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CAS No. : | 121-34-6 | MDL No. : | MFCD00002551 |
Formula : | C8H8O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WKOLLVMJNQIZCI-UHFFFAOYSA-N |
M.W : | 168.15 | Pubchem ID : | 8468 |
Synonyms : |
4-hydroxy-3-methoxybenzoic acid
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.92 |
TPSA : | 66.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.1 |
Log Po/w (MLOGP) : | 0.74 |
Log Po/w (SILICOS-IT) : | 0.73 |
Consensus Log Po/w : | 1.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.02 |
Solubility : | 1.6 mg/ml ; 0.00952 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.44 |
Solubility : | 0.615 mg/ml ; 0.00366 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.32 |
Solubility : | 8.1 mg/ml ; 0.0482 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.42 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | for 48 h; Inert atmosphere; Reflux | Synthesis of ethyl 4-hydroxy-3-methoxybenzoate: In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, a solution of vanillic acid (10 g, 59.49 mmol) in EtOH (400 mL) was added. To the above solution 600 mg (6.11 mmol) of cone. H2SO4 was added. The mixture was then stirred at reflux temperature for 48 h. The solution was rotary evaporated. Water (100 mL) was then added to the residue and the separated greenish oil was then removed by using separately funnel. Product was then dried in vacuo to obtain 11.45 g (98 percent) of ethyl 4-hydroxy-3-methoxybenzoate. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (dd, J= 8.5, 2.1 Hz, 1H), 7.53 (d, J= 1.8 Hz, 1H), 6.91 (d, J= 8.6 Hz, 1H), 4.33 (q, J= 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J= 7.3 Hz, 3H). HPLC-MS: Expected: 197 (MH+); Found: 197. |
98% | for 48 h; Reflux; Inert atmosphere | In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, a solution of 4-hydroxy-3- methoxybenzoic acid (10 g, 59.49 mmol) in EtOH (400 mL) was added. To the above solution 600 mg (6.11 mmol) of cone. H2SO4 was added. The mixture was then stirred at reflux temperature for 48 h. The solution was rotary evaporated. Water (100 mL) was then added to the residue and a greenish oily compound separates out. The greenish oil was then separated and then dried in vacuo to 11.45 g (98 percent) of ethyl 4-hydroxy-3- methoxybenzoate. (0284) 1H NMR (400 MHz, Chloroform-d) δ 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H). HPLC-MS: Expected: 197 (MH+); Found: 197 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sulfuric acid; sodium hydrogencarbonate; mercury In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate | EXAMPLE 2 Preparation of ethyl 4-hydroxy-3-methoxybenzoate (ethyl vanillate) 50 g of vanillic acid and 250 ml of methanol were introduced into a reactor. 40 ml of sulfuric acid was introduced dropwise using a dropping funnel; cooling was carried out if the alcohol boiled. The mixture was refluxed for 2 hours with stirring. The mixture was cooled to room temperature, poured into 100 ml of ice water, and the alcohol was evaporated off under reduced pressure. The aqueous phase was extracted three times with ethyl ether. The combined organic phases were washed with a saturated solution of sodium bicarbonate until the pH was neutral, then washed once with water to eliminate the salts. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure (200 mm of mercury=2.6600 Pa) to obtain the crude ester. The ethyl ester was distilled at 132° C. under a reduced pressure of 2 mm of mercury (266 PA), then crystallized from petroleum ether (40°-60° C. fraction) to provide ethyl vanillate having a purity of more than 97percent at a yield of 80percent. The ethyl vanillate has a spicy vanilla scent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With nitric acid In acetic acid at 20℃; for 0.5 h; | To a solution of vanillic acid (20 g, 119 mmol) in acetic acid (200 mL) was added 60percent nitric acid (9.7 mL, 126.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 0.5 h, and then poured into ice-water. The resulting precipitate was filtered off, washed with water, and dried under vacuum to give the product as a yellow powder. The yield was 11.28 g (44percent), mp: 216-219°C (216°C)2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride for 12h; Reflux; | 3-Methoxy-4-(3-methylphenoxy)benzoic Acid (18h) Methyl 4-hydroxy-3- methyoxybenzoate was prepared in quantitative yield by Fischer esterification of the corresponding benzoic acid (3.04 g, 18.1 mmol) refluxed 12 h in methanol (50 mL) with catalytic dry HC1 (2 mL, 2 M in ether). The phenol (546.6 mg, 3 mmol) was combined with 3-iodotoluene (654 mg, 1.0 eq) and Cu20 (515 mg, 1.2 eq) in collidine (1 mL). The mixture was heated to 200 °C for 1 h in a sealed tube. The resulting solution was extracted with ether and washed with 2 N HC1. Silica gel (up to 50% EtOAc in hexanes) gave the desired intermediate ether (435 mg, 53%). The methyl ester was saponified with LiOH (3 eq) in dioxane/water (1 :1, 9.6 mL) at r.t. The resulting solution was acidified with 2 N H2S04, concentrated, filtered and washed with water to give 18h (355 mg, 46%). NMR (CDC13) δ , 3.96 (s, 3H). |
100% | With hydrogenchloride In diethyl ether Reflux; | 3-Methoxy-4-(3-methylphenoxy)benzoic Acid (18h). Methyl 4-hydroxy-3-methyoxybenzoate was prepared in quantitative yield by Fischer esterification of the corresponding benzoic acid (3.04 g, 18.1 mmol) refluxed 12 h in methanol (50 mL) with catalytic dry HCl (2 mL, 2 M in ether). The phenol (546.6 mg, 3 mmol) was combined with 3-iodotoluene (654 mg, 1.0 eq) and Cu2O (515 mg, 1.2 eq) in collidine (1 mL). The mixture was heated to 200° C. for 1 h in a sealed tube. The resulting solution was extracted with ether and washed with 2 N HCl. Silica gel (up to 50% EtOAc in hexanes) gave the desired intermediate ether (435 mg, 53%). The methyl ester was saponified with LiOH (3 eq) in dioxane/water (1:1, 9.6 mL) at r.t. The resulting solution was acidified with 2 N H2SO4, concentrated, filtered and washed with water to give 18h (355 mg, 46%). 1H NMR (CDCl3) δ, 3.96 (s, 3H). |
100% | With thionyl chloride at 0 - 20℃; Inert atmosphere; | 4 [0502] Preparation of Compound Int-1-1 [0503] To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2 (207 mL, 2.85 mol) and stirred at 0°C. under N2 atmosphere. The reaction mixture was allowed warm up to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and the pH was adjusted to 7-8. The mixture was extracted with distilled water (100 mL) and EA (200 mL2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-1-1 (54.2 g, quant) [0504] 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H). |
100% | With thionyl chloride at 0℃; for 2h; Reflux; Inert atmosphere; | |
100% | With thionyl chloride at 0 - 20℃; for 15h; Inert atmosphere; | 2 Preparation of compound Int-l-l To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2 (207 mL, 2.85 mol) at 0 °C under N2 atmosphere. After stirring for 15 hours at room temperature, the reaction was adjusted to have pH of 7 to 8 with saturated aqueous NaHCCb solution and then diluted with distilled water (100 mL) and EA (400 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-l-l (54.2 g, quant). NMR (400 MHz, CDCb) d 7.64 (dd, = 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H) |
100% | With thionyl chloride at 20℃; for 72h; Inert atmosphere; | 4 4-Hydroxy-3-methoxybenzoic acid methyl ester (10) Under argon, at room temperature, to a suspension of isovanillic acid (10.0 g, 59 mmol) in absolute methanol (100 mL) was added dropwise thionyl chloride (3.9 mL, 53.1 mmol). The resulting mixture was stirred at room temperature for 72 hours then concentrated under reduced pressure. The solid residue was poured into cold H2O (40 mL) and basified, under stirring, with saturated aqueous solution of NaHCCL until pH7-8. The remaining precipitate was collected by filtration affording 4- hydroxy-3-methoxybenzoic acid methyl ester (10) (10.8 g, quantitative) as a light brown solid. 1 H NMR (250 MHz, CDCL) d 7.63 (dd, J = 8.3 and 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H) and 3.88 (s, 3H); LCMS C9H10O4 Rt = 5.248 min, ESI+ m/z = 182.9 (M+H). |
100% | With thionyl chloride at 0 - 20℃; Inert atmosphere; | 29 Preparation of compound L-12-1 To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCh (207 mL, 2.85 mol) and the resulting mixture was stirred at 0 °C under N2 atmosphere, and then stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. The reaction was adjusted to pH 7 to 8 with saturated aqueous NaHCCb solution and then diluted with distilled water (100 mL) and EA (200 mL x 2). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound L-12-1 (54.2 g, quant) NMR (400 MHz, CDCb) d 7.64 (dd, J= 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H). |
100% | With thionyl chloride at 0 - 20℃; for 15h; Inert atmosphere; | 4.4.8.7 Preparation of compound lnt-1 -1 To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2(207 mL, 2.85 mol) at 0 °C under N2 atmosphere. After stirring for 15 hours at room temperature, the reaction was adjusted to have pH of 7 to 8 with saturated aqueous NaHCO3solution and then diluted with distilled water (100 mL) and EA (400 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-1-1 (54.2 g, quant).1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J= 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J= 8.4Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H). |
98% | With thionyl chloride at 20℃; | |
98% | With sulfuric acid Reflux; | 6.1 (1) Synthesis of methyl 4-hydroxy-3-methoxybenzoate (9) (1) Synthesis of methyl 4-hydroxy-3-methoxybenzoate (9) To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL of methanol was added 0.3 mL of conc. sulfuric acid, and refluxed overnight. The pH of the solution was shifted into an alkaline zone by addition of 5% aqueous NaHCO3 solution. Following extraction with EtOAc, the extract was washed with a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford the compound 9 (0.107 g, 98%). Yellow oil; 1H NMR (400 MHz, Acetone-d6) δ 8.390 (s, 1H), 7.561 (d, J=8.0, 7.538 (s, 1H), 6.911 (d, J=8.4, 1H), 6.516 (s, 2H), 3.904 (s, 3H), 3.831 (s, 3H). |
98% | With sulfuric acid Reflux; | Synthesis of methyl 4-hydroxy-3-methoxybenzoate. To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL ofmethanol was added 0.3 mL of conc. Sulfuric acid, andrefluxed overnight. The pH of the solution was shifted intoan alkaline zone by addition of 5 % aqueous NaHCO3solution. Following extraction with EtOAc, the extract waswashed with a saturated NaCl aqueous solution. It wasdried over MgSO4 and the solvent was removed by concentrationunder reduced pressure to afford the methyl4-hydroxy-3-methoxybenzoate (0.107 g, 98 %).Yellow oil; 1H NMR (400 MHz, acetone-d6) δ 8.390 (s,1H), 7.561 (d, J = 8.0, 1H), 7.538 (s, 1H), 6.911 (d,J = 8.4, 1H), 6.516 (s, 2H), 3.904 (s, 3H), 3.831 (s, 3H). |
96% | With hydrogenchloride In lithium hydroxide monohydrate Reflux; | |
96.1% | With thionyl chloride at 0 - 65℃; for 8h; | 6.1 Example 6 (1) Place 40.0g (0.24mol) of vanillic acid in a 500mL three-necked flask, add 200mL of methanol, cool down to 0°C in an ice bath, drop 20.8mL (0.28mol) of thionyl chloride, control the dripping speed to keep the temperature below 10 °C, the dropwise addition was completed for 1 h, and the temperature was raised to 65 °C and refluxed for 7 h. MeOH and remaining thionyl chloride were evaporated under reduced pressure, the residue was dissolved in 200 mL of DCM, washed twice with 60 mL of saturated sodium bicarbonate, once with 60 mL of saturated NaCl, and dried over anhydrous sodium sulfate for 12 h. Suction filtration, the filtrate was evaporated to dryness, and the obtained light blue liquid was left for 10 min to solidify to obtain methyl 4-hydroxy-3-methoxybenzoate (near white solid, 41.6 g, yield 96.1%). |
94% | With sulfuric acid for 12h; Reflux; | Synthesis of compound I: A 250 mL, round-bottomed flask with a stirring bar, a solution of 4-hydroxy-3-methoxybenzoic acid (20 g, 118.94 mmol) was added slowly to a solution of methanol (100 mL) and concentrated sulfuric acid (10 mL). After being stirred for 12 h at reflux, saturated solution of sodium bicarbonate was added to adjust the pH to 7. Dichloromethane was added and the mixture was then filtered and the organic phase evaporated on a rotary evaporator and to obtain the compound 2 (20.37 g, 94 %). Compound 2 (20.4 g, 111.98 mmol) was added into a 500 mL, round-bottomed flask with a stirring bar, then benzyl bromide (18 mL), potassium carbonate (22 g, 156.8 mmol), DMF (200 mL) were added. It was stirred for 6 h at 80 °C. Then the reaction system was poured into right amount of water, white solid (3) was obtained by filtration (28.97 g, 95 %). Compound 3 (16.54 g, 60.74 mmol) was dissolved in CH3COOH (50 mL) and then added into a 250 mL, round bottomed flask with a stirring bar. Then HNO3 (25 mL) was added into the system slowly to keep the temperature of the reaction above 5 °C. The reaction temperature was raised to 50 °C and kept for another 2 h. After that the system was poured into water and pale yellow solid (I) was obtained6-8 (18.3 g, 95%, m.p.: 134-135 °C). |
