| 98% |
With thionyl chloride;Heating / reflux; |
To a solution of 3-bromophenylacetic acid (1 g, 4.65 mmol) in 20 mL MeOH at 0 C. was added thionyl chloride (0.51 mL, 1.5 eq.) dropwise. The resulting solution was then refluxed overnight under N2. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was taken up in EtOAc, washed with sat'd. NaHCO3 and brine, then dried over Na2SO4, filtered and evaporated to provide the methyl ester in 98% yield. 1HNMR (300 MHz, CDCl3) delta 7.57 (d, 1H, J=12 Hz); 7.29 (2H, dd, J=2.5, 0.8 Hz); 7.16 (m, 1H); 3.81 (s, 2H); 3.72 (s, 3H). |
| 98.7% |
With acetyl chloride; for 2h;Reflux; |
Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na2S04, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (0.525 g, 98.7%). LC-MS (ES) m/z = 229.0, 231.0 [M+H]+ . H NMR (400 MHz, DMSOd6) delta 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1 H). |
| 97% |
With thionyl chloride; at 10 - 20℃; for 2h; |
a) Synthesis of methyl(3-bromophenyl)acetate25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel and gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise at max. 10 C. with cooling and stirring, and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using conc. sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried and filtered. The solvent is subsequently removed.Yield: 25.44 g=0.111 mol=97% of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf about 0.9; HPLC: RT=2.43 min. |
| 97% |
With thionyl chloride; at 10 - 20℃; for 2h; |
a) Synthesis of methyl (3-bromophenyl)acetate 25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel with gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise with cooling and stirring at max. 10 C., and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using concentrated sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried, filtered and stripped off to dryness. Yield: 25.44 g=0.111 mol=97% of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf approx. 0.9 HPLC: RT=2.43 min. |
| 96% |
With hydrogenchloride; In water; at 20 - 58℃; for 2h; |
3-BROMOPHENYLACETIC acid (10000 mg, 46. 50MMOL) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58C for 2h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35% ACOET/HEXANES to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC- MS (MH+ 230 RT = 9.34 min). |
| 96% |
With acetyl chloride; at 0 - 25℃; for 5h; |
Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96% yield, 20 6g1H NMR (400MHz, CDCI3) delta 3 59 (s, 2H) 3 70 (s, 3H), 7 24-7 17 (m, 2H), 7 37-7 45 (m, 2H), LRMS ESI m/z 253 [M+Na]+ |
| 96% |
thionyl chloride; at 20℃; |
Intermediate 2. (3-Bromo-phenyl)-acetic acid methyl ester. <n="19"/>[0056] Step A: 3-Btauomophenyl acetic acid (1.17 g, 5.44 mmol) is dissolved inMeOH (15 tnL) containing catalytic amounts of thionyl chloride (0.2 tnL). The solution is stirred at room temperature overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCO3- The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 16 (1.20 g, 5.28 mmol, 96%) as an oil: 1H-NMR (400MHz, CDCl3) delta = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H"1") 229.1, found 229.0. |
| 95% |
With sulfuric acid;Reflux; |
3-Bromophenylacetic acid (100 g, 0.47 mol) was dissolved in methanol (1000 ml) and concentrated sulfuric acid (1 ml) added and the mixture heated at reflux overnight. The methanol was evaporated and the residue partitioned between dichloromethane (600 ml) and saturated aqueous sodium bicarbonate (200 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated to give methyl 2-(3-bromophenyl)acetate (102 g, 0.45 mol, 95%) as an oil. 1H NMR (400 MHz, CDCl3): delta ppm 7.43 (bt, 1H), 7.38 (dt, 1H), 7.15-7.19 (m, 2H), 3.68 (s, 3H), 3.58 (s, 2H) |
| 95% |
With sulfuric acid; for 5h;Dean-Stark; Reflux; |
2- (3-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in freshly distilled methanol (50 ml.) . Added cone. H2S04 (8 drops) and refluxed in a Dean-Stark apparatus for 3 hrs. Reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in CH2C12 (40 mL) and washed with sat. NaHC03 (30 mL x 2) and sat. NaCl (30 mL) . The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The crude product was chromatographed on silica gel (Hexanes/EtOAc, 5:1) to yield target compound 73. Yield 1.011 g, 95%. Rf = 0.60, H NMR (400 MHz, Chloroform-d) delta 7.47 - 7.43 (m, 1H) , 7.41 (dt, J = 6.5, 2.2 Hz, 1H) , 7.24 - 7.16 (m, 2H) , 3.70 (s, 3H) , 3.60 (s, 2H) ; [M+H]+ = 230.12 (APCI+) . |
| 94% |
With thionyl chloride; at 0 - 80℃; for 3h; |
[0180] To a solution of 2-(3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) in CH3OH (30 mL), was added SOCl2 (3.2 g, 27.0 mmol) at 0 C. Then the mixture was stirred at 80 C for 3 hours. The solvent was removed under reduced pressure to give methyl 2-(3- bromophenyl)acetate (5.0 g, yield: 94%); LC/MS: m/z (M++l) = 231. |
| 91% |
With sulfuric acid; at 40℃; for 16h; |
