* 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.
With water; triethylamine; sodium hydroxide In tetrahydrofuran at 50℃; for 5 h;
To a solution of methyl 4-(benzyloxy)-5-methoxy-2- nitrobenzoate (Harve Chem, 15 g, 47.3 mmol) in tetrahydrofuran (THF, 350 mL) was added a solution of aq. NaOH (56.7 mL, 142 mmol, 2.5M). The reaction was stirred at 50 °C for 5 h. The reaction was cooled to room temperature (RT) and then concentrated in vacuo to remove the THF. The remaining aqueous layer was acidified with aq. HC1 (6 N) to pH 2. The resulting yellow precipitate was filtered, washed with water, and dried under vacuum to give 4- (benzyloxy)-5-methoxy-2-nitrobenzoic acid (14.32 g, 100percent yield). LCMS (M+H) = 304.08; NMR (400MHz, METHANOL-d4) δ 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.45 - 7.31 (m, 3H), 7.29 (s, 1H), 5.23 (s, 2H), 3.98 (s, 3H).
100%
With water; sodium hydroxide In tetrahydrofuran at 50℃; for 5 h;
To a rt solution of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15 g, 47 mmol) inTHF (350 mL) was added 2.5 M aq. NaOH (56.7 mL, 142 mmol). The reaction was stirred at 50°C for 5 h. The reaction was cooled to rt and then concentrated in vacuo to remove the THF. Theremaining aqueous layer was acidified with 6 N aq. HCl to pH 2. The resulting yellow precipitatewas filtered, washed with water, and dried under vacuum to provide S1 (14.32 g, quant.).
92%
at 50℃; for 1 h;
4-Benzyloxy-5-methoxy-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated. Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring. Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield).1H NMR (500 MHz, DMSO-d6) : 7.69 (s, 1H), 7.36-7.47 (m, 5H),7.31 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).
92%
at 50℃; for 1 h;
4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated.Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring.Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield). 1H NMR (500 MHz, DMSO-d6) δ: 7,69 (s, 1H), 7,36-7,47 (m, 5H),7,31 (s, 1H), 5.24 (s, 21-1), 3.91 (s, 3H).
91%
With lithium hydroxide In methanol; water at 20℃; for 2 h;
A solution of 40 (2.3 g, 7.25 mmol) in MeOH (20 mL) was added a solution of LiOH (2.25 mL, 36.24 mmol) in water (5 mL). The reaction mixture was stirred at 20° C. for 2 h. The mixture was poured into water (50 mL), and washed with EtOAc (50 mL). The water phase was adjust pH to 3-4 with 2M HCl, and extracted with EtOAc (50 mL*3). It was washed with NaCl (25 mL), dried over Na2SO4 and concentrated in vacuo to give crude 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 41 (2.0 g, 6.59 mmol, 91percent yield) as white solid.
1.5 kg
With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 16 h; Large scale
To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H20 (20 L) was added LiOH H20 (332.68 g, 7.93 mol) in one portion at 20 °C to give a suspension, the reaction was stirred at this temperature for 16 h. TLC (petroleum ether: ethyl acetate = 2: 1) showed that the reaction was completed. The solvent was evaporated under vacuum to remove THF. The residue was acidified with 2N HC1 until pH = 2 to give a yellow
Reference：
[1] Patent: WO2016/209951, 2016, A1, . Location in patent: Paragraph 00146-00147
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5267 - 5271
[3] Patent: WO2018/53552, 2018, A2, . Location in patent: Paragraph 000473-000475
[4] Patent: WO2018/71455, 2018, A1, . Location in patent: Paragraph 0009; 00114; 00119-00121
[5] Patent: US2017/95570, 2017, A1, . Location in patent: Paragraph 0571; 0574
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[7] Patent: WO2018/195245, 2018, A1, . Location in patent: Page/Page column 27
2
[ 61032-41-5 ]
[ 61032-42-6 ]
Yield
Reaction Conditions
Operation in experiment
99.4%
With iron; ammonium chloride In methanol; water at 80℃; for 0.5 h; Inert atmosphere
8.0 g of compound II, 12.0 g of iron powder, 12.0 g of ammonium chloride, 60 ml of water, 120 ml of methylene chlorideThe mixture of alcohols was stirred at 80 ° C for 30 minutes under reflux. TLC analysis showed no starting material and was filtered off with 50 ml of methanol and50 ml of ethyl acetate, the filtrate was spin-dried, the solvent was added to 300 ml of water,Liter of ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate,Dried to give 7.2 g of a brown solid (Compound 3) in 99.4percent yield;
87%
With hydrogen In 1,2-dimethoxyethane at 20℃; for 7 h;
Example 6 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate); Into a glass vessel having an internal volume of 20 ml and equipped with a stirrer, a thermometer, a reflux condenser, and a balloon filled with hydrogen gas were placed 4.0 g (12.6 mmol) of methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate, 0.2 g of 3percent by mass platinum sulfided carbon powder (60percent moisture content) (manufactured by N.E. CHEMCAT CORPORATION), and 20 ml of dimethoxyethane, and the resultant mixture was reacted in a hydrogen gas atmosphere at room temperature for 7 hours with stirring. After completion of the reaction, the reaction mixture was allowed to stand for 10 days and then filtered, and the reaction mixture was concentrated under reduced pressure to obtain 3.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate as a pale brown solid (isolation yield: 87percent). Values of physical properties for the obtained methyl 2-amino-4-benzyloxy-5-methoxybenzoate are as follows. 1 H-NMR(CDCl3 , δ(ppm)); 3.81(3H,s), 3.83(3H,s), 5.09(2H,s), 5.37(2H,brs), 6.15(1H,s), 7.31-7.41(6H,m) CI-MS(m/e); 287(M+)
85%
Stage #1: With iron In ethanol; water for 3 h; Heating / reflux Stage #2: With sodium hydroxide In ethanol; water at 20℃;
Step 2c. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (Compound 204) A mixture of compound 203 (10 g, crude), iron powder (54 g, 0.96 mol), ethanol (100 mL), and H2O (20 mL) was stirred and heated to reflux for 3 hours. The mixture was cooled to room temperature and neutralized with aqueous sodium hydroxide (10percent). The reaction was filtered and the filtrate was concentrated to give a residue which was extracted with dichloromethane (200 mL*2). The combined organic layer was washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound 204 as a grey solid (14.5 g, 85percent): LCMS: 288 [M+1]+.