94.36% | With hydrogenchloride at 70℃; for 10h; | |
93% | With sulfuric acid for 16h; Heating; | |
93% | With sulfuric acid | |
92% | With sulfuric acid for 2h; Reflux; | 1.3.1 4-Hydroxy-3-methoxy-benzoic acid methyl ester (2) To a solution of vanillic acid 1 (3.00 g, 17.9 mmol) in methanol (100 mL) was added H2SO4 (98%, 2.5 mL). The mixture was heated under reflux for two hours, and after cooling was extracted three times with dichloromethane (3 x 50 mL). The combined organic layer was washed successively with 2 M NaHCO3 (20 mL) and brine (20 mL), followed by drying over anhydrous sodium sulphate, and concentrated under vacuum to yield compound 2 as colourless liquid (3.00 g, 16.5 mmol, 92%). M.p.: 62-65 °C (69-70 °C)1; 1H NMR: (400 MHz, CDCl3): δ 7.62-7.59 (dd, 1H, J = 8.4 Hz, 2.0 Hz, Ar), 7.52 (d, 1H, J = 1.2 Hz, Ar), 6.91 (d, 1H, J = 8.4 Hz, Ar), 3.89 (s, 3H, CH3OAr), 3.86 (s, 3H, COOCH3); 13C NMR: (400 MHz, CDCl3): 166.9 (C=O), 150.0, 146.2, 124.1, 122.1, 114.1, 111.7 (Ar), 56.0 (CH3OAr), 51.9 (COOCH3); ESI-TOF-HRMS: [M-H]+ calculated for C9H9O4: 181.0501, found 181.0508. |
91.5% | With hydrogenchloride In lithium hydroxide monohydrate for 12h; Heating / reflux; | 12.C C) 4-Hydroxy-3-methoxy benzoic acid methyl ester; A solution of 4-hydroxy-3methoxy benzoic acid (7.2 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (200 ml) and washed with water (50 ml) 10 % sodium bicarbonate solution (2 x 50 ml), water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 7.25 g of 4-hydroxy-3-methoxy benzoic acid methyl ester. (Yield = 91.5 %). 'H NMR CDC13 7.65 (lH, d, J 8Hz) 7.55 (1H, s) 6.95 (1H, d, J 8Hz) 6.15 (1H, bs, - OH) 3.95 (3H, s) 3.9 (3H, s). |
90% | With sulfuric acid for 8h; Reflux; | 3.1 4.3.1 Synthesis of methylvanillate Vanillic acid (15.0 g, 0.09 mol) was dissolved in methanol (75 mL). Sulfuric acid (2.1 mL) was added and the mixture was stirred and warmed to reflux for 8 h. After evaporation of methanol, the solid was dissolved in ethylacetate (60 mL), washed with a NaHCO3 solution (30 mL), water (2 times) and brine (1 time). The organic phase was evaporated under reduced pressure. Yield: 90%. 1H NMR (400 MHz, CDCl3, δ (ppm)): δ 7.45 (m, 2H, Ar), 6.88 (d, 1H, Ar), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3 ester). 13C NMR (400 MHz, CDCl3, δ (ppm)): δ 166,03 (OCH3 ester), 151.22 (Ar-C), 147.20 (Ar-C), 123.38 (Ar-C), 120.30 (Ar-C), 115.13 (Ar-C), 112.42 (Ar-C), 55.27 (OCH3), 51.60 (OCH3 ester). |
90.5% | With sulfuric acid for 48h; Reflux; | Synthesis of methyl 4-hydroxy-3-methoxybenzoate (1) To a 500 mL three-necked flask was added 4-hydroxy-3-methoxybenzoic acid (20.0 g, 0.19 mol)Methanol 250mL, concentrated sulfuric acid 0.8mL,Heated to reflux, after about 48h to stop the reaction.The methanol was distilled off, water was added to the residue, neutralized with a saturated K2CO3 solution,Extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate,Filtered, and the mother liquor was concentrated under reduced pressure to give a brown oil, washed with petroleum ether:Ethyl acetate (8: 1) was recrystallized,To give a white solid (1) (19.6 g, 90.5%), |
90.1% | With sulfuric acid Reflux; | 3.1 General procedure for the synthesis of compounds General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5%and water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives |
89% | With sulfuric acid Heating; | |
88.1% | With sulfuric acid at 100℃; for 2.5h; Autoclave; | 1.4 4) Synthesis of vanillic acid methyl ester 20.0 g Vanillic acid was dissolved in 250 mL of methyl alcohol, then 1 mL of concentrated sulfuric acid was added, and the mixture was stirred for 2.5 hours in a 100 ° C high pressure autoclave. The reaction solution was concentrated to 50 mL and dropped into 300 mL of 0 ° C water, and white crystals were precipitated. By filtration and drying, 19.1 g of the desired product was obtained. Yield: 88.1%, Melting point: 64 °C |
88.5% | With hydrogenchloride In lithium hydroxide monohydrate at 70℃; for 12h; | Synthesisof methyl 4-hydroxy-3-methoxybenzoate (2) To a solution ofvanillic acid (6.58 g, 39.13 mmol) in MeOH (50 ml) was added hydrochloric acid(4.4 ml). After stirring at 70 °C for 12 h, the solvent was removed undervacuum, affording an oily residue that was purified by flash chromatography.Elution with CH2Cl2/petroleum ether (3:1) afforded 2as a white solid (6.31 g, 88.5%), mp: 61.3-63.2°C. |
87% | With hydrogenchloride In lithium hydroxide monohydrate at 70℃; for 12h; | 1.1 The preparation of 6-methoxy-7-(3-N-morpholinylpropoxy)-3-nitro-4-N-anilino-quinoline is as follows: Step 1: 1 g of vanillic acid (5.95 mmol) was placed in a 50 mL round-bottomed flask. After 10 mL of methanol was added to dissolve the solution, 0.6 mL of concentrated hydrochloric acid was added and the mixture was heated to reflux at 70° C. for 12 hours. After completion of the reaction, 0.87 g of compound a, ie methyl vanillate, was obtained in a yield of 87%. Multiple reactions accumulate the mass of this compound. |
85.4% | With thionyl chloride at 20℃; for 20h; | |
68.2% | With sulfuric acid Reflux; | Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-methoxybenzoic acid (27a) To a solution of vanilic acid (0.67g, 4mmol) in 9ml of anhydrous methanol 0.25ml of Conc. Sulfuric acid (3.0mL) was added and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature,the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 5%sodium bicarbonate, water and brine. Then it was dried over sodium sulfate, filtered, and concentrated to get awhite solid (0.49 g, 68.2%). Methyl 4-hydroxy-3-methoxybenzoate (0.36g, 2mmol) and triphenylphosphine(2.62g, 10mmol) dissolved in 30 mL of dry THF at 0 °C. To the stirred mixture was added dropwise, over a periodof 2 h, a solution of N-(tertbutyloxycarbonyl)piperidin-4-ol (2.0g, 10 mmol) and DIAD (2.5g, 10 mmol) in 20mL of dry THF. The reaction mixture was stirred for 5 days at room temperature and monitored by TLC(Ethylacetate:Hexane-35:65) to see the consumption of starting material. The reaction mixture was diluted with50 mL of ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, andconcentrated to give a semisolid. This material was suspended in 100-200 mL of hexane/ethyl acetate (9:1),stirred, and filtered to remove triphenylphosphine oxide. Evaporation of the filtrate under reduced pressureyielded an oil that was purified by Flash column (hexane/ethyl acetate 6.5:3.5) to give an oil that solidified onstanding. This oil was then hydrolyzed to the free carboxylic acid using a similar procedure reported for thesynthesis of 11a. |
63% | With sulfuric acid for 24h; Reflux; Inert atmosphere; | |
With hydrogenchloride | ||
With sulfuric acid for 24h; | ||
With sulfuric acid | ||
With hydrogenchloride at 20℃; | ||
With sulfuric acid | ||
With sulfuric acid Heating; | ||
With sulfuric acid for 12h; Heating; | ||
With sulfuric acid at 40℃; for 2h; | ||
With sulfuric acid Reflux; | ||
With hydrogenchloride In diethyl ether for 12h; Reflux; | ||
With sulfuric acid for 12h; Reflux; | ||
With hydrogenchloride In lithium hydroxide monohydrate for 2h; Reflux; | ||
With thionyl chloride at 25℃; for 15h; Cooling with ice; | 3 Example 3 Preparation of Intermediate 3 5.502 g (2.73 mmol) of vanillic acid was weighed into a reaction flask containing 50 mL of anhydrous methanol.Then, 3 ml of SOCl2 was gradually added dropwise in an ice bath, and then the reaction solution was stirred at room temperature overnight.When the reaction was completed by TLC, the reaction mixture was concentrated under reduced pressure to give a white solid.White solid purity 95%,No further purification was carried out. | |
With sulfuric acid Reflux; | general procedure for the preparations of the methyl ferulate (2) and methyl vanillate (5) General procedure: To a stirred mixture of corresponding acids (5 mmol) in dry methanol (15 mL) was added concentrated sulfuric acid (0.027 mL, 0.5 mmol), and the reaction mixture was refluxed until the acid had completely reacted, as indicated by TLC. After cooling to 25 °C, ethyl acetate was added and the mixture washed with water and brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with (petroleum ether/EtOAc = 8:1) to afford the corresponding esters (90% yields), the 1H NMR data were in accordance with literature data (Yoshioka T et al. 2004). | |
With sulfuric acid for 8h; Reflux; | 4 Methyl Vanillate Synthesis 15 g of vanillic acid (0.09 mol) were dissolved in 75 mL of methanol. 2.1 mL of sulfuric acid were added and the mixture is stirred and warm to reflux for 8 h. After evaporation of methanol, the solid is dissolved in 60 mL of ethylacetate, washed with 30 mL of NaHCO3 solution, water (2 times) and brine (1 time). The organic phase is evaporated under reduced pressure. | |
With sulfuric acid for 8h; Reflux; | ||
With sulfuric acid for 10h; Reflux; | ||
With sulfuric acid Reflux; | ||
With thionyl chloride In methanol for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfuric acid; for 48h;Inert atmosphere; Reflux; | Synthesis of ethyl 4-hydroxy-3-methoxybenzoate: In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, a solution of vanillic acid (10 g, 59.49 mmol) in EtOH (400 mL) was added. To the above solution 600 mg (6.11 mmol) of cone. H2SO4 was added. The mixture was then stirred at reflux temperature for 48 h. The solution was rotary evaporated. Water (100 mL) was then added to the residue and the separated greenish oil was then removed by using separately funnel. Product was then dried in vacuo to obtain 11.45 g (98 %) of ethyl 4-hydroxy-3-methoxybenzoate. 1H NMR (400 MHz, Chloroform-d) delta 7.62 (dd, J= 8.5, 2.1 Hz, 1H), 7.53 (d, J= 1.8 Hz, 1H), 6.91 (d, J= 8.6 Hz, 1H), 4.33 (q, J= 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J= 7.3 Hz, 3H). HPLC-MS: Expected: 197 (MH+); Found: 197. |
98% | With sulfuric acid; for 48h;Reflux; Inert atmosphere; | In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, a solution of 4-hydroxy-3- methoxybenzoic acid (10 g, 59.49 mmol) in EtOH (400 mL) was added. To the above solution 600 mg (6.11 mmol) of cone. H2SO4 was added. The mixture was then stirred at reflux temperature for 48 h. The solution was rotary evaporated. Water (100 mL) was then added to the residue and a greenish oily compound separates out. The greenish oil was then separated and then dried in vacuo to 11.45 g (98 %) of ethyl 4-hydroxy-3- methoxybenzoate. (0284) 1H NMR (400 MHz, Chloroform-d) delta 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H). HPLC-MS: Expected: 197 (MH+); Found: 197 |
With sulfuric acid; for 10h;Reflux; | 4-Hydroxy-3-methoxybenzoic acid (20 g, 119 mmol) in ethanol (50 mL) was treated with concentrated sulfuric acid (3 mL) under reflux for 10 h. The solvent was evaporated until no longer liquid outflow. Water (20 mL) was added, extracting by adding respectively 30 mL ethyl acetate. After washing the organic phase with saturated NaCl solution (40 mL), drying it with anhydrous Na2SO4 and evaporating the solvent under reduced pressure. Crude product were purified by column chromatography, product 2 appeared. |
With hydrogenchloride; at 60℃; for 14h; | [0573j To a solution of 4-hydroxy-3-methoxybenzoic acid (6-A) (5 g, 29.7 mmol) in EtOH (20 mL) was added HC1. The mixture was stirred for 60C for 14 h. The reaction was concentrated to afford crude ethyl 4-hydroxy-3-methoxybenzoate (6-B) (4.6 g, 79% yield). | |
With sulfuric acid; In water; for 6h;Reflux; | General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | Hydroxychavicol (4-Allylbenzene-1,2-diol, 2); General Procedure General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
100% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | 28 Example 28 (vanillic acid demethylation) To a 100 ml eggplant flask were added aluminum triiodide (2.253 g), acetonitrile (40 ml), DIC (0.379 g) and Vanillic acid (0.838 g), heated to 80 ° C, and the reaction was stopped after stirring for 18 hours. Cold to room temperature after the eggplant bottle by adding 2mol / L dilute hydrochloric acid (lml) acidification, Extracted with ethyl acetate (50 ml X3) and the combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml) Washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness with a rotary evaporator, The residue was washed with dichloromethane (50 ml) and dried to dry weight, 0.768 g of protocatechuic acid white solid, yield 100%) was obtained. |
77% | With 1,4-dithio-D,L-threitol; phosphite dehydrogenase; phosphite ion; iron(II) sulfate; NADH In dimethyl sulfoxide at 30℃; for 7h; Enzymatic reaction; |
70% | With pyridinium hydrobromide perbromide In xylene for 1.5h; Heating; | |
65% | With pyridine; aluminium(III) iodide In acetonitrile at 80℃; for 18h; | General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 °C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%). |
65% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With pyridine; iodine; aluminium In acetonitrile for 18h; Reflux; Stage #2: With hydrogenchloride In water; acetonitrile at 20℃; | 12 Example 12 (vanillic acid demethylation) To a 100 ml eggplant flask were added iodine (2.100 g), aluminum powder (0.464 g) and acetonitrile (50 ml)Heated to reflux, stirring for 2 hours to the purple red of iodine disappears.Pyridine (1.622 g) and vanillic acid (0.844 g) were added and the reaction was continued for 18 hours. Stop stirring,After cooling to room temperature, 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. filter,The filtrate was evaporated to dryness with a rotary evaporator,The residue was purified by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 1,Volume ratio) to give the protocatechinic acid (white solid, 0.510 g, 65% yield). |
With hydrogenchloride at 150 - 160℃; im geschlossenen Rohr; | ||
With Pseudomonas fluorescens B56 (IFO 12055) at 30℃; for 8h; non-growing conditions; | ||
15.28 g | With aluminum (III) chloride; sodium iodide In dichloromethane at 30℃; for 5h; | 3.S2; 4.S2; 5.S2 S2: Add 15g of sodium iodide and 13g of aluminum chloride to the crude 4-hydroxy-3-methoxybenzoic acid solution, stir at 30°C for 5 hours,After the reaction, it was returned to room temperature, then poured into cold water, extracted with ethyl acetate, and the extract was rotary evaporated to obtain 15.28 g of protocatechuic acid with a yield of 99.2% and a product purity of 99.2% |
With 3-mercaptopropionic acid ethyl ester In aq. buffer at 30℃; for 24h; Inert atmosphere; Glovebox; Enzymatic reaction; | ||
With tetrahydrofuran; L-homocysteine; recombinant methionine synthase from Catharanthus roseus; recombinant O-demethylase from Sphingobium sp. SYK-6 In aq. buffer at 30℃; for 8h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloroform; chlorine | ||
With alkaline aqueous sodium hypochlorite solution |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | sulfuric acid; at 60℃; for 1h; | Vanillic acid (10 g) was heated at 6O0C for one hour with 10 ml acetic anhydride containing 2-3 drops of concentrated sulfuric acid. The hot mixture was poured into 100 ml ice cold water and extracted with 2x5 ml ether. The ether extract was dried and solvent removed, and finally dried on a vacuum line to obtain quantitative yield of acetyl vanillic acid as a dull white solid. |
85.5% | Vanillic acid (10.0 g) was added to a mixture of 150 mL of purified water and 16.5 mL of TEA, and 8.4 mL of acetic anhydride was added dropwise at 20C or lower. The mixture was stirred at room temperature overnight. Hydrochloric acid was added thereto to adjust the pH to 3.0, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered, washed with purified water and dried at 40C to obtain 10.7 g of the title compound as an ocher-colored solid. | |
77% | With sulfuric acid; at 80℃; for 6h;Inert atmosphere; | Ac2O (10 mL, 106 mmol) and vanillic acid (10 g, 59.5 mmol) were placed in a 100-mL round-bottom flask equipped with a magnetic stirring bar. A catalytic amount of H2SO4 (2 drops) was added and the mixture was heated to 80 C for 6 h. After the mixture was cooled to 0 C and H2O (100 mL) was added, the resulting yellow solid was collected by filtration, washed with H2O (4 × 10 mL) and air-dried at room temperature to obtain 10 (9.63 g, 77%) as a light-brown powder; mp 140-142 C (Lit.27 143-145 C).1H NMR (400 MHz, CDCl3): delta = 2.35 (s, 3 H, OCOCH3), 3.91 (s, 3 H,OCH3), 7.15 (d, J = 8.2 Hz, 1 H, H-5), 7.71 (d, J = 1.9 Hz, 1 H, H-2), 7.77(dd, J = 8.2, 1.9 Hz, 1 H, H-6).13C NMR (101 MHz, CDCl3): delta = 20.8 (ArOCOCH3), 56.2 (ArOCH3), 113.9(C-2), 123.1 (C-5), 123.6 (C-6), 128.0 (C-1), 144.5 (C-4), 151.3 (C-3),168.6 (ArCOCH3), 171.3 (COOH). |
72.9% | With sulfuric acid; at 80℃; for 4h; | General procedure: Ten grams of a monomer containing one or two hydroxyl groups were placed in a 100mL round-bottom flask on a magnetic stirring plate. Acetic anhydride was added in a slight stoichiometric excess with respect to the hydroxyl groups together with a catalytic amount of H2SO4. The mixture was heated to 80C and stirred for 4h. After cooling to 0C for 1h 200mL water was added to the mixture and the solution was filtered. The obtained crystals were washed with water and dried in vacuo at 40C overnight. All acetylated monomers were recrystallized at least once before usage in polymerization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 3-methoxy-4-hydroxybenzoic acid; methyl chloroformate With sodium hydroxide In water at 0 - 20℃; Stage #2: With hydrogenchloride In water | 1.A 1.A. Synthesis of 3-Methoxy-4-[(methoxycarbonyl)oxy]benzoic acid; 3-Methoxy-4-[(methoxycarbonyl)oxy]benzoic acid was synthesised according to the method described by K.Hallman (Tetrahedron: Asymmetry 10 (1999) 4037-4046): Vanillic acid (4 g, 23,8 mmoles) was dissolved in sodium hydroxide 0,5M (140 ml_, 70 mmoles) in water at 0°C under vigorous stirring. Methyl chloroformate (15 ml_, 37,9 mmoles) was added over a period of 10-15 minutes. The reaction was allowed to warm to room temperature then stirred overnight and quenched by adding HCI 2 M until a pH of 3 was reached. A white precipitate was obtained, filtered off, washed with water and finally dried. Yield : 93% of white crystals. |
80% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With sodium hydroxide Stage #2: methyl chloroformate In water at 5℃; for 4h; | |
With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydroxide for 5h; Heating; | |
92% | With sodium hydroxide for 5h; Heating; | |
71% | With sodium hydroxide for 5h; Heating; |
71% | Stage #1: 3-methoxy-4-hydroxybenzoic acid; 1-bromo-3-propanol With sodium hydroxide In water for 5h; Heating / reflux; Stage #2: With hydrogenchloride In water | 1.a Vanillic acid (C1)(114.5 g, 0.68 mol) was dissolved in a solution of sodium hydroxide (54.5 g, 1.36 mol) in water (40OmL). 3-Bromopropan-1-ol (101.3 g, 0.73 mol, 1.07 eq) was added and the mixture was heated under reflux for 5 hours. The mixture was cooled and acidified with 2.5 M HCI. The resulting precipitate was filtered and dried under vacuum. Recrystallisation from butan-2-one gave the product as an off white solid. (110 g, 71%). mp : 162°C; 1H NMR (DMSOd6, 400MHz) 57.56 (dd, 1H, J = 1.98 Hz, J = 8.39 Hz), 7.44 (d, 1 H, J = 1.96 Hz), 7.04 (d, 1H, J = 8.50 Hz), 4.55 (bs, 1H), 4.09 (t, 2H, J = 6.37 Hz), 3.80 (s, 3H, OMe), 3.57 (t, 2H, J = 6.20 Hz), 1.88 (p, 2H, J = 6.29 Hz); 13C NMR (IOO MHz, DMSO-Cf6) 5 167.1 , 152.0, 123.1 , 122.7, 112.0, 111.7, 65.3, 57.2, 55.4, 31.9; IR (CHCI3) 1673, 1596, 1585, 1517, 1425, 1271 , 1227, 1188, 1134, 1051 , 1026, 951 , 876, 814, 758 cm"1; MS (ES-) m/z (relative intensity) 225.04 ([M- H]"-, 100). |
With sodium hydroxide Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydroxide; In tetrahydrofuran; water; for 48h;Reflux; | A solution of diiodopropane (19.0 g, 58.6 mmol) in THF (75 mL) was added dropwise over a period of 4 hours to a vigorously stirred solution of vanilic acid (20.0 g, 119 mmol) in THF (150 mL) and aqueous NaOH (340 mL) at 65 in the absence of light (foil-wrapped flask) . After heating at reflux for 48 hours in the dark, the solution was cooled and the THF removed by evaporation in vacuo. The residue was extracted with EA, The aqueous layer was separated and acidified to pH 2 with conc. HCl. The resultant precipitate collected by filtration, washed, dried and recrystallised from glacial acetic acid to afford the corresponding bis-carboxylic acid (14.0 g, 34.7 mmol) . White solid, yield (60%) .. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In dichloromethane for 1h; Heating; | ||
With thionyl chloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; |
With thionyl chloride In 1,1-dichloroethane | 1.1 Potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl} butanoate Step 1 Potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl} butanoate 4-Hydroxy-3-methoxybenzoyl chloride, which was prepared from 4-hydroxy-3-methoxybenzoic acid (1.01 g) and thionyl chloride (0.53 ml), was dissolved in dichloroethane (10 ml). | |
With thionyl chloride In dichloromethane for 2.5h; | 1 2-(2-Methoxy-4-(spiro [benzo [b] pyrrolo [ 1 ,2-d] [1 ,4] oxazine-4,4 '- piperidine]-l'-ylcarbonyl)phenoxy)acetic acid [00512] Step 1: (4-Hydroxy-3-methoxyphenyl)(spiro [benzo [b] pyrrolo [1,2- d] [ 1 ,4] oxazine-4,4 '-piperidine] - 1 '-yl)methanone 4-Hydroxy-3-methoxy-benzoic acid (304 mg, 1.81 mmol) was stirred with thionyl chloride (645 mg, 395 μ, 5.42 mmol) in dichloromethane and 2 drops of DMF were added. After stirring for 2.5 h, the excess thionyl chloride and dichloromethane were removed in vacuo. The residue was added to a mixture of spiro[piperidine-4,4'-pyrrolo[2,l-c][l,4]benzoxazine] (500 mg, 1.81 mmol), 1,4-dioxane (6.5 mL), and triethylamine (760 μ, 5.42 mmol). The mixture was stirred for 18 h at 90 °C before it was cooled to room temperature and was evaporated to dryness. The residue was dissolved in ethyl acetate, filtered and washed with IN HC1 (2x), a saturated sodium bicarbonate solution (2x), and brine. The organic layer was dried over sodium sulfate and was evaporated to dryness. The residue was purified by column chromatography (0-100% EtO Ac/hex ane) to give (4-hydroxy-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[ 1 ,2-d] [ 1 ,4]oxazine-4,4'-piperidine]- 1 '-yl)methanone (394 mg, 56%). ESI-MS m/z calc. 390.2, found 391.2 (M+l)+; Retention time: 2.56 minutes (4 min run). | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; | Synthesis and structural characterization of oxadiazole derivatives General procedure: Furthermore, the acyl chloride was prepared by the reaction of compound 3 with SOCl2. Briefly, the compound 3 (2.58 g, 10 mmol) was suspended in 50 mL of dichloromethane. After a drop of (CH3)2NCHO was added, SOCl2 (1.16 mL, 16 mmol) was dropwisely added. The mixture was stirred at room temperature for 1 h then heated at 40 °C until the formed gas was removed completely. The solvent and excess of reagents were removed in vacuum, and the acyl chloride was used without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Reflux; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 16h; | 9 To a solution of 4-hydroxy-3-methoxy-benzoic acid (90.0 mg; 0.54 mmol) in DCM (1.8 mL) were added few drops of DMF. Oxalyl chloride (180 uL; 2.12 mmol) was added dropwise to this solution, which then was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum and the resulting yellow oil was dissolved in DCM (5.52 mL). This solution was added dropwise to a stirred mixture of l-(4-amino-phenyl)-cyclopentanecarbonitrile (100 mg; 0.54 mmol), prepared as in 3(B), and triethylamine (150 uL; 1.07 mmol) in DCM (4.6 mL). After stirring at room temperature for 3 hours, the solvent was evaporated under vacuum. The product was purified by preparative HPLC (Method Q), to yield the titled compound as a yellow oil (20.0 mg; 11% yield).1H NMR (300 MHz, CDC13) δ(ppm): 7.83 (br. s., 1 H), 7.64 (m, 2 H), 7.53 (d, 1 H), 7.43-7.50 (m, 2 H), 7.34 (dd, 1 H), 7.00 (d, 1 H), 3.99 (s, 3 H), 2.40-2.56 (m, 2 H), 1.84-2.17 (m, 6 H). LCMS (RT): 2.76 min (Method H); MS (ES+) gave m/z: 337.1 (MH+). | |
With thionyl chloride In N,N-dimethyl-formamide at 75 - 78℃; for 2h; | ||
With thionyl chloride In dichloromethane for 2h; Reflux; | 2.1. General procedure for the preparation of compounds 1-3 General procedure: Amides were prepared from corresponding acyl chloride, generatedin situ by reaction of carboxylic acid and thionyl chloride, followed bythe addition of 1-octylamine as previously described (Varela et al.,2018). Briefly, 1 mmol of corresponding carboxylic acid was reactedwith 1.5 mmol of thionyl chloride in dichloromethane (DCM) and refluxfor 2 h. After that, reaction mixture was cooled down to room temperatureand 1.5 mmol of triethylamine (TEA) was slowly added to thereaction mixture, followed by the addition of 1.5 mmol of N-octylaminepreviously dissolved in DCM. The reaction was stirred at room temperaturefor 18 h (Scheme 1). Reaction mixture was washed with purifiedwater, organic layer was dried with anhydrous Na2SO4 and solventevaporated. Crude material was purified through silica gel column usinghexane:ethyl acetate as eluent. | |
With thionyl chloride In dichloromethane for 2h; Reflux; | 2.1. General procedure for the preparation of compounds 1-3 General procedure: Amides were prepared from corresponding acyl chloride, generatedin situ by reaction of carboxylic acid and thionyl chloride, followed bythe addition of 1-octylamine as previously described (Varela et al.,2018). Briefly, 1 mmol of corresponding carboxylic acid was reactedwith 1.5 mmol of thionyl chloride in dichloromethane (DCM) and refluxfor 2 h. After that, reaction mixture was cooled down to room temperatureand 1.5 mmol of triethylamine (TEA) was slowly added to thereaction mixture, followed by the addition of 1.5 mmol of N-octylaminepreviously dissolved in DCM. The reaction was stirred at room temperaturefor 18 h (Scheme 1). Reaction mixture was washed with purifiedwater, organic layer was dried with anhydrous Na2SO4 and solventevaporated. Crude material was purified through silica gel column usinghexane:ethyl acetate as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydroxide In tetrahydrofuran; water for 48h; Heating; | |
