* 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] Synthetic Communications, 2007, vol. 37, # 10, p. 1665 - 1673
[2] Journal of Chemical Research - Part S, 1998, # 3, p. 136 - 137
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 10, p. 2477 - 2486
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 60,62
5
[ 6148-64-7 ]
[ 93-07-2 ]
[ 4687-37-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3978 - 3984
6
[ 93-07-2 ]
[ 5653-40-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5119 - 5135
[3] Patent: CN108484574, 2018, A,
7
[ 93-07-2 ]
[ 13794-72-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[2] Patent: CN103254139, 2016, B,
[3] Patent: CN103254140, 2016, B,
[4] Patent: CN105037279, 2017, B,
[5] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[6] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
[8] Patent: CN108484574, 2018, A,
8
[ 93-07-2 ]
[ 59084-72-9 ]
Reference：
[1] Patent: WO2018/151830, 2018, A1,
9
[ 93-07-2 ]
[ 21852-32-4 ]
Reference：
[1] Pest Management Science, 2000, vol. 56, # 10, p. 875 - 881
10
[ 93-07-2 ]
[ 37895-73-1 ]
[ 6286-46-0 ]
Yield
Reaction Conditions
Operation in experiment
82.37%
With hydrogenchloride; bromine In water at 20 - 30℃; for 3 h;
3,4-Dimethoxybenzoic acid (25.0 g) was suspended in concentrated hydrochloric acid (35percent) (500 mL), and bromine (23.0 g, 1.05 equivalents) was added dropwise to the resultant suspension at 25° C. Subsequently, the resultant mixture was stirred for seven hours. Water (500 mL) was added to the mixture, and the mixture was stirred for one hour. Thereafter, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-bromo-4,5-dimethoxybenzoic acid (34.47 g) (yield: 96.2percent). [0029] 1H-NMR(DMSO-d6, δ): 3.79(s,3H), 3.84(s,3H), 7.21(s,1H), 7.37(s,1H), 13.08(bs,1H). ; For evaluation of the effect of concentrated hydrochloric acid concentration, the aforementioned reaction was carried out under the following conditions (amount of bromine: 1.1 equivalents, reaction temperature: 20 to 30° C., and reaction time: three hours), while the concentration of concentrated hydrochloric acid employed was varied. The results are shown in Table 2.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1858, vol. 108, p. 60
12
[ 93-07-2 ]
[ 6702-50-7 ]
Reference：
[1] Journal of the Chemical Society, 1930, p. 817,818
13
[ 93-07-2 ]
[ 4998-07-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
With nitric acid In water at 60℃; for 6 h; Cooling with ice
To a 100 mL flask was added 3,4-dimethoxybenzoic acid (10 g,54.9 mmol) and nitric acid (50 mL, 20percent) in an ice-bath. The reactionmixture was then stirred at 60 °C for 6 h. After cooling to rt, themixture was poured onto ice-water. The solid was filtered, washedwith water, dried. The crude was purified by a silica gel column toafford 2-nitro-4,5-dimethoxybenaoic acid as a light yellow solid(9.6 g, yield 77percent). mp 195-197 °C; 1H NMR (CDCl3, ppm): d 7.42 (s,1H), 7.26 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H).
77%
at 60℃; for 6.5 h; Cooling with ice
3,4-Dimethoxybenzoic acid (10 g, 54.89 mmol) was added to a 250 ml pear-shaped flask.Under ice bath conditions, 150 ml of 20percent nitric acid was slowly added, and after stirring for 30 min, the ice bath was removed, and the reaction was heated at 60 ° C for 6 hours, and the reaction was completely confirmed by TLC. After the reaction was completed, the reaction solution was poured into a large amount of ice water and stirred for 30 min, and a solid was precipitated, suction filtered, and the filter cake was washed three times with water to obtain a yellow solid, which was passed through a silica gel column to obtain 9.6 g of yellow needle crystals, yield 77percent.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[2] Patent: CN108484574, 2018, A, . Location in patent: Paragraph 0121; 0122; 0123
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5119 - 5135
[4] Patent: WO2010/76810, 2010, A2, . Location in patent: Page/Page column 15
14
[ 93-07-2 ]
[ 709-09-1 ]
[ 4998-07-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1858, vol. 108, p. 60
[2] Chemische Berichte, 1876, vol. 9, p. 939[3] Chemische Berichte, 1878, vol. 11, p. 131
[4] Justus Liebigs Annalen der Chemie, 1896, vol. 293, p. 190
15
[ 7697-37-2 ]
[ 93-07-2 ]
[ 709-09-1 ]
[ 4998-07-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1858, vol. 108, p. 60
[2] Chemische Berichte, 1876, vol. 9, p. 939[3] Chemische Berichte, 1878, vol. 11, p. 131
[4] Justus Liebigs Annalen der Chemie, 1896, vol. 293, p. 190
With water; sodium hydroxide; In ethanol; at 60℃; for 1.5h;
Step 2: 3, 4-Dimethoxybenzoic acid[0536]To a mixed solvent of ethanol (20 mL) and water (10 mL) was added <strong>[2150-38-1]methyl 3, 4-dimethoxybenzoate</strong> (10.23 g, 52.17 mmol) , and sodium hydroxide (10.43 g, 260.87 mmol) was added to the mixture. The mixture was stirred at 60 for 1.5 hours, then ethanol was removed and the residue was dissolved in water (20 mL) . To the mixture was added hydrochloric acid (1 M) to adjust the pH of the mixture to 1. The mixture was extracted with ethyl acetate (25 mL × 3) . The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give the title compound as a white solid (9.16 g, 96.4) .[0537]MS-ESI: m/z 181.1 [M-H]-.
