| 97% |
sulfuric acid;Heating / reflux; |
(3,5-Dimethoxy-phenyl)-acetic acid (10.0 g, 50.96 mmol) was dissolved in anhydrous methanol (100 ml_) and HaSO4 (1 ml_) was added dropwise. The reaction mixture was refluxed overnight. Cooled to room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and washed with a saturated aqueous NaHCO3 solution, water and dried (Na2SO4). The solvent was evaporated in vacuo to obtain (3,5-dimethoxy-phenyl)- acetic acid methyl ester (10.4 g, 97%). To a solution of (3,5-dimethoxy-phenyl)- acetic acid methyl ester (10.4 g, 49.5 mmol) in dimethyl formamide (40 mL), POCI3 (5.4 mL, 59.4 mmol) was added at 550C. After the addition, the reaction mixture was heated at 10O0C for 10 min. and then stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with ethyl EPO <DP n="107"/>acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain (2-formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.0 g, 85%). (2-Formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (5.0 g, 21.0 mrnol) was dissolved in CH3CN (100 mL), NaH2PO4 (0.655 g, 5.46 mmol) in water (2 mL) and H2O2 (2.3 mL, 20.99 mmol, 30%) were added. The reaction mixture was cooled to O0C and a solution of NaO2CI (2.65 g, 29.4 mmol) in water (5 mL) was added slowly. The reaction mixture was stirred at room temperature for 4 hours before being quenched by the addition of Na2SO3 solution. The mixture was acidified with 2 N HCI and extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 2,4-dimethoxy-6-methoxycarbonylmethyl-benzoic acid (5.25 g, 98%). To a solution of 2,4-dimethoxy-6-methoxycarbonylmethyl- benzoic acid (5.25 g, 20.6 mmoi) in methanol (50 mL), a solution of NaOH (4.12 g, 103 mmol) in water (20 mL) was added and the reaction mixture was allowed to stir at room temperature for 3 hours. The solvent was removed, diluted with water and acidified with 2 N HCI. The compound was extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 94%). To a suspension of 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 19.36 mmol) in toluene (50 mL) and acetic anhydride (2.01 mL, 21.3 mmol) were refluxed for 2 hours. After cooling to 0 0C, the precipitated solid was filtered off and washed with heptane and hexane to obtain 6,8-dimethoxy-isochroman-1 ,3-dione (3.56 g, 83%). |
| 97% |
With sulfuric acid;Heating / reflux; |
(3,5-Dimethoxy-phenyl)-acetic acid (10.0 g, 51 mmol) was dissolved in anhydrous methanol (100 mL) and H2SO4 (1 mL) was added drop-wise. The reaction mixture was refluxed overnight and cooled to room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and washed with a NaHCO3 solution, water and dried (Na2SO4). The solvent was evaporated in vacuo to obtain <strong>[4670-10-4](3,5-dimethoxy-phenyl)-acetic acid</strong> methyl ester in 97% (10.4 g) yield. To a solution of <strong>[4670-10-4](3,5-dimethoxy-phenyl)-acetic acid</strong> methyl ester (10.4 g, 49.5 mmol) in dimethyl formamide (40 mL), POCl3 (5.4 mL, 59.37 mmol) was added at 55 C. After the addition, the reaction mixture was heated at 100 C. for 10 min and then stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain (2-formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.0 g, 85%). (2-Formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (5.0 g, 21 mmol) was dissolved in CH3CN (100 mL), NaH2PO4 (0.655 g, 5.46 mmol) in water (2 mL) and 30% H2O2 (2.3 mL, 21 mmol). The reaction mixture was cooled to 0 C. and a solution of NaO2Cl (2.65 g, 29.4 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 4 h before being quenched by the addition of Na2SO3 solution. The mixture was acidified with 2 N HCl and extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g, 98%). To a solution of 2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g, 20.6 mmol) in methanol (50 mL), a solution of NaOH (4.12 g, 103 mmol) in water (20 mL) was added and the reaction mixture was allowed to stir at room temperature for 3 h. The solvent was removed, diluted with water and acidified with 2 N HCl. The compound was extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 94%). To a suspension of 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 19.4 mmol) in toluene (50 mL) was added acetic anhydride (2.01 mL, 21.3 mmol) and the reaction mixture was heated to reflux for 2 h. After cooling to 0 C., the precipitated solid was filtered off and washed with heptane and hexane to obtain 6,8-dimethoxy-isochroman-1,3-dione (3.56 g, 83%).To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0 C. (bath temperature -20 C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0+ C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).The above mixture (6.0 g) was dissolved in H2SO4 (30%, 30 mL) and heated at 100 C. for 2 h. The reaction mixture was cooled to room temperature and the precipitated solid was filtered off to obtain a mixture of acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester and 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (5.5 g). The above mixture (5.5 g) was dissolved in methanol (30 mL), K2CO3 (3.09 g, 22.4 mmol) and water (10 mL) were added and the reaction mixture was stirred at room temperature for 6 h. The solvent was removed and acidified with dilute HCl. The compound was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to leave a residue which was purified by chromatography (silica gel, 230-250 mesh; 2% methanol in dichloromethane) to obtain 3-(4-hydroxy-3,5-dim... |