74% | With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃; for 22h; | 2 The 4-(benzyloxy)-3-methoxybenzoic acid used as starting material was prepared as follows:- To a stirred solution of 4-hydroxy-3-methoxybenzoic acid (5 g, 30 mmol) in THF (15 mL) was added a solution of sodium hydroxide (3 g) in water (37.5 mL). The resulting mixture was cooled to 0°C and a solution of benzyl chloride (4.1 mL, 34. 8 mmol) in THF (15 mL) was added. The resulting mixture was allowed to wann to room temperature then heated to 70°C for 18 hours then to 90°C for 4 hours. The mixture was cooled and evaporated. The residual aqueous mixture was washed with isohexane then acidified with 2M hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with isohexane and dried giving the title compound (5.76 g, 74%); NMR Spectrum: (DMSOd6) 3.83 (s, 3H), 5.19 (s, 2H), 7.14 (m, 1H), 7.40 (m, 6H), 7.55 (dd, 1H), 12.69 (m, 1 H) ; Mass Spectrum : M-H-257. |
63% | With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃; | 2.A 2.A. Synthesis of 3-Methoxy-4-benzyloxy-benzoic acid; To a stirred solution of vanillic acid (5g, 30 mmol) in THF(15 ml_), a solution of NaOH (3g) in water (37 ml.) is added. The medium is cooled at 0°C and a solution of benzyl chloride (4.1 ml_, 34.8 mmol) is added. The medium is allowed to warm to room temperature and is then heated at 70°C for 18 hours and then at 90°C for 4 hours. After cooling to room temperature, the organic solvent is evaporated and the residual aqueous phase is acidified with 2M HCI. The precipitate is filtered and washed with cyclohexane to afford 4.8g of white solid. Yield : 63%. |
63% | Stage #1: 3-methoxy-4-hydroxybenzoic acid; benzyl chloride With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃; Stage #2: With hydrogenchloride In water | |
With sodium hydroxide | ||
With aq. NaOH In tetrahydrofuran | 1 Synthesis of 4-Benzyloxy-3-methoxybenzoic acid (2) Synthesis of 4-Benzyloxy-3-methoxybenzoic acid (2) A solution of benzyl chloride (24.6 ml, 209 mmol, 1.1 eq.) in THF (100 ml) was added dropwise at 0° C. over 15 min, to a mechanically stirred solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid, 1) (30 g, 179 mmol) in THF (90 ml) and 2.0 M aq. NaOH (225 ml). The mixture was allowed to warm to room temperature and then heated under reflux for 48 hours. After cooling, the mixture was washed with hexane (2*100 ml) and the THF was removed in vacuo. The remaining aqueous phase was acidified to pH 1 with conc. HCl. The resulting precipitate was collected by filtration, washed with water and dried to afford 4-benzyloxy-3-methoxybenzoic acid (2) as a pale amorphous solid. Yield (after recrystallisation from EtOAc) 31 g (67%); mp 171-172° C; IR (cm-1) 3700-3200, 2820-3000, 2210, 2140, 1670, 1600, 1580, 1510, 1450, 1430, 1410, 1380, 1340, 1300, 1265, 1220, 1180, 1130-1110, 1030, 1010; 1H NMR (CDCl3+DMSO-d6) δ 7.60 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz 1H), 7.30-7.44 (m, 5H), 6.90 (d, J=8.4 Hz, 1H), 5.19 (s, 2H), 3.91 (s, 3H); 13C NMR (CDCl3+DMSO-d6) δ 168.3, 151.7, 148.8, 136.3, 128.5, 128.0, 127.2, 123.7, 123.5, 112.5, 112.2, 70.6, 55.9; MS (EI) (m/z, relative intensity) 258 (M+, 20), 91 (100), 79 (3), 65 (10), 51 (3); EI-HRMS m/z 258.0949 (calc'd for C15H14O4 m/z 258.0892). | |
With sodium hydroxide In ethanol; water | S.5.1 Synthesis Example 5 (1) To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux. Then, 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The precipitate was filtered, washed with H2O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171-172.5°C. | |
Stage #1: 3-methoxy-4-hydroxybenzoic acid; benzyl chloride With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 30.5h; Heating / reflux; Stage #2: With hydrogenchloride; water | Preparation of 4-benzyloxy-3-methoxy-benzoic acid 5.0 grams of 4-hydroxy-3-methoxy-benzoic acid and 15 mL of THF were combined at room temperature. 37.5 mL of 2 N NaOH was added and the mixture cooled on ice. 4.0 mL of benzyl chloride was diluted with THF and added to the reaction mixture in a dropwise manner over 30 minutes. After the addition was complete, the mixture was warmed to room temperature and then refluxed. After a total of 30 hours of reflux, the reaction mixture was cooled to room temperature and washed twice with hexane. The aqueous THF phase was concentrated in vacuo such that most of the THF was removed and a solid remained. 50 mL of 1 N NaOH was added to give a slurry. Concentrated HCl was added slowly until all the material dissolved and the product then precipitated out of the acidic solution. After the pH was adjusted to 1, a white precipitate was filtered off and washed with 10% HCl. The precipitate was dissolved in hot ethyl acetate, separately, dried over sodium sulfate, filtered and the filtrate evaporated. The resulting solid was recrystallized from hot ethyl acetate. The yield of the first crop was 3.34 grams. Additional material could be isolated from the filtrate. Proton NMR was in agreement with the proposed structure. (lit. ref. Synthesis 1990 pp. 81-84 by Thurston et. al.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate In tetrahydrofuran at 20℃; for 1.5h; | |
73% | With diisopropoxytitanium(III) tetrahydroborate In dichloromethane for 4h; Ambient temperature; | |
69% | With D-glucose In aq. phosphate buffer at 30℃; for 29h; Enzymatic reaction; | 2.10. Reduction with whole cell biocatalyst General procedure: Glucose (22.2 mM), E. coli BL21(DE3)/pETDuet-1-PPTase-CAR (wet cells, 10 g), and the substrate (20a, 5.0 mM) were mixed in the sodium phosphate buffer (100 mL, 100 mM, pH 8). The resulting mixture was incubated at 200 rpm in a rotary shaker at 30°C, and the reaction was monitored by GC. After 29 h, the pH of the reaction mixture was adjusted to 2-3 with 2 M HCl and the mixture was filtered through a Celite pad to remove the biomass. The resulting aqueous solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was puriedby a silica gel column to give the product. |
With hydrogen In aq. phosphate buffer at 50℃; for 24h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With potassium carbonate In acetone at 20℃; for 0.166667h; Stage #2: dimethyl sulfate In acetone for 6h; Reflux; | 4.1.2. General procedure for synthesis of methyl 3,4-dimethoxybenzoate(2d) 4-hydroxy-3-methoxybenzoic acid 1c (1.68 g, 10 mmol) were solubilizedin 20 ml of acetone and potassium carbonate (1.38 g, 10 mmol)was added. The mixture was stirred for 10 min at room temperature.Then of dimethyl sulfate (3.8 ml, 40 mmol) was added dropwise,keeping the reaction at reflux for 6 h. After this time, the reactionmixture was then filtered to remove K2CO3 and acetone was evaporated.The filtrate was diluted with distilled water (25 ml) and extracted withethyl acetate (3 × 20 ml). The organic phase was dried over anhydroussodium sulfate, and the solvent was removed in a rotary evaporator. Thecompound was obtained pure in 70% yield. |
With potassium carbonate In acetone for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With nitric acid; In acetic acid; at 20℃; for 0.5h; | To a solution of vanillic acid (20 g, 119 mmol) in acetic acid (200 mL) was added 60% nitric acid (9.7 mL, 126.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 0.5 h, and then poured into ice-water. The resulting precipitate was filtered off, washed with water, and dried under vacuum to give the product as a yellow powder. The yield was 11.28 g (44%), mp: 216-219C (216C)2. |
With nitric acid; acetic acid; at 10 - 23℃; | Vanillic acid (75g) was suspended in acetic acid (788g). The suspension was cooled to 10C to 15C and nitric acid (49g or 65% solution) was added over three hours at a rate which kept temperature between 10 C and 20 C. The resulting yellow orange was stirred for a further one hour at 18C to 23C. The suspension was filtered off, washed with acetic acid, then a mixture of acetic acid and water (1/2) and then water. Yield of 53% of a 87.9% pure product was obtained. The above crude product was suspended in acetic acid and warmed to 105C to 110C until an orange brown solution is obtained. The solution was transferred to the crystallization vessel via a charcoal filter (or polish filtration) at a temperature above 85C (optional step). The solution was then cooled to 80C to 85C. The mixture was stirred for one hour at 70C to 80C (optionally at 75C) during which crystallization occurred. The product suspension was cooled to 20C to 25C for 17 hours or stirred for at least 12h at 20 C to 25 C. The product suspension was filtered and washed with acetic acid, then acetic acid/ water (1/2) and finally water. The product was dried under vacuum at 50C to 55C. The yield of 70% corresponds to an overall yield of 44% for both parts of this preparation. The purity of the product assayed at 99.7% . The preceding crystallization step is optional and the solution may be transferred to the crystallization vessel via polish filtration instead of via a charcoal filter. The post crystallization suspension may be stirred for at least 12 hours at 20 C to 25 C as an alternative to 17 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H+ / ethanol 2: NaOEt 3: NaOH | ||
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 60 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: sodium hydroxide; water / ethanol / 2 h / Reflux |
Multi-step reaction with 3 steps 1: sulfuric acid / 24 h / Reflux; Inert atmosphere 2: potassium iodide; potassium carbonate / acetone / Inert atmosphere; Reflux 3: sodium hydroxide / ethanol / 2 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 75 °C / Inert atmosphere 2: sodium hydroxide / tetrahydrofuran / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide; potassium iodide; potassium carbonate In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide | 5 EXAMPLE 5 The starting material was prepared as follows: A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated. The residue was dissolved in ethanol (50 ml), 2M sodium hydroxide (50 ml) was added and the mixture heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%). 1H NMR Spectrum: (DMSOd6, TFA) 2.17-2.24(m, 2H); 3.10-3.16(m, 2H); 3.30(t, 2H); 3.52(d, 2H); 3.71(t, 2H); 3.82(s, 3H); 4.01(brd, 2H); 4.14(t, 2H); 7.08(d, 1H); 7.48(d, 1H); 7.59(dd, 1H). MS-ESI: 296 [MH]+ |
97% | With sodium hydroxide; potassium iodide; potassium carbonate In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide | 18 EXAMPLE 18 The starting material was prepared as follows: A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated. The residue was dissolved in ethanol (50 ml), 2 M sodium hydroxide (50 ml) was added and the mixture heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%). 1H NMR Spectrum: (DMSOd6; T1FA) 2.17-2.24(m, 2H); 3.10-3.16(m, 2H); 3.30(t, 2H); 3.52(d, 2H); 3.71(t, 2H); 3.82(s, 3H); 4.01(br d, 2H); 4.14(t, 2H); 7.08(d, 1H); 7.48(d, 1H); 7.59(dd, 1H) MS-ESI: 296 [MH]+ |
97% | With sodium hydroxide; potassium iodide; potassium carbonate In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide | 3 EXAMPLE 3 The starting material was prepared as follows: A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in ethanol (50 ml), 2M sodium hydroxide (50 ml) was added and the mixture was heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%). 1H NMR Spectrum: (DMSOd6, TFA) 2.17-2.24(m, 2H); 3.10-3.16(m, 2H); 3.30(t, 2H); 3.52(d, 2H); 3.71 (t, 2H); 3.82(s, 3H); 4.01(br d, 2H); 4.14(t, 2H); 7.08(d, 1H); 7.48(d, 1H); 7.59(dd, 1H) MS-ESI: 296 [MH]+ |
97% | Stage #1: 4-(3-chloropropyl)morpholine; 3-methoxy-4-hydroxybenzoic acid With potassium carbonate; potassium iodide In DMF (N,N-dimethyl-formamide) at 100℃; for 3h; Stage #2: With sodium hydroxide In ethanol; water at 90℃; for 2h; Stage #3: With hydrogenchloride In ethanol; water | 2 Example 2 A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5g, 26.8mmol), 3-morpholinopropyl chloride (9.5g, 58.0mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0g, 58mmol), potassium iodide (1.0g, 0.22mmol) and DMF (80ml) was stirred and heated at 100°C for 3 hours. The solid was removed by filtration and the volatiles were removed by evaporation. The residue was dissolved in ethanol (50ml), 2M sodium hydroxide (50ml) was added and the mixture heated at 90°C for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65g, 97%). 1H NMR Spectrum: (DMSOd6; TFA) 2.17-2.24(m, 2H); 3.10-3.16(m, 2H); 3.30(t, 2H); 3.52(d, 2H); 3.71(t, 2H); 3.82(s, 3H); 4.01(br d, 2H); 4.14(t, 2H); 7.08(d, 1H); 7.48(d, 1H); 7.59(dd, 1H) MS - ESI: 296 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide; potassium iodide; potassium carbonate; In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide; | The starting material was prepared as follows: A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g, 50 mmol), 3-(pyrrolidin-1-yl)propyl chloride (14.75 g, 0.1 mol), (prepared according to J. Am. Chem. Soc. 1955, 77. 2272), potassium carbonate (13.8 g, 0.1 mol) and potassium iodide (1.66 g, 10 mmol) in DMF (150 ml) was stirred and heated at 100 C. for 3 hours. The mixture was allowed to cool and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in ethanol (75ml), 2M aqueous sodium hydroxide (75 ml) was added and the mixture was heated at 90 C. for 2 hours. The mixture was concentrated by evaporation, acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.2 g, 77%). 1H NMR Spectrum: (DMSOd6, CF3CO2D) 2.2(m, 2H); 3.15(t, 2H); 3.3(t, 2H); 3.5(d, 2H); 3.7(t, 2H); 3.82(s, 3H); 4.05(d, 2H); 4.15(t, 2H); 7.07(d, 1H); 7.48(s, 1H); 7.59(d, 1H). MS-EI: 279 [M]+ |