With 1,3,5-trichloro-2,4,6-triazine; sodium carbonate; at 50℃; for 0.166667h;Sonication;
General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
93.4%
With sulfuric acid; for 2h;Reflux;
Add 2 g (9.4 mmol) of 3,4_-trimethoxybenzoic acid to a 100 mL round bottom flask, dissolve in 50 mL of methanol, and add 1 mL (20.1 mmol) of concentrated sulfuric acid dropwise. Heat reflux for 2 h and check the reaction by TLC After the completion of the reaction, the saturated sodium carbonate solution was adjusted to pH 7 and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and eluted. Column chromatography (PE: ETA = 10: 1, V / ) To give a white solid 2.0 g. Yield 93.4%, mp 52-55 C.
64%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; at 70℃; for 40h;
General procedure: The mixture of carboxylic acid, alcohol, and 1,3-dibromo-5,5-dimethylhydantoin was stirredin a 25 mL reactor tube at 70 C for 2-40 h. After reaction completion, the mixture was cooled toroom temperature and the alcohol was evaporated under reduced pressure. The isolation procedurewas as follows, except where noted dierently in the Supporting Information. The residue wasdissolved in 10 mL ethyl acetate and washed with a mixture of 1 mL saturated NaHCO3(aq), 1 mLsaturated Na2S2O3(aq), and 10 mL distilled water, and the water phase was extracted with ethyl acetate(2 10 mL). The organic layers were combined, dried over Na2SO4, and the solvent was evaporatedunder reduced pressure
With glycerol-based sulfonic acid functionalized carbon catalyst; for 6h;Reflux; Green chemistry;
General procedure: To a stirred solution of substituted aryl carboxylic acid 1 (0.15 mol) in methanol (0.75 mol) glycerol-based solid acid catalyst (28 wt% of aryl carboxylic acid) was added and heated to reflux for 6 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature. The catalyst was separated by filtration and was washed with methanol for recycle. Methanol was then distilled off under reduced pressure to get the pure methyl ester 2.
1070 g
With sulfuric acid; for 15h;Reflux; Large scale;
3,4-dimethoxybenzoic acid (1000g, 5.49mol) was suspended in methanol (5lt), and stirred. To this was added 95% sulphuric acid (200ml), and the mixture was then heated at reflux for ~15 hours, before cooling to room temperature overnight. The reaction mixture was carefully poured into saturated sodium bicarbonate solution with stirring, a white foamy precipitate formed. The product was extracted out with t-butyl methyl ether (3 x 4lt), then dried over sodium sulphate. The sodium sulphate was removed by filtration through a GF/F and the solvent removed under reduced pressure, to give a white solid, 1070g, GC 99.7%.
At 0 C, HCl gas was bubbled through a solution of formaldehyde (37% in water; 90 ml1 .2 mol) for 30 min. 3,4-dimethoxybenzoic acid 4 (10 g; 54.9 mmol) was added and the reaction mixture was heated to 70 C, while HCI gas was continued to bubble through the suspension. After 3 days, all volatiles were removed under reduced pressure and water (200 mL) was added. The pH was adjusted to pH = 7 by addition of aqueous NH3 solution. The solid product was separated by filtration and dried under reduced pressure to yield lactone 5 (9.88 g; 50.9 mmol; 93%) as an off-white solid. 1H NMR (d-DMSO): delta 7.26 (s, 1 H), 7.23 (s, 1 H), 5.27 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H).
