Reference：
[1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4116 - 4125
3
[ 99-36-5 ]
[ 5471-82-9 ]
[ 24078-21-5 ]
Reference：
[1] Patent: CN105820054, 2016, A, . Location in patent: Paragraph 0016
[2] Patent: CN106496038, 2017, A, . Location in patent: Paragraph 0025-0026
4
[ 24078-21-5 ]
[ 18595-14-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 5%-palladium/activated carbon; hydrogen In ethanolFlow reactor
General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
90%
Stage #1: With hydrogenchloride In water; ethyl acetate Stage #2: With zinc In water; ethyl acetate at 0 - 20℃; for 15.33 h; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate
Methyl 3-methyl-4-nitrobenzoate (23 g, 117.84 mmol) was dissolved in ethyl acetate (400 mL) and cond HCl (58 mL). Then the solution was cooled to 0 °C and Zn powder (46.2 g, 707 mmol) was added in portions over 20 min with stirring. The mixture was allowed to warm up to room temperature and stirring was continued for 15 h. The reaction mixture was passed through a bed of Celite and washed with ethyl acetate (100 mL). The filtrate was washed with satd NaHCO3 solution (4 .x. 100 mL), water (3 .x. 100 mL) and brine (2 .x. 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness to obtain the amino compound 5 (17.4 g, 90.0percent) as a colorless solid. mp 111-113 °C; 1H NMR (300 MHz, CDCl3) δ 2.18 (s, 3H), 3.85 (s, 3H), 4.02 (s, br, 2H), 6.65 (d, J = 8.1 Hz, 1H), 7.76-7.72 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 17.2, 51.7, 113.8, 119.5, 121.1, 129.4, 132.3, 149.5, 167.6; MS (ES) m/z 166 (M+1).
90%
With palladium on activated charcoal; hydrogen In methanol at 20℃;
To a solution of methyl 3-methyl-4-nitrobenzoate (50 g, 256.2mmol) in methanol (1.5L) was added palladium on carbon (2.5 g). Then H2 (g) was introduced and the reaction was stirred overnight at room temperature. The solids were filtered off and the resulting solution was concentrated in vacuo to afford methyl 4- amino- 3- methylbenzoate as a light yellow solid (38 g, 90percent). LCMS (ES, m/z): [M+H]+ 166.1
80%
With hydrogen In methanol at 20℃;
Step 2. Methyl 4-amino-3-methylbenzoate To a solution of methyl 3-methyl-4-nitrobenzoate (31 g, 158.83 mmol) in methanol (1000 mL) was added palladium on carbon (2 g), and the reaction was stirred overnight at room temperature under an atmosphere of H2(g). Then the solids were filtered out and filtrate was concentrated under vacuum to afford methyl 4-amino-3-methylbenzoate as a white solid (21 g, 80percent). LC/MS (ES, m/z): [M+H]+ 166.0 1H-NMR (300 MHz, CD3Cl) δ 7.74-7.77 (m, 2H), 6.52 (d, J=8.1 Hz, 1H), 4.09-4.11 (m, 2H), 3.87 (s, 3H), 2.20 (s, 3H)
62%
With iron; ammonium chloride In methanol; water for 4 h; Reflux
To a stirred solution of methyl 3-methyl-4-nitrobenzoate (50 g, 1.0 eq) in 1 L MeOH were added at rt a solution of NH4CI (137 g, 10 eq) in 60 mL H20 and Fe power (96 g, 7 eq), and the resulting mixture is heated at reflux for 4 h. The reaction mixture was allowed to cool to rt, filtered, and water was added. The mixture was extracted with EtOAc. The extract was dried, washed with water, and concentrated to give the desired product directly as a white solid (26 g, 62percent).