| 97.6% |
With sulfuric acid; for 24h;Heating / reflux; |
Example 3a 3,5-Dimethoxyphenylacetic acid methyl ester To a solution of 3,5-dimethoxyphenylacetic acid (1.99 g, 10.0 mmol) (Transworld) in methanol (20 ML) was added concentrated sulfuric acid (1.0 ML) and the reaction mixture was heated at reflux for 24 hours.The reaction mixture was concentrated in vacuo.The residue was then diluted with ethyl acetate (100 ML) and successively washed with water (50 ML) and brine (50 ML), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3,5-dimethoxyphenylacetic acid methyl ester as a black oil which was used in the next step without further purification. (Yield 2.05 g, 97.6%). |
| 97% |
With sulfuric acid;Reflux; |
(3,5-Dimethoxy-phenyl)-acetic acid (10.0 g, 51 mmol) was dissolved in anhydrous methanol (100 mL) and H2SO4 (1 mL) was added drop-wise. The reaction mixture was refluxed overnight and cooled to room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and washed with a NaHCO3 solution, water and dried (Na2SO4). The solvent was evaporated in vacuo to obtain <strong>[4670-10-4](3,5-dimethoxy-phenyl)-acetic acid</strong> methyl ester in 97% (10.4 g) yield. To a solution of <strong>[4670-10-4](3,5-dimethoxy-phenyl)-acetic acid</strong> methyl ester (10.4 g, 49.5 mmol) in dimethyl formamide (40 mL), POCl3 (5.4 mL, 59.37 mmol) was added at 55 C. After the addition, the reaction mixture was heated at 100 C. for 10 min and then stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain (2-formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.0 g, 85%). (2-Formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (5.0 g, 21 mmol) was dissolved in CH3CN (100 mL), NaH2PO4 (0.655 g, 5.46 mmol) in water (2 mL) and 30% H2O2 (2.3 mL, 21 mmol). The reaction mixture was cooled to 0 C. and a solution of NaO2Cl (2.65 g, 29.4 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 4 h before being quenched by the addition of Na2SO3 solution. The mixture was acidified with 2 N HCl and extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 2,4-dimethoxy-6-methoxycarbonylmethyl-benzoic acid (5.25 g, 98%). To a solution of 2,4-dimethoxy-6-methoxycarbonylmethyl-benzoic acid (5.25 g, 20.6 mmol) in methanol (50 mL), a solution of NaOH (4.12 g, 103 mmol) in water (20 mL) was added and the reaction mixture was allowed to stir at room temperature for 3 h. The solvent was removed, diluted with water and acidified with 2 N HCl. The compound was extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 94%). To a suspension of 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 19.4 mmol) in toluene (50 mL) was added acetic anhydride (2.01 mL, 21.3 mmol) and the reaction mixture was heated to reflux for 2 h. After cooling to 0 C., the precipitated solid was filtered off and washed with heptane and hexane to obtain 6,8-dimethoxy-isochroman-1,3-dione (3.56 g, 83%). |
| 93% |
With sulfuric acid; at 80℃; for 1h; |
To a stirred solution of 2-<strong>[4670-10-4](3,5-dimethoxyphenyl)acetic acid</strong> (2 g, 10.2 mmol, 1 equiv) in MeOH (20 mL) was added 2 drops of con. H2S04 and heated to 80 C for 1 h. MeOH was removed under vacuum, reaction mixture was dissolved in EtOAc, and organic layer was washed with saturated NaHC03, dried over Na2S04 and concentrated to afford the desired product as pale yellow liquid (2.14 g, 93%). LC-MS (ES) m/z = 21 1 [M+H]+. H NMR (400 MHz, CDCI3) delta 3.51 (s, 2 H), 3.69 (s, 3 H), 3.78 (s, 6 H), 6.37 - 6.38 (m, 1 H), 6.43 (d, J=4.0 |
|
With thionyl chloride; at 0 - 20℃; |
Step 4: Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate To a solution of 2-<strong>[4670-10-4](3,5-dimethoxyphenyl)acetic acid</strong> (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0 C, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatographymass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20mL) and extracted by EtOAc (3 x 20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H1404 requires: 210, found: 211 [M+H]. |
|
With thionyl chloride; In methanol; at 0 - 20℃; |
Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate To a solution of 2-<strong>[4670-10-4](3,5-dimethoxyphenyl)acetic acid</strong> (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0 C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3*20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210, found: 211 [M+H]+. |
| 1071 g |
With sulfuric acid;Reflux; Large scale; |
Example 1 Synthesis of Compound (I) Step 1 2-(3,5-Dimethoxyphenyl)acetic acid (1000 g) was charged into appropriately sized three- neck RBF equipped with a condenser and dissolved with methanol (10 L). Concentrated sulfuric acid (20 g) was added and a solution was brought to gentle boiling. Reaction progress was monitored by HPLC. The reaction mixture was transferred to appropriately sized RBF and concentrated to ca. 3 L. and then co-evaporated with DMSO (3 L) to about 4 L and the residue containing methyl 2-(3,5-dimethoxyphenyl)acetate (1071 g) was telescoped to Step 2. |
|
With thionyl chloride; at 0 - 20℃; |
To a solution of 2-<strong>[4670-10-4](3,5-dimethoxyphenyl)acetic acid</strong> (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0 C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210, found: 211 [M+H]+. |
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