66%
With hydrogenchloride; In water; at 90℃; for 5h;
Concentrated HCl (37%, 150 mL) was added to 3,4-dimethoxybenzoic acid 23 (10.0 g, 54.9 mmol), followed by aqueous formaldehyde (37%, 75 mL). The mixture was warmed to 90 C. and stirred at that temperature for 5 h. The solvent was removed and the residue was portioned between water (100 mL) and EtOAc (250 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layer was washed with 2.5 M NaOH, followed by water, and concentrated. The residue was purified by column chromatography (silica gel, 25 to 50% EtOAc in hexanes) to afford compound 24 (7.00 g, 66%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) delta 7.26 (s, 1H), 7.23 (s, 1H), 5.27 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H).
66%
With hydrogenchloride; In water; at 90℃; for 5h;
Concentrated HC1 (37%, 150 mL) was added to 3,4-dimethoxybenzoic acid 1 (10.0 g, 54.9 mmol), followed by aqueous formaldehyde (37%, 75 mL). The mixture was warmed to 90 C and stirred at that temperature for 5 h. The solvent was removed and the residue was portioned between water (100 mL) and EtOAc (250 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 chi 200 mL). The combined organic layers were washed with 2.5 M NaOH, followed by water, and concentrated. The residue was purified by column chromatography (silica gel, 25 to 50% EtOAc in hexanes) to afford compound 2 (7.00 g, 66%) as an off-white solid: FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) delta 7.26 (s, 1 H), 7.23 (s, 1 H), 5.27 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H).
58.65%
With hydrogenchloride; at 0 - 60℃;Heating / reflux;
A suspension of 3,4-dimethoxy-benzoic acid (353.5 g, 1.94 moles) in HCHO (1.7 l, 24.5 moles) under stirring was prepared and cooled in ice, saturated with gaseous HCl (340 g, 9.32 moles), then gradually warmed to 60 C. After one night the temperature was cooled to the room value and further HCl (300 g) was bubbled in, then the temperature was brought again to 60 C. for one night. The mixture was partially evaporated, taken up in water (1 l), neutralised with 28% NH4OH (1.5 l) and kept at cold for 2 hours, then filtered. The filtrate was washed with water up to neutrality, then crystallised from methanol (2 l) and dried under vacuum at 60C. to give 220 g of the title compound (yield: 58.65%). 1H-NMR (200 MHz, CDCl3) delta (ppm): 7.28 and 6.28 (2s, 2H); 5.20 (s, 2H); 3.95 and 3.91 (2s, 6H).
43.5%
With hydrogenchloride; In water; at 70℃; for 8h;
37% HCHO aqueous solution (60 mL) was added to a solution ofcompound 10 (14.58 g, 80.06 mmol) in conc. HCl (250 mL). The reactionmixture was heated at 70 C for 8 h. After the mixture was cooled,filtered and the filtrate was extracted with dichloromethane(70 mL×4). The combined organic phases were washed with saturatedNaHCO3 solution, water and brine orderly, dried over anhydrous sodiumsulfate and filtered, concentrated under reduced pressure to affordthe crude compound. The residue was recrystallized from ethanolto give compound 11 as a light brown solid, yield 43.5% (6.762 g), mp151.5-153.8 C (Lit.44 154-155 C).
30%
With hydrogenchloride; In water; at 90 - 100℃; for 6h;
A suspension of 3,4-dimethoxybenzoic acid (10 g, 54.9 mmol) in aqueous 37% HCl (126 ml, 1522 mmol) and a 37% solution in water of formaldehyde (25 ml, 54.9 mmol) were heated to 90 to 100 C. for 6 hours. Stirring was prolonged overnight at room temperature, and then the obtained insoluble material was removed by filtration. The filtrate was quenched with water (200 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layers were washed with aqueous 1N NaOH (100 ml) and then with brine (2×100 ml). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The obtained yellow solid was triturated with ethyl acetate to afford 5,6-dimethoxyisobenzofuran-1(3H)-one as a white solid (3.171 g, 16.33 mmol, 30% yield). MS/ESI+ 195.0 [MH]+.
