* 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.
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[1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 581 - 586
2
[ 104-01-8 ]
[ 531-95-3 ]
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3
[ 104-01-8 ]
[ 491-80-5 ]
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4
[ 104-01-8 ]
[ 108-73-6 ]
[ 491-80-5 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 12, p. 3005 - 3008
5
[ 104-01-8 ]
[ 13435-12-6 ]
[ 7087-68-5 ]
Reference：
[1] Patent: US2003/18193, 2003, A1,
6
[ 104-01-8 ]
[ 4693-91-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With thionyl chloride In benzene for 1 h; Heating / reflux
16.62g (0.1 mol) of 4-methoxyphenylacetic acid was dissolved in 10ml of benzene before 29ml (0. 2 mol) of thionylchloride was added thereto. Then, the solution was heated and refluxed, and was stirred for one hour. Thionylchloride remaining in the reaction solution and the solvent was condensed to be removed to obtain 4-methoxy-phenyl-acetyl chloride (compound I), a liquid phase product, at a quantitative yield. The product was used without purification.
100%
for 2 h; Reflux
General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
88%
With thionyl chloride In <i>N</i>-methyl-acetamide; water
(i) 4-Methoxyphenylacetyl chloride Thionyl chloride (200 ml) was added to 4-methoxyphenylacetic acid (78 g, 0.47 mole) followed by one drop of dimethylformamide. The reaction was heated at 65° C. for 4 hours and the solvent was removed under vacuum. The residue was distilled in vacuo (water aspirator) at 135° C. to give the product as a red oil (75.9 g, 88percent).
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Stage #1: With thionyl chloride In dichloromethane at 0 - 20℃; Stage #2: With ammonia In dichloromethane; water
Example 6N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-methoxyphenyl)-acetamidePreparation of the starting material 2-(4-Methoxyphenyl)acetamide. A solution of 2-(4-methoxyphenyl)acetic acid (500 mg, 3.00 mmol) in DCM (30 ml) was added thionyl chloride (0.4 ml, 4.5 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and continued to stirred overnight. Then aqueous ammonia (2 ml) was added to the reaction mixture. The white solid forming was filtered and dried under vacuum to obtained 350 mg (70percent) of 2-(4-methoxyphenyl)acetamide as a white solid.
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13
[ 104-01-8 ]
[ 77287-34-4 ]
[ 6343-93-7 ]
Reference：
[1] Yakugaku Zasshi, 1942, vol. 62, p. 532; engl. Ref. S. 169[2] Chem.Abstr., 1951, p. 2861
With potassium nitrate; trifluoroacetic acid; In acetonitrile; at -10℃;
4-methoxyphenylacetic acid (5.00 g, 30.09 mmol) was dissolved in acetonitrile (450 mE), to which trifluoroacetic acid (16.73 mE, 120.36 mmol) was added. The temperature thereof was lowered to 10 C. Potassium nitrate (2.56 g, 30.09 mmol) was slowly added thereto, followed by stirring. Upon completion of the reaction, a new spot was formed under the starting material, which was confirmed by TEC. Water was added thereto to terminate the reaction, followed by neutralization with potassium carbonate. The water layer was extracted twice with ethylacetate. The ethylacetate layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Then, recrystallization was performed by using MC/Hex (methylchloride/hexane) to give the target compound 2-(4-methoxy-3-nitrophenyl)acetic acid (4.30 g, 20.36 mmol, yield: 68%).j0329] ?H-NMR (300 MHz, CDC13) oe 7.81 (s, 1H), 7.50- 7.47 (m, 1H), 7.08 (d, J=8.7 Hz, 1H), 3.96 (s, 3H), 3.67 (s, 2H); EC/MS 212 [M+H].
With trifluoroacetic acid; trifluoroacetic anhydride; at 20℃; for 12h;Inert atmosphere;
General procedure: A 10 mL glass vial with a screw cap was charged with benzoic acid 4a (0.75 mmol, 1.0 equiv), anisole 1a (1.125 mmol, 1.5 equiv), TFAA (2 equiv) and TFA (0.8 mL). The reaction mixture was stirred at room temperature for 12 h and monitored by TLC or GC-MS. Upon completion, the solvent was removed under reduced pressure and the residue was subjected to silica gel flash column chromatography (hexanes : AcOEt) to give ketone product 3o.
84%
Step 2. 1,2-Bis(4-methoxyphenyl)ethanone A solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.12 mmol) in thionyl chloride (50 mL) was stirred for 3 hr at reflux and then concentrated in vacuo to give a residue, which was dissolved in dichloromethane (10 mL) and then added dropwise to a solution of anisole (6.51 g, 60.28 mmol) and AlCl3 (11.97 g, 90.00 mmol) in dichloromethane (120 mL). The resulting solution was stirred for 3 h at room temperature, then diluted with water (100 mL), extracted with dichloromethane (3×80 mL), dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with (1%2% ethyl acetate in petroleum ether) to afford 1,2-bis(4-methoxyphenyl)ethanone as a white solid (6.5 g, 84%).(ES, m/z): [M+H]+ 257.01H-NMR (300 MHz, CDCl3) delta 7.99-8.03 (m, 2H), 7.18-7.23 (m, 2H), 6.84-6.97 (m, 4H), 4.17 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 3H)
70%
General procedure: PPA (H6P4O13, polyphosphoric acid, 1.7 g, 5.0 mmol) was added to a solution of substituted arenes (3.3 mmol) and phenylacetic acids (3.0 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. TFAA (trifluoroacetic anhydride, 850 mg, 4.0 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 8 h. The solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (320 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc=8/1-4/1) afforded 3.
