, diluted with water (500 mL) and extracted with ethyl ether (2 x 300 mL), and the organic layers washed with brine (250 mL). The ethyl ether layers were combined, dried over MgS04, filtered, and concentrated as red oil. The crude material was purified by flash chromatography (silica gel, 0percent to 20percent EtOAc in hexanes). The appropriate fractions were combined, concentrated, dried from DCM to obtain [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (25.14 g, 84.2percent yield) as a white solid/oil. LC/MS calcd. for Ci6H23B04 (m/e) 290, obsd. 291 (M+H, ES+).
80% With potassium acetate In 1,4-dioxane at 20 - 80℃; for 5 h; Inert atmosphere A solution of ethyl 2-(3-bromophenyl)acetate (1 g, 4.1 mmol) in dioxane (20 mL) was degassed with argon, to this solution (bis-pinacolato)diboron (1.25 g, 4.9 mmol), KOAc (1.21 g, 12 mmol) and Pd(dppf)2Cl2 (100 mg, 0.1 mmol) were added at room temperature and the mixture was heated at 80° C. for 5 h. After complete consumption of the starting material as observed by LCMS and TLC, the reaction mixture was cooled to room temperature. The reaction mixture was evaporated to dryness under reduced pressure to give a residue which was dissolved in EtOAc. The un-dissolved inorganic material was filtered off and the filtrate was evaporated under vacuum to give the crude product which was purified by column chromatography (silica gel) to yield ethyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (888 mg, 80percent).LCMS: 92.13percent (254 nm, R.T.=3.25)
79% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 85℃; for 4 h; Inert atmosphere Step 1: Ethyl 2-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)acetate A suspension of ethyl 2-(4-bromophenyl)acetate (500 mg, 2.06 mmol),bis(pinacolato)diboron (1.05 mg, 4.11 mmol), and potassium acetate (606 mg, 6.17 mmol) in dioxane (4 mL) was degassed with bubbling nitrogen. PdC12(dppf)-CH2C12adduct (84.0 mg, 0.100 mmol) was added, and the reaction was heated to 85 °C for 4 h. The reaction was diluted with ethyl acetate (30 mL) and filtered through Celite. The organic layer was washed with brine, separated, and dried with sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (40 g column, gradient from 0percent to 20percent EtOAc/hexanes) to give the title compound (471 mg, 79percent) as a colorless oil. ‘H NMR (400MHz, CDC13) ö 7.79 (d, J7.9 Hz, 2H),7.32 (d, J=7.9 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.36 (s, 12H), 1.26 (t, J=7.2Hz, 3H); LCMS (M+H) = 291.3; HPLC RT = 1.03 mill (Column: BEH C18 2.1 x 50 mm;Mobile Phase A: Water with 0.05percent TFA; Mobile Phase B: Acetonitrile with 0.05percent TFA;Gradient: 2-98percent B over 1.6 mm; Flow: 0.8 mL/min).
79% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane at 85℃; for 4 h; Inert atmosphere A suspension of ethyl 2-(4-bromophenyl)acetate (500 mg, 2.06 mmol), bis(pinacolato)diboron (1.05 mg, 4.11 mmol), and potassium acetate (606 mg, 6.17 mmol) in dioxane (4 mL) was degassed with bubbling nitrogen. PdCl2(dppf)-CH2Cl2 adduct (84.0 mg, 0.100 mmol) was added, and the reaction was heated to 85° C. for 4 h. The reaction was diluted with ethyl acetate (30 mL) and filtered through Celite. The organic layer was washed with brine, separated, and dried with sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (40 g column, gradient from 0percent to 20percent EtOAc/hexanes) to give the title compound (471 mg, 79percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.36 (s, 12H), 1.26 (t, J=7.2 Hz, 3H); LCMS (M+H)=291.3; HPLC RT=1.03 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05percent TFA; Mobile Phase B: Acetonitrile with 0.05percent TFA; Gradient: 2-98percent B over 1.6 min; Flow: 0.8 mL/min).
72% With potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere PREPARATION 13
Ethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate
In a Schlenk tube, a mixture of (4-bromophenyl)acetate (1.0 g, 4.11mmol), bis(pinacolato)diboron (2.37 g, 9.34 mmol) and potassium acetate (1.38 g, 14 mmol) was dissolved in dioxane (40ml).
The mixture was purged (vacuum-argon three times) and [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (0.19 g, 0.23 mmol) and 1,1'-bis(diphenylphospheno)ferrocene (0.13 g, 0.23 mmol) were added.
The mixture was purged again (vacuum-argon three times) and stirred at 90 °C for 18 h.
The suspension was filtered off and the filtrated diluted with water and extracted three times with ethyl acetate.
The combined organic layers were washed with water and brine, and dried over anhydrous sodium sulphate.
Solvent was removed in vacuum and the residue was purified by the SP1.(R). automated purification system to give 0.86 g mmol (72percent) of the desired compound.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J=6.83 Hz, 3 H), 1.34 (s, 12 H), 3.62 (s, 2 H), 4.13 (q, J=7.03 Hz, 2 H), 7.22 - 7.34 (m, 2 H), 7.77 (d,
J=7.42 Hz, 2 H),
HPLC/MS (9 min) retention time 6.86 min.
LRMS: m/z 308 (M+1)

