* 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.
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 2, p. 133
[2] Journal of the American Chemical Society, 1938, vol. 60, p. 2972
[3] Journal of Organic Chemistry, 1944, vol. 9, p. 121
9
[ 196601-61-3 ]
[ 877-22-5 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1915, vol. 253, p. 40
10
[ 2426-85-9 ]
[ 877-22-5 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1915, vol. 253, p. 40
11
[ 90-05-1 ]
[ 877-22-5 ]
Reference：
[1] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1940, p. 235,237[2] Chem.Abstr., 1942, p. 1032
[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1940, p. 421,423[4] Chem.Abstr., 1941, p. 5101
12
[ 86-51-1 ]
[ 877-22-5 ]
Reference：
[1] Journal of the Chemical Society, 1923, vol. 123, p. 3174
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
16
[ 586-38-9 ]
[ 99-50-3 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
17
[ 586-38-9 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 2612-02-4 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
18
[ 109-72-8 ]
[ 60-29-7 ]
[ 90-05-1 ]
[ 877-22-5 ]
[ 2169-28-0 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 4537
19
[ 124-38-9 ]
[ 13052-77-2 ]
[ 877-22-5 ]
[ 19829-72-2 ]
Reference：
[1] Journal of Organic Chemistry, 1944, vol. 9, p. 121
20
[ 586-38-9 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 2612-02-4 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
21
[ 67-56-1 ]
[ 877-22-5 ]
[ 6342-70-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
for 16 h; Reflux
2-Hydroxy-3-methoxybenzoic acid (1.68 g, 9.28 mmol) was dissolved in MeOH (30 μl), and then H2SO4 (2 μl) was slowly added thereto and refluxed for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure by evaporation, diluted with EtOAc and washed with water.The organic solvent was dried over anhydrous MgSO4, filtered and concentrated by evaporation under reduced pressure. The resultant residue was separated and purified by silica gel chromatography (n-Hex / EtOAc = 5/1) to obtain the target compound methyl 2-hydroxy- Methoxybenzoate (1.62 g, 96percent).
91.2%
for 96 h; Heating / reflux
A Methyl 2-hydroxy-3-methoxybenzoate 25.5 g (0.152 mol) of 2-hydroxy-3-methoxy-benzoic acid are introduced into 250 ml of methanol containing 1 ml of sulfuric acid. The mixture is brought to reflux for 4 days, concentrated to dryness and then extracted with ethyl acetate. Washing is then carried out with water, a 10percent sodium carbonate solution, water and a sodium chloride solution. In this way, 25.2 g of desired compound are obtained. Yield: 91.2percent M.p.: 68-69° C.
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 9, p. 1447 - 1456
[2] Patent: KR2018/56603, 2018, A, . Location in patent: Paragraph 0441; 0453-0455
[3] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106
[4] Synthetic Communications, 1995, vol. 25, # 6, p. 915 - 920
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 5, p. 1612 - 1624
[6] Patent: US2004/10011, 2004, A1, . Location in patent: Page/Page column 29
[7] European Journal of Medicinal Chemistry, 1997, vol. 32, # 5, p. 385 - 396
[8] Justus Liebigs Annalen der Chemie, 1919, vol. 418, p. 102
[9] Justus Liebigs Annalen der Chemie, 1898, vol. 301, p. 356
[10] Archiv der Pharmazie (Weinheim, Germany), 1915, vol. 253, p. 40
[11] Xenobiotica, 1995, vol. 25, # 9, p. 951 - 961
[12] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 4, p. 613 - 624
[13] Organic Letters, 2010, vol. 12, # 8, p. 1732 - 1735
[14] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303
22
[ 877-22-5 ]
[ 6342-70-7 ]
Yield
Reaction Conditions
Operation in experiment
91.2%
With methanol; sulfuric acid In methanol for 96 h;
[0437] 25.5 g (0.152 mol) of 2-hydroxy-3-methoxybenzoic acid are introduced into 250 ml of methanol comprising 1 ml of sulphuric acid. The combined mixture is brought to reflux for 4 days and concentrated to dryness, and then the residue is extracted with ethyl acetate. The extract is subsequently washed with water, a 10percent sodium carbonate solution, water and a sodium chloride solution. [0438] In this way, 25.2 g of the desired compound are obtained. Yield: 91.2percent M.p.: 68-69° C.