Thionyl chloride (26 ml, 357.60 mmol, 1.64 g/ml) was added dropwise into the anhydrous methanol (100ml) at 0C. After the addition, p-methoxyphenylaceticacid16(9.90 g, 59.60 mmol) was added, the reaction was transferred to room temperature and reacted for 1h. The reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to give the compound17(11.91 g, 99% yield) as a white solid.1H NMR (400 MHz, CDCl3) delta 7.20 (d,J= 8.6 Hz, 2H), 6.89-6.83 (m, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.57 (s, 2H).HRMS (ESI) (m/z):calcdfor C10H12O3[M+H]+ 181.0865, found. 181.0861.
99%
With thionyl chloride; at 0 - 20℃; for 1.5h;
At 0 ,Constant pressure dropping funnel additionThionyl chloride(26ml, 357.60mmol, 1.64g / ml)To 100 ml of methanol, 4-methoxyphenylacetic acid (9.90 g, 59.60 mmol) was added. Transfer to room temperature and react for 1.5h. The methanol was removed by spinning, the ethyl acetate / water extraction was performed, and the ethyl acetate phase was rinsed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Ethyl acetate / n-hexane was recrystallized to obtain compound 21 (11.91 g, 99%) as a white solid
97%
With sulfuric acid; at 70℃; for 2h;
Intermediate 22 Methyl 2-(4-methoxyphenyl)acetate Into a 500-mL round-bottom flask, was placed 2-(4-methoxyphenyl)acetic acid (200 g, 1.20 mol), sulfuric acid (2 mL, 37.52 mmol) and MeOH (200 mL, 4.68 mol). The resulting solution was stirred for 2 h at 70C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with H20 (200 mL). The pH value of the solution was adjusted to 7 with sodium bicarbonate (5 mol/L). The resulting solution was extracted with DCM (3 x 300 mL) and the organic layers combined, dried (MgS04) and evaporated under reduced pressure. This resulted in methyl 2-(4-methoxyphenyl)acetate as brown oil (210g, 97%). 1H MR (300 MHz, CDC13, 26C) delta 3.78-3.89 (6H, s), 5.35 (1H, s), 6.85-6.90 (2H, d), 7.45-7.50 (2H, s).
96%
With sulfuric acid; for 16h;Heating / reflux;
Methyl (4-methoxyphenyl)acetate; A solution of 25.3 g (152 ml) of (4-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of cone, sulfuric acid and heated under reflux for 16 h. The <n="66"/>cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCI solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 26.4 g (96%) of colorless oil1H-NMR (DMSOd6): 3.59 (s, 2H), 3.60 (s, 3H), 3.73 (s, 3H), 6.87 (d, 8.6 Hz, 2H),7.17 (d, 8.6 Hz, 2H).MS (API-ES,pos) m/z = 181 [M+H]+
96.4%
With thionyl chloride; at 0℃; for 4h;Reflux;
Thionyl chloride (2.5 mg, 0.021 mmol, 0.003 equiv.) was addedto a solution of 2-(4-methoxyphenyl) acetic acid (1156 mg, 7 mmol, 1 equiv.) in methanol (5 mL) at0 C. Then, the reaction solution was refluxed for 4 h. The solution was concentrated under reducedpressure to give 3, which was used in the next step without further purification. Colorless oil. Yield:1215 mg, 96.4%. 1H NMR (600 MHz, CDCl3) delta 7.20 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 3.79(s, 3H), 3.68 (s, 3H), 3.57 (s, 2H). 13C NMR (150 MHz, CDCl3) delta 172.5, 158.8, 130.4, 126.2, 114.1, 55.4,52.1, 40.4. ESI-MS m/z 203.0 [M + Na]+.
96.82%
With sulfuric acid; at 40 - 50℃; for 2h;Large scale;
4-methoxyphenylacetic acid (35.00 kg), methanol (140 L) and sulfuric acid (1.03 kg) were stirred at 40 to 50 C. for 2 hours. A 25% caustic soda solution (3.37 kg) was added to the reaction solution, followed by concentration under reduced pressure. Toluene (140 L) and water (17.5 L) were added to the residue, and the mixture was stirred and then allowed to stand and separated. A 25% caustic soda solution (1.69 kg) and water (17.5 L) were added to the organic layer and the mixture was stirred and then allowed to stand and separated. The organic layer was washed with water and then concentrated under reduced pressure to obtain 4-methoxyphenylacetic acid methyl ester (36.75 kg, yield 96.82%).
95%
With hydrogenchloride; for 2h;Heating / reflux;
A solution of (4-methoxyphenyl) acetic acid (10 g, 0.06mol) in 5% methanolic HC12 was heated at reflux for 2hrs.After cooling to room temperature water was added andextracted with Et20. The combined organic extracts werewashed with saturated aqueous NaHC03 solution, dried (MgS04) ,filtered, and concentrated in vacua to afford (26) as paleyellow oil (10.34 g, 95%).1E NMR (400 MHz) 8 3.57 (s, 2H), 3.68 (s, 3H), 3.79 (s, 3H),6.86 (d, J= 8.6 Hz, 2H), 7.19 (d, J= 8.6 Hz, 2H).13C NMR (100MHz) 5 40.19, 51.92, 55.16, 113.92, 125.97,130.21, 158.62, 172.30.IR (thin film) cm"1 821, 1249, 1439, 1514, 1612, 1737, 2955.