Reference：
[1] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[2] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1107 - 1112
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4582 - 4589
[4] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[5] Zeitschrift fur Anorganische und Allgemeine Chemie, 2014, vol. 640, # 1, p. 159 - 167
[6] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[7] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 34
[8] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[9] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0258
[10] Chemische Berichte, 1895, vol. 28, p. 597
[11] European Journal of Medicinal Chemistry, 1983, vol. 18, # 4, p. 307 - 314
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[13] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 81 - 84
5
[ 67-56-1 ]
[ 3113-71-1 ]
[ 24078-21-5 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 0 - 80℃; for 1 h;
Step 1. Methyl 3-methyl-4-nitrobenzoate To a solution of 3-methyl-4-nitrobenzoic acid (30 g, 165.61 mmol) in methanol (300 mL), was added thionyl chloride (25 mL) dropwise with stirring at 0° C. After stirring for 1 h at 80° C., the resulting mixture was concentrated under vacuum to give residue, which was dissolved in petroleum ether (100 mL) and filtrated to give methyl 3-methyl-4-nitrobenzoate as a white solid (31 g, 96percent). LC/MS (ES, m/z): [M+H]+ 196.0 1H-NMR (300 MHz, CD3Cl) δ 7.99-8.04 (m, 3H), 3.98 (s, 3H), 2.64 (s, 3H)
89%
for 15 h; Reflux
To a solution of 3-methyl-4-nitrobenzoic acid (25.0 g, 138 mmol) in anhydrous methanol (400 mL) was added concd H2SO4 (2 mL), at room temperature. The resulting solution was refluxed for 15 h. The reaction mixture was concentrated. The solid was filtered and washed with cold methanol and dried to obtain the ester 4 (24 g, 89percent) as a colorless solid. mp 78-80 °C.
82.3%
Reflux
General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5percentand water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives
37%
Reflux
To a solution of 2 (3-methyl-4-nitrobenzoic acid, 4.53 g, 29.98 mmol) in MeOH (25 mL) was added conc. H2SO4 (97 percent, 2.66 mL, 48.41 mmol) at room temperature. The turbid reaction mixture became clear during heating at reflux for overnight and then it was cooled to room temperature to be a suspension. The precipitates were filtered and washed with cold MeOH. Recrystallization in MeOH, filtration and drying then gave 3 (1.67 g, 37 percent) as a yellow crystalline solid. Rf: 0.5 (EtOAc:Hex =1:5); m.p. 79.5–80.0 C; IR (film, cm−1) 3118 and 3046( =C-H), 2959 (-C-H), 1732 (C=O), 1585 (Ar), 1520 (N=O), 1429 (Ar), 1344 (N=O); 1H NMR (in CDCl3, δ) 2.63 (s, 3H, CCH3), 3.96 (s, 3H, OCH3), 7.98 (s, 2H), 8.03 (s, 1H) [aromatic protons]; 13C NMR (in CDCl3, δ) 20.30 (CCH3), 52.94 (OCH3), 124.80, 128.28, 133.70, 133.96, 134.23, 152.10 (aromatic carbons), 165.56 (C=O); HR-FABMS [M+H]+ calcd for C9H10NO4 m/z 196.0610, found 196.0608.
37%
at 20℃;
Concentrated sulfuric acid (H2504, 97percent, 2.66 ml,48.41 mmol) is added to a solution containing the compound2 (3-methyl-4-nitrobenzoic acid, 4.53 g, 29.98 mmol) in methanol (MeOH) (25 ml) at the room temperature. After an overnight reflux under agitation, the cloudy reactant mixture becomes clear and then cooled down at the room temperature into a suspension. The precipitate is filled out and washed with cold water. A recrystallization with methanol and a filtration and drying process yields the compound 3 (1.67 g, 37percent) as yellowish solid crystals
Reference：
[1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 33
[2] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[3] Chemical Communications, 2007, # 5, p. 504 - 506
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4582 - 4589
[5] Chemistry - An Asian Journal, 2010, vol. 5, # 7, p. 1573 - 1585
[6] Natural Product Research, 2018, vol. 32, # 5, p. 572 - 575
[7] Chemistry - A European Journal, 2006, vol. 12, # 26, p. 6865 - 6879
[8] Zeitschrift fur Anorganische und Allgemeine Chemie, 2014, vol. 640, # 1, p. 159 - 167
[9] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1107 - 1112
[10] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 1, p. 7 - 12
[11] Patent: US2017/22243, 2017, A1, . Location in patent: Paragraph 0030; 0031
[12] Chemische Berichte, 1895, vol. 28, p. 597
[13] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1692 - 1695
[14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[15] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 81 - 84
[16] Patent: CN105753708, 2016, A, . Location in patent: Paragraph 0003; 0006
a) Methyl 3-methyl-4-nitrobenzoate To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 ml) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 ml) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (2*100 ml), and drying at 40° C. under vacuum, to afford 103 g (95percent) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; m.p. 83°-85° C.; NMR (250 MHz, CDCl3), 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2 CH3), 8.01 (m, 3H).