2-Hydroxy-3-methoxybenzoic acid (1.68 g, 9.28 mmol) was dissolved in MeOH (30 mul), and then H2SO4 (2 mul) was slowly added thereto and refluxed for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure by evaporation, diluted with EtOAc and washed with water.The organic solvent was dried over anhydrous MgSO4, filtered and concentrated by evaporation under reduced pressure. The resultant residue was separated and purified by silica gel chromatography (n-Hex / EtOAc = 5/1) to obtain the target compound methyl 2-hydroxy- Methoxybenzoate (1.62 g, 96%).
91.2%
sulfuric acid; for 96h;Heating / reflux;
A Methyl 2-hydroxy-3-methoxybenzoate 25.5 g (0.152 mol) of 2-hydroxy-3-methoxy-benzoic acid are introduced into 250 ml of methanol containing 1 ml of sulfuric acid. The mixture is brought to reflux for 4 days, concentrated to dryness and then extracted with ethyl acetate. Washing is then carried out with water, a 10% sodium carbonate solution, water and a sodium chloride solution. In this way, 25.2 g of desired compound are obtained. Yield: 91.2% M.p.: 68-69 C.
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 3h;
General procedure: To a mixture of commercially available phloroglucinol (1.2 equiv) and an appropriate substituted salicylic acid (1 equiv), 20 mL of Eaton's reagent (P2O5-CH3SO3H) was added slowly. The mixture was stirred for 3 h at 80 °C, cooled to rt, and poured onto ice. After vigorous stirring at rt for 2 h, a brown solid was precipitated. The solid was collected by filtration, washed with water (pH .similar. 6), and dried at 60 °C. In most instances, this intermediate 1,3-dihydroxy-9H-xanthen-9-one was used without further purification.
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 2h;
General procedure: 2,6-dihydroxybenzoic acid (5.0 g, 32.4 mmol) andphloroglucinol (4.09 g, 32.4 mmol) were added to Eaton?s reagent (20 mL) and heated on an 80 °Coil bath for 2 h. After cooling to r.t., the dark-brown solution was transferred slowly to crushedice while being vigorously stirred. The mixture was filtered and the filter cake was washed withwater, dried, and purified by flash column chromatography to afford xanthone 3 as a yellow solid(2.3 g, yield: 29percent).
To a solution of 3 -methoxy salicylic acid (9, 500 mg, 2.97 mmol) in 10 mL of DMF was added benzyl chloride (880 mu, 7.63 mmol) and K2C03 (1.16 g, 8.41 mmol). The resulting mixture was heated to reflux at 120 °C under nitrogen and stirred overnight. The reaction was vacuum filtered and the filtrate was concentrated to a dark brown oil. The oil was purified via a silica plug using CH2C12 as an eluant, after which removal of solvent under vacuum gave an off-white oil (763 mg, 2.19 mmol). Yield = 74percent.
2-Hydroxy-N-((2R,3R,4S,5R)-4-hydroxy-5-hydroxymethyl-2-{6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-tetrahydro-furan-3-yl)-3-methoxy-benzamide[ No CAS ]
Example II (S)-N-[3-(1-Azabicyclo[2.2.2]octyl)]-5-chloro-3-methoxy-2-(1-125[I]iodopropen-3-yl)oxy-benzamide. (Radioactive analog of 15 (TDP 984) from Table I). Treatment of <strong>[877-22-5]3-methoxysalicylic acid</strong> with sulfuryl chloride in chloroform for 14 h at 23° C. gave 5-chloro-<strong>[877-22-5]3-methoxysalicylic acid</strong>.
