* 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] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[2] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[3] Patent: US2014/235634, 2014, A1,
[4] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[5] Patent: CN105541736, 2016, A,
[6] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
[7] Patent: CN105884699, 2016, A,
[8] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[9] Patent: WO2006/117552, 2006, A1,
3
[ 56441-97-5 ]
[ 61032-41-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 0℃; for 1.66667 h;
Methyl-4-Benzyloxy-3-methoxy Benzoate (5.00 g, 18.4 mmol) was dissolved in Ac20 (23.5 mL) and cooled to 0°C. Cu(N03)2 (5.05g, 27.0 mmol) was added in small portions overminutes. After 90 mi LCMS indicated product formation. The mixture was poured into ice- water and stirred for 45 minutes. Crude product was recovered by centrifugation, rinsed with water, and dried. The crude product was purified via silica-gel chromatography onCombiflash system using a petroleum ether/ethyl acetate gradient. 5.80g (99percent), off-white solid. ‘H NMR (CD3OD, ö in ppm): 7.62 (s, 1H), 7.45 (d, 2H), 7.40 (t, 2H), 7.35 (m, 1H), 7.25 (s, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H). MS (ESI-QMS): mlz = 318.03 (M+H).
98%
Stage #1: With nitric acid; acetic acid In water at -10℃; for 0.333333 h; Stage #2: With sodium hydroxide In water
Step 2b. Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (Compound 203) A mixture of HNO3 (45 mL, 0.963 mol) and HOAc (45 mL) was placed in an ice-bath and stirred. Compound 202 (10.3 g, 50 mmol) in 200 ml HOAc was added dropwise. After addition, the reaction mixture was stirred at -10° C. for 20 min. The mixture was poured onto a mixture of ice and water (250 mL) and was neutralized by the addition of aqueous sodium hydroxide solution (40percent). The precipitate was isolated by filtration, washed with water and dried to yield title compound 203 as a grey solid (30 g, 98percent): LCMS: 318 [M+1]+.
98.7%
at 0 - 20℃; for 0.5 h;
A solution of 39 (2.0 g, 7.34 mmol) in HOAc (5.0 mL) was added to a mixture of HOAc (5.0 mL) and HNO3 (20.6 mL, 441 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 30 min. The mixture was poured into ice water (100 mL) and adjust pH to 5-6. The mixture was filtered, and the filtrates was concentrated to give methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate 40 (2.3 g, 7.25 mmol, 98.7percent yield) as a yellow solid.
97.1%
at -10℃; for 0.333333 h;
A mixture of HNO3 (95percent, 1000 mL) and acetic acid (1000 mL) was placed in an ice bath and stirred. Compound 119 (440 g, 1.62 mol) in acetic acid (2500 mL) was added dropwise at −10° C. After addition, the mixture was stirred at −10° C. for 20 min, then poured onto a mixture of ice and water (2 L). The mixture was neutralized by the addition of saturated aqueous sodium hydroxide solution to pH 7 and solid precipitated out. The precipitate was collected by filtration, washed with water (300 mL×3) and dried to yield 120 (495 g, yield 97.1percent) as a grey solid
95%
at 50℃; for 2 h;
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 percent). 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 percent). 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, 95percent, m.p.: 134-135 °C).
94.7%
at 0 - 20℃; for 6.5 h;
Fuming nitric acid (5.8mL, 13.6mmol) was added dropwise to a solution of methyl 3-methoxy-4-benzyloxybenzoate (4, 3.7g, 13.3mmol) in glacial acetic acid (34mL) at 0–5°C and this mixture was stirred at 0–5°C for 30min and then for 6hat room temperature. The reaction mixture was poured on ice/ water (120mL) and the resulting precipitate was filtered and washed with chill water, dried to afford 4.0g of the product as a light yellow solid with a yield of 94.7percent. Mp: 128–130°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.90 (s, 3H), 3.95 (s, 3H), 5.23 (s, 2H), 6.89 (s, 1H), 7.28 (s, 1H), 7.33–7.50 (m, 5H).