95%
With sulfuric acid; at 100℃; for 0.25h;Microwave irradiation;
A solution of 5.02g of 4-methoxyphenylacetic acid, 47, (30.20mmol, 1.0 eq), 1.8mL of conc. sulfuric acid (33.69mmol, 1.2 eq) in 10mL of methanol was heated to 100C by microwave irradiation for 15min. The solvent was removed under reduced pressure. The oily residue was taken up in 100mL of dichloromethane and washed with saturated sodium bicarbonate solution (3×75mL). The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give 5.16g (95%) of a yellow oil [36]. 1H NMR (250MHz, CDCl3): delta=7.20 (d, 2H, 3J=8.7Hz, 2H,6H-PhOMe), 6.86 (d, 2H, 3J=8.8Hz, 3H,5H-PhOMe), 3.80 (s, 3H, C(O)CH3), 3.69 (s, 3H, -COOCH3), 3.57 (s, 2H, -CH2-); ESI-MS: m/z=178.8 [M-H]-.
93%
With sulfuric acid; at 0 - 80℃;
2-(2-(3,5-dimethylisoxazol-4-yl)benzofuran-5-yl)-N-((2,4-dimethylphenyl)(phenyl)methyl)-2- methylpropanamidea) methyl 2-(4-methTo a solution of 2-(4-methoxyphenyl)acetic acid (10.0 g, 60.24 mmol) in MeOH (80 mL) at 0 C was added dropwise cone. H2S04 (5 mL). The reaction was then refluxed at 80 C overnight. The reaction mixture was cooled to rt and MeOH was distilled out under reduced pressure. The resultant residue was dissolved in water and neutralized (pH=7) using saturated aq. NaHCC>3. The aqueous layer was extracted with EtOAc (3 x 100 mL), dried over Na2S04, and distilled under reduced pressure to provide the title compound (1 1.0 g, 93%). lH NMR (400 MHz, CDC13) delta ppm 7.22 (d, 2H), 6.87 - 6.90 (m, 2H), 3.81 (s, 3H), 3.71 (s, 2H), 3.59 (s, 3H).
89%
With sulfuric acid; for 5h;Reflux; Inert atmosphere;
(4-Methoxyphenyl)acetic acid (13) (30.30 g, 182.3 mmol) in concd H2SO4 (15.2 mL, 273.5 mmol) and MeOH (100 mL) was heated at reflux for 5 h. The light yellow solution was cooled to r.t., diluted with H2O (400 mL), and extracted with C6H6 (4 × 150 mL). The combined organic phases were washed with H2O (200 mL), 5% aq NaHCO3 (200mL), and H2O (200 mL). The solvents were removed by rotary evaporation, and the residue was distilled to give methyl (4-methoxyphenyl)acetate (29.35 g, 89%) as a colorless liquid; bp 98-102 C/1 torr(Lit.11b 116-117 C/2.5 torr).DIBAL-H in CH2Cl2 (1.0 M; 5.96 mL, 5.96 mmol) was transferred by syringe to a solution of methyl (4-methoxyphenyl)acetate (1.024 g, 5.68mmol) in PhMe (20 mL) at -78 C. After stirring for 1.5 h, the reaction mixture was quenched by the addition of aq HCl (1 N; 4 mL). The cloudy white mixture was stirred at -78 C for 15 min, allowed to warm to r.t. over 15 min, diluted with aq HCl (1 N; 20 mL), and extracted with Et2O (4 × 40 mL). The combined organic phases were washed with sat. aq NaHCO3 (40 mL) and dried over MgSO4. Removal of the solvents by rotary evaporation, followed by distillation of the residue, furnished 14 (686.4 mg, 80%) as a clear liquid; bp (Kugelrohr,1.8 torr) 150 C (Lit.11c 110-115 C/1 torr).
81%
With sulfuric acid;Reflux;
General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5% NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;
P-methoxy phenylacetic acid (90.0g, 542mmol), tetrahydrofuran (700 ml of), sodium borohydride (31.0g, 819mmol) and boron trifluoride etherate (108.5g, 894mmol) added to the reaction flask and the reaction was stirred at room temperature, the reaction was complete after adding an appropriate amount of water to provide an alkaline pH, extraction, washing, drying, the organic phase was concentrated under reduced pressure to give nearly colorless oil methoxybenzyl alcohol (81.0 g of), a yield of 98.3%.
63%
With 1,1,3,3-Tetramethyldisiloxane; copper(II) bis(trifluoromethanesulfonate); In toluene; at 80℃; for 16h;sealed tube;
General procedure: In a sealed tube, 29 mg Cu(OTf)2 (0.08 mmol, 8 mol %) and 0.7 mL TMDS (537 mg, 4 mmol, 8 Si-H mol/mol substrate) were introduced to a solution of aliphatic carboxylic acid (1 mmol) in 1.5 mL toluene. After stirring 16 h at 80 C, the reaction mixture was cooled to room temperature and quenched with 4 mL H2O. The organic layer was extracted with CH2Cl2, dried with anhydrous MgSO4, and evaporated under reduced pressure. The crude was purified by silica gel column chromatography to obtain the alcohol.