84.7%
With acetic acid; zinc In methanol; water for 3 h; Reflux
A mixture of compound 5 (2.0g, 6.2mmol), zinc powder (1.2g, 19mmol), glacial acetic acid (3.6mL, 63.3mmol) in methanol: H2O (33: 3mL) was stirred at reflux for 3h. The reaction mixture was filtered while hot and the solid was washed with CH3OH. The solvent was removed from filtrate and the resulting solid was diluted with water (50mL) and subsequently extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate and saturated saline solution, and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 6 as a light yellow solid (84.7percent). Mp: 131–133°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.83–3.84 (d, J=3.7Hz, 6H), 5.14 (s, 2H), 5.52 (s, 2H), 6.16 (s, 1H), 7.26–7.42 (m, 6H).
84.7%
at 20℃; for 3 h; Reflux
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (6.2 mmol, 2.0 g) was added to a 100 ml reaction flask followed by MeOH / H2(63 mmol, 3.6 ml) was slowly added dropwise, and the mixture was heated under reflux for 3 hours. The resulting mixture was stirred for 3 hours at room temperature, followed by addition of zinc powder (19 mmol, 1.2 g).After completion of the reaction, the residue was filtered off, the methanol was removed from the filtrate, and then 50 ml of water was added thereto. The mixture was extracted with ethyl acetate (30 ml x 2), and the organic phase was separated and washed successively with saturated sodium hydrogencarbonate X 2) and saturated sodium chloride (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was dried to give 1.5 g of 2-amino-4- benzyloxy-5-methoxybenzoate, yieldpercent 84.7,
81%
With iron; ammonium chloride In methanol; water at 105℃;
A suspension of 120 (495 g, 1.56 mol), Fe (305.7 g, 5.46 mol) and NH4Cl (337.0 g, 6.24 mol) in a mixture of methanol/H2O (1500 mL/500 mL) was stirred at 105° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (1500 mL), stirred for 3 h at room temperature and filtered. The filtrate was washed with water (500 mL×3) and brine (500 mL×3), then dried over Na2SO4. The solution was concentrated in vacuum to give 121 (363.8 g, yield=81percent) as a light brown solid
67%
With iron; acetic acid In methanol for 4 h; Heating / reflux
Iron powder (46.2 g, 0.828 mol) is added to a suspension of methyl A- (benzyloxy)-5-methoxy-2-nitrobenzoate (52.5g, 165.6 mmol) in acetic acid (95 ml) and MeOH (200 ml). The reaction is then heated to reflux for 4 hours. The hot reaction mixture is then filtered through diatomaceous earth with 10percent MeOH/CH2Cl2. The filtrate is concentrated in vacuo, dissolved in EtOAc, and passed through hydrous magnesium silicate using EtOAc. The organic phase is concentrated in vacuo and triturated with 30percent EtOAc/Hexane to provide methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (31.94 g, 67percent).