94.7%
at 0 - 20℃; for 6.5 h; Cooling with ice
34 ml of glacial acetic acid, fuming nitric acid (13.6 mmol, 5.8 ml) was added to a 100 ml round-bottomed flask and stirred at 0 ° C in an ice bath. Methyl 3-methoxy-4-benzyloxybenzoate 13.3 mmol, 3.7 g) was slowly added to the solution in portions and the reaction was continued at 0 ° C for 30 minutes and then at room temperature for 6 hours.The reaction solution was slowly poured into 120 ml of ice water, stirred to precipitate solid, filtered, washed with a small amount of ether and dried to give 4.0 g of yellow solid as 2-nitro-4-benzyloxy-5-methoxybenzene acid methyl ester, yieldpercent 94.7
93.9%
at -5 - 25℃; for 16 h; Cooling with ice
will be 53 ml of concentrated nitric acid and 105 ml of acetic acid mixed latter ice-bath lower the temperature to -5 °C, will 14.0g compound a is dissolved in 15 ml of acetic acid, then will contain compounds acetic acid solution of concentrated nitric acid and dropping slowly added to the mixed solution of acetic acid, to the reaction solution after the dipping 20-25°C, reaction 16 hours, TLC analysis of the, raw materials after complete reaction, the reaction solution is poured into the ice water, extraction with ethyl acetate, washed with saturated sodium chloride solution, the organic phase with saturated sodium bicarbonate solution to alkaline, then saturated sodium chloride solution used for washing, drying by anhydrous magnesium sulphate, filtered filtrate obtained turns on lathe does 15.3g white solid (compound b), this product can be directly used for the next reaction, yield 93.9percent;
88%
With nitric acid; tin(IV) chloride In dichloromethane at -20℃; for 0.333333 h;
Preparation of 2-nitro-4-benzyloxy-5-methoxy-methylbenzoate 1.15 g of 4-benzyloxy-3-methoxy-methylbenzoate was dissolved in 30 mL anhydrous dichloromethane under a nitrogen atmosphere. The mixture was cooled in a slush bath consisting of carbon tetrachloride and dry ice (-25 C). 6.83 mL of tin(IV)chloride (1.0 M in CH2Cl2) was added to an addition funnel followed by 368 μL of 90percent nitric acid. This solution was dripped into the reaction mixture over 5 minutes. The resulting reaction mixture was stirred for 15 minutes in the slush bath, an equal volume of water added and the mixture warmed to room temperature. The resulting layers were separated and the aqueous phase extracted two times with ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with methanol to give the product as a pale yellow solid in 88percent yield. Proton NMR was consistent with the proposed structure. (lit. ref. Organic Letters 1999 vol 1(11) pp 1835-37)
86%
With nitric acid In acetic acid at 50℃; for 5 h;
4.1.4 Methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate (12) To a suspension of intermediate 11 (10.1 g, 37 mmol) in AcOH (100 mL) was slowly added 70percent HNO3 (20 mL). Subsequently, the mixture was heated to 50 °C for 5 h, then cooled to room temperature and poured into ice water (500 mL). After stirring for 1 h, the resulting precipitate was filtered off, washed with water and dried to obtain the nitro compound 12 as a white solid. Yield: 86percent, mp: 126-128 °C.
70%
With nitric acid In acetic acid for 22 h;
To a suspension of methyl 4-(benzyloxy)-3-methoxybenzoate (141.2 g, 0.519 mol) in acetic acid (400 ml) 160 ml of nitric acid is slowly added. After 20 hours, the reaction is treated with additional nitric acid (100 ml). At 22 hours, the reaction is quenched by addition of ice and then water. The resulting solids are filtered and washed with water three times. Solids are then dried via vacuum oven to provide methyl 4-(benzyloxy)-5- methoxy-2-nitrobenzoate (115 g, 70percent).