To a THF solution (0.2 M) of 4-methoxyphenylacetic acid (1 eq.) was added borane- methylsulfide complex (1.25 eq.) dropwise at 0 0C. The resulting solution was allowed to warm slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with 10% HCl. The organic layer was separated, washed further with 1 N aq. NaOH, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil that solidified upon standing.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
Commercially available 4-methoxyphenylacetic acid (16. 6g, 0.1 mol) was dissolved in acetic acid (120 mL) and stirred vigorously at approximately 0 C. A solution of elemental bromine (16.0 g, 0.1 mol) in acetic acid (40 mL) was added dropwise over 45 minutes, ensuring that the mixture did not freeze. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was collected, washed with water, brine and 5% aqueous NAHS03, filtered and concentrated in vacuo to give 3-bromo-4-methoxyphenylacetic acid (24.24 g, 98%) as a yellow powder.
86.0%
With bromine; acetic acid; at 20℃; for 24h;
To a 500mL round bottom flask was added 4-methoxy-phenylacetic acid (16.6g, 0.1mol), dissolved in acetic acid (150 mL), was added dropwise acetic acid (50 mL) diluted bromine (5.6mL, 0.11mol) at room temperature, dropwise completed, at room temperature 24h, quenched with a solution of sodium sulfite the unreacted bromine, the solvent was evaporated under reduced pressure, (50 mL), suction filtered, the filter cake was washed with water to give the residue in water, drained, and the filter cake was collected and dried to give a white solid after (20.9 g, yield 86.0%).
86.0%
In acetic acid; at 20℃; for 24h;
To a 500mL round bottom flask was added 4-methoxy-phenylacetic acid (16.6g, 0.1mol), dissolved in acetic acid (150 mL), was added dropwise acetic acid (50 mL) diluted bromine (5.6mL, 0.11mol) at room temperature, dropwise completed, at room temperature 24h, quenched with a solution of sodium sulfite the unreacted bromine, the solvent was evaporated under reduced pressure, (50 mL), suction filtered, the filter cake was washed with water to give the residue in water, drained, and the filter cake was collected and dried to give a white solid after (20.9 g, yield 86.0%).
86%
With bromine; In acetic acid; at 20℃; for 24h;
500mL round bottom flask was added 4-methoxy phenylacetic acid (16. 6g, 0. Lmol), with acetic acid (150 mL) was dissolved, was added dropwise acetic acid (50 mL) was diluted bromine (5. 6mL, 0 at room temperature. Llmol ), dropping was completed, the reaction at room temperature for 24h, quenched with a solution of sodium sulfite unreacted bromine complete, the solvent was evaporated under reduced pressure, (50 mL), suction filtered, the filter cake was washed with water to give the residue in water, drained, collected cake and dried to give a white solid (20. 9g, yield 86.0%)
With bromine; acetic acid; at 20℃;Product distribution / selectivity;
(1) Preparation of Compound 139; A?B; To a stirred solution of A (166 g, 1.0 mol) in AcOH (2.0 L) was added bromine (56 mL, 1.1 mol) drop-wise at room temperature. The solution was stirred overnight. When the reaction was completed, the solvent was evaporated off. The residue was extracted with EtOAc, washed with water and concentrated to give 225 g of B.
(5S,8R,13R,15aS)-8-[(S)-2-Amino-3-(4-methoxy-phenyl)-3-oxo-propionylamino]-5-hydroxymethyl-4,7,15-trioxo-tetradecahydro-10,11-dithia-3a,6,14-triaza-cyclopentacyclotetradecene-13-carboxylic acid[ No CAS ]
REFERENCE EXAMPLE 114 Methyl 2,4-dioxo-3-(4-methoxybenzyl)-1,2,3,4-tetrahydroquinazoline-5-carboxylate 4-Methoxyphenylacetic acid (11.5 g, 69.4 mmol) was suspended in toluene (200 ml) and then admixed sequentially with triethylamine (11.6 ml, 85.2 mmol) and diphenylphosphoric azide (17.9 ml, 85.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then heated under ref lux for 3 hours. The mixture was combined with <strong>[34529-06-1]dimethyl 3-aminophthalate</strong> (13.1 g, 62.4 mmol) obtained in Reference Example 102 and then heated under reflux further for 20 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluted with n-hexane-ethyl acetate (10:1, v/v) to give the title compound (8.49 g, 40%) as a white crystal. This product was used in the next reaction without further purification. 1H-NMR (CDCl3) delta: 3.77 (3H, s), 4.01 (3H, s), 5.14 (2H, s), 6.78-6.90 (3H, m), 7.09 (1H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz), 7.60 (1H, d, J=8.2 Hz), 9.52 (1H, bs).