Example 18; Preparation of Methyl (3-Bromophenyl)acetateA stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40 0C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexanes) to give the title compound (19.8 g, 91 % yield) as a colorless oil.LC-MS (Method 10-90): Rt 3.36 min; mlz 300.4 [M + H]+; 229.6 [M+]. 1H NMR (CD3OD) delta 7.48(s, IH); 7.44(d, IH); 7.26-7.25(m, 2H); 3.71(s, 3H); 3.66(s, 2H). |
| 90% |
toluene-4-sulfonic acid; for 3h;Reflux; |
Step 1 : [00152] To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol (150 ml_) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1). This gave (3-bromophenyl)acetic acid methyl ester as a colorless oil (11.7 g, 90%). 1H NMR (400 MHz, CD3OD): delta = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H)1 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min. |
| 90% |
With toluene-4-sulfonic acid; for 3h;Reflux; |
[0095] Step 1 : To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol(150 mL) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1 ). This gave (3- bromophenyl)acetic acid methyl ester as a colorless oil (1 1.7 g, 90%). 1H NMR (400 MHz, CD3OD): delta = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H), 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min. |
| 86.1% |
With thionyl chloride;Reflux; |
Methyl 2-(3-bromophenyl) acetateBrTo the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) wasadded SOCI2(2 mL). The reaction solution was stirred and heated to reflux overnight.After the reaction was completed, 200mL of water and 30 mL of NaHCO3 aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2504. After filtration and evaporation of the solvent, the product (11 .Og, 86.1 %) was obtained. |
| 86.1% |
With thionyl chloride;Reflux; |
To the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) was added SOCI2 (2 mL). The reaction solution was stirred and heated to reflux overnight. After the reaction was completed, 200mL of water and 30 mL of NaHCOs aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the product (1 1 . Og, 86.1 %) was obtained. |
|
acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a colourless oil, 20.6g.1H nmr (CDCl3, 400MHz) delta: 3.59 (s, 2H), 3.70 (s, 3H), 7.17-7.24 (m, 2H), 7.37-7.45 (m, 2H) LRMS :m/z ES+ 253 [M+Na]+. |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly-added to a solution of (3-bromo- phenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400MHz, CDCI3) : 8 : 3.59 (2H, s), 3.70 (3H, s), 7.17-7. 24 (2H, m), 7.37-7. 45 (2H, m); LRMS ESI m/z 253 [M+Na] + |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400 MHz, CDCl3): delta=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+253. |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Preparation 28: Methyl (3-bromophenyl)acetate Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6g). 1H NMR (400MHz, CDCl3): delta = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 253. |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Preparation 3 (3-Bromo-phenyl)-acetic acid methyl ester Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over 5 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane, dried (sodium sulphate) and concentrated under reduced pressure to give the title compound as a colourless oil, 20.6g. 1H NMR (CDCl3, 400MHz) delta: 3.59(s, 2H), 3.70(s, 3H), 7.17-7.24(m, 2H), 7.37-7.45(m, 2H) LRMS:m/z ES+ 253 [M+Na]+ |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7 ml, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400 MHz, CDCl3): delta=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+253. |
|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 16h; |
A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and 4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, 1N phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure to provide the title compound. |
|
With thionyl chloride; at 20℃; |
[0030] Step A: 3-Bromophenyl acetic acid 34 (1.17 g, 5.44 mmol) is dissolved inMeOH (15 mL) containing catalytic amounts of thionyl chloride (0.2 mL). The solution is stirred at rt overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCCb. The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 35 as an oil: 1H-NMR (400MHz, CDCl3) delta = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (ss 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H4) 229.1, found 229.0. |
|
With thionyl chloride; at 65℃; for 5h; |
Step 1: (3-Bromo-phenyl)-acetic acid methyl ester To 3-bromophenylacetic acid (5.03 g, 23.4 mmol) in MeOH (50 mL) was added thionyl chloride (3.4 mL, 46.8 mmol), and the reaction was stirred at 65 C. for 5 hours. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The mixture was basified with 1N aqueous NaOH, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacua and the residue dissolvedin dichloromethane, dried (sodium sulfate) and concentrated in vacua to givethe title compound as a colourless oil (20.6g). |
|
With acetyl chloride; at 0 - 20℃; for 5h; |