Reference：
[1] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0047
[2] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[3] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
[4] Patent: EP2123627, 2009, A1, . Location in patent: Page/Page column 6-7
[5] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 26-27
[6] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[7] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0058; 0059
[8] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[9] Patent: US2014/235634, 2014, A1, . Location in patent: Paragraph 0390; 0393
[10] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[11] Patent: WO2008/109613, 2008, A1, . Location in patent: Page/Page column 214
[12] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 53
[13] Patent: US2007/208164, 2007, A1, . Location in patent: Page/Page column 14-15
[14] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5342 - 5346
[16] Patent: WO2006/117552, 2006, A1, . Location in patent: Page/Page column 64-65
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
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
10
[ 2426-87-1 ]
[ 61032-41-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
11
[ 121-34-6 ]
[ 61032-41-5 ]
Reference：
[1] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2647 - 2650
12
[ 61032-41-5 ]
[ 27883-60-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
for 1 h;
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (4.1 mmol, 1.3 g) in trifluoroacetic acid (8 ml) was refluxed for 1 hour. TFA was removed by decantation, and water and extracted with ethyl acetate. the combined organic phase was concentrated to column chromatography to obtain 0.796 g, 2-nitro-4-hydroxy-5-methoxybenzoate, yieldpercent 86,
84%
With methanesulfonic acid In dichloromethane for 3 h;
EC2093 (5.80 g, 18.2 mmol) was dissolved in CH2C12 (10 mL). A mixture of 2.5 mL CH2C12 and 2.5 mL of CH3SO2OH was added and the mixture stuffed. After 3 hours, LCMS indicatedproduct formation. The solvent was removed and the product was purified via silica-gel chromatography on a Combiflash system using a CH2C12 / CH3OH gradient to provide EC1882 3.46g (84percent), as off-white solid. ‘H NMR (CD3OD, ö in ppm): 7.35 (s, 1H), 7.2 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H). MS (ESI-QMS): mlz = 225.78 (M-H).
Reference：
[1] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0064; 0065
[2] Patent: WO2016/148674, 2016, A1, . Location in patent: Page/Page column 114
[3] Bioorganic and medicinal chemistry, 2004, vol. 12, # 16, p. 4337 - 4350
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 15, p. 6518 - 6545
[5] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
13
[ 61032-41-5 ]
[ 10097-32-2 ]
[ 27883-60-9 ]
Reference：
[1] Patent: US2002/26052, 2002, A1,
14
[ 61032-41-5 ]
[ 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
[ 61032-41-5 ]
[ 162364-72-9 ]
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5342 - 5346
[3] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[4] Patent: CN105541736, 2016, A,
[5] Patent: CN105884699, 2016, A,
[6] Patent: WO2006/117552, 2006, A1,
With boron trichloride; In dichloromethane; at -78℃; for 3h;Inert atmosphere;
[0631] To a brown solution of compound Int-1-3 (24.8 g, 78.2 mmol) in DCM (500 mL) at -78C. under N2 atmosphere was added 1M BCl3 in DCM (93.8 mL, 93.8 mmol, 1.2 eq.) and stirred for 3 hours. After the reaction was quenched with MeOH (100 mL), the mixture was allowed to warm up to room temperature and then concentrated under reduced pressure. The resultant residue was dissolved in DCM (600 mL). The resultant mixture was washed with saturated NaHCO3 (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4, filtered. Removal of solvent gave Int-2-1 (17.5 g, 98%) as yellow solid. [0632] 1H NMR (400 MHz, CDCl3) delta 7.47 (s, 1H), 7.14 (s, 1H), 6.03 (s, 1H), 4.02 (s, 3H), 3.90 (s, 3H).
86%
With trifluoroacetic acid; for 1h;
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (4.1 mmol, 1.3 g) in trifluoroacetic acid (8 ml) was refluxed for 1 hour. TFA was removed by decantation, and water and extracted with ethyl acetate. the combined organic phase was concentrated to column chromatography to obtain 0.796 g, 2-nitro-4-hydroxy-5-methoxybenzoate, yield% 86,
84%
With methanesulfonic acid; In dichloromethane; for 3h;
EC2093 (5.80 g, 18.2 mmol) was dissolved in CH2C12 (10 mL). A mixture of 2.5 mL CH2C12 and 2.5 mL of CH3SO2OH was added and the mixture stuffed. After 3 hours, LCMS indicatedproduct formation. The solvent was removed and the product was purified via silica-gel chromatography on a Combiflash system using a CH2C12 / CH3OH gradient to provide EC1882 3.46g (84%), as off-white solid. ?H NMR (CD3OD, oe in ppm): 7.35 (s, 1H), 7.2 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H). MS (ESI-QMS): mlz = 225.78 (M-H).
With acetic anhydride; copper(II) nitrate; at 0℃; for 1.66667h;
Methyl-4-Benzyloxy-3-methoxy Benzoate (5.00 g, 18.4 mmol) was dissolved in Ac20 (23.5 mL) and cooled to 0C. 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 (99%), off-white solid. ?H NMR (CD3OD, oe 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%
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 (40%). The precipitate was isolated by filtration, washed with water and dried to yield title compound 203 as a grey solid (30 g, 98%): LCMS: 318 [M+1]+.
98.7%
With nitric acid; acetic acid; at 0 - 20℃; for 0.5h;
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, 98.7% yield) as a yellow solid.