57%
With copper(I) nitrate trihydrate In acetic anhydride for 2.5 h; Cooling with ice
Refering to FIG.27, 4-Benzyloxy-5-methoxy-benzoic acid methyl ester 1 (13.6 g, 50 mmol) was dissolved in acetic anhydride (130 mL). Copper nitrate trihydrate (15.1 g, 62.5 mmol) was added in small portions over period of 30 minutes. After stirring for 1 h reaction mixture was poured on ice and stirred for 1 h. Precipitate was filtered off, washed with water and dried thoroughly. Material was recrystallized from ethyl acetate to afford 9.1 g of 2 (57percent yield). 1H NMR (500 MHz, CDCl3) : 7.52 (s, 1H), 7.36-7.46 (m, 5H), 7.09 (s, 1H), 5.22 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H). LC/MS: retention time 3.18 min. (ESI) C16H15NO6 calculated for [M+H]+ 318; found 340 (M+Na).
57%
for 1.5 h;
4-Benzyloxy-5-methoxy-benzoic acid methyl ester 1 ( 13.6 g, 50 mmol) was dissolved in acetic anhydride (130 mL). Copper nitrate trihydrate (15.1 g, 62.5 mmol) was added in small portions over period of 30 minutes. After stirring for 1 h reaction mixture was poured on ice and stirred for 1 h. Precipitate was filtered off, washed with water and dried thoroughly. Material was recrystallized from ethyl acetate to afford 9.1 g of 2 (57percent yield). 1H NMR (500 MHz, CDCl3) δ: 7.52 (s, 1 H), 7.36-7.46 (rn, 5H), 7.09 (s, 1H), 5.22 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H). LC/MS: retention time 3.18 min. (ESI) C16H16NO6 calculated for [M+H]+318; found 340 (M+Na).
Reference：
[1] Patent: WO2016/148674, 2016, A1, . Location in patent: Page/Page column 114
[2] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 26
[3] Patent: US2017/95570, 2017, A1, . Location in patent: Paragraph 0571; 0573
[4] Patent: US2014/235634, 2014, A1, . Location in patent: Paragraph 0390; 0392
[5] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2647 - 2650
[6] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
[7] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[8] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0056; 0057
[9] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0046
[10] Patent: US2006/142570, 2006, A1, . Location in patent: Page/Page column 16
[11] Patent: US2007/149523, 2007, A1, . Location in patent: Page/Page column 13
[12] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[13] Patent: US2007/208164, 2007, A1, . Location in patent: Page/Page column 14
[14] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6796 - 6805
[15] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[16] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[17] Patent: WO2008/109613, 2008, A1, . Location in patent: Page/Page column 214
[18] Patent: WO2018/53552, 2018, A2, . Location in patent: Paragraph 000469-000471
[19] Patent: WO2018/71455, 2018, A1, . Location in patent: Paragraph 0009; 00114-00118
[20] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[21] Patent: US2006/135782, 2006, A1, . Location in patent: Page/Page column 23
[22] Patent: US2002/26052, 2002, A1,
[23] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6728 - 6737
[24] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 53
[25] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[26] Patent: WO2006/117552, 2006, A1, . Location in patent: Page/Page column 64-65
[27] Patent: WO2018/195245, 2018, A1, . Location in patent: Page/Page column 26
4
[ 3943-74-6 ]
[ 100-39-0 ]
[ 56441-97-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
General Procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methyl-piperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline.; Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
Syntheses of Intermediates. General procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline. Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r. t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
99%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99 percent) as a grey solid which was used without further purification. LC/ESI-MS: m/z = 273 [M+H]+; Rt = 3.82 min.
99%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99percent) as a grey solid which was used without further purification. LC/ESI-MS: m/z=273 [M+H]+; Rt=3.82 min.
97%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5 h;
4.1.3 Methyl 4-benzyloxy-3-methoxybenzoate (11) To a solution of methyl vanillate (10) (1.82 g, 10 mmol) in DMF (10 mL) were added K2CO3 (1.38 g, 10 mmol) and benzyl bromide (2.05 g, 12 mmol). The mixture was heated at 60 °C for 5 h. After cooling to room temperature, water was added and the product was extracted with CH2Cl2. The organic phase was washed with water and brine. After drying over Na2SO4, the solvent was removed to yield intermediate 11 as a white solid. Yield: 97percent, mp: 77-79 °C.