30%
With hydrogenchloride; In water; at 90 - 100℃; for 6h;
Example 28 (S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)- phenyl)-2-(2-(5,6-dimethoxy-1 ,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1 -oxide (Compound 156) Scheme 28 Step 1 : Preparation of 5,6-dimethoxyisobenzofuran-1 (3H)-one (152) A suspension of 3,4-dimethoxybenzoic acid (10 g, 54.9 mmol) in aqueous 37% HCI (126 ml, 1522 mmol) and a 37% solution in water of formaldehyde (25 ml, 54.9 mmol) were heated to 90-100C for 6 hours. Stirring was prolonged overnight at room temperature and then the obtained insoluble material was removed by filtration. The filtrate was quenched with water (200 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with aqueous 1 N NaOH (100 ml) and then with brine (2 x 100 ml). The organic phase was dried over Na2S04, filtered and evaporated to dryness. The obtained yellow solid was triturated with ethyl acetate to afford 5,6-dimethoxyisobenzofuran-1 (3H)-one as a white solid (3.171 g, 16.33 mmol, 30% yield). MS/ESI+ 195.0 [MH] +.
With hydrogenchloride; at 65℃; for 2h;
3,4-dimethoxybenzoic acid (5.0 g, 27 mmol) was added to Formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65C for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (16 ml), followed by neutralizing with dilute aqueous ammonia (concentrated aqueous ammonia : water = 2 : 3). The precipitated crystals were collected by filtration, washed with water, followed by drying to give 4.0 g of 4,5-dimethoxyphthalide.
With hydrogenchloride; In water; at 90℃; for 4.75h;
A mixture of 3,4-dimethoxy-benzoic acid (10 g) in 37% HCl (150 ml) and formaldehyde (25 ml, 37 wt. % solution in water) was heated to 90 0C for 4 3A hours, and then insoluble material was removed by filtration. The filtrate was quenched with water (200 ml) and extracted three times with ethyl acetate (200 ml). The combined organic layers were washed with aqueous NaOH (40 ml, 2.5 M) and water (100 ml). The organic solvent was dried over anhydrous Na2SO4, filtered and evaporated to dryness Yield: 8.9 g 1R NMR (DMSO-d6): delta = 7.27 (IH, s), 7.24 (IH, s), 5.28 (2H, s), 3.88 (3H, s), 3.84 (3H, s).
After putting 182.2 g (1.0 mol) of 3,4-dimethoxy- benzoic acid into a 2,000 mE four-necked flask equipped with a stirrer, a thermometer, and a reflux cooling tube, 800 g of water was added thereto and stirred so as to disperse 3,4-dimethoxybenzoic acid. Subsequently, 133.3 g (1.00 mol) of a 30% sodium hydroxide aqueous solution was added. The liquid temperature was then reduced to 0 C., and 150.1 g (0.53 mol (1.05 equivalent)) of 1,3-dibromo-5, 5-dimethylhydantoin (DI3H) was added at a liquid temperature of 0 to 5 C. Completion of the dropwise addition was followed by stirring for one hour at a liquid temperature of 0 to 5 C. After completion of the reaction, 1.28 g (0.01 mol) of sodium sulfite was added followed by addition of 100 g of toluene and raising the liquid temperature to 70 C. The organic phase was removed by a liquid separation operation, and 104.2 g (1.0 mol) of 35% hydrochloric acid was added dropwise to the acquired aqueous phase and stirred for one hout Precipitated crystals were collected by filtration and dried under reduced pressure to acquire 239.4 g (99.9% purity, 91.6% yield) of 2-bromo-4,5-dimethoxybenzoic acid.
With bromine; acetic acid; at 50℃; for 72h;
Example 3; Synthesis of 4-bromo-6,7-dimethoxyphthalazine; [00196] Step 1. Into a 500 mL round bottom flask containing a solution of 3,4- dimethoxybenzoic acid (18.2 g, 99.91 mmol) in AcOH (250 mL) was added Br2 (17.6 g, 110.00 mmol). The resulting solution was stirred for 3 days while the temperature was maintained at 50 0C. The reaction mixture was cooled to room temperature and the solid product was collected by filtration. The filter cake was washed with hexanes and dried to provide 1O g of crude 2-bromo-4,5-dimethoxybenzoic acid as a white solid.
With hydrogenchloride; bromine; In water; at 25℃; for 7h;
Example 1 (Compound (1)?Compound (2)) 3,4-Dimethoxybenzoic acid (25.0 g) was suspended in concentrated hydrochloric acid (35%) (500 mL), and bromine (23.0 g, 1.05 equivalents) was added dropwise to the resultant suspension at 25 C. Subsequently, the resultant mixture was stirred for seven hours. Water (500 mL) was added to the mixture, and the mixture was stirred for one hour. Thereafter, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-bromo-4,5-dimethoxybenzoic acid (34.47 g) (yield: 96.2%). 1H-NMR(DMSO-d6, delta): 3.79(s,3H), 3.84(s,3H), 7.21(s,1H), 7.37(s,1H), 13.08(bs,1H).