97.1%
With nitric acid; acetic acid; at -10℃; for 0.333333h;
A mixture of HNO3 (95%, 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 97.1%) as a grey solid
95%
With nitric acid; acetic acid; at 50℃; for 2.0h;
A 250 mL, round-bottomed flask with a stirring bar, a solution of 4-hydroxy-3-methoxybenzoic acid (20 g, 118.94 mmol) was added slowly to a solution of methanol (100 mL) and concentrated sulfuric acid (10 mL). After being stirred for 12 h at reflux, saturated solution of sodium bicarbonate was added to adjust the pH to 7. Dichloromethane was added and the mixture was then filtered and the organic phase evaporated on a rotary evaporator and to obtain the compound 2 (20.37 g, 94 %). Compound 2 (20.4 g, 111.98 mmol) was added into a 500 mL, round-bottomed flask with a stirring bar, then benzyl bromide (18 mL), potassium carbonate (22 g, 156.8 mmol), DMF (200 mL) were added. It was stirred for 6 h at 80 C. Then the reaction system was poured into right amount of water, white solid (3) was obtained by filtration (28.97 g, 95 %). Compound 3 (16.54 g, 60.74 mmol) was dissolved in CH3COOH (50 mL) and then added into a 250 mL, round bottomed flask with a stirring bar. Then HNO3 (25 mL) was added into the system slowly to keep the temperature of the reaction above 5 C. The reaction temperature was raised to 50 C and kept for another 2 h. After that the system was poured into water and pale yellow solid (I) was obtained6-8 (18.3 g, 95%, m.p.: 134-135 C).
94.7%
With nitric acid; acetic acid; at 0 - 20℃; for 6.5h;
Fuming nitric acid (5.8mL, 13.6mmol) was added dropwise to a solution of <strong>[56441-97-5]methyl 3-methoxy-4-benzyloxybenzoate</strong> (4, 3.7g, 13.3mmol) in glacial acetic acid (34mL) at 0-5C and this mixture was stirred at 0-5C 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 94.7%. Mp: 128-130C; 1H NMR (CDCl3, 300MHz): delta (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%
With nitric acid; acetic acid; at 0 - 20℃; for 6.5h;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, yield% 94.7
93.9%
With nitric acid; acetic acid; at -5 - 25℃; for 16.0h;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 20-25C, 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 93.9%;
92%
With acetic anhydride; copper(II) nitrate; at 0℃; for 6.0h;Inert atmosphere;
[0509] To a solution of compound Int-1-2 (79.8 g, 0.29 mol) in acetic anhydride (550 mL) under N2 atmosphere at 0C. was added copper (II) nitrate hemi-(pentahydrate) (75.0 g, 0.32 mol). The mixture was stirred at 0C. for 6 h, the reaction was quenched with ice water (800 mL) and a solid precipitated out. The solid was filtered and washed with distilled water (100 mL) and hexane (200 mL2) to obtain compound Int-1-3 (85.5 g, 92%). [0510] 1H NMR (400 MHz, CDCl3) delta 7.52 (s, 1H), 7.45-7.35 (m, 5H), 7.08 (s, 1H), 5.22 (s, 2H), 3.98 (s, 3H), 3.91 (s, 3H).
91%
Step 2. Methyl 4-benzyloxy-3-methoxybenzoate (10.9 g, 40.0 mmol) was converted into methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate (11.6 g, 36.6 mmol, 91%) as described in US 02/0026052 A1, page 51, referent example 15. LC/ESI-MS: m/z=318 [M+H]+; Rt=3.85 min.
91 - 94%
Step 2. Crude material of step 1 (40.0 mmol) was converted into methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate or methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate, respectively, in 91-94% yield as described in US 02/0026052 A1, page 51, reference example 15.
88%
With nitric acid; tin(IV) chloride; In dichloromethane; at -20℃; for 0.333333h;
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 muL of 90% 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 88% 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 5.0h;
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 70% 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: 86%, mp: 126-128 C.
70%
With nitric acid; In acetic acid; for 22.0h;
To a suspension of <strong>[56441-97-5]methyl 4-(benzyloxy)-3-methoxybenzoate</strong> (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, 70%).
57%
With copper(I) nitrate trihydrate; In acetic anhydride; for 2.5h;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 (57% 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%
With copper(II) nitrate trihydrate; acetic anhydride; for 1.5h;
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 (57% yield). 1H NMR (500 MHz, CDCl3) delta: 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).
Step 2. Crude material of stap 1 (40.0 mmol) was converted into methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate or methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate, respectively, in 91-94% yeld as described in US 02/0026052 A1, page 51, referance example 15.
With nitric acid; In acetic acid;
REFERENCE EXAMPLE 15 Methyl 5-methoxy-2-nitro-4-(benzyloxy) benzoate Nitric acid (27 mL of a 70% solution) was added dropwise to a suspension of methyl 3-methoxy-4-(benzyloxy) benzoate (14.5 g, 53.0 mmol) in 150 mL of acetic acid. The mixture was stirred at room temperature for 15 minutes and then was heated at 50 C. for 4 hours. The reaction was cooled to room temperature and poured into ice. The precipitate was collected by filtration, washed with water and dried to provide 16.4 g of methyl 5-methoxy-2-nitro-4-(benzyloxy) benzoate as an off-white solid, mp 104-105 C.; MS (ES) m/z 318.1 (M+1). Analysis for C16H15NO6: Calcd: C, 60.57;H, 4.76; N, 4.41. Found: C, 60.39;H, 4.70; N, 4.28.