With sodium hydroxide; nitric acid; acetic anhydride;
Step 1 Methyl 2-(3-Nitro4-methoxyphenyl)acetate An oven-dried 2-L, 3-neck round bottom flask, equipped with a mechanical stir motor, a low-temperature thermometer and an equalizing dropping funnel, was charged with acetic anhydride (631 mL) and subsequently cooled to -78 C. Fuming nitric acid (Baker, 90%, 27 mL) was added dropwise via the dropping funnel protected with a drying tube filled with CaCl2. After addition was completed, the reaction temperature was allowed to warm to 20 C. over 1 h. The reaction mixture was cooled to -78 C. again and added 4-methoxyphenylacetic acid (50 g, 0.28 mol) dropwise via the dropping funnel. After stirring at -50 C. for 1 h., the reaction mixture was allowed to warm to -30 C. over 20 min. and then cooled to -50 C. again. The reaction mixture was quenched with H2O (500 mL) at -50 C. and warmed up to room temperature and stirred for 0.5 h. The reaction mixture was partitioned between CH2Cl2 (500 mL) and H2O. The aqueous layer was extracted with CH2Cl2 (3*500 mL). The combined CH2Cl2 extracts were concentrated in vacuo to give a yellow oil. This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0 C. and stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 (500 mL) and H2O. The aqueous layer was extracted with CH2Cl2 (3*500 mL). The combined CH2Cl2 extracts were stirred with 2 M NaOH solution (1 L) for 1 h. The layers were separated and the organic layer was washed with H2O (500 mL), brine (500 mL), dried over Na2SO4 and filtered. The solvents were removed in vacuo to afford crude product as a light yellow solid (56 g). Purification by recrystallization from MeOH (600 mL) gave product. Yield 48 g (77%).
EXAMPLE 20 7-Chloro-3-(4-hydroxyphenyl)-2(1H)-quinolone 2-Amino-4-chlorobenzyl alcohol (4 g, 25.3 mol) and 4-methoxyphenyl acetic acid (14.0 g, 76.4 mmol) were reacted in a similar manner to that described in Example 19 to give 7-chloro-3-(4-methoxyphenyl)-2(1H)-quinolone; mp 256-257 C. (ethyl acetate).
2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]piperidine[ No CAS ]
2,6-dimethyl-1-[2-(4-methoxyphenyl)ethyl]piperidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; triethylamine; In benzene;
EXAMPLE 18 4-Methoxyphenylacetic acid (41.5 g., 0.25 mole) was converted to the corresponding acid chloride with 47.7 g. (0.4 mole) of thionyl chloride in benzene using the procedure described above in Example 1. The acid chloride thus produced (36.8 g., 0.2 mole) was reacted with 24.1 g. (0.21 mole) of 2,6-dimethylpiperidine in ether in the presence of 24.2 g. (0.24 mole) of triethylamine using the procedure described above in Example 1. The resulting 2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]piperidine (38.8 g., 0.15 mole) was reduced with lithium aluminum hydride and the product isolated in the form of the hydrochloride salt to give 15.32 g. of 2,6-dimethyl-1-[2-(4-methoxyphenyl)ethyl]piperidine hydrochloride, m.p. 195-200 C.
With thionyl chloride; triethylamine; In benzene;
Example 18 4-Methoxyphenylacetic acid (41.5 g., 0.25 mole) was converted to the corresponding acid chloride with 47.7 g. (0.4 mole) of thionyl chloride in benzene using the procedure described above in Example 1. The acid chloride thus produced (36.8 g., 0.2 mole) was reacted with 24.1 g. (0.21 mole) of 2,6-dimethylpiperidine in ether in the presence of 24.2 g. (0.24 mole) of triethylamine using the procedure described above in Example 1. The resulting 2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]piperidine (38.8 g., 0.15 mole) was reduced with lithium aluminum hydride and the product isolated in the form of the hydrochloride salt to give 15.32 g. of 2,6-dimethyl-1-[2-(4-methoxyphenyl)ethyl]piperidine hydrochloride, m.p. 195-200 C.
With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;
Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.
With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;
Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.
With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;
Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.
DIISOPROPYLAMINE (7. 4ml, 52. [8MMOL)] was added to anhydrous THF under argon. The solution was stirred and cooled to-35C in a dry ice/acetone bath and N-butyl lithium (1.6M, 31. 2ml, 50.4mmol) was added via a syringe over 2-3 mins, controlling the exotherm to [BELOW-20C.] After the addition was complete the reaction was cooled to-70C and a solution of 4-methoxyphenylacetic acid (3.89g, [24MMOL)] in THF (48ml) was transferred to the reaction mixture via a cannula, adding the solution dropwise and keeping the temperature below-55C. The reaction was stirred for 10 mins [AT-70C] and then allowed to warm up to [- L5C.] A solution [OF N-METHYL-N-METHOXY-4-FLUOROPHENYLCARBAMOYL] (4. [38G,] 26. [4MMOL)] in THF (48ml) was added via a dropping funnel dropwise, while the reaction mixture exothermed to [0C.] After addition was complete, the reaction was allowed to warm up to room temperature and stirred for 1.5 hours. The reaction was added to a stirred solution of concentrated hydrochloric acid [(13ML)] in water [(250ML),] and was stirred for 10 mins before the addition of ether. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine and dried (MgS04). The solvent removed in vacuo to give a sticky solid. This was triturated with methanol, and the resultant solid was dried under high vacuum to give a white solid (2.2g). Mp [107-109C] ; NMR [(200MHZ)] 3.78 (3H, s), 4.17 (2H, s), 6.87 (2H, d), 7.13 (4H, m), 8.03 (2H, dd).
Example 6N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-methoxyphenyl)-acetamidePreparation of the starting material 2-(4-Methoxyphenyl)acetamide. A solution of 2-(4-methoxyphenyl)acetic acid (500 mg, 3.00 mmol) in DCM (30 ml) was added thionyl chloride (0.4 ml, 4.5 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and continued to stirred overnight. Then aqueous ammonia (2 ml) was added to the reaction mixture. The white solid forming was filtered and dried under vacuum to obtained 350 mg (70percent) of 2-(4-methoxyphenyl)acetamide as a white solid.