With sodium hydroxide; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | The starting material was prepared as follows: A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4g, 50mmol), 3-(pyrrolidin-1-yl)propyl chloride (14.75g, 0.1mol), (J. Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (13.8g, 0.1mol) and potassium iodide (1.66g, 10mmol) in DMF (150ml) was stirred and heated at 100C for 3 hours. The mixture was allowed to cool and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in ethanol (75ml), 2M aqueous sodium hydroxide (75ml) was added and the mixture was heated at 90C for 2 hours. The mixture was concentrated by evaporation, acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.2g, 77%). 1H NMR Spectrum: (DMSOd6, CF3CO2D) 2.2(m, 2H); 3.15(t, 2H); 3.3(t, 2H); 3.5(d, 2H); 3.7(t, 2H); 3.82(s, 3H); 4.05(d, 2H); 4.15(t, 2H); 7.07(d, 1H); 7.48(s, 1H); 7.59(d, 1H) MS - EI: 279 [M·]+ | |
With aqueous sodium hydroxide; concentrated aqueous hydrochloric acid; potassium iodide; potassium carbonate; In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide; | A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g), 3-(pyrrolidin-1-yl)propyl chloride (J. Amer. Chem. Soc., 1955, 77, 2272; 14.75 g), potassium carbonate (13.8 g), potassium iodide (1.66 g) and DMF (150 ml) was stirred and heated to 100 C. for 3 hours. The mixture was allowed to cool to ambient temperature, filtered and the filtrate was evaporated. The residue was dissolved in ethanol (75 ml), 2N aqueous sodium hydroxide solution (75 ml) was added and the mixture was heated to 90 C. for 2 hours. The mixture was concentrated by evaporation and acidified by the addition of concentrated aqueous hydrochloric acid. The resultant mixture was washed with diethyl ether and then purified by column chromatography using a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH 2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzoic acid hydrochloride (12.2 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.2 (m, 2H), 3.15 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.7 (t, 2H), 3.82 (s, 3H), 4.05 (d, 2H), 4.15 (t, 2H), 7.07 (d, 1H), 7.48 (s, 1H), 7.59 (d, 1H). |
With sodium hydroxide; concentrated aqueous hydrochloric acid; potassium iodide; potassium carbonate; In hydrogenchloride; methanol; ethanol; N,N-dimethyl-formamide; | A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g), 3-(pyrrolidin-1-yl)propyl chloride (J. Amer. Chem. Soc., 1955, 77, 2272; 14.75 g), potassium carbonate (13.8 g), potassium iodide (1.66 g) and DMF (150 ml) was stirred and heated to 100 C. for 3 hours. The mixture was allowed to cool to ambient temperature, filtered and the filtrate was evaporated. The residue was dissolved in ethanol (75 ml), 2N aqueous sodium hydroxide solution (75 ml) was added and the mixture was heated to 90 C. for 2 hours. The mixture was concentrated by evaporation and acidified by the addition of concentrated aqueous hydrochloric acid. The resultant mixture was washed with diethyl ether and then purified by column chromatography using a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluding with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzoic acid hydrochloride (12.2 g); NMR Spectrum: (DMSOd; and CF3CO2D) 2.2 (m, 2H), 3.15 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.7 (t, 2H), 3.82 (s, 3H), 4.05 (d, 2H), 4.15 (t, 2H), 7.07 (d, 1H), 7.48 (s, 1H), 7.59 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 90℃; | 12 Example 12; 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl] amino] phenyl]-benzamide vanillate; A solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid; Fluka, Buchs, Switzerland; 694 mg, 4 mmol) in ethanol (50 mL) is added to a solution of 4- [ (4-methyl-1-piperazinyl) methyl]- N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol (150 mL at 90°C). The solution is evaporated to dryness under reduced pressure and the resulting residue is re-crystallized from ethanol-acetone. The product is filtered-off and dried to afford 4- [ (4-methyl-1-piperazinyl) methyl]-N- [4-methyl-3- [ (4- (3- pyridinyl)-2-pyrimidinyl] amino] phenyl]-benzamide, vanillate as a crystalline solid, having the following analytical properties: Analysis found: C, 66.61 ; H, 6.18 ; N, 14.74 ; O, 12.86%. H2O, 0.84%. Calculated for C37H39N705-0. 31 H20 : C, 66.59 ; H, 5.98 ; N, 14.69 ; O, 12.73%. H2O, 0.84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A. Esterification of 3-methoxy-4-hydroxybenzoic Acid to Yield ethyl-3-methoxy-4-hydroxybenzoate. | ||
(i) Estenrfication of 3-methoxy-4-hydroxybenzoic acid to Yield ethyl-3-methoxy-4-hydroxybenzoate. | ||
(i) Esterification of 3-methoxy-4-hydroxybenzoic acid to yield ethyl-3-methoxy-4-hydroxybenzoate. |
A. Esterification of 3-methoxy-4-hydroxybenzoic acid to yield ethyl-3-methoxy-4-hydroxybenzoate. | ||
A. Esterification of 3-methoxy-4-hydroxybenzoic Acid to Yield Ethyl-3-methoxy-4-hydroxybenzoate. | ||
A. Esterification of 3-methoxy-4-hydroxybenzoic Acid to Yield ethyl-3-methoxy-4-hydroxybenzoate. | ||
With sulfuric acid; In ethanol; dichloromethane; | A. Esterification of 3-methoxy-4-hydroxybenzoic acid to yield ethyl-3-methoxy-4-hydroxybenzoate A solution of 100 g of 3-methoxy-4-hydroxybenzoic acid and 17 g of concentrated sulfuric acid in 300 mL of absolute ethanol was heated at reflux overnight. The mixture was concentrated and the residue poured into water. Methylene chloride was added and the solution washed successively with water, dilute sodium bicarbonate and water, then dried and concentrated. Yield: 118 g | |
A. Esterification of 3-methoxy-4-hydroxybenzoic acid to yield ethyl-3-methoxy-4-hydroxybenzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In ethanol | 5.1 Synthesis of 2,6,9-tris(4-hydroxy-3-methoxybenzoyloxy)anthracene (1) To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux, then 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2 O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The resulting precipitate was filtered, washed with H2 O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171°-172.5°. 1 H-NMR δ ppm (DMSO-d6): 3.81 (3H, s, CH3 O-), 5.16 (2H, s, ARCH2 O-), 7.13 (1H, d, J=8Hz, Ar 5-H), 7.33-7.44 (5H, m, ArH), 7.47 (1H, d, J=2Hz, Ar 2-H), 7.54 (1H, dd, J=2Hz and 8Hz, Ar 6-H). IR (KBr-disk) ν cm-1: 1676 (COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sulfuric acid; sodium hydrogencarbonate; mercury; In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | EXAMPLE 2 Preparation of ethyl 4-hydroxy-3-methoxybenzoate (ethyl vanillate) 50 g of vanillic acid and 250 ml of methanol were introduced into a reactor. 40 ml of sulfuric acid was introduced dropwise using a dropping funnel; cooling was carried out if the alcohol boiled. The mixture was refluxed for 2 hours with stirring. The mixture was cooled to room temperature, poured into 100 ml of ice water, and the alcohol was evaporated off under reduced pressure. The aqueous phase was extracted three times with ethyl ether. The combined organic phases were washed with a saturated solution of sodium bicarbonate until the pH was neutral, then washed once with water to eliminate the salts. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure (200 mm of mercury=2.6600 Pa) to obtain the crude ester. The ethyl ester was distilled at 132 C. under a reduced pressure of 2 mm of mercury (266 PA), then crystallized from petroleum ether (40-60 C. fraction) to provide ethyl vanillate having a purity of more than 97% at a yield of 80%. The ethyl vanillate has a spicy vanilla scent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In tetrahydrofuran at 20℃; | 24.A Example 24Atert-butyl {3-[(4-chlorobenzyl)(4-hydroxy-3-methoxybenzoyl)amino]propyl}carbamate; 6.81 g (40.5 mmol) 3-methoxy-4-hydroxybenzoic acid, 11.0 g (36.8 mmol) tert-butyl {3-[(4- chlorobenzyl)amino]propyl}carbamate, 5.97 g (44.2 mmol) HOBT and 14 ml (84.7 mmol) diiso- propylethylamine are dissolved in 200 ml THF. 6.6 ml (42.3 mmol) N,N-diisopropylcarbodiimid are added at rt. The mixture is stirred over night, before diluted with ethyl acetate and water. The aqueous layer is acidified with IN hydrochloric acid and then extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (gradient cyclohexane / ethyl acetate from 3:1 to 1 :1) to afford 14.4 g (87% of th.) of the title compound.LC-MS (method 5): R, = 2.24 min; m/z = 449 (M+H)+1H-NMR (300 MHz, DMSO-dβ): δ = 9.41 (s, IH), 7.45-7.25 (m, 4H), 6.96 (s, IH), 6.87-6.72 (m, 3H), 5.50 (d, IH), 4.58 (bs, 2H), 3.75 (bs, 3H), 3.24 (bs, 2H), 2.85 (bs, 2H), 1.68 (m, 2H), 1.35 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; | 1.2 Step 2; To a solution of the product from step 1 (2.9 g), 4-hydroxy-3-methoxybenzoic acid (3.5g, 20.6 mmol) and HOBt (2.8 g, 20.6 mmol) in 80 mL dichloromethane under nitrogen, was added diisopropylcarbodiimide (2.6 mL, 20.6 mmol) dropwise. The reaction was stirred at room temperature for 12 hours. The solvent was removed under vacuum. The resulting residue was purified by column chromatography to afford the product (4.8 g, 14.4 mmol, 84%). 1HNMR (400MHz, CDCl3) 57.64 (IH, dd, J = 8.4, 1.2 Hz), 7.56 (IH, d, J = 1.2 Hz), 7.30 (5H, m), 6.93 (IH, d, J = 8.4 Hz), 4.49 (2H, t, J = 5.6 Hz), 3.92 (3H, s), 3.31 (2H, t, J = 5.6 Hz), 2.94 (3H, s). |
84% | With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; Inert atmosphere; | 1.2 Step 2 To a solution of the product from step 1 (2.9 g), 4-hydroxy-3-methoxybenzoic acid (3.5 g, 20.6 mmol) and HOBt (2.8 g, 20.6 mmol) in 80 mL dichloromethane under nitrogen, was added diisopropylcarbodiimide (2.6 mL, 20.6 mmol) dropwise. The reaction was stirred at room temperature for 12 hours. The solvent was removed under vacuum. The resulting residue was purified by column chromatography to afford the product (4.8 g, 14.4 mmol, 84%). 1HNMR (400 MHz, CDCl3) δ7.64 (1H, dd, J=8.4, 1.2 Hz), 7.56 (1H, d, J=1.2 Hz), 7.30 (5H, m), 6.93 (1H, d, J=8.4 Hz), 4.49 (2H, t, J=5.6 Hz), 3.92 (3H, s), 3.31 (2H, t, J=5.6 Hz), 2.94 (3H, s). |
84% | With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With caesium carbonate In methanol; water at 20℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 11h; Inert atmosphere; | 3.4.1. General procedure for the synthesis of benzyl esters 10a-c and 16 General procedure: A solution of phenol (3a-c, 1.50 g), in aqueous methanol (90%), was deprotonated with Cs2CO3 (0.5 equiv). The solution was stirred at room temperature for 30 min and then concentrated. The solvent was evaporated at reduced pressure and then co-evaporated with toluene (2×10 mL). The caesium salt obtained was suspended in anhydrous DMF (10 mL), cooled to 0 °C and treated with benzyl bromide (1.0 equiv). After 1 h stirring, the solution was allowed to warm to room temperature and stirring was continued for a further 10 h before the solvent was removed under reduced pressure. The residue was then taken up into water (2×20 mL) and then extracted with EtOAc (200 mL) and the combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. Pure product was obtained by flash chromatography of the residue using Pet Et2O/EtOAc (40:60). |
12% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With caesium carbonate In methanol; water at 20℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; | 376 [1318] Cesium carbonate (1.0 g, 5.9 mmol) as added to vanillic acid (2.0 g. 12 mmol) suspended in 90% aq. MeOH (20 mL). The mixture was stirred at r.t. for 30 mins. The solvents were removed and the crude product was dried by co-evaporating (2x) with toluene. The cesium salt was re-dissolved in DMF (15 mL). Benzyl bromide was added, and the mixture was stirred at r.t. overnight. The mixture was diluted with LA, washed with water and brine, dried and concentrated. The product was purified by silica gel chromatography (hexane:EA) to yield 618-1 (0.4 g, 12%). |
With potassium carbonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With magnesium iodide for 10h; neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium tetrahydroborate; 1% Pd/C; water; potassium hydroxide In methanol at 20℃; for 72h; In air; | |
79% | With potassium phosphate; carbon dioxide; CrH6Mo6O24(3-)*3H3N*3H(1+) In dimethyl sulfoxide at 80℃; for 24h; Green chemistry; | |