With nitric acid; In acetic acid;
Commercially available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted in 5 steps to 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-quinazolme 15 (35% overall yield).[17,18] The only significant modification involved an improved workup of the nickel chloride hexahydrate-sodium borohydride reduction of the nitro intermediate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy intermediate 16, followed by alkylation with propargyl bromide in acetonitrile, gave 13 in a 65% yield for 2 steps. This method involved an additional step, and the overall yield was greater. In addition, the final 7-hydroxy intermediate 16 could be used to generate other products [19].
With nitric acid; In acetic acid; at 0 - 60℃; for 1.16667h;
To a solution of <strong>[56441-97-5]4-benzyloxy-3-methoxy-benzoic acid methyl ester</strong> (7.08 g, 26 mmol) in acetic acid (50 ml), at O0C, was added dropwise nitric acid (7 ml) over 10 minutes. The reaction mixture was warmed to room temperature and then stirred at 60 0C for 1 hour. The reaction mixture was poured into water, extracted with DCM (3x125 ml) and the combined organic extracts were washed with water, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated to provide the title compound as a pale yellow solid (7.5 g). LC/MS purity: 95 %, m/z 318 [M+H]+. 1H NMR (300 MHz, CDCI3) delta: 7.55 (1 H, s), 7.53-7.39 (5H, m), 7.11 (1H, s), 5.23 (2H, s), 3.99 (3H1 s), 3.92 (3H, s).
With water; triethylamine; sodium hydroxide; In tetrahydrofuran; at 50℃; for 5h;
To a solution of methyl 4-(benzyloxy)-5-methoxy-2- nitrobenzoate (Harve Chem, 15 g, 47.3 mmol) in tetrahydrofuran (THF, 350 mL) was added a solution of aq. NaOH (56.7 mL, 142 mmol, 2.5M). The reaction was stirred at 50 C for 5 h. The reaction was cooled to room temperature (RT) and then concentrated in vacuo to remove the THF. The remaining aqueous layer was acidified with aq. HC1 (6 N) to pH 2. The resulting yellow precipitate was filtered, washed with water, and dried under vacuum to give 4- (benzyloxy)-5-methoxy-2-nitrobenzoic acid (14.32 g, 100% yield). LCMS (M+H) = 304.08; NMR (400MHz, METHANOL-d4) delta 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.45 - 7.31 (m, 3H), 7.29 (s, 1H), 5.23 (s, 2H), 3.98 (s, 3H).
100%
With water; sodium hydroxide; In tetrahydrofuran; at 50℃; for 5h;
To a rt solution of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15 g, 47 mmol) inTHF (350 mL) was added 2.5 M aq. NaOH (56.7 mL, 142 mmol). The reaction was stirred at 50C for 5 h. The reaction was cooled to rt and then concentrated in vacuo to remove the THF. Theremaining aqueous layer was acidified with 6 N aq. HCl to pH 2. The resulting yellow precipitatewas filtered, washed with water, and dried under vacuum to provide S1 (14.32 g, quant.).
97%
With sodium hydroxide; In tetrahydrofuran; methanol; at 20 - 65℃; for 5h;
[0512] To a solution of compound Int-1-3 (85.5 g, 0.27 mol) in THF (800 mL) and MeOH (300 mL) was added 2N NaOH (404 mL, 0.81 mol). After stirring for 5 hr at 65C., the reaction was cooled to room temperature and adjusted to pH 2 by addition of 2N HCl solution, and then extracted with distilled water (100 mL) and EA (300 mL2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue solid was collected and washed with hexane to obtain compound Int-1-4 (79.2 g, 97%). [0513] 1H NMR (400 MHz, DMSO-d6) delta 7.69 (s, 1H), 7.47-7.35 (m, 5H), 7.03 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).
92%
With methanol; sodium hydroxide; at 50℃; for 1h;
4-Benzyloxy-5-methoxy-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated. Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring. Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92% yield).1H NMR (500 MHz, DMSO-d6) : 7.69 (s, 1H), 7.36-7.47 (m, 5H),7.31 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H).
92%
With methanol; sodium hydroxide; at 50℃; for 1h;
4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated.Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring.Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92% yield). 1H NMR (500 MHz, DMSO-d6) delta: 7,69 (s, 1H), 7,36-7,47 (m, 5H),7,31 (s, 1H), 5.24 (s, 21-1), 3.91 (s, 3H).
91%
With lithium hydroxide; In methanol; water; at 20℃; for 2h;
A solution of 40 (2.3 g, 7.25 mmol) in MeOH (20 mL) was added a solution of LiOH (2.25 mL, 36.24 mmol) in water (5 mL). The reaction mixture was stirred at 20 C. for 2 h. The mixture was poured into water (50 mL), and washed with EtOAc (50 mL). The water phase was adjust pH to 3-4 with 2M HCl, and extracted with EtOAc (50 mL*3). It was washed with NaCl (25 mL), dried over Na2SO4 and concentrated in vacuo to give crude 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 41 (2.0 g, 6.59 mmol, 91% yield) as white solid.