95%
With thionyl chloride In methanol; water
d. Methyl 3-methyl-4-nitrobenzoate To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 mL) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 mL) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (100 mL twice), and drying at 40° C. under vacuum, to afford 103 g (95percent) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; mp 83°-85° C.; NMR (250 MHz, CDCl3): 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2 CH3), 8.01 (m, 3H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 16h;Reflux;
To a solution of 3 (1.33 g, 7.43 mmol) in anhydrous CCl4 (34 m:) were added benzoyl peroxide (200 mg, 0.83 mmol) and NBS (1.98 g, 11.14 mmol) at room temperature. The reaction mixture was heated at reflux for 16 h and then it was cooled to room temperature. After filtration and washing with hexane, the filtrate was concentrated in vacuo and the obtained residue was column chromatographed on silica gel to give both 4 (0.98 g, 48 %) as a white solid, and a byproduct, 3-dibromomethyl-4-nitrobenzoic acid methylester (0.89 g, 34 %) as a white solid. Rf: 0.4 (EtOAc:Hex = 1:10); m.p. 117.0-117.5 C; IR (film, cm-1) 3124 and 3053 (=C-H), 3002 and 2952 (-C-H), 1722 (C=O), 1586 (Ar), 1529 (N=O), 1442 (Ar), 1356 (N=O), 1277 (CH2-Br, bending), 624 (C-Br); 1H NMR (in CDCl3, delta) 3.99 (s, 3H, OCH3), 4.83 (s, 2H, CH2Br), 8.06 (d, 1H, J = 8.43 Hz), 8.13 (dd, 1H, J = 8.49 and 1.77 Hz), 8.24 (d, 1H, J = 1.59 Hz) [aromatic protons]; 13C NMR (in CDCl3, delta) 28.09 (CBr), 53.17 (OCH3), 125.80, 130.83, 133.28, 133.95, 134.80, 150.72 (aromatic carbons), 164.85 (C=O); HR-FABMS [M+H]+ calcd for C9H9BrNO4 m/z 273.9715, found 273.9711.
34%; 48%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 20℃; for 16h;
Benzoyl peroxide (200 mg, 0.83 mmol) and n-bromosuccinimide (1.98 g, 11.14 mmol) are added to a solution containing the compound 3 (1.33 g, 7.43 mmol) dissolved in anhydrous CC14 (34 ml) at the room temperature. The reactant mixture is subjected to a 16-hour reflux under agitation and then cooled down to the room temperature. The mixture is filtered and washed with hexane. The filtrate is concentrated under vacuum, and the residue is purified by colunm chromatography to yield a compound 4 (0.98 g, 48%) as a white solid and 3-dibromomethyl-4-nitrobenzoic acid methylester (0.89 g, 34%) as a white solid by-product.
A solution of <strong>[24078-21-5]3-methyl-4-nitro-benzoic acid methyl ester</strong> (24.99 g, 128.1 mmol) and N,N-dimethylformamide dimethyl acetal (40.0 mL, 300 mmol) was heated at 1400C for 22.5 h. After cooling to rt, the reaction mixture was concentrated and the residue was crystallized from MeOH to give a purple solid.This solid was dissolved in THF (500 mL) and water (500 mL), and sodium periodate (62.62 g, 292.8 mmol) was added followed by additional sodium periodate (15.6 g, 72.9 mmol) two hours later. After stirring at rt for an additional 1 h, the reaction mixture was filtered through Celite washing with EtOAc (2 L). The filtrate was washed with saturated NaHCO3 (600 mL) and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was passed through a pad of silica gel, washing with CH2Cl2/hexanes (75%- 100%). The filtrate was concentrated and dried to give 3-formyl-4-nitro-benzoic acid methyl ester as yellowish solid. MS (EI): cal'd 210.0 (MH+), exp 210.2 (MH+).