95%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;
Step 2a. Methyl 4-(benzyloxy)-3-methoxybenzoate (Compound 202) To a mixture of compound 201 (18.2 g, 0.1 mol), potassium carbonate (34.55 g, 0.25 mol) in N,N-dimethylformamide was added benzylbromide (14.5 ml, 0.105 mol) dropwise. The reaction was then heated to 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate 500 mL. The organic layer was washed with water and brine (100 mL), dried over MgSO4, filtered and concentrated to give the title compound 202 as a white solid (26 g, 95percent): LCMS: 273 [M+1]+.
95%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6 h;
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 percent). 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 percent). 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, 95percent, m.p.: 134-135 °C).
91%
With potassium carbonate In acetone at 45℃; for 3.5 h;
To a mechanically stirred solution of methyl vanillate (103.5 g, 0.568 mol) and benzyl bromide (101.36 ml, 0.852 mol) in acetone (800 ml) at room temperature powdered K2CO3 (196.25 g, 1.4 mol) is added The reaction is heated to 45° C for 3.5 hours, cooled and filtered. The filtrate is concentrated in vacuo and the residue dissolved in EtOAc (300 ml) and washed with water (100 ml) three times saturated. NaHCψ3 (100 ml x 2), and brine. The organic layer is dried over Na2SO4 and concentrated in vacuo to provide 224.72g of a white solid. The solid is then triturated in hexane (300 ml) and filtered to provide methyl 4-(benzyloxy)-3-methoxybenzoate (141.45 g, 91percent).
86.6%
With potassium carbonate In acetone for 12 h; Heating / reflux
D) 4-Benzyloxy-3-methoxy benzoic acid methyl ester; Potassium carbonate (3.45 g; 25 mmol) was added to a solution of 4-hydroxy- 3-methoxy benzoic acid methyl ester (3.6 g; 20 mmol) and benzyl bromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 4.64 g of 4-benzyloxy-3-methoxy benzoic acid methyl ester (Yield = 86.6percent)
82.2%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
A solution of methyl 4-hydroxy-3-methoxybenzoate 38 (3.0 g, 16.5 mmol) in DMF (100 mL) was added benzyl bromide (4.22 g, 24.7 mmol) and K2CO3 (4.56 g, 32.9 mmol). The reaction mixture was stirred at 100° C. for 3 h. The mixture was concentrated in vacuo and was dissolved in water (50 mL), extracted with EtOAC (30 mL*2), washed with NaCl (30 mL), dried over Na2SO4. It was concentrated and purified by silica chromatography (0-30percent EtOAc in petroleum ether) to give methyl 4-(benzyloxy)-3-methoxybenzoate 39 (3.8 g, 13.5 mmol, 82.2percent yield) as a white solid. LCMS (5-95AB/1.5 min): RT=0.787 min, [M+H]+ 272.9
Reference：
[1] Patent: US2007/21446, 2007, A1, . Location in patent: Page/Page column 14
[2] Patent: EP1785420, 2007, A1, . Location in patent: Page/Page column 18
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6728 - 6737
[4] Patent: EP1746096, 2007, A1, . Location in patent: Page/Page column 23
[5] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[6] Patent: US2007/149523, 2007, A1, . Location in patent: Page/Page column 13
[7] Patent: EP1674466, 2006, A1, . Location in patent: Page/Page column 26
[8] Patent: EP1674467, 2006, A1, . Location in patent: Page/Page column 26
[9] Patent: US2006/142570, 2006, A1, . Location in patent: Page/Page column 16
[10] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[11] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6796 - 6805
[12] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 26
[13] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2647 - 2650
[14] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[15] Patent: WO2008/109613, 2008, A1, . Location in patent: Page/Page column 214
[16] Patent: WO2005/113489, 2005, A1, . Location in patent: Page/Page column 93
[17] Patent: US2017/95570, 2017, A1, . Location in patent: Paragraph 0571; 0572
[18] Synlett, 2010, # 5, p. 753 - 756
[19] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[20] Patent: EP1489077, 2004, A1, . Location in patent: Page 40
[21] Patent: US2006/135782, 2006, A1, . Location in patent: Page/Page column 23
[22] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 53