1.5 kg
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h;Large scale;
To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H20 (20 L) was added LiOH H20 (332.68 g, 7.93 mol) in one portion at 20 C to give a suspension, the reaction was stirred at this temperature for 16 h. TLC (petroleum ether: ethyl acetate = 2: 1) showed that the reaction was completed. The solvent was evaporated under vacuum to remove THF. The residue was acidified with 2N HC1 until pH = 2 to give a yellow
With iron; ammonium chloride; In methanol; water; at 80℃; for 0.5h;Inert atmosphere;
8.0 g of compound II, 12.0 g of iron powder, 12.0 g of ammonium chloride, 60 ml of water, 120 ml of methylene chlorideThe mixture of alcohols was stirred at 80 C for 30 minutes under reflux. TLC analysis showed no starting material and was filtered off with 50 ml of methanol and50 ml of ethyl acetate, the filtrate was spin-dried, the solvent was added to 300 ml of water,Liter of ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate,Dried to give 7.2 g of a brown solid (Compound 3) in 99.4% yield;
87%
With hydrogen;3percent by mass platinum sulfided carbon; In 1,2-dimethoxyethane; at 20℃; for 7h;Product distribution / selectivity;
Example 6 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate); Into a glass vessel having an internal volume of 20 ml and equipped with a stirrer, a thermometer, a reflux condenser, and a balloon filled with hydrogen gas were placed 4.0 g (12.6 mmol) of <strong>[61032-41-5]methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate</strong>, 0.2 g of 3% by mass platinum sulfided carbon powder (60% moisture content) (manufactured by N.E. CHEMCAT CORPORATION), and 20 ml of dimethoxyethane, and the resultant mixture was reacted in a hydrogen gas atmosphere at room temperature for 7 hours with stirring. After completion of the reaction, the reaction mixture was allowed to stand for 10 days and then filtered, and the reaction mixture was concentrated under reduced pressure to obtain 3.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate as a pale brown solid (isolation yield: 87%). Values of physical properties for the obtained methyl 2-amino-4-benzyloxy-5-methoxybenzoate are as follows. 1 H-NMR(CDCl3 , delta(ppm)); 3.81(3H,s), 3.83(3H,s), 5.09(2H,s), 5.37(2H,brs), 6.15(1H,s), 7.31-7.41(6H,m) CI-MS(m/e); 287(M+)
85%
Step 2c. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (Compound 204) A mixture of compound 203 (10 g, crude), iron powder (54 g, 0.96 mol), ethanol (100 mL), and H2O (20 mL) was stirred and heated to reflux for 3 hours. The mixture was cooled to room temperature and neutralized with aqueous sodium hydroxide (10%). The reaction was filtered and the filtrate was concentrated to give a residue which was extracted with dichloromethane (200 mL*2). The combined organic layer was washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound 204 as a grey solid (14.5 g, 85%): LCMS: 288 [M+1]+.
84.7%
With acetic acid; zinc; In methanol; water; for 3h;Reflux;
A mixture of compound 5 (2.0g, 6.2mmol), zinc powder (1.2g, 19mmol), glacial acetic acid (3.6mL, 63.3mmol) in methanol: H2O (33: 3mL) was stirred at reflux for 3h. The reaction mixture was filtered while hot and the solid was washed with CH3OH. The solvent was removed from filtrate and the resulting solid was diluted with water (50mL) and subsequently extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate and saturated saline solution, and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 6 as a light yellow solid (84.7%). Mp: 131-133C; 1H NMR (CDCl3, 300MHz): delta (ppm) 3.83-3.84 (d, J=3.7Hz, 6H), 5.14 (s, 2H), 5.52 (s, 2H), 6.16 (s, 1H), 7.26-7.42 (m, 6H).
84.7%
In methanol; water; at 20℃; for 3h;Reflux;
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (6.2 mmol, 2.0 g) was added to a 100 ml reaction flask followed by MeOH / H2(63 mmol, 3.6 ml) was slowly added dropwise, and the mixture was heated under reflux for 3 hours. The resulting mixture was stirred for 3 hours at room temperature, followed by addition of zinc powder (19 mmol, 1.2 g).After completion of the reaction, the residue was filtered off, the methanol was removed from the filtrate, and then 50 ml of water was added thereto. The mixture was extracted with ethyl acetate (30 ml x 2), and the organic phase was separated and washed successively with saturated sodium hydrogencarbonate X 2) and saturated sodium chloride (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was dried to give 1.5 g of 2-amino-4- benzyloxy-5-methoxybenzoate, yield% 84.7,
81%
With iron; ammonium chloride; In methanol; water; at 105℃;
A suspension of 120 (495 g, 1.56 mol), Fe (305.7 g, 5.46 mol) and NH4Cl (337.0 g, 6.24 mol) in a mixture of methanol/H2O (1500 mL/500 mL) was stirred at 105 C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (1500 mL), stirred for 3 h at room temperature and filtered. The filtrate was washed with water (500 mL×3) and brine (500 mL×3), then dried over Na2SO4. The solution was concentrated in vacuum to give 121 (363.8 g, yield=81%) as a light brown solid
67%
With iron; acetic acid; In methanol; for 4h;Heating / reflux;
Iron powder (46.2 g, 0.828 mol) is added to a suspension of methyl A- (benzyloxy)-5-methoxy-2-nitrobenzoate (52.5g, 165.6 mmol) in acetic acid (95 ml) and MeOH (200 ml). The reaction is then heated to reflux for 4 hours. The hot reaction mixture is then filtered through diatomaceous earth with 10% MeOH/CH2Cl2. The filtrate is concentrated in vacuo, dissolved in EtOAc, and passed through hydrous magnesium silicate using EtOAc. The organic phase is concentrated in vacuo and triturated with 30% EtOAc/Hexane to provide methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (31.94 g, 67%).