With phosphorus trichloride; In chlorobenzene; at 150℃; for 1h;
<strong>[877-22-5]3-methoxysalicylic acid</strong> (190) (4.4 g, 23.6 mmol) and 4-amino-3-nitrobenzotrifluoride (191) (4.86 g, 23.6 mmol) were added to chlorobenzene (44 ml). PCl3(1.03 ml, 0.5eq) was added thereto and the mixture was heated at 150 °C for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (toluene) and the following recrystallization from n-hexane to give a desired product (192) (7.47 g, 85 percent). NMR(CDCl3)deltappm:4.16(3H, s, OMe), 7.07 (1H, s, Ar-H), 7.13 (1H, dAB, J=6Hz Ar-H), 7.89 (1H, dAB, J=6Hz Ar-H), 8.21 (1H, dAB, J=6Hz Ar-H), 8.50 (1H, s, Ar-H), 9.21 (1H, dAB, J=6Hz Ar-H), 12.27 (1H, s, NH).
2-hydroxy-N,3-dimethoxy-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Reference Example 36 To a mixture of N,O-dimethylhydroxylamine hydrochloride (6.38 g) and N,N-dimethylformamide (100 ml) was added triethylamine (6.62 g), and the mixture was stirred at room temperature for 30 min. <strong>[877-22-5]3-Methoxysalicylic acid</strong> (10.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.54 g) and 1-hydroxybenzotriazole (10.02 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction mixture, and the mixture was successively washed with water and aqueous potassium carbonate solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:2-->2:1, v/v) to give 2-hydroxy-N,3-dimethoxy-N-methylbenzamide (8.23 g, yield 65percent) as a colorless oil. 1H-NMR (300 MHz, CDCl3) delta:3.40 (3 H, s), 3.65 (3 H, s), 3.91 (3 H, s), 6.81 (1 H, dd, J=7.8, 8.4 Hz), 6.97 (1 H, dd, J=1.2, 7.8 Hz), 7.45 (1 H, dd, J=1.2, 8.4 Hz), 10.49 (1 H, s).
With methanol; sulfuric acid; In methanol; for 96h;
[0437] 25.5 g (0.152 mol) of 2-hydroxy-3-methoxybenzoic acid are introduced into 250 ml of methanol comprising 1 ml of sulphuric acid. The combined mixture is brought to reflux for 4 days and concentrated to dryness, and then the residue is extracted with ethyl acetate. The extract is subsequently washed with water, a 10% sodium carbonate solution, water and a sodium chloride solution. [0438] In this way, 25.2 g of the desired compound are obtained. Yield: 91.2% M.p.: 68-69 C.
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 1h;Heating / reflux;
5 g of 3-methoxy-salicylic acid were suspended in 40 ml dichloromethane and 10 ml of thionyl chloride and 0.5 ml of DMF were added. The mixture was refluxed for 1 hour and the solvent evaporated, the temperature being maintained below 40 C., to give 5 g of a white solid which was used as such in the following step
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 12h;
General procedure: Thionyl chloride (1.46 mL, 20.0 mmol) was added to a suspension of salicylic acid (4.0 mmol) in DCM (20 mL), followed by a catalytic amount of DMF (0.80 mmol). The reaction mixture was stirred overnight at room temperature. The solvent and residual thionyl chloride were removed under reduced pressure and the crude residue was used immediately without further purification. The crude was resuspended in DCM (20 mL), 4-aminobenzonitrile (945 mg, 8.0 mmol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM, washed with 1M HCl solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (hexanes in ethyl acetate 0-100%) afford the salicylamides.
Benzyl 2-hydroxy-3-methoxybenzoate To 2-hydroxy-3-methoxybenzoic acid (10.0 g, 60 mmol) in DMF (50 mL) was added 60percent NaH (2.64 g, 66 mmol) at 0-5° C. The ice bath was removed after 15 minutes and the reaction mixture was stirred for 1 hour. Benzyl bromide (7.2 mL, 60 mmol) was added to the mixture and it was stirred overnight at room temperature. The crude mixture was poured into water (200 mL) and extracted with 25percent ethyl acetate/hexanes. The combined organics were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 5percent ethyl acetate /hexanes) afforded an off-white solid (9.46 g, 61percent). 1H NMR (300 MHz, CDCl3) delta10.97 (s, 1H), 7.40 (m, 6H), 7.05 (d, 1H, J=8.0 Hz 6.81 (apparent t, 1H, J=8.3 Hz), 5.39 (s, 2H), 3.90 (s, 3H). MS calcd for C15H15O4 [M+H]+259.097, found 259.109.