Reference: [1] Patent: WO2006/86609, 2006, A2, . Location in patent: Page/Page column 152-153
[2] Patent: US2014/206686, 2014, A1, . Location in patent: Paragraph 0452-0454
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7920 - 7939,20
[4] Patent: WO2013/189865, 2013, A1, . Location in patent: Page/Page column 30
[5] Patent: US2012/295874, 2012, A1, . Location in patent: Page/Page column 230
[6] Patent: WO2015/100282, 2015, A1, . Location in patent: Page/Page column 274; 275
[7] Patent: US2016/176864, 2016, A1, . Location in patent: Paragraph 0783; 0784
[8] Patent: EP2394998, 2011, A1, . Location in patent: Page/Page column 19-20
[9] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10479 - 10497
[10] Patent: US2010/152257, 2010, A1, . Location in patent: Page/Page column 17
[11] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6608 - 6612
[12] Patent: WO2011/159550, 2011, A2, . Location in patent: Page/Page column 79
  • 25
  • [ 14062-25-0 ]
  • [ 25015-63-8 ]
  • [ 859169-20-3 ]
Reference: [1] Patent: WO2013/45479, 2013, A1, . Location in patent: Page/Page column 21-22
  • 26
  • [ 14062-25-0 ]
  • [ 706811-25-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 27
  • [ 14062-25-0 ]
  • [ 146533-41-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 28
  • [ 14062-25-0 ]
  • [ 362052-00-4 ]
Reference: [1] Patent: WO2013/45447, 2013, A1,
[2] Patent: US2013/79377, 2013, A1,
[3] Patent: US2013/79320, 2013, A1,
  • 29
  • [ 14062-25-0 ]
  • [ 769944-71-0 ]
Reference: [1] Patent: CN108409638, 2018, A,
  • 30
  • [ 14062-25-0 ]
  • [ 1227159-85-4 ]
Reference: [1] Patent: US2011/301122, 2011, A1,
[2] Patent: US2013/196964, 2013, A1,
  • 31
  • [ 14062-25-0 ]
  • [ 1215205-50-7 ]
YieldReaction ConditionsOperation in experiment
85% With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 21℃; for 12 h; General procedure: To a 5 mL Schlenk tube were added aryl / heteroaryl acetates 3 (1.0 mmol, 1.0 equiv.), vinyl diphenylsulfonium triflate (434.4 mg, 1.2 mmol, 1.2 equiv.) and DMSO (5 mL). The mixture was stirred at room temperature for 2 min and to the mixture was added DBU (456 mg, 3 mmol, 3.0 equiv.). The mixture was stirred for 12 hours at room temperature till the reaction was complete. To the resulting mixture was added saturated ammonium chloride solution (25 mL), and the mixture was then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with H2O (2 x 30 mL), dried with anhydrous sodium sulfate. After concentration, product 4 was purified using column chromatography on silica gel using an appropriate eluent.
Reference: [1] Tetrahedron Letters, 2018, vol. 59, # 14, p. 1443 - 1445
  • 32
  • [ 14062-25-0 ]
  • [ 106-93-4 ]
  • [ 1215205-50-7 ]
YieldReaction ConditionsOperation in experiment
26% With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 20℃; Example 14A
Ethyl 1-(4-bromophenyl)cyclopropanecarboxylate
1.45 g (36.2 mmol) of sodium hydride in mineral oil (60percent pure) were initially charged in 100 ml of DMF. A mixture of 4.0 g (16.5 mmol) of ethyl (4-bromophenyl)acetate and 6.5 g (34.6 mmol) of 1,2-dibromoethane was dissolved in 50 ml of THF and slowly added dropwise.
The mixture was stirred at RT overnight.
The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution.
The organic phase was separated off, dried over magnesium sulphate and filtered, and the filtrate was concentrated.
The residue was purified by preparative HPLC [Reprosil C18, 10 μm, 250 mm*40 mm (30percent methanol/70percent water to 100percent methanol) over a run time of 25 min].
After HPLC control, the product-containing fractions were combined and concentrated.
This gave 1.15 g (26percent of theory) of a liquid.
GC-MS [Method 5]: Rt=5.45 min; MS(ESIpos): m/z=268/270 (M+)
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.09 (t, 3H), 1.16-1.20 (m, 2H), 1.46-1.50 (m, 2H), 4.02 (q, 2H), 7.26-7.31 (m, 2H), 7.47-7.51 (m, 2H)
Reference: [1] Patent: US2016/318866, 2016, A1, . Location in patent: Paragraph 0642; 0643; 06444; 0645
Recommend Products
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 14062-25-0 ]