With oxygen; sodium hydroxide In 2-methoxy-ethanol at 80.04℃; for 8h; Inert atmosphere; | The substrates were activated by NaOH General procedure: The importance of NaOH to activate the substrate was confirmedby control experiments. No reaction occurred when no alkali wasadded (Entries 1-4 in Table 1). However, when equivalent molarof NaOH was added, the reaction proceeded smoothly. The phe-nomenon was reinforced when the 4-methyl guaiacol sodium saltwas used as the substrate. We concluded that the p-cresol sodiumsalt was much easier to be oxidized than 4-methyl guaiacol, whichcould be explained by the higher electron-donating ability of thephenolate anion than that of hydroxyl group. Namely, the abstrac-tion of proton from the hydroxyl group by alkali was a key stepduring the oxidation of p-cresols. |
Multi-step reaction with 4 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: silver(l) oxide; sodium hydroxide / 0.5 h / 20 °C 4: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 4 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: sodium hydroxide; nitrobenzene / 2 h / 170 °C 4: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 7 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: pyridinium p-toluenesulfonate 4: sodium hydride 5: diisobutylaluminium hydride / toluene / 0.5 h / 0 °C / Sealed tube 6: sodium hydroxide; nitrobenzene / 2 h / 170 °C 7: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 8 steps 1.1: silver(l) oxide 2.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3.1: potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 20 °C 4.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1.5 h / -78 °C / Sealed tube; Inert atmosphere 4.2: 3 h / -78 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 24 h / 0 - 20 °C 6.1: palladium on activated charcoal; hydrogen / tetrahydrofuran / 20 °C 7.1: sodium hydroxide; nitrobenzene / 2 h / 170 °C 8.1: sodium hydroxide; nitrobenzene / 2 h / 170 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With pyridine; dihydrogen peroxide; iodine In water at 40℃; for 2h; Stage #2: With hydrogenchloride In water at 20℃; | 3 A mixed solution of 0.345 g (2.1 mmol) of 4-hydroxy-3-methoxybenzoic acid, 0.27 g (1.05 mmol) of molecular iodine and 0.45 g (5.7 mmol) of pyridine was stirred at 40°C, and 0.26 g (2.31 mmol as hydrogen peroxide) of a 30% aqueous hydrogen peroxide solution was dropped thereto over 0.4 hour. After the completion of addition of the aqueous hydrogen peroxide, the reaction solution was maintained at 40°C, and stirred for 1.6 hours. The total reaction time was 2 hours. Then, 1.0 g of a 20% aqueous sodium sulfite solution was added thereto. At room temperature, the reaction solution was added little by little to 4 g of a 2N aqueous hydrochloric acid solution under stirring. After the whole amount of the reaction solution was added thereto, 15 g of water was added thereto. The precipitated crystals were separated by filtration and vacuum dried at 70°C to obtain 0.525 g of crystals. According to analyses of the crystals and the mother liquid with high performance liquid chromatography, conversion of 4-hydroxy-3-methoxybenzoic acid was 100%, selectivity of 4-hydroxy-3-methoxy-5-iodobenzoic acid was 93% on both substrate basis and iodine basis, isolated yield of 4-hydroxy-3-methoxy-5-iodobenzoic acid was 87%, and crystal purity thereof was 99.7%. |
72% | With sodium hypochlorite; sodium iodide; sodium hydroxide In methanol; water at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With cucumber juice at 30 - 35℃; for 48h; Inert atmosphere; Green chemistry; | |
55% | With copper dichloride In water at 200℃; for 6h; Inert atmosphere; Autoclave; | |
2 Lignin is converted into 2-methoxyphenol by first contacting lignin with molecular oxygen and a cobalt (II) catalyst to generate vanillic acid. Next, the vanillic acid is isolated from the lignin. Then, the vanillic acid is decarboxylated with a decarboxylase |
Enzymatic reaction; | 12 Example 12 - Generation of 2-Methoxyphenol (aka GuaiacoD [00344] Lignin is converted into 2-methoxyphenol by first contacting lignin with molecular oxygen and a cobalt (II) catalyst to generate vanillic acid. Next, the vanillic acid is isolated from the lignin. Then, the vanillic acid is decarboxylated with a decarboxylase | |
With hydrogen In water at 170℃; for 4h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5,10,15,20-tetra(4-chlorophenyl)porphyrin manganese(III) chloride; oxygen; sodium hydroxide In methanol at 64.84℃; for 3.5h; | 2.2 Typical procedure for oxidation of 2-methoxy-4-methylphenol using molecular oxygen catalyzed by metalloporphyrins General procedure: To a 100 mL three-neck round bottom flask equipped with a magnetic stirring bar, condenser, and an oxygen gas inlet was added 2-methoxy-4-methylphenol (4.14 g, 30 mmol), catalyst (7.2 mg), sodium hydroxide (6 g, 0.15 mol) and methanol (20 mL). Oxygen (0.1 MPa) was continuously introduced into the flask at flow rate of 0.1 L min-1 while the temperature was kept at 338 K (the boiling point of methanol). After the reaction was completed, the mixture was cooled to room temperature and the products were quantitatively analyzed by HPLC |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cobalt(II,III) oxide; oxygen In isopropyl alcohol at 80℃; for 6h; Autoclave; | ||
With air; manganese-doped cobalt mixed oxide In acetonitrile at 140℃; for 2h; Autoclave; | ||
With oxygen In para-xylene at 120℃; for 6h; |
With dihydrogen peroxide In acetonitrile at 80℃; for 3h; | Catalytic reactions General procedure: Oxidation of lignin model compound wase undertaken in a150 mL semi-batch reactor equipped with a stirrer. In a typical procedure, 10 mmol of model compound, 50 ml of acetonitrileand 15 mmol of H2O2 were added, followed by 50 mg ofcatalyst (based the active species). After reaction at 80 °C for3 h, the catalyst was filtered off and the solvent wasevaporated under reduced pressure. The residues weredissolved in 25 μL of pyridine in the presence of 3,4-dimethoxytoluene as an internal standard for GC-MS analysis.For the lignin oxidation, the oxidized lignin were recovered byfiltration, and the obtained lignin sample was then dried at40 °C in vacuum for next analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 3.1.3. General Procedure for the Preparation of Ligustrazine Derivatives 1c-5c (Scheme 2) General procedure: Compound 1 (3.0 mmol) and hydroxybenzoic acid (3.0 mmol) were dissolved in dry DMF (25 mL),then NaHCO3 (4.0 mmol) was added and the mixture was kept at room temperature for 12 h under nitrogen atmosphere. Then reaction mixture was poured into ice-water and the crude product was extracted with ethyl acetate. After drying the organic layer over anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude products were purified by flash chromatography and recrystallization from acetone. |
67.5% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 12h; | 15 (3,5,6-trimethylpyrazin-2-yl)methyl 4-hydroxy-3-methoxybenzoate (4c). Weighed 10.87 mmol of 2-bromomethyl-3,5,6-trimethylpyrazine and 10.87 mmol of vanillic acid in a 50 ml round-bottom flask and added 25 ml of DMF. After the mixture was dissolved, 10.0 mmol of sodium bicarbonate was added. , stirring at room temperature for 12h, TLC monitoring reaction material disappeared, the reaction was stopped, the reaction solution was added a lot of saturated NaCl solution dispersion, 400ml ethyl acetate was extracted twice, the ethyl acetate layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in 5 ml of chloroform, and 4.4 g of silica gel was added and evaporated under reduced pressure. The eluent was eluted with petroleum ether:acetone=10:1 to obtain 2.216 g of a white solid. M.P.: 147.8-148.4°C, yield 67.5%. |
40.7% | With potassium carbonate In acetone for 5h; Reflux; | 4 Synthesis of LQC-T3 (Compound 3) 2-bromomethyl-3,5,6-trimethylpyrazine 2.60 mmol prepared in Example 1 and vanillic acid 3.26 mmol were put into a 25 ml three-necked flask and 18 ml acetone was added. Kalium carbonate 5 mmol was added after the mixture was dissolved. The reaction liquid was heated and refluxed for 5 h. The reaction was stopped when the raw materials were basically disappeared by TLC detection. The kalium carbonate was removed by filtration. The filtrate was condensed to contain a small amount of acetone, silica gel 2.0 g was added to evaporate to dryness at a reduced pressure and was agitated. The resultant mixture was eluted with benzene: ethyl acetate=7.5:1 as the eluent to obtain a colorless crystal 0.32 g. The yield was 40.7% and the melting point was 151.4-152.3° C. FAB-MS m/z 303 [M+H]+. The hydrogen spectrum and carbon spectrum NMR data of compound 3 were as follows:1HNMR (500 MHz, CDCl3): 7.6336.897 (m, 3H, Ar-H), 5.407 (s, 2H, O-CH2), 2.581 (s, 3H, 6-CH3), 2.524 (s, 3H, 5-CH3), 2.510 (s, 3H, 3-CH3), 6.196 (s, H, 4-OH), 3.907 (s, 3H, -OCH3);13CNMR (125 MHz, CDCl3): 165.9 (-COOH), 124.4 (Ar-C-1), 111.8 (Ar-C-2), 151.3 (Ar-C-3), 150.3 (Ar-C-4), 114.1 (Ar-C-5), 121.7 (Ar-C-6), 65.7 (-CH2-O), 56.1 (O-CH3), δC of pyrazine ring: 149.3 (C-2), 145.1 (C-3), 146.2 (C-5), 149.0 (C-6), 21.6 (6-CH3), 21.4 (5-CH3), 20.6 (3-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1.5h; Inert atmosphere; | 3.1.1. General Procedure for the Preparation of Ligustrazine Derivatives 1a-5a (Scheme 1) General procedure: Compound 1 (9.0 mmol) and the corresponding hydroxybenzoic acid (3.0 mmol) were dissolved indry DMF, then K2CO3 (6.0 mmol) was added and the mixture was kept at 85 °C for 1.5 h under a nitrogen atmosphere. The warm reaction mixture was poured into ice-water and the crude product was extracted with ethyl acetate. After drying the organic layer over anhydrous Na2SO4 and evaporating the solvent under vacuum, the crude products were purified by flash chromatography and recrystallization from acetone. |
62.5% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; | 13 (3,5,6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate(4a). Weigh 10.14mmol of 2-bromomethyl-3,5,6-trimethylpyrazine and 5.07mmol of vanillic acid into 50ml round bottomIn a flask, 30 ml of DMF was added. After the mixture was dissolved, 5 mmol of potassium carbonate was added, and the mixture was stirred at 85° C. for 2 h. The reaction was monitored by TLC.The material disappeared and the reaction was stopped. A large amount of saturated NaCl solution was added to the reaction solution, and 300 ml of ethyl acetate was extracted twice.The ethyl acetate layer was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, the residue was dissolved in 4 ml of chloroform, and 3.8 g of silica gel was added to the residue for evaporation under reduced pressure.The eluent was eluted with petroleum ether:acetone=8:1 to obtain 1.382 g of a white solid. M.P.: 108.8-109.6°C, yield 62.5% |
60% | With potassium carbonate In N,N-dimethyl-formamide for 4h; Reflux; | 5 Synthesis of LQC-T4 (Compound 4) 2-bromomethyl-3,5,6-trimethylpyrazine 6.52 mmol prepared in Example 1 and vanillic acid 3.26 mmol were put into a 25 ml three-necked flask and 18 ml DMF was added. Kalium carbonate 8 mmol was added after the mixture was dissolved, the resultant mixture was heated and refluxed for 4 h. The reaction was stopped when the raw materials were basically disappeared by TLC detection. The kalium carbonate was removed by filtration. Then the reaction liquid was diluted by adding saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate for 3 times. The extract was combined and evaporated to dryness. The residue was re-dissolved with a small amount of acetone, silica gel 4 g was added and the resultant sample was evaporated to dryness at reduced pressure and was agitated. The obtained mixture was eluted with benzene:ethyl acetate=6:1 as the eluent to obtain a white powder 0.92 g. The yield was 60.0% and the melting point was 78.5-79.4° C. FAB-MS m/z 437 [M+H]+.The hydrogen spectrum and carbon spectrum NMR data of compound 4 were as follows:1HNMR (500 MHz, CDCl3): 7.6357.036 (m, 3H, Ar-H), 5.406 (s, 2H, COO-CH2), 5.248 (s, 2H, Ar-O-CH2), 2.5962.492 (s, 18H, pyrazine ring-CH3), 3.706 (s, 3H, OCH3);13CNMR (125 MHz, CDCl3): 165.9 (-COOH), 123.5 (Ar-C-1), 112.6 (Ar-C-2), 151.4 (ArC-3), 152.1 (Ar-C-4), 112.7 (Ar-C-5), 122.8 (Ar-C-6), 70.7 (-CH2-O ether), 65.7 (-CH2-O ester), 56.0 (O-CH3), δC of pyrazine ring: ester structure part 151.3 (C-2), 145.1 (C-3), 149.0 (C-5), 149.3 (C-6), 21.6 (6-CH3), 21.4 (5-CH3), 20.6 (3-CH3). Ether structure part 150.1 (C-2), 145.1 (C-3), 148.6 (C-5), 149.2 (C-6), 21.6 (6-CH3), 21.4 (5-CH3), 20.6 (3-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 60℃; for 96h; | The compounds 4-hydroxy-3-methoxybenzoic acid (0.97g, 5.78mmol) and <strong>[51762-67-5]3-nitrophthalonitrile</strong> (1.0g, 5.78mmol) were dissolved in dry DMF (30ml) and anhydrous K2CO3 (1.59g, 11.56mmol) was added in portions over 2h. After stirring for 4 days at 50-60C, the reaction mixture was treated with diluted HCl under ice cooling. The pure precipitate that formed was filtered, washed with water to neutralize and dried. Yield: 1.15g (68%). M.p. 238-240C. Anal. Calc. for C16H10N2O4: C, 65.31; H, 3.43; N, 9.52; O, 21.75. Found: C, 65.20; H, 9.19; N, 3.23; O, 21.58%. FT-IR (KBr), numax/(cm-1): 3084 (Ar-CH), 2921-2851 (aliphatic CH), 2231 (C?N), 1675 (C=O), 1574-1458 (C=C), 1277 (Ar-O-Ar), 1247, 1182, 983, 756, 650, 509, 456. 1H NMR (d-DMSO 500MHz, delta ppm): 7.81 (dd, 1H, Ar-H), 7.76 (t, 1H, Ar-H), 7.49 (dd, 1H, Ar-H), 7.12 (dd, 1H, Ar-H), 7.64 (dd, 1H, Ar-H), 7.69 (s, 1H, Ar-H), 3.79 (s, 3H, OCH3). UV-Vis lambdamax (nm) (log epsilon) in DMSO: 297 (4.35). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide In ethanol at 65℃; for 8h; | 212 Example 212.4: Synthesis of 4-(benzyloxy) -3-methoxybenzoic acid To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 mL) and a sodium hydroxide solution (2.0 M, 350 mL) was added benzyl bromide (140.0 g, 823.5 mmol). The mixture was stirred at 65 ° C. for 8 hours, concentrated, co-concentrated with water (2 × 400 mL) to about 400 mL, and acidified to pH 3.0 with 6N hydrochloric acid. The solid was collected by filtration, recrystallized from ethanol, and dried under vacuum at 45 ° C to obtain the title compound (63.6 g, 83% yield). ESI MS m / z: 281.2 ([M + Na] +). |