4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenol; Step 1.; To a 2M solution of LDA in heptane (commercial rade; 66.2 ml) at 0C, under nitrogen, it was added 4-methoxyphenyl acetic acid (5.5 g; 33.09 mmol). After stirring at 0C for 40 minutes it was added iodomethane (13. 18 ml ; 211. 78 mmol). Allowed to warm to rt and stirred additional 30 minutes. The reaction mixture was then added to 200 ml of saturated ammonium chloride. Extracted 3x150 ml of ethyl ether. The aqueous phase was acidified with 1N HCl and extracted 2x150ml with ethyl ether. The latter organic phases were dried over sodium sulfate and concentrated to afford 5. 8 g of an oil which corresponded to a 2.5:1 mixture of 2-(4-methoxyphenyl)-2-methylpropanoic acid (bis-methylation product) to 2- (4-methoxyphenyl)propanoic acid (monomethylation product) which was used in the next step without any further purification.
413 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to -65 C., under a nitrogen atmosphere, 300 ml of THF are added, followed dropwise by a solution of 55 g of 4-methoxyphenylacetic acid in 70 ml of THF and the mixture is kept stirred for 3 hours at a temperature of less than -45 C. 64.5 g of <strong>[35112-28-8]methyl 2,4-dichlorobenzoate</strong> are then added dropwise and the mixture is kept stirred while the temperature is allowed to rise to 0 C. The reaction mixture is poured over an ice/1 liter 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluted with heptane and then with the heptane/AcOEt mixture to (90/10; v/v). 29 g of the expected compound are obtained.
1A) 1-(2,4-Dichlorophenyl)-2-(4-methoxyphenyl)ethanone 367 ml of NaHMDS (2M in THF) are added to 250 ml of THF and the mixture is cooled to -70 C. 54 g of (4-methoxyphenyl)acetic acid are then added; the mixture is left stirring for 2 hours and then 49 g of <strong>[35112-28-8]methyl 2,4-dichlorobenzoate</strong> are added. The reaction mixture is allowed to return to 10 C. and poured onto 2 litres of ice-cold HCl (2N), and the product is extracted with ether. After drying with a saturated sodium bicarbonate solution and then a saturated NaCl solution, drying the organic phase and evaporating, the product crystallizes from heptane; 32 g of the expected compound are obtained.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; at 0 - 70℃;
Step I: To a stirred solution of 6-bromo-3,4-dihydro-2H-benzo(1,4Joxazine (1.5 g, 7.0 mmol) in dichloromethane - dimethylforrnamide (1:1 mixture. 40 ml) was added 4- methoxyphenyl acetic acid (1.8 g, 10.5 mmol), HOBt (2.4 g, 17.5 mmol), diisopropyiethylamine (4.8 ml, 28 mmol ). EDCI.HCI (3.4 g . 17.5 mmol) at 0 C After 15 rnin, reaction mixture was heated to 70 C for 15 h. quenched by the addition of water. After usual work up, the compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to furnish 1-(6-bromo-2,3-dihydro-benzo[1.4]oxazin-4-yl)- 2-(4-methoxy-phenyl)-ethanone (1.8 g).1H NMR (400 MHz, CDCI3): delta 3.79 (s, 3H), 3.86 (bs, 4H), 4.14 (bs. 2H): 6.76 (ds J * 8.4 Hz, 1H), 6.86 (d. J « 8.8 Hz. 2H)1 7,16 (d, J * 8.4 Hz: 4H). MS (ES) iWz 364.0 (M+2).
With triethylamine; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃;
To a solution of [4-(methyloxy)phenyl]acetic acid (2.156 g, 12.97 mmol), ethyl 3- amino-1 H-pyrrole-2-carboxylate (2 g, 12.97 mmol) and triethylamine (1.989 mL, 14.27 mmol) in acetonitrile (60 mL) at RT was added drop-wise a solution of DCC (4.28 g, 20.76 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 2h before being filtered. The filtrate was concentrated under reduced pressure and extracted with EtOAc/ water then washed successively with sat. NaHC03 and brine. The organic layer was dried over Na2S04 and evaporated. The crude solid was dissolved in DCM and precipitated with cyclohexane, filtered and dried to give the desired product ethyl 3-([4-(methyloxy)phenyl]acetyl}amino)-1 H-pyrrole-2- carboxylate (1.5 g, 4.96 mmol, 38.2 % yield) as a cream powder. LCMS: (M+H)+ : 303; Rt: 2.83 min.
16A) 1-(2-Chloro-4-fluorophenyl)-2-(4-methoxyphenyl)ethanone 230 ml of a 2M solution of NaHMDS in THF are introduced into 250 ml of THF under nitrogen. The solution is cooled to -60 C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at -60 C., 33 g of <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> are added and the mixture is stirred at -60 C. for 45 min and then allowed to return to 0 C. The reaction medium is poured onto 500 ml of ice-cold 2N HCl and extracted with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying, concentrating to dryness and then crystallizing from pentane, 27.4 g of the expected compound are obtained.