With hydrogenchloride; bromine; In water; at 25℃; for 7h;
General procedure: A 10.0 g of 3,4-dimethoxybenzoic acid, Awas suspended in Conc. HCl (35 %, 200 mL) and Br2 (25 g, 1.1 eq) wasadded drop wise to the resultant suspension at 25 Cand the mixture was stirred for 7 h. Water (200 mL) was added to the mixturefor the precipitation of acid, filtered, and dried the product 2-bromo-4,5-dimethoxybenzoicacid The pure product obtained column chromatography was analyzed byNMRTo a 10.0 g, of 2-bromo-4,5-dimethoxybenzoicacid, B diethylmalonate (100 mL) and copper bromide (551.7 mg, 10 mol %) wasadded and the resulting suspension was degassed under nitrogen at 0 C. Sodium hydride (60 % in mineral oil, 3.7 g)was added in portions over 20-25 min. After addition, the mixture was heated to90 C for 2 h, cooled to room temperature, 500 mlwater was added and the mixture was extracted twice with Ethyl acetate (150 mLX 2). The aqueous layer was acidified with 6N HCl and extracted withdichloromethane. The solvent was removed under vacuum to offer the 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4,5-dimethoxybenzoic acid. The above solid wasdissolved in 100 mL THF and then 7.7 g of sodium hydroxide in 100 mL watercontaining was added drop wise. The mixture was stirred overnight at roomtemperature. Reaction progress was monitored by TLC. THF was evaporated, andthen the resulting aqueous layer was extractedwith ethyl acetate (100 mL). The organic layer was dried over sodium sulphate,filtered and concentrated to afford the 4,5-dimethoxy homophthalic acid, C that was confirmed by NMR analysis.
With hydrogenchloride; bromine; In water; at 25℃; for 7h;Sealed tube;
A 10.0g of 3,4-dimethoxybenzoic acid was suspended in Conc. HCl (35%, 200 ml) andBr2 (25 g, 1.1 eq) was added drop wise to the resultant suspensionat 25 C and the mixture was stirred for 7h. Water (200 ml) was added to the mixture for the precipitation of acid,filtered, and dried the product 2-bromo-4,5-dimethoxybenzoic acid The pureproduct obtained column chromatography was analyzed by NMR
EXAMPLE 1 5,6-Dimethoxy-3H-isobenzofuran-1-one A suspension of 3,4-dimethoxy-benzoic acid (353.5 g, 1.94 moles) in HCHO (1.7 l, 24.5 moles) was prepared under mechanic stirring, cooled in ice, saturated with gaseous HCl (340 g, 9.32 moles), then gradually brought to 60 C. After one night the temperature was brought to the room values and further HCl (300 mg) was bubbled, then the temperature was brought again to 60 C. for one night. The mixture was brought to small volume, taken up with water (1 l), neutralised with 28% NH4OH (1.5 l) and kept at cool for 2 hours, then filtered. The filtrate was washed with water up to neutrality, then crystallized from CH3OH (2 l) and dried under vacuum at 60 C. to give 220 g of the title compound (yield: 58.65%). 1H-NMR (CDCl3): 7.28 and 6.28 (2s, 2H); 5.20 (s, 2H); 3.95 and 3.91 (2s, 6H).