With hydrogenchloride; sodium hydroxide; potassium carbonate; In ethanol; water; N,N-dimethyl-formamide;
PREPARATIVE EXAMPLE 21 2-Hydroxy-3-methoxybenzoic acid (15.66 g, 93 mmol), DMF (200 ml), potassium carbonate (51.4 g, 372 mmol) and pentyl bromide (29 ml, 233 mmol) were mixed, and this solution was stirred at 90° C. for 1 hour. DMF was evaporated under reduced pressure, and water (100 ml) was added. The aqueous layer was extracted 3 times with ethyl acetate (150 ml). The organic layers were combined, washed twice with saturated brine (70 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. To the obtained residue were added a 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml), and the mixture was refluxed under heating for 1 hour. A 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml) were further added, and the mixture was refluxed under heating for 2 hours. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make this solution acidic. The aqueous layer was extracted 3 times with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1-1/1) to give 3-methoxy-2-pentyloxybenzoic acid (20.5 g, 97percent) as a pale-yellow oil. 1 H-NMR (CDCl3)delta: 7.22(1H, d, J=7.35 Hz), 7.20-7.09(2H, m), 4.26(2H, t, J=6.96 Hz), 3.91(3H, s), 1.90-1.79(2H, m), 1.50-1.30(4H, m), 0.92(3H, t, J=7.0 Hz).
benzyl (3-methoxy-2-pentyloxyphenyl)carbonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With diphenylphosphoranyl azide; triethylamine; benzyl alcohol; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; argon; toluene;
PREPARATIVE EXAMPLE 26 2-Hydroxy-3-methoxybenzoic acid (7.15 g, 30 mmol), toluene (60 ml), triethylamine (4.6 ml, 33 mmol) and diphenylphosphoryl azide (7.11 ml, 33 mmol) were mixed in a reaction vessel replaced with argon, and this solution was stirred at room temperature for 1 hour and then for 2.5 hours while heating from 45° C. to 100° C. Benzyl alcohol (3.41 ml, 33 mmol) was added, and the mixture was refluxed under heating for 2 hours. To this reaction mixture was added ice water (60 ml) to stop the reaction, and the aqueous layer was extracted 3 times with ethyl acetate (50 ml). The organic layers were combined, washed twice with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=9/1) to give benzyl (3-methoxy-2-pentyloxyphenyl)carbonate (8.41 g, 82percent) as a pale-yellow oil. 1 H-NMR (CDCl3)delta: 7.73(1H, d, J=8.1 Hz), 7.42-7.31(6H, m), 7.01(1H, t, J=8.4 Hz), 7.0 (1H, d, J=8.4 Hz), 5.21(2H, s), 3.99(2H, t, J=6.8 Hz), 3.84(3H, s), 1.80-1.67(2H, m), 1.5-1.3(4H, m), 0.90(3H, t, J=7.1 Hz). FABMS (m/z): 344[M+ H+ ] (45), 343(100), 300(65).
With sodium hydroxide; sodium iodide; In methanol;
EXAMPLE 1 Methyl-5-iodo-3-methoxysalicylate (1) The esterification of <strong>[877-22-5]3-methoxysalicylic acid</strong> was performed according to the literature. Bishop, J. E., et al., J. Med. Chem. 34, 1612-1624 (1991).The ester product (1.68 g, 9.20 mmol) was dissolved in methanol (35 mL). Sodium iodide (1.38 g, 9.20 mmol) and sodium hydroxide (0.34 g, 9.2 mmol) were added, and the solution was cooled to 0° C. To this solution aqueous sodium hypochlorite (17.25 g, 5percent naCIO) was added dropwise. The colorless slurry mixture was stirred for 1 h at 0°-3° C., then treated with 10percent aqueous sodium thiosulfite. The mixture was adjustedto pH 7 using 5percent aqueous HCI. Ether (50 mL) was added and the layers were separated. The ether layer was washed with brine and dried over anhydrous sodium sulfate. After the ether was evaporated, the crude orange solid waspurified by column chromatography (silica gel, CHCI3) to obtain 1.2 g (43percent) of the iodoproduct; m.p. 104° C. (lit4 110°-112° C.). The spectra were the the same as those published in the literature. Yue, E. W., et al., J. Org. Chem. 56, 5451-5456 (1991).