[23] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[24] RSC Advances, 2016, vol. 6, # 46, p. 40238 - 40249
[25] Patent: WO2006/117552, 2006, A1, . Location in patent: Page/Page column 63-65
5
[ 3943-74-6 ]
[ 100-44-7 ]
[ 56441-97-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;
A mixture of methyl vanillate (300.0 g, 1.65 mol), benzyl chloride (230 mL, 1.81 mol) and potassium carbonate (345 g, 2.5 mol) in N,N-dimethyl formamide (1000 mL) was heated to 100° C. for three hours. The reaction was cooled to room temperature, poured into ice water (1500 mL) and stirred for 1 h. The resultant solid was filtered and washed by water (300 mL×3), then dried to give 119 (440 g, yield=98.0percent) as a white solid
97%
With potassium carbonate In acetonitrile at 90℃; for 2 h; Inert atmosphere
under the protection of nitrogen added in the reaction bottle 10.0g3-methoxy-4-hydroxy benzoic acid, 19.0g potassium carbonate, 7.0g benzyl chloride and 80 ml of acetonitrile, the mixture to the 90 °C reflux reaction 2 hours, using n-hexane: ethyl acetate = 4 volume ratio: 1 as a developing solvent of TLC analysis of the mixture; complete reaction of raw materials, cooling filter, by 150 ml ethyl acetate wash the filter cake, filtrate turns on lathe does, column chromatography, using hexane: ethyl acetate = 5 volume ratio: 1 of the mixed solution to elute, get 14.5g pure white solid (compound a), yield 97.0percent;
Reference：
[1] Patent: US2014/235634, 2014, A1, . Location in patent: Paragraph 0390; 0391
[2] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0045
[3] ACS Chemical Biology, 2012, vol. 7, # 3, p. 552 - 562
[4] Journal of the Chemical Society, 1950, p. 864,866
6
[ 1486-53-9 ]
[ 74-88-4 ]
[ 56441-97-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In acetone for 16 h; Heating / reflux
Preparation of 4-benzyloxy-3-methoxy-methylbenzoate 2.84 g of 4-benzyloxy-3-methoxy-benzoic acid was combined with 3.04 g of potassium carbonate and 1.03 mL of iodomethane in 100 mL of acetone. The mixture was refluxed for 16 hours, cooled to room temperature and diluted with dichloromethane. The slurry was filtered and washed with dichloromethane and the filtrate concentrated to dryness. The solids were redissolved in dichloromethane, washed twice with water, dried over sodium sulfate and filtered. The filtrate was concentrated to a clear, colorless oil which was triturated with methanol to give a white solid in 90percent yield (2.7 grams). Proton
A catalytic amount of concentrated H2SO4 was added to a solution of compound 3 (5.4g, 20.9mmol) in 50mL of methanol and the mixture was refluxed for 10h. It was allowed to cool. The product crystallization from solution gave pure 4 (4.5g) as a white solid with a yield of 80percent. Mp: 70–72°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.90 (s, 3H), 3.95 (s, 1H), 5.23 (s, 2H), 7.32–7.57 (m, 5H), 7.58 (s, 1H), 7.60–7.61 (d, J=2.0Hz, 1H), 7.63–7.64 (d, J=1.8Hz, 1H).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
8
[ 67-56-1 ]
[ 1486-53-9 ]
[ 56441-97-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sulfuric acid In methanol for 10 h; Reflux
A solution of 3-methoxy-4-benzyloxybenzoic acid (20.9 mmol, 5.4 g) in 50 ml of methanol was added to a 250 ml reaction flask, and 1 ml of concentrated sulfuric acid was slowly added dropwise with stirring. The mixture was heated under reflux for 10 hours.Concentrated and crystallized from methanol, filtration, the filter cake washed with a small amount of methanol, and dried to give a white solid 4.5g, 3-methoxy-4-benzyloxy-benzoic acid methyl ester Yieldpercent 80,
Reference：
[1] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0054; 0055
9
[ 121-33-5 ]
[ 56441-97-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
10
[ 100-44-7 ]
[ 56441-97-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
11
[ 2426-87-1 ]
[ 56441-97-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
12
[ 121-34-6 ]
[ 56441-97-5 ]
Reference：
[1] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2647 - 2650
13
[ 56441-97-5 ]
[ 27883-60-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[2] Patent: WO2016/148674, 2016, A1,