With potassium carbonate; In acetonitrile; at 80℃;
General procedure: To the flame dried K2CO3 (14.5 g, 0.104 mol), were added 2-chloro-1-(2,4-difluorophenyl)ethanone (5.0 g, 0.026 mol) and 3,4-dichloro phenyl acetic acid (5.38 g, 0.026 mol) in acetonitrile (100 ml) at room temperature and the reaction mixture was refluxed for 4 h. It was then cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated and purified by column chromatography using pet ether-ethyl acetate (90:10) as eluent to give pure compound 3-(3,4-dichlorophenyl)-4-(2,4-difluorophenyl) furan-2(5H)-one (18b); Yield: 81%; Nature: Yellow solid; M. p. 127 0C; IR (Chloroform): nu max 1145, 1164, 1272, 1361, 1429, 1472, 1593, 1611, 1648, 1754, 2934, 3021, 3082, 3105 cm-1. 1H NMR (200 MHz, CDCl3): delta 5.18 (s, 2H), 6.84-6.98 (m, 2H), 7.15-7.26 (m, 2H), 7.41 (d, J=8 Hz, 1H), 7.55 (d, J=2 Hz, 1H). 13C NMR (200 MHz, CDCl3): delta 71.0 (d), 105.2 (t), 112.5 (d), 114.5(d), 125.7, 128.0, 129.5, 130.5 (2C), 130.9 (d), 132.7, 133.1, 152.3, 159.5 (dd), 164.6 (dd), 171.6. MS (ESI) m/z: 362.94 (M + Na).
[00263] Step 1 : To a -78 C solution of diisopropylamine (5.84 mL, 41.7 mmol) in THF (12 mL) was added a solution of 2.5 M butyllithium (16.7 mL, 41.7 mmol) in hexanes via a syringe. The mixture was stirred at -78 C for 10 minutes, warmed to 0 C for 5 minutes and cooled to -78 C for 10 minutes. A solution of 2-(4-methoxyphenyl)acetic acid (3.30 g, 19.9 mmol) in THF (12 mL) was added to the lithium diisopropylamide ("LDA") solution at - 78 C using a cannula. The reaction mixture was stirred at -78 C for 20 minutes, warmed to ambient temperature and stirred for 45 minutes. A solution of 1,3,2-dioxathiolane 2,2-dioxide (2.46 g, 19.9 mmol) in THF (12 mL) was added via a syringe. Dimethyl ether ("DME") (10 mL) was added, and the reaction mixture was refluxed for 16 hours. Cool to ambient temperature and concentrated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3 X). The combined organics were washed with saturated NaHC03, dried, filtered and concentrated to give 3-(4- methoxyphenyl)dihydrofuran-2(3H)-one (2.22 g, 58.2%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To a round-bottom flask (500 mL) that contained a solution of aryl sulfonamide (6 mmol), 4-dimethyaminopyridine (DMAP, 13 mmol), and 1-[3-(dimethyamino)-propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 13 mmol) in CH2Cl2 (150 mL) was added the synthesized phenylacetic acid (6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h, then cooled to 5 C, and acidified to pH 1 with addition of HCl aqueous solution (10%), which was followed by extraction with CH2Cl2/MeOH (9:1, 3 × 100 mL). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to silica gel chromatography or crystallization if necessary to afford the compounds (20-44) (Scheme 2).
With triethylamine; In toluene; at 80℃; for 3h;Inert atmosphere;
General procedure: NEt3 (0.57 mL, 4.00 mmol) was added dropwise to a suspension of 3-methoxyphenylacetic acid (0.60 g, 4.00 mmol) and [Ti(eta5-C5H5)2Cl2] (0.50 g, 2.00 mmol) in toluene (50 mL) at room temperature. The reaction mixture colour changed immediately from deep red to orange and was then stirred for 3 h at 80 C. The mixture was decanted and filtered to remove the triethylammonium chloride salt. The filtrate was then concentrated and cooled to -30 C to give orange crystals of the complex which were isolated by filtration.
With sodium sulfate; In methanol; at 50℃; for 24h;
General procedure: To a solution of substituted indole-3-carbaldehyde 1 (1.5 mmol) in methanol (5 mL) were addedsuccessively Na2SO4 (0.3 g), propargylamine 2 (1.1 equiv), acid 3 (1.1 equiv) and isonitrile 4(1.1 equiv) in a 25 mL RBF equipped with a magnetic stir bar. The reaction mixture was stirredat 50 C for 24 h. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and was extracted with water (50 mL). The organic layer was washed with brine(50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtain residuewhich was subjected to silica gel column chromatography (80% EtOAc in heptane) to afford thedesired product 5a-q as solid.
2-(4-methoxyphenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h;
General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%).