With sodium tetrahydroborate; nickel(II) chloride hexahydrate;
Commercially available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted in 5 steps to 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-quinazolme 15 (35% overall yield).[17,18] The only significant modification involved an improved workup of the nickel chloride hexahydrate-sodium borohydride reduction of the nitro intermediate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy intermediate 16, followed by alkylation with propargyl bromide in acetonitrile, gave 13 in a 65% yield for 2 steps. This method involved an additional step, and the overall yield was greater. In addition, the final 7-hydroxy intermediate 16 could be used to generate other products [19].
Preparation of 2-amino-4-benzyloxy-5-methoxy-methylbenzoate 6.5 g of 2-nitro-4-benzyloxy-5-methoxy-methylbenzoate was dissolved in 2:1 CH2Cl2/MeOH (138 mL). 1.56 g of nickel chloride hexahydrate was added and the resulting green solution stirred until all solids dissolved. The reaction mixture was then cooled on ice and 2.56 g of sodium borohydride added slowly in 4 portions, with each portion being added at 7-8 minute intervals. After the last addition was complete, all the solvent was removed to result in a gray solid. 150 mL of cold 10% HCl was added and the mixture washed with a 100 mL rinse of 10% HCl. The aqueous phase extracted three more times with ethyl acetate. The organic phases were combined and dried over sodium sulfate. After filtration, the filtrate was concentrated to a pink-orange solid, which was recrystallized from methanol. The final productproduct (2.13 grams) was isolated as a pale orange-brown solid. Proton NMR was consistent with the proposed structure. (lit. ref. Organic Letters 1999 vol 1(11) pp 1835-37).
With iron(III) chloride; iron; acetic acid; In ethanol; water;
A mixture of <strong>[61032-41-5]4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester</strong> (6.00 g, 18.91 mmol), iron powder (5.91 g, 105.9 mmol) and iron (III) chloride (307 mg, 1.89 mmol) in EtOH (12 ml), acetic acid (48 ml) and water (2.4 ml) was heated at reflux for 4 hours. The reaction mixture was cooled, filtered and the solids washed with EtOAc. The filtrate was concentrated and the residue purified by column chromatography (15-70 % EtOAc: Heptane) to provide the title compound as a pale yellow solid (5.09 g).LC/MS purity: 92 %, m/z 288.1 [M+H]+. 1H NMR (300 MHz, CDCI3) delta: 7.53-7.31 (6H, m), 6.33 (1 H, s), 5.10 (2H, s), 3.94 (3H, s), 3.90 (3H, s).
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
Step 3. In a 1l Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
100%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
Step 3. In a 1 L Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
100%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
Step 3. In a 1 1 Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
100%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 750.075 Torr; for 5h;
4.1.5 Methyl 2-amino-4-hydroxy-5-methoxybenzoate (13) A solution of intermediate 12 (11.7 g, 37 mmol) in MeOH (250 mL) was treated with H2 (1.0 bar, room temperature) in the presence of 10% palladium on charcoal (1.17 g, 1.1 mmol Pd). After completion (5 h), the catalyst was removed by filtration, and the solvent was evaporated to obtain the aniline 13 as a white solid quantitatively. Mp: 122-124 C.
100%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
Step 3. In a 1L Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
98%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
In a 11 Schlenk flask filled with argon, <strong>[61032-41-5]methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate</strong> (11.60 g, 36.6 mmol) andpalladium on charcoal (1.17 g, 10 % Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. Theargon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction.The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0 mmol, 98 %) which was used without further purification. LC/ESI-MS: m/ z= 166 [M-CH4O+H]+; Rt = 2.17 min
98%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran;
Step 3. In a 1 l Schlenk flask filled with argon, methyl 4benzyloxy-5-methoxy-2-nitrobenzoate (11.60 g, 36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0 mmol, 98%) which was used without further purification LC/ESI-MS: m/z=166 [M-CH4O+H]+; Rt=2.17 min.
98%
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
In a 1 1 Schlenk flask filled with argon, <strong>[61032-41-5]methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate</strong> (11.60 g, 36.6 mmol) and palladium on charcoal (1.17 g, 10 % Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0 mmol, 98 %) which was used without further purification. LC/ESI-MS: m/z = 166 [M-CH4O+H]+; Rt = 2.17 min.