Example 81 11-Oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid (Compound No: BI2) 2-Hydroxy-3-methoxy-benzoic acid (1.68g) was dissolved in methanol and several drops of concentrated sulfuric acid were added to the solution as a catalyst. The mixture was heated under reflux and monitered by TLC. Upon completion, the solvent was evaporated by a rotary evaporator and the residue was dissolved in water, adjusted to a pH of 6 with 1 mol/L aqueous sodium hydroxide, and extracted by ethyl acetate. The organic layer was washed by saturated NaHCO3, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to obtain a white solid (1.70g). In the following steps, the compound was prepared by means of a procedure similar to that used for Example 74, with other reaction conditions following those known in the art.
General procedure: To a solution of benzoic acid derivatives (1.1 mmol) in anhydrous THF (50 ml) was added dicyclohexylcarbodiimide (DCC, 1.1 mmol) in anhydrous THF (5 ml) and the reaction mixture was stirred at room temperature. After 5 min, a solution of the amine 4a or 4b in THF (5 ml) was added to this reaction mixture, and then was stirred at room temperature overnight. The precipitate was filtered off, and the solvent was evaporated. The organic layer was dried over anhydrous MgSO4 and the solvents were evaporated to give 5a-5i, which were purified using column chromatography (silica gel, CHCl3: MeOH, 95:5).
General procedure: To a solution of benzoic acid derivatives (1.1 mmol) in anhydrous THF (50 ml) was added dicyclohexylcarbodiimide (DCC, 1.1 mmol) in anhydrous THF (5 ml) and the reaction mixture was stirred at room temperature. After 5 min, a solution of the amine 4a or 4b in THF (5 ml) was added to this reaction mixture, and then was stirred at room temperature overnight. The precipitate was filtered off, and the solvent was evaporated. The organic layer was dried over anhydrous MgSO4 and the solvents were evaporated to give 5a-5i, which were purified using column chromatography (silica gel, CHCl3: MeOH, 95:5).
[Cu(3-methoxysalicylate)2(2-aminomethylpyridine)2][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; water; at 20℃;
Ligand 2-aminomethylpyridine (1 mmol) was added to an aqueous solution (5 mL) of copper acetate (0.5 mmol) and after few minutes <strong>[877-22-5]3-methoxysalicylic acid</strong> (1 mmol) was washed down with ethanol (about 50 mL). The blue pure solution was left to crystallize at room temperature. Dark blue crystals were then separated and they were suitable for X-ray structure determination. [Cu(3-MeOsal)2(ampy)2]. Anal. Calc. for (2): C, 55.8; H, 5.0; N, 10.0. Found: C, 54.8; H, 4.9; N, 9.1percent.
2-(hydroxydiphenylmethyl)-6-methoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
Synthesis of2-(hydroxydiphenylmethyl)-6-methoxyphenol A solution of bromobenzene (30.40 g, 193 mmol) in ether (140 mL) was added dropwise during 1.2 h to a suspension of magnesium turnings (8.67 g, 357 mmol) in ether (20 mL). The reaction mixture was heated under reflux for 2 h. After cooling to room temperature, <strong>[877-22-5]3-methoxysalicylic acid</strong> (6.00 g, 35.7 mmol) in ether (140 mL) was added dropwise during 60 min, and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was treated as described above to give 2.42 g (22percent) of the target compound. 1H-NMR: 7.34-7.22 (m, 10 H), 6.85 (d, J = 8.2, 1 H), 6.70 (t, J = 8.0, 1 H), 6.36 (s, 1 H), 6.13 (d, J = 8.0, 1 H), 5.00 (s, 1 H), 3.88 (s, 3 H). 13C-NMR: 146.94, 146.06, 143.35, 132.56, 127.83, 127.78, 127.23, 122.33, 119.00, 110.34, 82.18, 56.17.