(2R,3aR,4R,9bR)-1,5-di-(tert-butoxycarbonyl)-8-methoxycarbonyl-4-[3-(benzyloxy)propyl]-2-(hydroxymethyl)-2,3,3a,4-tetrahydro-9bH-pyrrolo[3,2-c]quinoline[ No CAS ]
methyl-4-(tert-butylcarbonylamino)-3-[(6R)-2,2,11,11,12,12-hexamethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-8-en-6-ylimino]methyl}benzoate[ No CAS ]
methyl-4-(tert-butylcarbonylamino)-3-{(E)-[(6R,Z)-2,2,11,11,12,12-hexamethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-8-en-6-ylimino]methyl}benzoate[ No CAS ]
methyl-4-(tert-butylcarbonylamino)-3-{(E)-[(6R,E)-2,2,11,11,12,12-hexamethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-8-en-6-ylimino]methyl}benzoate[ No CAS ]
(2R,3aR,9bS)-5-(tert-butoxycarbonyl)-8-methoxycarbonyl-4-(tert-butyldimethylsilyloxy)-2-[(tert-butyldiphenylsilyloxy)methyl]-2,3,3a,4-tetrahydro-9bH-pyrrolo[3,2-c]quinoline[ No CAS ]
(2R,3aR,9bS)-1,5-di-(tert-butoxycarbonyl)-8-methoxycarbonyl-4-(tert-butyldimethylsilyloxy)-2-[(tert-butyldiphenylsilyloxy)methyl]-2,3,3a,4-tetrahydro-9bH-pyrrolo[3,2-c]quinoline[ No CAS ]
3-Formyl-4-nitro-benzoic acid methyl ester. A solution of <strong>[24078-21-5]3-methyl-4-nitro-benzoic acid methyl ester</strong> (24.99 g, 128.1 mmol) and N,N-dimethylformamide dimethyl acetal (40.0 mL, 300 mmol) was heated at 1400C for 22.5 h. After cooling to rt, the reaction mixture was concentrated and the residue was crystallized from MeOH to give a purple solid. This solid was dissolved in THF (500 mL) and water (500 mL), and sodium periodate (62.62 g, 292.8 mmol) was added followed by additional sodium periodate (15.6 g, 72.9 mmol) two hours later. After stirring at rt for an additional 1 h, the reaction mixture was filtered through Celite washing with EtOAc (2 L). The filtrate was washed with saturated NaHCO3 (600 mL) and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was passed through a pad of silica gel, washing with CH2Cl2/hexanes (75percent- 100percent). The filtrate was concentrated and dried to give 3-formyl-4-nitro-benzoic acid methyl ester as yellowish solid. MS (EI): cal'd 210.0 (MH+), exp 210.2 (MH+).
With a stirrer,A thermometer and a dropping funnel were charged in a 2L three-necked flask35 g of 2,4-dimethylnitrobenzeneAnd 4 g of tetrabutylammonium bromide,And 1000 mL of distilled water was added,Into the water bath,Heated to 90 ,Start the agitator to 300r / min speed stirring;During the stirring,And 85 g of potassium permanganate was added in three portions,After stirring for 1 h,The filtrate was immediately separated by filtration,And the pH was adjusted to 3 with a sulfuric acid solution having a mass concentration of 30percentInto the Buchner funnel,Washed with deionized water and then filtered three times to obtain solid powder; A 2 L three-necked flask equipped with a mechanical stirrer was charged with 70 g of the above separated solid powderAnd 700mL concentration of 40percent methanol solution,Into the water bath,Was heated to 90 20min after dissolution was slowly added dropwise by pipette 50mL concentration of 0.2mol / L sulfuric acid solution,Dropping speed control so that the drop is completed within 30min,Reflux reaction 2h after filtration,Washing and drying to obtain light yellow crystal;50 g of the light yellow crystals obtained above were placed in a stoppered Erlenmeyer flask,10 g of potassium permanganate was added,And then the mixture into the water bath,Heating to 40 degrees Celsius,Stirring with a glass rod for 10 minutes to obtain a mixed liquid;To the above mixture, 20 mL of an acetic acid solution having a mass concentration of 30percent was addedAnd 3 g iron powder,Into the ultrasonic oscillator,Ultrasonic vibration reaction 30min,Ultrasonic power of 100W,Ultrasound frequency of 25KHz,After the end of the ultrasound, the reaction solution was extracted with n-hexane,The organic phase was separated,Into a distillation device,Heated to 85 ° C,After the removal of n-hexane by distillationTo give methyl 3-aldehyde-4-nitrobenzoate.
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