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 750.075 Torr;
In a 1 l Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; for 16h;
into a 500-mL round-bottom flask, was placed a mixture of methyl 4-(henzvloxv)-5-methoxy- 2-nitrobenzoate (15.00 g, 47.2.7 mmol, 1.00 eq.), MeOH (150 mL) and 10% Pd/C (3.00 g). The mixture was degassed and purged with hydrogen for 3 times. The resulting mixture was allowed to stir at 25 C for 16 h. The solids were filtered out. The filtrate was concentrated under reduced pressure to provide crude product of methyl 2-an:iino-4-hy droxy-5-methoxybenzoate as a gray solid(8.5 g, 91%). LCMS (ES) [M*ij m/z 198.1.
methyl 4-hvdroxy-5-methoxy-2-nitrobenzoate[ No CAS ]
[ 27883-60-9 ]
Yield
Reaction Conditions
Operation in experiment
3.5 g (97%)
In methanol; dichloromethane;
REFERENCE EXAMPLE 16 Methyl 4-hvdroxy-5-methoxy-2-nitrobenzoate To a -78 C. solution of methyl 5-methoxy-2-nitro-4-(benzyloxy) benzoate (5 g, 15.6 mmol) in 100 mL of dichloromethane was added dropwise a solution of boron trichlolide (46 mL of a 1M solution in methylene chloride, 46 mmol). After 5 minutes, 130 mL of methanol was added and the solution was allowed to warm to room temperature. The solvents were removed in vactto and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional methylene chloride and the organic layers were combined and dried over sodium sulfate. The solution was passed through a plug of hydrous magnesium silicate, concentrated in vacuo and dried to provide 3.5 g (97%) of methyl 4-hydroxy-3-methoxy-6-nitrobenzoate as a yellow solid, mp 101-102 C.; MS (ES) m/z 226.1 (M+1). Analysis for C9H9NO6: Calcd: C: 47.58;H: 3.99; N: 6.17. Found:C: 47.60;H: 3.94; N: 6.14.
With hydrogenchloride; sodium hydroxide; sodium methylate; iron; formamide; In methanol; chloroform; water; acetic acid; N,N-dimethyl-formamide;
Production Example 26: 7-(Benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15.0 g) was dissolved in acetic acid (200 ml) at room temperature. Iron (powder) (13.2 g) was then added tothe solution. The temperature of the mixture was raised to 90C, and the mixture was then stirred for one hr. The resultant gray solid was filtered through Celite, followed by washing with acetic acid. Concentrated hydrochloric acid was added to the mother liquor. The solvent was then removed by distillation under the reduced pressure. This resulted in the precipitation of a solid. The solid was collected by filtration, was washed with ethyl acetate and ether, and was dried through a vacuum pump. Subsequently, chloroform and methanol were added to the solid to prepare a suspension, and a 10% aqueous sodium hydroxide solution was then added to dissolve the solid, followed by extraction with chloroform. After washing with water, the organic layer was dried over sodium sulfate. Next, the organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 9.5 g (yield 70%) of a crude product of methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml). Formamide (0.46 ml) and sodium methoxide (373 mg) were added to the solution. The mixture was heated to 100C and was stirred overnight. The reaction solution was cooled to room temperature, and 10 ml of water was then added to the cooled reaction solution. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with water and ether, and was then dried through a vacuum pump to give 566 mg (yield 87%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): delta 3.88 (s, 3H), 5.25 (s, 2H), 7.23 (s, 1H), 7.33 - 7.49 (m, 6H), 7.97 (s, 1H), 12.06 (br, 1H)
With potassium carbonate; sodium sulfate; In water; N,N-dimethyl-formamide;
Production Example 25: Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate Commercially available methyl vanillate (50 g) and potassium carbonate (76 g) were dissolved in N,N-dimethylformamide (200 ml). Benzyl bromide (33 ml) was added dropwise to the solution over a period of 10 min. The mixture was stirred at room temperature overnight. Water (200 ml) was added thereto, followed by extraction with ethyl acetate. Saturated brine was then added to the organic layer, and the mixture was extracted with ethyl acetate. Sodium sulfate was added to the organic layer to dry the organic layer. Next, the organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 68 g of a white solid.
With copper nitrate hemi(pentahydrate); at 0℃; for 6h;Inert atmosphere;
Compound Int-l-2 (79.8 g, 0.29 mol) was dissolved in acetic anhydride (550 mL) under N2 atmosphere and then cooled to 0 C. Copper (II) nitrate hemi-(pentahydrate) (75.0 g, 0.32 mol) was added portion-wise. After stirring for 6 hours at 0 C the reaction was quenched with ice water (800 mL). The solid was filtered and washed with distilled water (100 mL) and hexane (400 mL) to obtain compound Int-l-3 (85.5 g, 92%). 7.52 (s, 1H), 7.45-7.35 (m, 5H), 7.08 (s, 1H), 5.22 (s, 2H), 3.98 (s, 3H), 3.91 (s, 3H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