[3] Patent: CN105884699, 2016, A,
14
[ 56441-97-5 ]
[ 155666-33-4 ]
Reference：
[1] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[2] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
15
[ 56441-97-5 ]
[ 162364-72-9 ]
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[2] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[3] Patent: CN105541736, 2016, A,
[4] Patent: CN105884699, 2016, A,
[5] Patent: WO2006/117552, 2006, A1,
With potassium carbonate; In acetone; for 16.0h;Heating / reflux;
Preparation of 4-benzyloxy-3-methoxy-methylbenzoate 2.84 g of 4-benzyloxy-3-methoxy-benzoic acid was combined with 3.04 g of potassium carbonate and 1.03 mL of iodomethane in 100 mL of acetone. The mixture was refluxed for 16 hours, cooled to room temperature and diluted with dichloromethane. The slurry was filtered and washed with dichloromethane and the filtrate concentrated to dryness. The solids were redissolved in dichloromethane, washed twice with water, dried over sodium sulfate and filtered. The filtrate was concentrated to a clear, colorless oil which was triturated with methanol to give a white solid in 90% yield (2.7 grams). Proton
7-methoxy-8-{3-[7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine-5-one-8-yloxy]propoxy}-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one[ No CAS ]
7-methoxy-8-{5-[7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine-5-one-8-yloxy]pentyloxy}-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one[ No CAS ]
With sodium hydroxide; In methanol; for 4.0h;Heating / reflux;
E) 4-Benzyloxy-3-methoxy benzoic acid; A solution of sodium hydroxide (2.0 g) in methanol (50 ml) was added to a solution of 4-benzyloxy-3-methoxy benzoic acid methyl ester (4.64 g) in methanol (50 ml) and refluxed for 4 hrs. After removal of methanol under reduced pressure the residue was dissolved in water (150 ml) and washed with ethyl acetate (2 x 50 ml). The aqueous layer was acidified with 2N hydrochloric acid to pH 2. The precipitated product was collected by filtration which on drying under vacuum provided 4.17 g of 4-benzyloxy- 3-methoxy benzoic acid. (Yield = 74%) 'H NMR CDCl3 7.7 (1H, d, J = 8Hz) 7.63 (1H, s) 7.3-7.5 (5H, m) 6.92 (1H, d, J 8Hz) 5.25 (2H, s) 3.98 (3H, s)
(1) Benzyl bromide (3.59 ml) and potassium carbonate (5.69 g) were added to an acetone (50 ml) solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g), and heated at reflux for 4 hours. After removing solid matter by filtration and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 7.47 g of <strong>[56441-97-5]methyl 4-benzyloxy-3-methoxybenzoate</strong>.(2) An aqueous 2 M sodium hydroxide solution (13.72 ml) was added to an ethanol (15 ml) solution of the above-obtained 4-benzyloxy compound (7.47 g), and heated at reflux for 2 hours. After evaporating the solvent under reduced pressure, 2M hydrochloric acid was added, and the thus-precipitated crystals were filtered, thereby giving 7.00 g of the desired compound.
General procedure: A borosilicate flask was equipped with a magnetic stir bar, and neat or solid arene (0.2-0.8mmol) was added. Addition of hexafluoroisopropanol or trifluoroethanol (2-5 ml) to providea 0.2M solution was followed by the addition of solid phthaloyl peroxide (1, 1.3 equiv.) in portions over 90 s. The reaction flask was placed in a heated oil bath (23-50 C). After 3-24 h, the flask was removed from the oil bath and cooled to ambient temperature (23 C). The reaction was then concentrated, and under positive N2 pressure (to avoid potential air oxidation of the phenolic product) MeOH (3 ml) and saturated aqueous NaHCO3 solution (0.2 ml) were added and the solution was stirred. After 12 h, the reaction was quenched with phosphate buffer (5 ml, pH 7.0) and extracted with EtOAc (10 ml x 33), and the combined organic layers were washed with brine (5 ml), dried over Na2SO4 and concentrated. The crude material was purified by silica-gel column chromatography to afford the desired phenolic product. For full experimental details and characterization of new compounds, see Supplementary Information.
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