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3- bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400MHz, CDCI3) : 6 : 3.59 (2H, s), 3.70 (3H, s), 7.17-7. 24 (2H, m), 7.37-7. 45 (2H, m). LRMS ESI m/z 253 [M+Na] +. |
| 4.9 g |
With hydrogenchloride; In water; for 3h;Reflux; |
(3-Bromophenyl)acetic acid 11 (5.0 g, 23.3 mmol) and methanol (50 mL) were refluxed for 3 h in the presence of 0.2 mL of concentrated hydrochloric acid (HCl) to give the methyl (3-bromophenyl)acetate. After neutralization with saturated NaHCO3 and washing with brine, a pure product was obtained from the diethyl ether extract. This methyl acetate (4.9 g, 21.4 mmol) in dry THF (35 mL) was added dropwise to a stirred solution of 2.0 mol/L lithium diisopropylamide (LDA) (12.9 mL, 25.8 mmol) in THF/ethylbenzene/heptane at -78 C under argon (Ar), and after 30 min, iodomethane (CH3I) (2.0 mL, 32.2 mmol) was added slowly. The resulting solution was stirred for 5 h with the temperature changed from -78 to -40 C, then evaporated to dryness, and extracted with CH2Cl2 (50 mL). Evaporation of the solvent and purification of the residue by silica gel chromatography (n-hexane/AcOEt, 20:1) yielded the title compound as a colorless liquid (77.2%). 1H NMR (CDCl3) delta: 1.49 (3H, d, J = 7.1 Hz, alpha-CH3), 3.67 (3H, s, CO2CH3), 3.68 (1H, q, J = 7.1 Hz, CH), 7.18 (1H, t, J = 7.5 Hz, Ar-H5), 7.23 (1H, dt, J = 7.8, 1.7 Hz, Ar-H6), 7.38 (1H, dt, J = 7.3, 1.8 Hz, Ar-H4), 7.44 (1H, st, J = 1.7 Hz, Ar-H2). FAB-MS (m/z): 243.02 (M++H, calcd for C10H1279BrO2: 243.00). |
| 1.97 g |
With thionyl chloride; at 0℃; for 2h;Reflux; |
Example 5A: Methyl 2-(3 -bromophenyl)acetate j00225j 3-Bromophenylacetic acid (2.0 g, 9.30 mmol) was dissolved in MeOH (46.5mL) and cooled to 0 C. SOC12 (3.39 mL, 46.5 mmol) was added carefully dropwise.The reaction was then heated to reflux at for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 100% EtOAc in hexanes to yield Example 5A (1 .97g, 8.60 mmol). 1H NMR (400 MHz, CHLOROFORM-cl) oe ppm 7.44 (1 H, s), 7.36 - 7.43 (1 H, m), 7.15 -7.24 (2 H, m), 3.70 (3 H, s), 3.60 (2 H, s). |
|
With sulfuric acid; at 20℃; for 18h; |
[3-BROMOPHENYLACETIC] acid (14. [38G,] 66.90mmol) is dissolved in methanol (100 ml). Concentrated sulfuric acid (2 [ML)] is added dropwise and the reaction mixture is stirred at room temperature for 18 hours. 80% of the solvent is removed in vacuo and the reaction mixture is partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer is washed with water (150 ml) and brine (150 ml), dried over [MGSO4,] filtered and the solvent removed in vacuo to give the title compound. [1H] nmr [(CDCIA,] 400 MHz); 7.20 (m, 2H), 6.95 (m, 2H), 3.50 (s, 3H), 3.35 (s, 2H) |
|
With acetyl chloride; for 24h; |
a) (3-Bromo-phenyl)-acetic acid methyl ester; Acetyl chloride (5mL) was added to a solution of (3-bromo-phenyl)-acetic acid (1Og) in I0 methanol (25OmL). Evaporation after 24 hours afforded the subtitle product, as an oil (10.9g).1H NMR (300 MHz, CDCl3) delta 7.46 - 7.37 (m, 2H), 7.23 - 7.16 (m, 2H), 3.70 (s, 3H), 3.60 (s, 2H). |
|
With thionyl chloride; at 65℃; for 5h; |
Step 1: (3-Bromo-phenyI)-acetic acid methyl ester[00501] To 3-bromophenylacetic acid (5.027g, 23.4mmol) in MeOH (5OmL) was added thionyl chloride (3.4mL, 46.8mmol), and the reaction was stirred at 650C for 5 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. IN Aqueous NaOH was added to adjust the pH to basic, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO^ filtered, and concentrated to give the title compound. |
|
sulfuric acid;Heating / reflux; |
Example Il:; (5-{4-[2-(2,4-Dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl- isoxazol-3-yl} -phenyl)-acetic acid. [00159] Step A: 3-Bromophenyl acetic acid 45 (1.17 g, 5.44 mmol) is dissolved in MeOH (15 mL) containing catalytic amounts of cone. H2S04 (0.2 mL). The solution is heated to reflux overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHC03. The organic layer is dried (MgS04), filtered and concentrated to afford the methyl ester 46 as an oil: ¹H-NMR (400MHz, CDC13) No. = 7.44 (s, 1H), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, 1H), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calculated for C9HioBr02 (M+H+) 229.1, found 229.0. |
|
With hydrogenchloride; at 0 - 20℃; |
Hydrogen chloride is bubbled through MeOH (80 mL) and the solution is stirred at O0C for 10 minutes. (3-bromo-phenyl)-acetic acid (30 g, 139.5 mmol) is added in portions and the reaction is stirred overnight, while warming to room temperature. The solution is concentrated in vacuo and the residue is dissolved in EtOAc (200 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3-bromo-phenyl)-acetic acid methyl ester (32 g) used in the next step without further purification. MS: 230 (M+H); 1H NMR (300 MHz, CDCl3): delta 7.45 (2H, m), 7.25 (2H, m), 3.72 (3H, s), 3.6 (2H, s). |
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