(1) <strong>[877-22-5]3-Methoxysalicylic acid</strong> 3 (16.8 g, 0.1 mol), 200 mL of toluene, and 14.6 mL of thionyl chloride were placed into a round-bottomed flask and the reaction mixture was heated under reflux about 5 h. About one third of the solvent was removed by distillation, the solution was transferred into a flat-bottomed flask and a flow of dry methylamine was passed through the solution. The resultant suspension was filtered, the mother liquor was collected and dried with anhydrous sodium sulfate for several hours. The major portion of toluene was distilled off, the residual concentrate was cooled, and the precipitated product was separated and recrystallized from ethyl alcohol. Yield 64percent. 1H NMR (CDCl3, delta, ppm, J, Hz): 2.99 (d, 3H, J = 4.9, N?CH3), 3.87 (s, 3H, O?CH3), 6.61 (s, 1H, NH), 6.77 (t, 1H, J = 8.0, 5-H), 6.94 (dd, 1H, J = 8.0, 1.3, 4-H), 7.03 (dd, 1H, J = 8.1, 1.4, 6-H), 11.89 (s, 1H, OH).
5-amino-3-(4-methoxyphenyl)pyridin-2(1H)-one[ No CAS ]
2-hydroxy-3-methoxy-N-(5-(4-methoxyphenyl)-6-oxo-1,6-dihydropyridin-3-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To the mixture solution of 2-hydroxybenzoic acid (141mg, 1.02mmol) in DMF(10mL)were added with EDC (254mg, 1.32mmol) and HOBt (179mg, 1.32mmol). After the reaction mixture was stirred at room temperature for 10min, 5-amino-3-(4-methoxyphenyl)pyridin-2(1H)-one (7a, 220mg, 1.02mmol) and triethylamine (514mg, 5.09mmol) were added slowly, which was stirred under 100°C overnight. Upon completion of the reaction, the reaction mixture was treated with water (60mL) and extracted with ethyl acetate (40mL×3). The organic layer was washed with salt solution (40mL), dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was chromatographed on silica gel using DCM and methanol. Pure fractions were collected and concentrated, giving the desired compounds 8a?8z in good yield.
2-hydroxy-3-methoxy-N-(6-oxo-5-(m-tolyl)-1,6-dihydropyridin-3-yl) benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To the mixture solution of 2-hydroxybenzoic acid (141mg, 1.02mmol) in DMF(10mL)were added with EDC (254mg, 1.32mmol) and HOBt (179mg, 1.32mmol). After the reaction mixture was stirred at room temperature for 10min, 5-amino-3-(4-methoxyphenyl)pyridin-2(1H)-one (7a, 220mg, 1.02mmol) and triethylamine (514mg, 5.09mmol) were added slowly, which was stirred under 100°C overnight. Upon completion of the reaction, the reaction mixture was treated with water (60mL) and extracted with ethyl acetate (40mL×3). The organic layer was washed with salt solution (40mL), dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was chromatographed on silica gel using DCM and methanol. Pure fractions were collected and concentrated, giving the desired compounds 8a?8z in good yield.
N-(5-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyridin-3-yl)-2-hydroxy-3-methoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To the mixture solution of 2-hydroxybenzoic acid (141mg, 1.02mmol) in DMF(10mL)were added with EDC (254mg, 1.32mmol) and HOBt (179mg, 1.32mmol). After the reaction mixture was stirred at room temperature for 10min, 5-amino-3-(4-methoxyphenyl)pyridin-2(1H)-one (7a, 220mg, 1.02mmol) and triethylamine (514mg, 5.09mmol) were added slowly, which was stirred under 100°C overnight. Upon completion of the reaction, the reaction mixture was treated with water (60mL) and extracted with ethyl acetate (40mL×3). The organic layer was washed with salt solution (40mL), dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was chromatographed on silica gel using DCM and methanol. Pure fractions were collected and concentrated, giving the desired compounds 8a?8z in good yield.