Aryls

Chemical Structure| 41841-16-1

[ 41841-16-1 ]

Methyl 2-(4-bromophenyl)acetate

Similarity: 0.96

Chemical Structure| 1261862-72-9

[ 1261862-72-9 ]

Ethyl 2-(3-bromo-2-methylphenyl)acetate

Similarity: 0.94

Chemical Structure| 150529-73-0

[ 150529-73-0 ]

Methyl 2-(3-bromophenyl)acetate

Similarity: 0.94

Chemical Structure| 105986-54-7

[ 105986-54-7 ]

Ethyl 4-(4-bromophenyl)butanoate

Similarity: 0.94

Chemical Structure| 40640-98-0

[ 40640-98-0 ]

Ethyl 3-(4-bromophenyl)propanoate

Similarity: 0.94

Bromides

Chemical Structure| 41841-16-1

[ 41841-16-1 ]

Methyl 2-(4-bromophenyl)acetate

Similarity: 0.96

Chemical Structure| 1261862-72-9

[ 1261862-72-9 ]

Ethyl 2-(3-bromo-2-methylphenyl)acetate

Similarity: 0.94

Chemical Structure| 150529-73-0

[ 150529-73-0 ]

Methyl 2-(3-bromophenyl)acetate

Similarity: 0.94

Chemical Structure| 105986-54-7

[ 105986-54-7 ]

Ethyl 4-(4-bromophenyl)butanoate

Similarity: 0.94

Chemical Structure| 40640-98-0

[ 40640-98-0 ]

Ethyl 3-(4-bromophenyl)propanoate

Similarity: 0.94

Esters

Chemical Structure| 41841-16-1

[ 41841-16-1 ]

Methyl 2-(4-bromophenyl)acetate

Similarity: 0.96

Chemical Structure| 1261862-72-9

[ 1261862-72-9 ]

Ethyl 2-(3-bromo-2-methylphenyl)acetate

Similarity: 0.94

Chemical Structure| 150529-73-0

[ 150529-73-0 ]

Methyl 2-(3-bromophenyl)acetate

Similarity: 0.94

Chemical Structure| 105986-54-7

[ 105986-54-7 ]

Ethyl 4-(4-bromophenyl)butanoate

Similarity: 0.94

Chemical Structure| 40640-98-0

[ 40640-98-0 ]

Ethyl 3-(4-bromophenyl)propanoate

Similarity: 0.94