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;
3,4-Dimethoxybenzoic acid (100 mg, 0.55 mmol) was dissolved in DMF (1 mL). EDC (124.6 mg, 0.65 mmol) and HOBt (81 mg, 0.6 mmol) were added, followed by N- methylmorpholine (0.71 mL, 0.65 mmol). The resulting solution was agitated for 1 h. 3- Aminomethylphenyl-carbamic acid tert-butyl ester (111 mg, 0.5 mmol) was then added and the resulting mixture was agitated overnight. The reaction mixture was diluted with 4 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2 x 5 mL), NaHCO3 (saturated aqueous, 2 x 5 mL), and brine (1 x 5 mL), dried, and the solvents were evaporated to provide 190 mg (quantitative yield) of (3-[(3,4-dimethoxy-benzoylamino)- methyl]-phenyl}-carbamic acid tert-butyi ester, which was dissolved in dichloromethane (2 mL). SCX (1.14 g, 1.0 mmol) was added and the resulting mixture was agitated for 48 h. The reaction mixture was filtered and the solids were washed with dichloromethane (2 x 2 mL) and methanol (2 x 2 mL). The product was eluted with NH3 in methanol (7 N, 2 x 2 mL). The solvents were evaporated to provide 112 mg (78% yield) of 7V-(3-amino- benzyl)-3,4-dimethoxy-benzamide as a white solid, which was used directly. 3,4-Dihydro- lH-isoquinoline-2,6-dicarboxylic acid 2-tert-buty{ ester (19.1 mg, 0.069 mmol), EDC <n="106"/>(19.2 mg, 0.1 mmol), and HOBt (12.2 mg, 0.09 mmol) were combined in a reaction tube, and DMF (1 mL) was added. To the resulting solution was added N-methylmorpholine (0.013 mL, 0.12 mmol), and the mixture was agitated for 1 h. The intermediate prepared above, Lambda/-(3-amino-benzyl)-3,4-dimethoxy-benzamide (17 mg, 0.059 mmol), was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated overnight. The reaction mixture was diluted with 6 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2 x 2 mL), NaHCO3 (saturated aqueous, 2 x 2 mL), and brine (1 x 2 mL), dried, and concentrated to 32 mg of 6-{3-[(3,4-dimethoxy-benzoylamino)- methyl]-phenylcarbamoyl}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester as an oil, which was redissolved in dichloromethane (1 mL) and treated with SCX (284 mg, 0.25 mmol). The resulting mixture was agitated overnight. The reaction mixture was filtered and the solids were washed with dichloromethane (2 x 2 mL) and methanol (2 x 2 mL). The product was eluted with NH3 in methanol (7 N, 2 x 2 mL), and the eluant was evaporated. The resulting residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (20 mg, 77% yield - 2 steps), MS analysis electrospray, 446 (M+H).
[(1aS,1bS,2S,5aR,6S,6aS)-2-(β-D-glucopyranosyloxy)-1b,5a,6,6a-tetrahydro-6-hydroxyoxireno[4,5]cyclopenta[1,2-c]pyran-1a(2H)-yl]methyl 3,4-dimethoxybenzoate[ No CAS ]
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 8h;
General procedure: A mixture ofcompound 10 (0.15 g, 0.772 mmol), HOBt (0.23 g,1.70 mmol), EDCI (0.37 g, 1.93 mmol), benzoic acid(0.19 g, 1.54 mmol), and TEA (0.32 mL, 2.32 mmol) indry DMF (20 mL) was stirred at 80 C for 8 h. The mixturewas quenched with water (40 mL), then extracted withethyl acetate (3 x 40 mL). The combined organic layerextracts were washed with brine, dried over anhydrousMgSO4, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography.The desired product was obtained as white solid (0.13 g,56.4 %).
With hydrogenchloride; bromine; In water; at 20 - 30℃; for 3h;
3,4-Dimethoxybenzoic acid (25.0 g) was suspended in concentrated hydrochloric acid (35%) (500 mL), and bromine (23.0 g, 1.05 equivalents) was added dropwise to the resultant suspension at 25 C. Subsequently, the resultant mixture was stirred for seven hours. Water (500 mL) was added to the mixture, and the mixture was stirred for one hour. Thereafter, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-bromo-4,5-dimethoxybenzoic acid (34.47 g) (yield: 96.2%). [0029] 1H-NMR(DMSO-d6, delta): 3.79(s,3H), 3.84(s,3H), 7.21(s,1H), 7.37(s,1H), 13.08(bs,1H). ; For evaluation of the effect of concentrated hydrochloric acid concentration, the aforementioned reaction was carried out under the following conditions (amount of bromine: 1.1 equivalents, reaction temperature: 20 to 30 C., and reaction time: three hours), while the concentration of concentrated hydrochloric acid employed was varied. The results are shown in Table 2.
With hydrogenchloride; bromine; In water; at 20℃; for 3h;
3,4-Dimethoxybenzoic acid (25.0 g) was suspended in concentrated hydrochloric acid (35%) (500 mL), and bromine (23.0 g, 1.05 equivalents) was added dropwise to the resultant suspension at 25 C. Subsequently, the resultant mixture was stirred for seven hours. Water (500 mL) was added to the mixture, and the mixture was stirred for one hour. Thereafter, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-bromo-4,5-dimethoxybenzoic acid (34.47 g) (yield: 96.2%). [0029] 1H-NMR(DMSO-d6, delta): 3.79(s,3H), 3.84(s,3H), 7.21(s,1H), 7.37(s,1H), 13.08(bs,1H). ; The same reaction as described above was carried out under different reaction conditions (i.e., the amount of bromine, the reaction temperature, and the reaction time were varied). Table 1 shows the relationship between reaction conditions and yield. In Table 1, ?A? represents 3-bromo-4,5-dimethoxybenzoic acid; ?B? 3,4-dimethoxybenzoic acid; ?C? 1,2-dibromo-4,5-dimethoxybenzene; ?E? 2,3-dibromo-4,5-dimethoxybenzoic acid; and ?F? 2,6-dibromo-4,5-dimethoxybenzoic acid.