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide; In water; at 60℃; for 8h;
General procedure: To the stirred solution of Phenol (1.0 mmol) and Tetrabutylammoniumiodide (10molpercent) in acetone (41.0 mmol) was added dropwise a solution of 70percent TBHP (2.2eq) in water over the period of 5 minitus. The reaction was stirred at 60 C under open air atmosphere for 8h. Completion of the reaction was monitored by thin layer chromatography (TLC) . The reaction mixture was cooled to room temperature and the residue was diluted with water and extracted using ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and evaporated to afford the crude product which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) to afford the pure product. The product was confirmed by 1H, 13C NMR, IR and Mass spectroscopic analysis.
4-methoxy-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With pyridine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(I) bromide; In para-xylene; at 120℃; for 36h;Schlenk technique; Green chemistry;
CuBr 6 mg (0.04 mmol), TEMPO 5 mg (0.03 mmol), compounded in a 25 mL Schlenk reaction tubeBenzimidazole 47 mg (0.4 mmol),<strong>[877-22-5]3-methoxysalicylic acid</strong> 34 mg (0.2 mmol), p-xylene (0.5 mL), and then pyridine 33 muL (0.4 mmol) were added and the reaction was stirred and refluxed at 120°C for 36 hours.Cool to room temperature, transfer all to a 25 mL flask, spin off the solvent on a rotary evaporator, add an appropriate amount of silica gel to spin dry, and then use a 300-400 mesh silica gel column. The developing solvent used is petroleum ether:ethyl acetate=16: 1 to 6:1, that is, compound III-15 7mg, yield 14percent; white solid
[CuL2H2O] (2). A mixture of <strong>[877-22-5]3-methoxysalicylic acid</strong> (1.68 g,1 102 mol), phenol (2.82 g, 3 102 mol) and 1,3-dicyclohexyl-carbodiimide(2.06 g, 1 x 102 mol) in THF (100 mL) was stirred for 24 h at room temperature. The solution was filtered off and THF eliminated with use of a rotavapor. The resulting oil was poured into 2-propanol (40 mL) and diethylenetriamine (1.03 g,1 x 102 mol) in 2-propanol (10 mL) was added dropwise, refluxed for thirty minutes and then cooled down to room temperature under stirring. Addition of diethyl oxide (60 mL) induced formation of a white precipitate which was filtered off, and washed with diethyl oxide. A mixture of this crude precipitate (0.25 g,1 103 mol) with copper acetate (0.20 g, 1 103 mol) and piperidine (0.2 mL, 2 103 mol) in acetone (30 mL) was refluxed and stirred for 30 min. The resulting violet precipitate was filtered off from the cooled solution. Crystals suitable for X-ray diffractionwere obtained by slow diffusion of acetone to a methanol/watersolution of the isolated complex. Note that the colour change from violet (CuL2) to blue (CuL2H2O) observed during the crystallization process is due to water coordination. Yield: 0.10 g (30percent). Anal. Calc.for C12H23CuN3O6 (368.88): C, 39.07; H, 6.28; N, 11.39. Found: C,38.91; H, 6.18; N, 11.28. IR (ATR): 3221m, 3119m, 2911m,2872m, 1591w, 1566s, 1532s, 1448m, 1433s, 1391s, 1336m,1259w, 1225s, 1202s, 1149w, 1106w, 1080m, 1064m, 1001w,964w, 853w, 804w, 739m, 614w.
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.