83% | With sodium hydroxide In ethanol at 65℃; for 8h; | 19 Example 19. 4-(benzyloxy)-3-methoxybenzoic acid 4-Hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in the mixture of ethanol (350 ml) and NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 x 400 ml) to -400 ml. acidified with 6 M HQ to pi I 3.0, filtered the solid, crystallized with EtOH, dried over the oven at 45 °C with vacuum to afford the title compound (63.6 g, 83% yield). |
83% | With sodium hydroxide In ethanol at 65℃; for 8h; | 8 Example 8. 4-(benzyloxy)-3-methoxybenzoic acid Example 8. 4-(benzyloxy)-3-methoxybenzoic acid 4-Hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmoi) in the mixture of ethanol (350 ml) and NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 x 400 ml) to 400 ml, acidified with 6 M HC1 to pH 3.0, filtered the solid, crystallized with EtOH,dried over the oven at 45 °C with vacuum to afford the title compound (63.6 g, 83% yield). ESI MS mlz+ 281.2 (M + Na). ESI MS mlz+ 281.2 (M + Na). |
83% | With sodium hydroxide In ethanol; water at 65℃; for 8h; | 91 Example 91. Synthesis of 4-(benzyloxy)-3-methoxybenzoic acid (238). To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 ml) and aq. NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 × 400 ml) and concentrated to ~400 ml, acidified to pH 3.0 with 6 N HCl. The solid was collected by filtration, crystallized with EtOH, dried at 45 °C under vacuum to afford the title compound (63.6 g, 83% yield). ESI MS m/z 281.2 ([M+Na]+). |
83% | With sodium hydroxide In ethanol; water at 65℃; for 8h; | |
83% | With sodium hydroxide In ethanol; water at 65℃; for 8h; | 80 Example 80. Synthesis of 4- (benzyloxy) -3-methoxybenzoic acid. To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 ml) and aq. NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol) . The mixture was stirred at 65 for 8 h, concentrated, co-evaporated with water (2 × 400 ml) and concentrated to 400 ml, acidified to pH 3.0 with 6 N HCl. The solid was collected by filtration, crystallized with EtOH, dried at 45 under vacuum to afford the title compound (63.6 g, 83%yield) . ESI MS m/z 281.2 ( [M+Na] +) . |
83% | With sodium hydroxide In ethanol; water at 65℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With human-soluble catechol O-methyltransferase; disodium ethylenediamine tetraacetic acid; magnesium chloride; Cleland's reagent In aq. buffer at 37℃; for 14h; Enzymatic reaction; | 1.5 General Procedure for determination of the meta/para alkylation ratio General procedure: Reactions were carried out with purified hsCOMT (1.0 mg/mL, 40 μM, 0.02 eq), catechols (2 mM, 1.0 eq), allyl-SAM/SAM (3 mM, 1.5 eq) at 37 °C in reaction buffer (50 mM Tris, pH 8.0, 100 μM MgCl2, 100 μM DTT, 10 μM EDTA.2Na). A fast ultrafiltration was carried out onto the reaction mixture after 14 h incubation using Millipore’s Amicon Ultra-0.5 10K centrifugal filter device. The filter liquor part for 1c was concentrated under reduced pressure and went for NMR directly after adding CD3OD. 1d reaction mixture was treated in the same way except the additional acidification with 1 M HCl after ultrafiltration and CDCl3 was used as the NMR detecting solvent. The meta/para methylation ratio of 1c and 1d was 2.1:1 and 3:1 by comparison with reported 1.3~1.6:1 and 4.2:15-6, respectively. Ratio determined by HPLC was calculated by the peak area of each generated isomers in the filter liquor part. The mobile phase composition differed slightly depending on the substrate. In the case of 1e, the solvent system consisted of a mixture of 30% methanol, 1 mM 1-heptane sulfonic acid sodium salt and 50 mM Na2HPO4 at pH 2.5. For the Boc group protected dopamine 1f, the solvent system consisted of water (A) and methanol (B). The gradient used was 40% A, 60% B in 8 min, a linear gradient to 100% B in 12 min. For 1g, the mobile phase was 45% 50 mM Na2HPO4 at pH 5.2 and 55% methanol. For 1h, the mobile phase was 50% 50 mM Na2HPO4 at pH 5.2 and 50% methanol. For 1i, the mobile phase was 65% 50 mM Na2HPO4 at pH 5.2 and 35% methanol. | |
With ethylenediaminetetraacetic acid; magnesium(II); Niastella koreensis catechol O-methyltransferase Enzymatic reaction; regiospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With disodium hydrogenphosphate; potassium dihydrogenphosphate; chloramphenicol; magnesium sulfate; ammonium chloride; thiostrepton A; sodium chloride; calcium chloride; In water; at 30℃; for 168h;Enzymatic reaction; | (0185) Metabolite production was first tested on M9 minimal media containing 0.1percent vanillic acid as carbon source and ammonium chloride as the nitrogen source. Extracts from R. jostii (ligAB) grown on M9 media containing 0.1percent vanillic acid showed a new peak at retention time 9.8 min with m/z 167.7 (MH+) and 189.7 (MNa+) matching the retention time and mass spectrum of authentic 2,4-pyridinedicarboxylic acid. No metabolite production was observed using wild-type R. jostii RHA1 under the same conditions. Maximal 2,4-PDCA production was observed after 5 and 7 days fermentation. 2,4-PDCA production decreased after 10-12 days. The yield of 2,4-PDCA was determined by comparison with a standard curve of authentic material to be 112 mg per litre culture media. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pDRf1-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h; | Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enoyl-CoA-hydratase; feruloyl-CoA-synthetase In dimethyl sulfoxide at 30℃; for 5h; Microbiological reaction; | 3 Example 3 Increase of Chromosomal Ech-Fcs Expression Leads to High Conversion Rates and High Vanillin Molar Yields Feruloyl-CoA-synthetase (fcs) and enoyl-CoA-hydratase/aldolase (ech) catalyze the conversion of ferulic acid to vanillin. We assumed that the conversion rate of ferulic acid should be directly proportional to the number of these two metabolic enzymes in the cell, if the required cofactors, ATP and CoA-SH, are available in excess or regenerated. Using the upp counterselection system, the strong tac promoter (Ptac) and lacIq were integrated immediately upstream of ech and fcs in the chromosome of GN276 in order to control the expression of these two genes (FIG. 2). (0188) The resulting strain was designated GN299. After induction of ech and fcs expression with IPTG, bioconversion assays were conducted with this strain. After 5 h, nearly all of the 10 mM ferulic acid were converted to 1.1 mM vanillyl alcohol, 0.2 mM vanillic acid and 8.3 mM of vanillin, corresponding to a molar yield of 83% (FIG. 4d). After 18 h conversion, the vanillin concentration slightly decreased to 7.6 mM accompanied with an increase of vanillyl alcohol and vanillic acid to 1.6 mM and 0.4 mM, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; | Procedure 1 General procedure: In a 100 mL flask equipped with magnetic stirring, the organic acid (1.35 mmol, 200 mg) was dissolved in dimethylformamide (DMF, 2.7 mL) and trimethylamine (0.14 mL, 1.35 mmol). The solution was cooled in an ice bath (0 °C). Then, 4-chlorobenzylamine (1.35 mmol) was added. Soon after a 1.35 mmol solution of BOP in CH2Cl2 (10 mL) was added to the flask. The reaction was stirred at 0 °C for 30 min, and then for an additional period, at room temperature for 2 h. After the reaction, the CH2Cl2 was removed under reduced pressure and the solution was poured into a separatory funnel containing water (10 mL) and EtOAc (10 mL). The product was extracted with EtOAc (3 × 10 mL). The organic phase was washed sequentially with 1 N HCl, water, 1 M NaHCO3 and water (10 mL of each); dried with Na2SO4, filtered and concentrated in a rotavapor. The amide was purified by gel chromatography on a silica gel column using as the mobile phase an EtOAc:Hex mixture gradient of increasing polarity. |
With benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
203 g | With sulfuric acid; at 60℃; for 9h; | To a flask equipped with a stirrer, (1.2 mol) of 4-hydroxy-3-methoxybenzoic acid (compound represented by the formula (A-1)) was added to the reaction vessel of the cooler and the thermometer, Acetic acid 700mL, Acetic anhydride (133 g), 1.3 mol (1.3 mol) Sulfuric acid 3g, heated to 60 C reaction for 9 hours. To the reaction solution was added water 1 L, After stirring for 2 hours while cooling with ice, The precipitated solids are filtered. The resulting solid was washed with water and washed with 1 L of water. By drying the solid, 203 g of the compound represented by the formula (A-2) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; for 1.66667h; | General procedure: The TN salts/molecular salts was preparedby grinding an equimolar mixture containing 200mg (1 mmol) of TN and 1mmol of correspondingcarboxylic acids/PTSA wetted with few drops of waterwas manually grounded in an agate mortar for 100minutes until a dried powder was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.6% | With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 60 - 80℃; for 4h; | To 10 mL of DMF were added 0.5 g of vanillic acid, 0.51 g of EDC, 0.44 g of HOBt, 1.44 mL of TEA and 0.99 g of <strong>[122368-54-1]2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine</strong>, and the mixture was stirred at 60 to 80C for 4 hours. 10 mL of EtOAc and 10 mL of purified water were added to the reaction mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic layer was washed three times with 10 mL of purified water, dried over Na2SO4 and filtered. The filtrate was distilled under reduced pressure and purified by flash column chromatography to obtain 0.40 g of the title compound as a pale yellow solid. Yield: 31.6% 1H NMR (400MHz, DMSO-d6) delta 9.41 (brs, 1H), 8.47 (d, J = 4.0 Hz, 1H), 7.81 (t, J = 7.0, 1H), 7.57(d, J = 8.0 Hz, 1H), 7.44?6.94(m, 6H), 6.84?6.67(m, 3H), 5.71(s, 1H), 3.87(s, 3H), 3.74?3.69(m, 2H), 3.37(brs, 2H), 1.85(brs, 2H), 1.72(brs, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 50℃; | 1 g tenofovir alafenamide free base was dissolved in 10 mL acetone at 50 °C, filtered and mixed with 0.35 g (1 equivalent) vanillic acid to obtain a solution. The solution was stirred at about 21 °C overnight to form a slurry. The slurry was isolated by filtration and dried at 50 °C under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | In a round bottomed flask equipped with a magnetic stir bar and a nitrogen inlet, a mixture of vanillic acid (501 mg, 2.98 mmol), EDC hydrochloride (571 g, 2.98 mmol) and HOBt-hydrate (456 mg, 2.98 mmol) and DIPEA (0.86 mL, 8.97 mmol) in 18 mL DMF were added. The mixture was then stirred at room temperature for one hour. To the above solution, 2- (piperidin-4-yl)-lH-benzo[d]imidazole (600 mg, 2.98 mmol) was added. The mixture was stirred at room temperature for ovemight. To the reaction mixture water was added, precipitate was filtered and dried in vacuo yielding 724 mg of (4-(lH-benzo[cf]imidazol-2-yl)piperidin-l- yl)(4-hydroxy-3-methoxyphenyl)methanone as crude product. To the crude product, CH2CI2 was added, white precipitate formed was filtered and then dried in vacuo to give 334 mg (32 %) of the desired product. (0349) XH NMR (400 MHz, DMSO-d6) delta 12.19 (s, 1H), 9.40 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 7.6 Hz, 1H), 7.19 - 7.02 (m, 2H), 6.93 (s, 1H), 6.89 - 6.64 (m, 2H), 3.75 (s, 3H+1H masked), 3.20 - 2.94 (m, 4H), 2.10 - 1.88 (m, 2H), 1.75 (q, J= 13.5, 13.