With 1,10-Phenanthroline; oxygen; copper diacetate; potassium hydroxide; In dimethyl sulfoxide; at 140℃; under 3000.3 Torr; for 2h;Autoclave;
General procedure: The catalytic reactions were performed in a 10-mL autoclave reactor with an internal Teflon insert. Typically, 0.5 mmol of secondary alcohols, 0.04 mmol of Cu(OAc)2 and 0.04 mmol of ligand, 1 mmol of base, and 2 mL of solvent were added to the reactor.Then, the reactor was charged with 0.4 MPa O2 and heated to the desired temperature under magnetic stirring. When the reaction reached completion, the reaction mixture was diluted with 4 mL of methanol, and the catalyst was separated via centrifugation.The acid product was esterified with addition of 40 mul of BF3OEt2 at 100 C for 6 h in Ar atmosphere. In reaction condition optimization experiment, the products were identified and quantified using gas chromatography-mass spectrometry (GC-MS) and an Agilent7890A/5975C instrument equipped with an HP-5 MS column (30 m in length, 0.25 mm in diameter). p-Xylene was used as the internal standard. In the substrate scope experiment, the product was isolated and identified by NMR. The procedure for the isolation of the product is as follows: after the reaction completed, the reactor was cooled to room temperature in water and vented the gas.The reaction mixture was acidified with HCl 1.0 M (pH 1-2,15 mL) and then extracted with Et2O (3 x 20 mL). Next, the combined organic layers were washed with HCl 1.0 M (pH 1-2,3 10 mL), dried over anhydrous Na2SO4, and filtered and the Et2O was rotary evaporated. Solid products obtained were vacuum dried for 10 h at 60 C.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h;
General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
De-methylated Linezolid was synthesized and acylated with desired carboxylic acids by the procedure described earlier. Demethylation of the compounds obtained after acylation with dimethoxy aryl carboxylic acids to get desired diol was carried out as per general procedure below. (Step-3 in the Scheme 4, above)
With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; Sealed tube;
General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography.
2-(3,4-diimethoxyphenyl)benzoxazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; at 70 - 80℃;
2-(3,4-Diimethoxyphenyl)benzoxazol-5-amine (11) was prepared by heating <strong>[137-09-7]2,4-diaminophenol dihydrochloride</strong> (0.01?mol) and 3,4-dimethoxybezoic acid (0.01?mol) in presence of cyclizing agent PPA (24?g) at 70-80?C for 6-7?h. After the completion of reaction, mixture was poured into ice cold water, neutralized with an excess of 10?N NaOH and extracted with toluene, dried over anhydrous sodium sulfate and evaporated under vacuum. The product obtained was boiled with 100?mg of charcoal in ethanol and filtered. After evaporation, the crude product obtained was recrystallized from ethanol.
C) 1-(3,4-Dimethoxybenzoyl)-<strong>[4295-36-7]2,3-dihydroquinolin-4(1H)-one</strong> A mixture of <strong>[4295-36-7]2,3-dihydroquinolin-4(1H)-one</strong> (2.70 g), ethylene glycol (2.1 mL), p-toluenesulfonic acid monohydrate (1.80 g), molecular sieves (4A, 3.00 g) and toluene (100 mL) was stirred under the conditions for 3 hours. The reaction mixture was cooled to room temperature. Then, sodium bicarbonate was added thereto, and the mixture was diluted with water, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of 3,4-dimethoxybenzoic acid (3.40 g) in THF (50 mL), a catalytic amount of DMF and oxalyl chloride (1.9 mL) were added at 0C, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and then, the mixture was dried in a nitrogen atmosphere. The obtained solid was dissolved in THF (100 mL). To the solution, the oil obtained above and triethylamine (3.9 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and water was added thereto, followed by extraction with ethyl acetate. The extract was washed with 6 N hydrochloric acid, and then, the solvent was distilled off under reduced pressure. THF and 6 N hydrochloric acid were added to the residue, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure again, and water was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. Toluene was added thereto, and the insoluble matter was filtered off. Then, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.90 g). MS: [M+H]+ 311.9.