2-hydroxy-3-methoxy-5-(4-nitro-phenylazo)-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General method for synthesis of diazonium salts; A solution of an aromatic amine (5 mmol), 1.5 ml of water and 1.5 ml concentrated HCl kept cooled in an ice-salt bath (0 °C). A solution of sodium nitrite (5.5 mmol) in 1.5 ml of water added slowly with stirring. The mixture kept at 0 °C. for the next step10,11. The other diazonium salts synthesized in a similar procedure.Fig. (1) show synthesis of diazonium salt. General method for synthesis of azo compounds; The prepared solution of diazonium salt was added portion wise to a solution prepared from salicylic acid derivatives (5.4 mmol) and10 ml of 2.5 M aq. Sodium hydroxide. The mixture kept with stirring at (0-5 °C) for 3-5 hours. The mixture then acidified with conc. HCl (1.5 ml) up to pH ? 3. The precipitated compound separated and washed with H2O. The desired product dried and recrystallized with glacial acetic acid10,11.Fig. (2) show synthesis of azo compounds. The melting points, names and the percentage of yield are given in Table (1).
2-hydroxy-3-methoxy-5-(3-nitro-phenylazo)-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General method for synthesis of diazonium salts; A solution of an aromatic amine (5 mmol), 1.5 ml of water and 1.5 ml concentrated HCl kept cooled in an ice-salt bath (0 °C). A solution of sodium nitrite (5.5 mmol) in 1.5 ml of water added slowly with stirring. The mixture kept at 0 °C. for the next step10,11. The other diazonium salts synthesized in a similar procedure.Fig. (1) show synthesis of diazonium salt. General method for synthesis of azo compounds; The prepared solution of diazonium salt was added portion wise to a solution prepared from salicylic acid derivatives (5.4 mmol) and10 ml of 2.5 M aq. Sodium hydroxide. The mixture kept with stirring at (0-5 °C) for 3-5 hours. The mixture then acidified with conc. HCl (1.5 ml) up to pH ? 3. The precipitated compound separated and washed with H2O. The desired product dried and recrystallized with glacial acetic acid10,11.Fig. (2) show synthesis of azo compounds. The melting points, names and the percentage of yield are given in Table (1).
5-(4-carboxy-phenylazo)-2-hydroxy-3-methoxy-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General method for synthesis of diazonium salts; A solution of an aromatic amine (5 mmol), 1.5 ml of water and 1.5 ml concentrated HCl kept cooled in an ice-salt bath (0 °C). A solution of sodium nitrite (5.5 mmol) in 1.5 ml of water added slowly with stirring. The mixture kept at 0 °C. for the next step10,11. The other diazonium salts synthesized in a similar procedure.Fig. (1) show synthesis of diazonium salt. General method for synthesis of azo compounds; The prepared solution of diazonium salt was added portion wise to a solution prepared from salicylic acid derivatives (5.4 mmol) and10 ml of 2.5 M aq. Sodium hydroxide. The mixture kept with stirring at (0-5 °C) for 3-5 hours. The mixture then acidified with conc. HCl (1.5 ml) up to pH ? 3. The precipitated compound separated and washed with H2O. The desired product dried and recrystallized with glacial acetic acid10,11.Fig. (2) show synthesis of azo compounds. The melting points, names and the percentage of yield are given in Table (1).
To a stirred solution of 2-hydroxy-3-methoxybenzoic acid (1 Og, 59.5mmol, 1 eq) in DMF (100ml_) was added EDC.HCI (17.1 Og, 89.2mmol, 1 .5eq) and HOBt (12.06g, 89.2mmol, 1.5eq) at 0C under argon atmosphere followed by DiPEA (37.1 1 ml_, 208.1 mmol, 3.5eq) and the resulting mixture stirred for 15min at the same temp. Then, 2,4,4-trimethylpentan-2-amine (1 1 97mL, 71 4mmol, 1 2eq) was added dropwise at 0C and allowed to warm up to RT over 48h. TLC analysis indicated formation of a less polar spot. The reaction mixture was diluted with water (500ml_) and extracted with EtOAc (2x200ml_). The organic layer was washed with water (2x100ml_), dried over Na2S04 and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel 100-200 mesh) using 5% EtOAc in petroleum ether as an eluent to provide the desired compound (7g, 42.14%) as an off white solid. LC-MS: m/z 280.28 (M + H).
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