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5-carboxyvanilate decarboxylase from Sphingmonas paucimobilis SYK-6 species, protein 1; In aq. phosphate buffer; dimethyl sulfoxide; at 30℃; for 24h;pH 8.5;Enzymatic reaction; | General procedure: lyophilized whole cells (1g) were resuspended in phosphate buffer (30mL, pH 5.5, 100mM) and were rehydrated for 30min. The substrate was added as 600muL stock solution (DMSO) to yield a final concentration of 50mM, followed by addition of KHCO3 (3M, 9g, final pH 8.5). The mixture was shaken at 30C and 200rpm. After 24h the reaction mixture was centrifuged (13,000rpm, 15min). The aqueous phase was acidified with 5M HCl and extracted with EtOAc. The organic phase were combined and subjected to silica gel column chromatography to yield the compound 2P as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; butanone; at 20℃; for 24h; | Weigh 2gTenofovir alafenamide0.7056g vanillic acid,Add 4 mL of a mixed solvent of methyl ethyl ketone and water to obtain a suspension.The suspension was stirred at room temperature for 24 h.Filtered, solid dried,You canA white powder of tenofovir alafenamide-vanillic acid eutectic. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulfur trioxide trimethylamine complex; sodium hydrogencarbonate; sodium hydroxide In water at 20℃; for 96h; | 2.5. General sulfation procedure General procedure: To a solution of phenol (1 eq) and NaOH (3 eq) in water were addedNaHCO3 (4 eq) and SO3•NMe3 complex (2.5 eq). The reaction mixturewas stirred at room temperature for four days and concentrated invacuo. The crude product was subjected to HPLC purification [0-5 min(0% B), 5-20 min (0-100% B) at a flow of 2.5 mL/min; buffer A=ammonium acetate 5mM (water) and buffer B=ammoniumacetate 5mM (MeOH)] to afford the corresponding sulfate ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | To a 1L reaction flask equipped with a stirrer, thermometer, Dean-Stark trap and a condenser was charged 120 g of guaiacol and heated to 120, 139g of KOH (38.96in water, 1eq to guaiacol) was added into the mixture at 120 over 2 h while removing water by distillation. Distillation is carried out until no water was distilled out.[0096]Molar ratio of guaiacol to KOH was 1 at the start of the reaction.[0097]480g ofN-methyl-pyrrolidone (NMP) with 120g of guaiacol was charged into the flask. Water is removed by distillation under vacuum (< 180 mbar) . Further distillation to remove NMP under < 50 mbar to further remove water from NMP, total 67.5 g liquid was distilled out. The mixture was cooled down to room temperature.[0098]The reaction mixture (674g) was charged into the pressure reactor 20 barg CO2was introduced and heated to 118, kept CO2pressure at 20 barg, and stirred the mixture for 2h at 118.[0099]The reaction mixture has been filtered at 85. 250g of filtration cake was obtained and 433g of filtrate was obtained. The cake was washed with 170g of NMP and filtrated. 223g of filtration cake and 172g of filtrate were obtained. Both filtrates comprising notably NMP and guaiacol have been recycled to the 1L reaction flask for a next batch.[0100]Specifically, the 433 g filtrate, which mainly contains NMP, guaiacol and unreacted GAK (potassium guaiacolate) , was mixed with 23.7 g 98H2SO4, in order to convert unreacted GAK to guaiacol. Then, NMP and guaiacol was distillated out at 140 under vacuum (60-250 mbar) . The collected NMP and guaiacol, which was totally 383g, including 106g of guaiacol and 277.1g of NMP determined by HPLC, would then be used in next batch by mixing with fresh guaiacol and NMP.[0101]The 172 g filtrate, which mainly contains NMP and guaiacol was distillated at 140 under vacuum (60-250 mbar) . The collected NMP and guaiacol, which was totally 161g, including 20g of guaiacol and 140g of NMP determined by HPLC, would then be used in next batch by mixing with fresh guaiacol andNMP.[0102]The cake was dissolved into 508g of water and pH of the solution has been adjusted to 2-3 with a 30sulfuric acid solution for 30 mins and then a filtration was carried out. 258g of filtration cake was obtained and 579g of filtrate was obtained. This filtrate has been then treated as wastewater.[0103]The cake is then washed with 508g of water and a filtration is then carried out. 170g of filtration cake was obtained, while 592g filtrate was obtained. This filtrate has been then treated as wastewater.[0104]The cake was then dried at 90 for 4 h in order to obtain 77.5g of white solid, which is 4-hydroxy-3-methoxybenzoic acid, i.e., para-vanillin acid.[0105]For final product, the purity is determined by High Performance Liquid Chromatograph (HPLC) , which is>99.[0106]Yield is calculated as below: mass of real product (para-vanillin acid) /mass of theoretical para-vanillin acid is 48.[0107]The conversion of guaiacol, with respect to vanillic acid, ortho-vanillic acid and diacid derivative, is calculated as follows:[0108](1) The weightof guaiacol, vanillic acid, ortho-vanillic acid and diacid derivative was determined by HPLC with external standard reference method. In this particular case, they were 22.31, 11.76, 1.82, and 0.25, respectively. The rest of weightwas NMP and other minor impurities.[0109](2) This weightwas then normalized, by deducting NMP and other impurities. In this particular case, the normalized weightof guaiacol, vanillic acid, ortho-vanillic acid and diacid derivative were 61.73, 32.54, 5.04, and 0.69, respectively.[0110](3) Then, this normalized weightwas converted to normalized molar, in order to calculate the conversion of guaiacol. In this particular case, the molarof guaiacol, vanillic acid, ortho-vanillic acid and diacid derivative were 68.68, 26.73, 4.14, and 0.45, respectively.[0111](4) The conversion of guaiacol is defined as: (1-normalized molarof guaiacol) *2, since there was 1 eq. extra guaiacol introduced into the reactor with NMP. In this particular case, the conversion of guaiacol (1-68.68) *262.63[0112]Selectivity of para to orthomolarof para/molarof ortho87/13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 20h; Inert atmosphere; | 7 4 mmol of tyrosol was added to the reactor under nitrogen protection.Then add 6 mmol of triphenylphosphine,4 mmol of 3-methoxy-4-hydroxybenzoic acid and 10 mL of tetrahydrofuran,6 mmol of diisopropyl azodicarboxylate was added dropwise at 0 ° C.After the completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 20 hours.After the reaction was completed, the reaction solution was evaporated to dryness, and the residue was dissolved in ethyl acetate.Then, it was washed 4 times with saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution, respectively.Dry anhydrous sodium sulfate, filter and remove salt,Concentrated to give a concentrate; with dichloromethane,A mixture of methanol in a 1:1 volume ratio is used as a solvent.The concentrate is subjected to column chromatography,Isolated 3-methoxy-4-hydroxybenzoic acid-4-hydroxyphenethyl ester,The yield is 80%. |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.23% | In methanol; at 65℃; for 12.0h;Inert atmosphere; | Under a nitrogen atmosphere,Dissolve 0.01 mol of vanillic acid in the reactor in 35 ml of methanol.Dissolve 0.01 mol of <strong>[107-43-7]betaine</strong> in 20 ml of methanol,And added dropwise to the reactor in which vanillic acid is dissolved,Heated to 65C,Ionized to salt reaction for 16 hours;After the reaction is completed,The solution was concentrated under vacuum to 1/8 of the reaction solution, and the crystals were frozen.And filtered,Washing and separating to obtain a <strong>[107-43-7]betaine</strong> vanillic acid ion salt crystal product,Drying in a vacuum oven for 48 hours yielded 2.66 g of <strong>[107-43-7]betaine</strong> vanillic acid ion salt with a purity of more than 99%.The yield was 93.23%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.82% | In methanol; acetonitrile; at 50℃; for 4h; | The <strong>[184475-35-2]gefitinib</strong> 446.9mg, 168.2mg vanillic acid is added to 46ml of acetonitrile and 10ml of mixed solvent of methanol, 50 deg.] C water bath for 4 hours, filtered hot, placed in a beaker, sealed with parafilm, bar-hole, slowly cooled to 20 was allowed to stand for 2 days to precipitate colorless needles, it was filtered, dried at room temperature to give 24h <strong>[184475-35-2]gefitinib</strong> - vanilloid methanol solvate co-crystals, yield 93.82%, purity 99.92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Piper nigrum 4-coumarate:CoA ligase isoform 3; ATP; magnesium chloride; In aq. buffer; at 25℃; for 0.75h;pH 7.5;Enzymatic reaction; | General procedure: The enzyme kinetic parameters were measured spectrophotometrically as described [22]. Each reaction contained 0.3 mM CoA, 2.5 mM MgCl2 and 2.5 mM ATP in 100 mM Tris-HCl (pH 7.5). For kinetic analyses, at least six concentrations of each substrate (coumaric, ferulic, 3,4-methylenedioxycinnamic, and piperic acids) ranging from 6.25 to 200 mM and 11 to 94 mg of each purified 4CL in a total volume of 1 ml reaction mixture were reacted in triplicate. For the assay of cinnamic acid, the acid concentration was between 15 mM and 600 mM and CoA was at 0.7 mM. The sample was set-up on ice and transferred to a water bath at 25C to equilibrate temperature for 1 min. The reaction was started by addition of CoA. The formation of the thioester products were followed at 311 nm for cinnamoyl-, 333 nm for 4-coumaroyl-, 346 nm for feruloyl-, 346 nm for 3,4-methylenedioxycinnamoyl-, and 368 nm for piperoyl-CoA, and the concentration of these products were calculated using the corresponding extinction coefficients of 22, 21, 19, 19, and 30.8 mM-1 cm-1, respectively [18,23,24]. To estimate the formation of 3,4-methylenedioxycinnamoyl-CoA, the same extinction coefficient, and lambdamax as feruloyl-CoA were extrapolated. The reaction was followed for 15 min until the linearity of the reaction was maintained. The reaction at 50 mM substrate concentration was allowed to proceed for another 30 min and then the mixture was stood in a boiling water bath for 3 min before scanning on spectrophotometer. Negative control was run with the combined, boiled enzymes, each at the same concentration as the individual reaction. Piperonylic acid was allowed to react for 45 min without kinetic measurement. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.12% | In methanol; at 0 - 50℃; | General procedure: The PILs were synthesised based on the method discussed byChennuri et al. [23] with some modifications. Basically, an equimolaramount of acid (salicylic and vanillic acid) and base (2-(methylamino)ethanol, <strong>[16369-21-4]2-(propylamino)ethanol</strong>, and 2-(butylamino)ethanol) weremixed through neutralisation reaction. Initially, 0.05 mol of the basewas transferred into a two-neck round-bottomed flask equipped witha reflux condenser and immersed in an ice bath. The reaction was performedin a reflux condenser tominimise the evaporation of the volatilebase. Subsequently, 0.05 mol of acid was dissolved in 50 mL methanoland added dropwise into the base under vigorous stirring. The temperaturewas maintained around 0 to 5 C while adding the acid since thereaction is exothermic. After that, the methanol was removed undervacuum using rotary evaporator at 50 C for 5 to 6 h. The name, abbreviationand chemical structure of the synthesised PILs are summarisedin Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; potassium iodide In tetrahydrofuran at 20℃; for 12h; | 1 Example 1: Preparation of 3,7-dimethyl-1,6-octadien-3-yl 4-hydroxy-3-methoxybenzoate (VL) The compound of formula 1 (10 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, chloromethyl methyl ether (12 mmol, 1.2 eq), 500 μL of triethylamine and (1 mmol, 0.1 eq) potassium iodide were added, and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the solvent was evaporated and concentrated, extracted with saturated brine and DCM, the organic layer was dried over anhydrous sodium sulfate, evaporated and concentrated to obtain the compound of formula 3 with a yield of 89%. |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 4 Example 4 Under a nitrogen environment, compound 1 (1.68 g, 10 mmol) and CH3OCH2Cl (1.2 g, 15 mmol) were dissolved in 25 mL of dry DMF, and then K2CO3 (5.5 g, 40 mmol) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was poured into 100 mL ice water, and the pH value was adjusted to 2. Extract with dichloromethane, wash with saturated brine once, and dry the organic phase with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was compound 2, which could be directly used in the next reaction. |
Tags: 121-34-6 synthesis path| 121-34-6 SDS| 121-34-6 COA| 121-34-6 purity| 121-34-6 application| 121-34-6 NMR| 121-34-6 COA| 121-34-6 structure
[ 62089-34-3 ]
3-Methoxy-5-methylbenzoic acid
Similarity: 0.96
[ 1570-05-4 ]
3,4-Bis(benzyloxy)benzoic acid
Similarity: 0.94
[ 62089-34-3 ]
3-Methoxy-5-methylbenzoic acid
Similarity: 0.96
[ 1570-05-4 ]
3,4-Bis(benzyloxy)benzoic acid
Similarity: 0.94
[ 4442-54-0 ]
2,3-Dihydro-1,4-benzodioxine-6-carboxylic acid
Similarity: 0.96
[ 62089-34-3 ]
3-Methoxy-5-methylbenzoic acid
Similarity: 0.96
[ 1570-05-4 ]
3,4-Bis(benzyloxy)benzoic acid
Similarity: 0.94
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H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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