1-palmitoyl-2-veratroyl-sn-glycero-3-phosphocholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 40℃; for 72h;Inert atmosphere; Darkness;
The GPC CdCl2 complex (2) was prepared according to the procedure described before [16].In the next step, cadmium complex of GPC was acetylated with methoxybenzoic acids in positionssn-1 and sn-2. To a stirred suspension of GPC CdCl2 complex (100 mg, 0.23 mmol) in 6 mL ofanhydrous CH2Cl2 acids 1a or 1b (0.92 mmol), DMAP (56 mg, 0.46 mmol) and, finally, DCC (200 mg,0.97 mmol) dissolved in 6 mL of the anhydrous CH2Cl2 were added. The mixture was stirred at 40 Cunder a nitrogen atmosphere for 72 h. Next (TLC), the formed precipitate was filtered off using theSchott funnel. The ion-exchange resin (DOWEX 50W X8, H+ form) was added to the filtrate in order todislodge DMAP. The solution was strongly stirred for 30 min; after this time, the resin was filtered offunder reduced pressure, and the solvent was evaporated in vacuo. The crude product was purified bycolumn chromatography.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide;
General procedure: To a solution of corresponding acids (RCOOH, 0.63 mmol), HOBt (170 mg, 1.26 mmol), EDCI (242 mg, 1.26 mmol), and DIPEA (0.208 mL, 1.26 mmol) were added to DMA (60 mL), and then 4 (186 mg, 1.26mmol) were added, the mixture was stirred overnight. The mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-nitrophenethyl)amide (5) in a good yield. And to a solution of 5 in MeOH was added 10% Pd/C under H2 at reflux overnight, then the mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-aminophenethyl)amide (6) in a good yield. Then the mixture of 3 and 6 was added NaCNBH3 in MeOH and the solution was stirred under reflux overnight. After reaction completed, the solvent was removed under reduced pressure and the residue was dissolved in water, the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to afford the corresponding compounds (7-26) in good yields.
With water; dihydrogen peroxide; In aq. phosphate buffer; ethanol; at 75℃; for 4h;Sealed tube;
General procedure: In a typical reaction, 125 ML phosphate buffer (0.2 mol L-1, pH 7),90 ML distilled water, 265 ML AuNPs-GQDs18 (0.72 g L-1, 0.01 mg gold)were mixed. Then, 0.1 mg substrate in 50 ML ethanol was dried at 50 Cin an open bottle. The bottle was sealed after the AuNPs-GQDs18 solutionand 20 ML fresh H2O2 (30 g L-1) was injected into it. The reactionmixture was heated at 75 C for 4 h in a horizonal oscillator. The conversionand yield were determined by HPLC. The catalyst could be recoveredby dialysis (8000-140,000 Da) and reused for 2 times (seeTable S3).
With potassium acetate; palladium diacetate; at 80℃; under 760.051 Torr; for 24.0h;
0.6 mmol of potassium acetate and 0.3 mmol of 3,4-dimethoxybenzoic acid,Palladium acetate 0.03 mmol, peroxydi-tert-butyl ether 0.6 mmol,0.8 mL of hexafluoroisopropanol was added to a 15 mL reaction tube.The mixture was placed in an oil bath at 80 C, and reacted in an air atmosphere at a pressure of 1 atm for 24 hours;After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water.The organic phase is dried over anhydrous Na2SO4.Filtration, concentration and purification by thin layer chromatography gave 18.8 mg of the desired product.White solid,The yield was 32%.
2-chloro-8-(3,4-dimethoxyphenyl)-1-propyl-7H-purin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With trichlorophosphate; at 120 - 125℃; for 72h;
A mixture of 1.1 (1.0 g, 5.43 mmol), 10.1 (0.99 g, 5.43 mmol) and POCl3 (10 mL) were heated at 120-125 C for 72 hours. Reaction completion was confirmed by TLC, mixture was cooled to 20-25 C. It was then concentrated under vacuuo and to the residue cold water was added slowly and solid material was separated. It was filtered off and washed with cold water, dried under vacuuo. The crude product was purified by column chromatography using silica gel (230-400 mesh) and 0.5 to 4 % methanol in DCM as an eluent to obtain 10.2 as a pale yellow solid. (1.1 g, 58 %) ESI-MS(m/z): 349.2 (M + 1); 1HNMR Not recorded
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