N,4-Dimethoxy-N-methylbenzamide (12s, Q= OCH3). To a suspension of 4- methoxyphenylacetic acid (1.02 g, 6.6 mmol) in DCM (21 ml) oxalyl chloride (1,2 ml, 13.8 mmol, 2.1 eq.) was added at 0C. After 3.5 h at 0C a slightly yellow solution was formed. The solution was added dropwise during 1 h to a suspension of N,O-dimethylhydroxylamine hydrochloride (1.09 g, 11 mmol) and triethylamine (9.6 ml, 6.91 g, 68 mmol, 10 eq.) in DCM(17 ml) at 0C. After 4 h when the temperature had reached it water (25 ml) was added to the reaction mixture. The organic phase was separated, washed with aq. sat. NaHCO3 (2x25 ml), aq. sat. NaC1 (20 ml), dried over Na2SO4 and concentrated at reduced pressure to afford a slightly yellow oil (0.83 g, 64%). The crude product was purified by silica gel flash chromatography (hept/EtOAc 3:1 to 0:1) to afford a colourless oil 12s (0.71 g, 55%).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 23℃;Inert atmosphere;
General procedure: To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid (12.0 mmol, 1.00 equiv) and dry dichloromethane (13 mL). The solution was stirred under nitrogen while DMAP (approx. 50 mg) and the alcohol (12.0 mmol, 1.00 equiv) were added. The solution was cooled to 0 C using an ice water bath and DCC (2.72 g, 13.2 mmol, 1.10 equiv) was added. The mixture was allowed to stir for five minutes at 0 C, and then the ice water bath was removed and the mixture was allowed to warm to 23C. Upon completion (as determined by TLC analysis), the heterogeneous mixture was filtered through Celite, rinsing with dichloromethane (20 mL). The filtrate was concentrated, suspended in dichloromethane, and filtered through Celite, washing with dichloromethane (20 mL). The filtrate was washed with 0.5 M aqueous hydrochloric acid (2 x 50 mL) and saturated aqueous sodium bicarbonate (1 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid ester (10.0 mmol, 1.00 equiv), p-ABSA (2.88 g, 12.0 mmol, 1.20 equiv), and dry acetonitrile (35 mL). The solution was stirred under nitrogen and cooled to 0 C using an ice water bath. DBU (1.65 mL, 11.0 mmol, 1.10 equiv) was added by syringe rapidly in one portion, and the reaction mixture was allowed to warm to 23 C and stir overnight. Upon completion (as determined by TLC analysis) or after 24 hours, whichever came first, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. The aryl diazoacetates were obtained in 12-50% yield over two steps.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
General procedure: An equimolar mixture of aralkanoic acid hydrazides 3 andsubstituted aromatic acids were mixed in phosphorous oxychlorideand heated under reflux at 107 C for 3 h. The reaction progresswasmonitored by thin layer chromatography. After consumption of thestarting material; the reaction mixture was cooled to room temperatureand poured into crushed ice which becomes precipitated.These precipitates was filtered, washed with cold water and diethylether, filtered and crystallized on methanol to get 2,5-disubstituted-1,3,4-oxadiazoles 4a-k. The product was purifiedwith column chromatography. 2.3.2. 2,5-Bis(4-methoxybenzyl)-1,3,4-oxadiazole (4a)Off white solid; yield: 71%; Rf: 0.64 (n-hexane: ethyl acetate,8:2); FTeIR (n/cm1): 3026 (sp2 CH), 2945 (sp3 CH), 1579 (CN),1551, 1498 (CC of phenyl ring); 1H NMR (400 M Hz, DMSO-d6)d 7.19e7.00 (m, 4H, aromatic proton), 6.98e6.89 (m, 2H, aromaticproton), 6.88e6.68 (m, 2H, aromatic proton), 3.66 (s, 2H, aliphaticCH2), 3.64 (s, 3H, methoxy proton), 3.60 (s, 2H, aliphatic CH2); 13CNMR (100 MHz, DMSO-d6) d 158.4, 155.1, 149.3, 147.0, 130.0, 127.6,125.8, 120.5, 114.1, 120.0, 56.1, 55.9, 31.5.
71%
With trichlorophosphate; at 107℃; for 3h;
The equimolar mixture of aralkanoic hydrazide (3) and substituted aromatic acids was mixed with phosphorus oxychloride and heated at reflux at 107 C. for 3 hours. The reaction process was monitored by thin layer chromatography, after which the starting material was consumed, the reaction mixture was cooled to room temperature and poured on ice to precipitate. These precipitates were filtered, washed with cold water and diethyl ether, filtered and crystallized with methanol,As a final product the 2 and 5-position substituted in 1,3,4-oxadiazole compound 4a to 4k was obtained.The product obtained was purified by column chromatography
2-(4-methoxybenzyl)-1H-benzo[d]imidazol-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; for 16h;Reflux;
General procedure: To a solution of the corresponding substituted alkyloxybenzene-1,2-diamine 4 (2.26 mmol) in 6N HCl (10 mL), corresponding acid 5 (6.80 mmol) was added. The resulting solution was refluxed for 16 h. The reaction mixture was cooled to 0 °C, diluted with EtOAc, and then pH was adjusted to ~ 7 by using solid NaHCO3, extracted with EtOAc. The combined organic extracts were washed with brine solution, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The crude mixture was subjected to flash silica gel (230?400 mesh) column chromatography to afford the title compounds 6a?f and 6h?s.
With [2,2]bipyridinyl; nitromethane; copper(II) sulfate; In nitromethane; N,N-dimethyl-formamide; at 130.0℃; for 8.0h;
General procedure: A round-bottom flask was charged with arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or 4 (1.0 mmol), CuSO4 (10 mol%), and 2,2?-bipyridyl (20 mol%). A pre-oxygen degassed solvent system of DMF/nitroalkane (1.5:0.5 mL) was added to above mixture. The resulting mixture was heated at 130 C for 8 h. The reaction progress was monitored by using TLC. After completion of the reaction, water was added to the mixture and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (anhyd Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (230-400 mesh silica gel, EtOAc/n-hexane) to afford imidazoles 3 or 5.
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(4-methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.
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